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TO @Richard67637214 :
re:
$NWBO Standard PUMPER move. DON'T REFUTE FACTS, JUST DISTORT AND DISTRACT FROM THE TRUTH. 8 years HOLDING and these clowns love to BLOCK but COMMENT AND are still saying the same sh*t. MY MOTIVATION IS PLAIN TO SEE. VOTE NO ON MANAGEMENTS $41 MIL OPTIONS LET THEM BUY OPEN MARKET https://t.co/WTwKoFc3Xe
— Richard (@Richard67637214) May 29, 2024
☑️Long-term survivors have now been followed for over 10 years
— Allen Turner (@AllenTurner206) May 8, 2024
☑️OS (placebo: 7.7 months, poly-ICLC: 52.5 months, and resiquimod: 16.7 months)
☑️PFS (placebo: 5.5 months, poly-ICLC: 31.4 months and resiquimod: 8.1 months)#DCVax #Mercidencel $NWBO https://t.co/ef3TaWGUFH
hyperopia
Re: Lykiri post# 694029
Sunday, May 26, 2024 8:09:30 PM
694185
Lykiri, thanks for the thoughtful post. I agree that it’s likely that Northwest Bio’s marketing application was high quality, and did not require additional information to be requested from the MHRA, as stated in the 1st quarter report. I also agree that it is highly likely that the application has received priority review.
I personally don’t believe that we can deduce the exact timing of the final decision by the timing of the ASM, or anything that Les said, since the company will only have a general idea of where the MHRA is in the process (and because Les has not exactly been reliable about timing). It appears to me that they have passed the first assessment phase and are now somewhere in the second phase, but it is difficult to know how long this phase will take with the backlog of inspections, and understaffed inspectors at the MHRA. I say this because Les said that no negative disclosures were required in the quarterly report, and he was talking about scheduling site visits, which generally occur after the initial scientific assessment. The company may also be able to deduce where the MHRA is in the process, if their questions change from questions about the application itself, to questions about defining the label, (whether enough evidence was presented for the label to be broad - for all gliomas, or simply for nGBM and rGBM) and post-approval risk management plans, etc.
It seems somewhat irrelevant (to me) to be trying to determine exactly when the assessment started, and counting days in the 150-day assessment timeline when the MHRA hasn’t been close to completing a single assessment in this timeline that was established four years ago. Having said that - I personally don’t know what the second validation date of March 7th means, but I believe that it was determined on or by that date, that the application was complete, and of high quality, so no further information will be officially requested by the MHRA, and the application is entitled and “confirmed” to receive priority review.
I think that, for the purposes of the MHRA’s own timeline, (since they track this) the official assessment (and timeclock) started at the first MHRA validation date of January 24th. I believe that they intend to complete the assessment as soon as they can, but with backlogs, it may take more than 150 days. However, I’ve always hoped the MHRA could pull a rabbit out of its hat for Northwest Bio.
Lykiri
Re: None
Sunday, May 26, 2024 8:10:22 AM
Post#
694029
of 694559
May 9, 2024
Les Goldman says "they are on track for accelerated approval (150- day assessment)" witch is new information.
We know that Northwest Biotherapeutics has requested the MHRA to allow the 150-day assessment route.
December 21, 2023
The MAA seeks approval for commercialization of DCVax-L for both newly diagnosed and recurrent glioblastoma (GBM). The application also requests to be considered under the MHRA’s rapid 150-day review pathway, which the agency has established for new medicines for serious unmet medical needs.
https://nwbio.com/northwest-biotherapeutics-announces-marketing-authorization-applications-submitted-uk-mhra-dcvax-l-glioblastoma/
The MHRA offers only a 150-day assessment timeline for all high-quality marketing authorisation applications (MAAs).
https://www.gov.uk/guidance/guidance-on-150-day-assessment-for-national-applications-for-medicines
I believe that Northwest Biotherapeutics' MAA is well-qualified as a high-quality market authorization application.
October 13, 2023
“The Company strongly believes that after so many years of work on the DCVax-L program, taking some additional time to help ensure that the full MAA package is as strong as it can be is especially important since the Company plans to submit applications to multiple regulators.
https://nwbio.com/northwest-biotherapeutics-provides-update-on-near-term-plans-for-submission-of-marketing-authorization-application/
+ Les Goldman comment regarding accelerated approval in the UK. (Summer 2020)
CHATgpt
The criteria for qualifying for the 150-day assessment route in the UK are designed to ensure that the applications submitted to the MHRA meet specific standards of quality, safety, and efficacy. Here are some key criteria that pharmaceutical companies typically need to fulfill in order to qualify for this expedited review route:
1. **Comprehensive Data:** Applicants must provide a thorough and well-documented set of data on the quality, safety, and efficacy of the drug. This includes results from preclinical studies, clinical trials, manufacturing processes, and stability testing.
2. **Adherence to Good Manufacturing Practices (GMP):** The drug manufacturing facilities must adhere to Good Manufacturing Practices to ensure the quality and consistency of the product. The MHRA may conduct inspections to verify compliance with GMP standards.
3. **Compliance with Regulatory Guidelines:** The MA application should demonstrate compliance with relevant regulatory guidelines and requirements set forth by the MHRA and the European Medicines Agency (EMA), where applicable. This includes submitting all necessary documentation and following standardized procedures.
4. **Innovative or High Medical Need:** Drugs that offer significant therapeutic benefits for patients or address unmet medical needs are often prioritized for the 150-day assessment route. Innovative therapies or those targeting rare diseases may qualify for expedited review.
5. **Early Engagement with the MHRA:** It is advisable for applicants to engage with the MHRA early in the drug development process to discuss regulatory requirements, potential challenges, and any specific considerations for the application. This proactive approach can help streamline the review process.
6. **Risk Management Plan:** The application should include a comprehensive risk management plan to identify, evaluate, and mitigate potential risks associated with the drug, including pharmacovigilance strategies for monitoring safety post-approval.
7. **Benefit-Risk Assessment:** The applicant must provide a detailed benefit-risk assessment that weighs the therapeutic benefits of the drug against potential risks to patient safety. This assessment is crucial for the MHRA to evaluate the overall suitability of the drug for marketing authorization.
By meeting these criteria and submitting a high-quality MA application that aligns with the requirements set by the MHRA, pharmaceutical companies can increase their chances of qualifying for the 150-day assessment route and benefit from the expedited regulatory review process. This pathway aims to facilitate timely access to safe and effective medicines for patients while upholding rigorous regulatory standards.
I believe that Northwest Biotherapeutics' MAA is well-qualified and received confirmation as a high-quality market authorization application. Additionally, on March 7, the Company received confirmation that they were allowed to pursue the 150-day accelerated route. IMO
CHATgpt
The timeline for receiving confirmation that your Marketing Authorization Application (MAA) qualifies for the 150-day assessment route after submission to the Medicines and Healthcare products Regulatory Agency (MHRA) can vary depending on various factors. However, in general, the process typically unfolds as follows:
1. **Validation of MAA:** Upon submission of the MAA to the MHRA, the initial step is the validation process. During validation, the MHRA reviews the application to ensure that it contains all the necessary information and documentation required for assessment. This step typically aims to confirm that the application is complete and meets the basic regulatory requirements.
2. **Notification of Validation:** Once the validation process is complete, the MHRA will notify the applicant that the MAA has been validated. This notification typically confirms that the application has met the initial validation requirements and is proceeding to the next stage of assessment.
3. **Qualification for the 150-Day Assessment Route:** Following validation, the MHRA will then assess the application to determine if it qualifies for the 150-day assessment route. This assessment involves evaluating whether the application meets the specific criteria for expedited review under the 150-day pathway, as discussed in the previous responses.
4. **Confirmation of Qualification:** If the MAA meets the criteria for the 150-day assessment route, the MHRA will inform the applicant that their application has been qualified for expedited review. This notification typically confirms that the application will be subject to the accelerated 150-day timeline for regulatory assessment.
The time between the initial validation of the MAA and confirmation of qualification for the 150-day assessment route can vary, but applicants can generally expect to receive communication from the MHRA within a few weeks to a couple of months, depending on the complexity of the application and the workload of the regulatory authority.
It is important for applicants to engage proactively with the MHRA during the submission process, seek clarification on any requirements or issues that may arise during validation, and maintain open communication to ensure a smooth transition to the expedited review pathway if the application qualifies for the 150-day assessment route.
Overall, while the specific timing of notifications may vary, the MHRA strives to provide timely and transparent communication throughout the regulatory review process to support efficient evaluation of MA applications and expedite access to new medicines for patients in the UK.
flipper4
uesday, April 30, 2024 4:57:06 PM
So I’m not certain people realize what’s going on. A few once promising immune approaches
are dropping by the wayside. Gilead’s program, using an antibody targeting a protein (cd47) on both healthy cells (whoops) and cancer cells was discontinued in blood cancers and all solid tumor cancers. Additionally, Standard Car-T therapy against proteins (bcma and cd19) expressed by healthy cells and blood/lymph B cell cancers received a black box (April 18, 224) warning because it can cause multiple other cancers and/or stay in the body, as transgenes, causing other mutations for decades. Similarly, Infiltrating lymphocyte therapy, which first uses chemotherapy to destroy the immune system cells, was halted a few months ago and restarted due to grade 5 adverse reactions. Also, Company after company going after one or a limited subset of cancer antigens are not able to avoid tumor escape. Most of them readily admit this.
The new head of engineering and manufacturing at Advent is not most recently from Roche, he is from Autolous (six years) a Car-T company hit hard by the scientific outcome of Car-T therapy. Through no fault of his own, the Car-T therapy industry is dealing with very serious safety issues.
All of the strategies employed by big pharma above knew going into it that they were risking either safety, tumor escape or both, but economics, intellectual property and/or other hurdles pushed them into questionable or outright poor and very expensive risks/decisions.
Re: flipper44 post# 688143
Tuesday, May 28, 2024 3:10:31 PM
Post#
694484
of 694490
Flipper, Thanks again for posting this. This is the backdrop from which DCVax as a new immune approach and technology platform emerges. It is often easy to get caught up in the near term events and deadlines, but big picture is society has to evolve out of this medieval period where cancer treatments come with significant risk of severe side effects and despite that still does not cure the underlying cancer.
I believe we are at a moment of history with the coming DCVax approval. Years from now, we may come to realize this time, now, was our coming into of a new renaissance period in medicine.
Re: beartrap12 post# 691439
Tuesday, May 28, 2024 12:15:41 PM
Post#
694418
of 694489
MAA approval within the next few weeks is possible... Don't be fooled by FUDsters attempts to take Les Goldman's - very positive - comments on the big biz show out of context.
Thanks again to Beartrap for post# 691439:
And as for "that" comment:
I don't believe it was specially about the UK's MAA. In the sentences before, Les talks about getting all approvals but the UK, which is the first, is important. He also talked at length about how the company cannot discuss any details about the trial because it can jeopardize approvals. I think he meant they need to wait for other commercial approvals.
The MHRA has a timeline (IN CALENDAR DAYS) that they stick to. Regardless of how you personally want to estimated the timeline for their decision, 2024 is the year we hear back from the MHRA if they approval the MAA for DCVAX (VERY LIKELY IMHO) 😁
My posts are my own opinion and do not represent investment, legal, or medical advice.
Margin Buu
Re: beartrap12 post# 691439
Tuesday, May 28, 2024 12:15:41 PM
Post#
694418
of 694487
MAA approval within the next few weeks is possible... Don't be fooled by FUDsters attempts to take Les Goldman's - very positive - comments on the big biz show out of context.
Thanks again to Beartrap for post# 691439:
And as for "that" comment:
I don't believe it was specially about the UK's MAA. In the sentences before, Les talks about getting all approvals but the UK, which is the first, is important. He also talked at length about how the company cannot discuss any details about the trial because it can jeopardize approvals. I think he meant they need to wait for other commercial approvals.
The MHRA has a timeline (IN CALENDAR DAYS) that they stick to. Regardless of how you personally want to estimated the timeline for their decision, 2024 is the year we hear back from the MHRA if they approval the MAA for DCVAX (VERY LIKELY IMHO) 😁
My posts are my own opinion and do not represent investment, legal, or medical advice.Augiep796
Re: None
Monday, May 27, 2024 4:02:22 PM
Post#
694291
of 694487
Thank you for your email, the 150 calendar days.
Please accept our apology for the late reply.
Kind regards
Ibrahim
MHRA Customer Experience Centre
Communications and engagement team
10 South Colonnade, Canary Wharf, London E14 4PU
Telephone 020 3080 6000
gov.uk/mhra
Stay connected
For information on how the Agency uses your personal data and your data protection rights, please see our three centres' Privacy Notices: MHRA, CPRD and NIBSC.
The Medicines and Healthcare Regulatory Agency have launched RegulatoryConnect, a service that provides the capability to track applications and view live authorisation details.
For all future application status update enquiries, please sign in to the RegulatoryConnect Portal here, which will guide you through the steps to access the new service and view the current status.
DISCLAIMER This email and any files transmitted with it are confidential. If you are not the intended recipient, any reading, printing, storage, disclosure, copying or any other action taken in respect of this email is prohibited and may be unlawful. If you are not the intended recipient, please notify the sender immediately by using the reply function and then permanently delete what you have received. Incoming and outgoing email messages are routinely monitored for compliance with the Department of Health's policy on the use of electronic communications. For more information on the Department of Health's email policy, click DHTermsAndConditions
Can you tell me if the 150 day timeline for MAA approval is counted as calendar days or working days?
sentiment_stocks
Monday, May 27, 2024 9:51:46 PM
Nemesis… you didn’t have any tumor to make the vaccine. So there is no way Northwest could have put you in the trial nor made your vaccine.
Hence, your own long survival could never have counted towards the DcVax-L trial’s long tail (made up of patients that were ALL treated with a vaccine made from their own DCs and their own tumors).
TABLE OF CONTENTS
https://www.sec.gov/ix?doc=/Archives/edgar/data/1072379/000110465924064263/tm2415047d3_pre14a.htm
PRELIMINARY PROXY STATEMENT
NOTICE OF THE ANNUAL MEETING OF STOCKHOLDERS
TO BE HELD ON JUNE 29, 2024
Dear Stockholder:
You are hereby cordially invited to attend the 2024 Annual Meeting of Stockholders of Northwest Biotherapeutics, Inc., (the “Company”) which will be held on Saturday, June 29, 2024 at 1:30 p.m. (local time) at the offices of Gibson, Dunn & Crutcher LLP, 1050 Connecticut Avenue NW, Washington, DC 20036, and any adjournments or postponements of the Annual Meeting.
Stockholders may attend the Annual Meeting in person, or may connect from a remote location through an audio-only link to the Annual Meeting (as explained below). Prior to the meeting, the Company will issue a notice with information on how to access the audio-only connection. Stockholders who cannot attend the Annual Meeting will need to vote prior to the meeting as the audio-only link will not enable voting during the meeting.
Following the Annual Meeting, there will be an informal discussion period as time permits. Stockholders may submit written questions to the Company prior to 6:00 p.m. Eastern Time on Monday, June 10, 2024.
We are holding the Annual Meeting for the following purposes:
1.
To elect two members to our Board of Directors to serve as a Class I Directors for a term of three years;
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2.
To ratify the appointment of Cherry Bekaert LLP as our independent registered public accounting firm for the fiscal year ending December 31, 2024;
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3.
To ratify the same option awards that were made in 2020 to the named executive officers and for which the stockholders already voted in favor in an advisory vote at the 2021 Annual Meeting and in a ratification vote at the 2022 Annual Meeting;
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4.
To ratify the same option awards that were made in 2020 to the non-executive Directors on the Board of Directors, and that were previously reported and previously approved by stockholders at the 2022 Annual Meeting;
?
5.
To approve, on an advisory basis, the Company’s executive compensation; and
?
6.
To act upon such other matters as may properly come before the meeting or any adjournments or postponements thereof.
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These matters are more fully described in the attached proxy statement, which is made a part of this notice. At this point, we are not aware of any other business to be transacted at this Annual Meeting.
Only stockholders of record on our books at the close of business on May 9, 2024 will be entitled to attend and to vote at the Annual Meeting and any adjournments or postponements of the Annual Meeting. For 10 days prior to the Annual Meeting, a list of stockholders entitled to vote will be available for inspection at our principal executive offices located at 4800 Montgomery Lane, Suite 800, Bethesda, Maryland 20814. This list also will be available for inspection at the Annual Meeting. If you would like to view the stockholder list, please call our executive offices at (240) 497-9024 to schedule an appointment.
The items to be considered are summarized in this Notice of the Annual Meeting of Stockholders and more fully described in this Proxy Statement. The Notice of the Annual Meeting of Stockholders, the Proxy Statement and the enclosed proxy card are expected to first be mailed and made available starting on or about June [3], 2024 to all record holders of shares of our common stock as of the close of business on May 9, 2024. Shares of our common stock represented by proxies will be voted as described in the Proxy Statement or as specified by each stockholder.
TABLE OF CONTENTS
A copy of our Annual Report on Form 10-K, as amended, for the fiscal year ended December 31, 2023 which contains our consolidated financial statements for the fiscal year ended December 31, 2023, and other information of interest to stockholders, accompanies this notice and the attached proxy statement. This notice, the attached proxy statement and our 2023 Annual Report on Form 10-K, as amended, for the fiscal year ended December 31, 2023 are also available, free of charge, in PDF and HTML format at http://www.edocumentview.com/NWBO and will remain posted on this website at least until the conclusion of the meeting.
If you have any questions or need assistance voting your shares, please contact our proxy solicitation agent, Georgeson LLC:
[MISSING IMAGE: lg_georgesonric-4c.jpg]
1290 Avenue of the Americas, 9th Floor
New York, NY 10104
Stockholders, Banks and Brokers Call Toll-Free (866) 529-0508
Monday through Friday, 9:00 AM EDT?—?11:00 PM EDT
Saturday, 12:00 PM EDT?—?6:00 PM EDT
We strongly recommend voting before the Annual Meeting, even if you plan to attend the meeting in person, to avoid any last minute issues relating to the identification of the shares.
All stockholders may vote when contacted by the Company’s proxy solicitation agent, Georgeson LLC. The attached proxy statement provides more information regarding the attendance and voting procedures.
A beneficial stockholder whose shares are held through an intermediary banker/broker, rather than at Computershare, also has two other voting options in addition to the option to vote by calling or being called by Georgeson:
•
The first additional voting option is to vote prior to the meeting through their banker/broker.
?
•
The second additional voting option is to fill out the Voter Information Form (VIF) included in the proxy statement materials, submit the VIF to Broadridge, receive a legal proxy from Broadridge and then submit that legal proxy to Computershare. If you are using this method, we request that you submit your vote before 6:00 p.m., Eastern Time on Monday, June 10, 2024. It may take a number of days to receive the legal proxy after application.
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Stockholders who attend the Annual Meeting in person may also vote at the meeting.
We strongly recommend that all stockholders vote through the proxy solicitor as this method is much faster, easier, has far less steps, and is generally more efficient than the VIF form method.
This proxy statement subsequently provides more details and numbers to call with any questions concerning procedures for the Annual Meeting.
The Company also stands ready to help in any way.
By Order of the Board of Directors,
/s/ Linda F. Powers???????? ??? ????
?
Chairperson of the Board of Directors
June [3], 2024
TABLE OF CONTENTS
WHETHER OR NOT YOU PLAN TO ATTEND THE ANNUAL MEETING, PLEASE PROMPTLY VOTE ONLINE, BY PHONE, OR COMPLETE, SIGN, DATE AND RETURN THE ENCLOSED PROXY CARD IN THE ACCOMPANYING ENVELOPE. NO POSTAGE NEED BE AFFIXED IF THE PROXY CARD IS MAILED IN THE UNITED STATES.
IMPORTANT NOTICE REGARDING THE AVAILABILITY OF PROXY MATERIALS FOR THE MEETING TO BE HELD ON JUNE 29, 2024:
The Notice of Annual Meeting and Proxy Statement and 2023 Annual Report is available at:
http://www.edocumentview.com/NWBO
TABLE OF CONTENTS?
TABLE OF CONTENTS
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Page
?
PROXY STATEMENT
? ? ? ? 1 ? ?
PROPOSAL NO. 1?—?ELECTION OF DIRECTORS
? ? ? ? 4 ? ?
PROPOSAL NO. 2?—?RATIFICATION OF APPOINTMENT OF INDEPENDENT REGISTERED PUBLIC ACCOUNTING FIRM
? ? ? ? 7 ? ?
PROPOSAL NO. 3?—?RATIFICATION OF THE SAME OPTION AWARDS THAT WERE
MADE IN 2020 TO THE NAMED EXECUTIVE OFFICERS AND FOR WHICH THE
STOCKHOLDERS ALREADY VOTED IN FAVOR IN AN ADVISORY VOTE AT THE 2021
ANNUAL MEETING AND IN A RATIFICATION VOTE AT THE 2022 ANNUAL
MEETING
? ? ? ? 8 ? ?
PROPOSAL NO. 4?—?RATIFICATION OF THE SAME OPTION AWARDS THAT WERE MADE IN 2020 TO THE NON-EXECUTIVE DIRECTORS ON THE BOARD OF DIRECTORS, AND THAT WERE PREVIOUSLY REPORTED AND PREVIOUSLY APPROVED BY STOCKHOLDERS AT THE 2022 ANNUAL MEETING
? ? ? ? 17 ? ?
PROPOSAL NO. 5?—?ADVISORY VOTE TO APPROVE EXECUTIVE COMPENSATION
? ? ? ? 22 ? ?
SECURITY OWNERSHIP OF CERTAIN BENEFICIAL OWNERS AND MANAGEMENT
? ? ? ? 23 ? ?
CORPORATE GOVERNANCE MATTERS
? ? ? ? 25 ? ?
EXECUTIVE COMPENSATION
? ? ? ? 28 ? ?
PRINCIPAL ACCOUNTANT FEES AND SERVICES
? ? ? ? 45 ? ?
OTHER MATTERS
? ? ? ? 46 ? ?
ADDITIONAL INFORMATION
? ? ? ? 47 ? ?
APPENDIX A
? ? ? ? A-1 ? ?
APPENDIX B
? ? ? ? B-1 ? ?
i
TABLE OF CONTENTS?
NORTHWEST BIOTHERAPEUTICS, INC.
4800 Montgomery Lane
Suite 800
Bethesda, Maryland 20814
PROXY STATEMENT
FOR THE ANNUAL MEETING OF STOCKHOLDERS
TO BE HELD ON JUNE 29, 2024
This proxy statement is being furnished in connection with the solicitation of proxies by the Board of Directors of Northwest Biotherapeutics, Inc. (“we,” “us,” “our” or the “Company”) for use at the Annual Meeting of Stockholders (the “Annual Meeting”), to be held on Saturday, June 29, 2024 at 1:30 p.m. Eastern Time, and any adjournments or postponements of the Annual Meeting.
The Board of Directors, or the “Board,” is soliciting proxies for the purposes set forth in the accompanying Notice of the Annual Meeting of Stockholders.
Record Date and Share Ownership
Only stockholders of record on our books at the close of business on May 9, 2024 will be entitled to attend and vote at the Annual Meeting and any adjournments or postponements of the Annual Meeting. As of the close of business on May 9, 2024, we had 1,210,879,427 shares of common stock outstanding and 1,211,971 shares of preferred stock outstanding. Each share of common stock entitles the record holder to one vote on each matter to be voted upon at the Annual Meeting. Each share of preferred stock is convertible into 25 shares of common stock and hence entitles the record holder to 25 votes on each matter to be voted upon at the Annual Meeting. Copies of the Notice of the Annual Meeting of Stockholders, this proxy statement, the enclosed proxy card and the 2023 Annual Report are expected to be mailed to stockholders of record on or about June [3], 2024. Exhibits to the 2023 Annual Report will be provided to any stockholder at no charge upon written or oral request to our corporate secretary at the address set forth under “Communication with the Board of Directors” below.
Attending the Annual Meeting and Voting
Only stockholders of record on our books at the close of business on May 9, 2024 will be entitled to attend and to vote at the Annual Meeting and any adjournments or postponements of the Annual Meeting.
Stockholders may attend the Annual Meeting in person, or may connect from a remote location through an audio-only link to the Annual Meeting. Prior to the Annual Meeting, the Company will issue a notice with information on how to access the audio-only connection.
Stockholders who cannot attend the Annual Meeting will need to vote prior to the meeting, using the procedures described below, as the audio-only link will not enable voting during the meeting.
If you plan to attend the Annual Meeting and vote in person, we will provide you with a ballot upon your arrival. However, if you hold your shares in the name of a broker, bank or other nominee, you must bring an account statement or letter from the nominee indicating that you were the beneficial owner of the shares on May 9, 2024, the record date for voting. If you plan to vote in person at the meeting, please bring valid identification. Even if you currently plan to attend the meeting, we recommend that you also submit your proxy as described below so that your vote will be counted if you later decide not to attend the meeting.
Voting Procedures
Shares represented by a properly executed proxy in the form that accompanies this proxy statement will be voted at the Annual Meeting and, if you provide instructions on the proxy, will be voted in accordance with those instructions. If you hold shares in your own name, you may vote by proxy online, by telephone using the toll-free number listed on the enclosed proxy card, or by marking, dating, signing and mailing the enclosed proxy card in the prepaid envelope provided. If you vote online or by telephone, please do not also mail the enclosed proxy card. If you return your proxy to the Company, but fail to provide instructions with
1
TABLE OF CONTENTS
your proxy as to how your shares should be voted, your shares will be voted according to the recommendations of our Board on each of the Proposals. If other matters come before the Annual Meeting, the persons named as proxies will vote on such matters in accordance with their best judgment. We have not received any notice of other matters that may properly be presented at the Annual Meeting.
All stockholders may vote when contacted by the Company’s proxy solicitation agent, Georgeson LLC, or by contacting Georgeson. The contact information is as follows:
[MISSING IMAGE: lg_georgesonric-4c.jpg]
1290 Avenue of the Americas, 9th Floor
New York, NY 10104
Stockholders, Banks and Brokers Call Toll-Free (866) 529-0508
Monday through Friday, 9:00 AM EDT?—?11:00 PM EDT
Saturday, 12:00 PM EDT?—?6:00 PM EDT
A beneficial stockholder whose shares are held through an intermediary banker/broker, rather than at
Computershare, also has two other voting options in addition to the option to vote by calling or being called
by Georgeson:
•
The first additional voting option is to vote prior to the meeting through their banker/broker.
?
•
The second additional voting option is to fill out the Voter Information Form (VIF) included in the proxy statement materials, submit the VIF to Broadridge, receive a legal proxy from Broadridge and then submit that legal proxy to Computershare. If you are using this method, we request that you submit your vote before 6:00 p.m., Eastern Time on Monday, June 10, 2024. It may take a number of days to receive the legal proxy after application.
?
Stockholders who attend the Annual Meeting in person may also vote at the Meeting.
We strongly recommend that all stockholders vote through the proxy solicitor as this method is much faster, easier, has far less steps, and is generally more efficient than the VIF form method.
We bear the expense of soliciting proxies. Our directors, officers or employees may also solicit proxies personally or by telephone, email, facsimile or other means of communication. We do not intend to pay additional compensation for doing so. The Company has retained Georgeson LLC to solicit proxies for the Annual Meeting, and may use the services of other third-parties to solicit proxies for the Annual Meeting (in which case the Company may also compensate such other third-parties for services rendered). We might reimburse banks, brokerage firms and other custodians, nominees and fiduciaries representing beneficial owners of our common stock for their expenses in forwarding soliciting materials to those beneficial owners.
Revoking a Proxy
You may revoke your proxy at any time prior to the start of the Annual Meeting by delivering written instructions to our corporate secretary at the address set forth under “Communication with the Board of Directors” below. Attendance at the Annual Meeting will not itself be deemed to revoke your proxy unless you vote at the Annual Meeting. If you are a beneficial owner of shares of common stock held in “street name,” you may submit new voting instructions by contacting your broker, bank or other nominee.
Quorum Required
A quorum of stockholders is necessary to hold a valid meeting of stockholders. A majority of shares entitled to vote generally in the election of directors at the Annual Meeting which are present in-person at the Annual Meeting or represented by proxy shall constitute a quorum at the Annual Meeting. Shares which abstain from voting on a particular matter and “broker non-votes,” or shares held in “street name” by brokers, banks or other nominees who indicate on their proxies that they do not have discretionary authority to vote such shares on a particular matter, are counted for purposes of determining whether a quorum exists.
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TABLE OF CONTENTS
Votes Required for Approval; Broker Non-Votes
Each share of common stock is entitled to one vote on the matters to be voted on at the Annual Meeting, and each share of preferred stock is entitled to twenty-five votes on the matters to be voted on at the Annual Meeting. As of May 9, 2024, there were 1,210,879,427 shares of our common stock outstanding and entitled to vote at the Annual Meeting, and 1,211,971 shares of preferred stock entitled to vote at the Annual Meeting.
For Proposal No. 1, the directors will be elected by a plurality of all votes properly cast at the Annual Meeting, assuming a quorum is present. For Proposal No. 2, the affirmative vote of a majority of the votes cast with respect to such matter is required to ratify the appointment of Cherry Bekaert LLP as our independent registered public accounting firm for the fiscal year ending December 31, 2023. For Proposal No. 3, the affirmative vote of a majority of the votes cast by disinterested stockholders with respect to such matter is required to ratify the same option awards that were made in 2020 to the Company’s named executive officers and for which the stockholders already voted in favor in an advisory vote at the 2021 Annual Meeting and in a ratification vote at the 2022 Annual Meeting. For Proposal No. 4, the affirmative vote of a majority of the votes cast by disinterested stockholders with respect to such matter is required to ratify the same option awards that were made in 2020 to the non-executive directors on the Board of Directors, and that were previously reported and previously approved by stockholders at the 2022 Annual Meeting. For Proposal No. 5, the affirmative vote of a majority of the votes cast with respect to such matter is required to approve, on an advisory basis, the compensation of our named executive officers.
With respect to “routine” matters, a bank, brokerage firm, or other nominee has the authority (but is not required) to vote its clients’ shares if the clients do not provide instructions. When a bank, brokerage firm, or other nominee votes its clients’ shares on routine matters without receiving voting instructions, these shares are counted both for establishing a quorum to conduct business at the meeting and in determining the number of shares voted “for,” “against” or “abstaining” with respect to such routine matters.
With respect to “non-routine” matters, a bank, brokerage firm, or other nominee is not permitted under the rules governing self-regulatory organizations, or SRO rules, to vote its clients’ shares if the clients do not provide instructions. The bank, brokerage firm, or other nominee will so note on the voting instruction form and this constitutes a “broker non-vote.” “Broker non-votes” will be counted for purposes of establishing a quorum to conduct business at the Annual Meeting, but not for determining the number of shares voted “for,” “against,” “abstaining” or “withheld from” with respect to such non-routine matters.
For Proposals No. 1 through No. 5, abstentions and broker non-votes, if any, will have no effect with respect to such matters.
Proxy Solicitation
The Company has retained the services of Georgeson LLC, and may retain the services of other third-parties, to solicit the proxies of certain stockholders for the Annual Meeting. The cost of such services to be rendered by Georgeson LLC is estimated to be $80,000, plus reimbursement of reasonable out-of-pocket expenses. In addition, certain of the Company’s officers and employees (who will receive no extra compensation for their services) may solicit proxies.
Householding
Stockholders of record who reside at the same address will receive a single copy of our 2023 Annual Report, Proxy Statement and Notice of the Annual Meeting. Each stockholder in the household, however, will receive a separate proxy card. This process, known as “householding,” reduces the volume of duplicate information received at your household and helps to reduce our expenses. If you would like to receive a separate copy of any of these materials, please call or write us at the address set forth under “Communication with the Board of Directors” below, and we will promptly deliver the requested materials to you.
If you receive multiple copies of our 2023 Annual Report, Proxy Statement and Notice of the Annual Meeting and wish to receive a single copy in the future, please contact us at the address set forth under “Communication with the Board of Directors” below, and we will modify our future mailings in accordance with your request. If you hold your shares in “street name,” you should contact your broker or nominee regarding combining mailings.
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PROPOSAL NO. 1?—?ELECTION OF DIRECTORS
Directors and Nominee for Director
We have a classified Board of Directors currently consisting of two Class I Directors (Dr. Alton L. Boynton and Ambassador J. Cofer Black), one Class II Director (Mr. Pat Sarma) and two Class III Directors (Ms. Linda F. Powers and Dr. Navid Malik). Pat Sarma was appointed to the Board in March 2024 as a Class II Director to complete the remainder the term of Mr. Jerry Jasinowski, who retired from the Board in March 2024 for medical reasons. Mr. Sarma was recommended to the Company’s Nominations Committee by an executive officer.
At each annual meeting of stockholders, the applicable Class directors are elected to succeed those whose terms are expiring. This year, two Class I Directors will be presented to the stockholders for election to a three-year term that expires at the Annual Meeting to be held in 2027. As a Class II Director, Mr. Sarma’s term expires at the Annual Meeting to be held in 2025, and the Class III Directors were elected in December 2022 to a term that expires at the Annual Meeting to be held in 2026.
The persons named in the enclosed proxy will vote to elect Dr. Alton L. Boynton and Ambassador J. Cofer Black as Class I Directors unless your proxy is marked otherwise. Dr. Boynton and Ambassador Black have indicated their willingness to serve, if elected. If either should be unable to serve, the person acting under the proxy may vote the proxy for a substitute nominee. We have no reason to believe that Dr. Boynton and Ambassador Black will be unable to serve if elected.
Set forth below is the name and age of each member of our Board (including Dr. Boynton and Ambassador Black, the nominees for election as Class I Directors), and the positions and offices held by the member, the member’s principal occupation and business experience during at least the past five years, the names of other publicly held companies of which the member serves as a director and the year of the commencement of the member’s term as a member of our Board.
Vote Required for Approval
Directors are elected by a plurality of the votes cast at the Annual Meeting. This means that the Class I nominees receiving the highest number of votes cast will be elected.
Voting by the Proxies
The proxies will vote your shares of common stock in accordance with your instructions. If you are a stockholder of record, and you return a signed and dated proxy card, unless you mark your proxy card to withhold authority to vote, your shares of common stock will be voted for the election of the nominee named in this proxy statement.
If you are a beneficial owner of shares of common stock held in street name and you do not provide your broker with voting instructions, under the SRO rules governing brokers, your broker may not vote your shares on the election of directors.
Recommendation
We recommend that you vote FOR Dr. Alton L. Boynton and Ambassador J. Cofer Black as Class I Directors.
Family Relationships
There are no family relationships between any of our directors or executive officers.
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Directors
Information with respect to the number of shares of common stock beneficially owned by each director, directly or indirectly, as of May 9, 2024 appears below under the heading “Security Ownership of Certain Beneficial Owners and Management.”
Name
? ?
Age
? ?
Position
?
Linda F. Powers ? ?
68
? ? Class III Director, Chairperson, President and Chief Executive
Officer, Chief Financial and Accounting Officer ?
J. Cofer Black ? ?
74
? ? Class I Director ?
Dr. Alton L. Boynton ? ?
79
? ? Class I Director, Chief Scientific Officer and Secretary ?
Pat Sarma ? ?
79
? ? Class II Director ?
Dr. Navid Malik ? ?
55
? ? Class III Director ?
Director Biographies
Linda F. Powers. Ms. Powers has served as the Chairperson of our Board of Directors since her appointment on May 17, 2007, Chief Executive Officer and President since June 8, 2011 and Chief Financial and Accounting Officer since June 8, 2020. Ms. Powers served as a managing director of Toucan Capital Fund II from 2001 to 2010, and Toucan Capital Fund III from 2010 to 2018. She also had over 16 years’ prior experience in corporate finance and restructurings, mergers and acquisitions, joint ventures and intellectual property licensing. Ms. Powers has served on the Maryland Stem Cell Research Commission since its establishment in 2006, and served as the Chair for its first two years of operations. Ms. Powers previously served on the boards of the Rosalind Franklin Society, M2GEN (an affiliate of Moffitt Cancer Center), a Steering Committee of the National Academy of Sciences evaluating government research funding, and several Governors’ commissions on the development of biotech and other technology industries. For more than six years, Ms. Powers taught an annual internal course at the National Institutes of Health for the bench scientists and technology transfer personnel on the development and commercialization of medical products. Ms. Powers serves on the boards of several private biotechnology companies. Ms. Powers holds a B.A. from Princeton University, where she graduated magna cum laude and Phi Beta Kappa. She also earned a J.D., magna cum laude, from Harvard Law School. We believe Ms. Powers’ background and experience make her well qualified to serve as a Director.
J. Cofer Black. Ambassador Black was appointed to the Board of Directors in January 2016. Ambassador Black is an internationally renowned U.S. government leader and expert in cybersecurity, counterterrorism and national security. In addition to serving on company boards, he presently serves as an independent consultant. Between 2009 and 2016, he served as Vice President for Global Operations at Blackbird Raytheon Technologies, a division of Raytheon Company, a NYSE-listed security company. From 2004 until 2008, he provided strategic guidance and business development as Vice Chairman of Blackwater Worldwide and as Chairman of Total Intelligence Solutions. During 2002?—?2005, he was appointed by the President of the United States to serve as the Ambassador, Coordinator for Counterterrorism, reporting directly to the Secretary of State for developing, coordinating and implementing American counterterrorism policy. Prior to his role as Ambassador, he served a 28-year career in the Central Intelligence Agency, reaching Senior Intelligence Service (SIS-4) level as Director, Counterterrorist Center (D/CTC), where he managed 1,300 professional personnel and an annual operational budget of more than one billion dollars. Ambassador Black is experienced representing the United States at the Head of State level, managing media as a diplomatic spokesperson and in public speaking as keynote speaker both as a senior U.S. Government official and business leader. Ambassador Black has received numerous awards and recognitions throughout his career, including the Distinguished Intelligence Medal (the CIA’s highest award for achievement). Ambassador Black received a B.A. in International Affairs from the University of Southern California in 1973 and an M.A. in International Affairs from the University of Southern California in 1974. We believe Ambassador Black’s background and experience in business management and information technology make him well qualified to serve as a Director.
Alton L. Boynton, Ph.D. Dr. Boynton co-founded our Company, has served as our Chief Scientific Officer and a Director since our inception in 1998, was appointed our Chief Operating Officer in August 2001,
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was appointed President in May 2003, and served as Chief Executive Officer from June 2007 to June 2011. Prior to founding our Company, Dr. Boynton headed the Molecular Oncology research lab at the Pacific Northwest Research Foundation (the original foundation of Bill Hutchinson, from which the Fred Hutchinson Cancer Center was spun off). Dr. Boynton also served as Director of the Department of Molecular Medicine of Northwest Hospital from 1995 to 2003 where he coordinated the establishment of a program centered on carcinogenesis. Prior to joining Northwest Hospital, Dr. Boynton was Associate Director of the Cancer Research Center of Hawaii, The University of Hawaii, where he also held the positions of Director of Molecular Oncology of the Cancer Research Center and Professor of Genetics and Molecular Biology. Dr. Boynton has over 170 publications, three edited books, and 300 abstracts. Dr. Boynton received his Ph.D. in Radiation Biology from the University of Iowa in 1972. We believe Dr. Boynton’s background and experience make him well qualified to serve as a Director.
Pat Sarma. Mr. Sarma was appointed to the Board of Directors in March 2024. Mr. Sarma brings decades of experience as a business executive and as a venture capital investor. One of the companies he founded and built was American Megatrends Inc. (AMI), which developed hardware, software and firmware components of PC-based systems. AMI developed the AMIBIOS firmware program for IBM-PC compatibility. The BIOS (Basic Input Output System) is the heart of PC-compatibility and all application programs access the BIOS in reading from or writing to peripheral units such as drives, keyboards, mouse, etc. AMI also developed, among other software, the AMI RAID Controller and Management software that was the fastest performer in the industry during the 1990’s and early 2000’s. Mr. Sarma’s interests in AMI were acquired in 2001, and thereafter he became a venture capital investor in the private equity markets. He was an owner for a number of years of the N.J. Devils team in the National Hockey League, and has invested in a diverse range of industries including medical and environmental companies. Mr. Sarma received a Master’s Degree in Industrial Engineering and Operations Research from Georgia Tech and a Bachelor’s Degree in Mechanical Engineering from the University of Madras. We believe that Mr. Sarma’s background and experience make him well qualified to serve as a director.
Dr. Navid Malik. Dr. Malik was appointed to the Board of Directors in April 2012. Dr. Malik is currently Head of Research and an Executive Director at The Life Sciences Division, a UK Investment Bank (since 2018). From January 2012 to December 2015, Dr. Malik was previously the Head of Life Sciences Research at Cenkos Securities Plc. in the U.K., an institutional stockbroking securities firm. From September 2011 through January 2012, Dr. Malik was the Head of Life Sciences Research at Sanlam (Merchant Securities), a global financial services firm. Dr. Malik was Partner and Head of Life Sciences at Matrix Investment Banking Division, Matrix Group, a financial services firm in London, from December 2008 through September 2011. Dr. Malik was a Senior Pharmaceuticals and Biotechnology Analyst at Wimmer Financial LLP from September 2008 through December 2008, and was the Senior Life Sciences Analyst at Collins Stewart Plc from January 2005 through September 2008. In 2011, Dr. Malik was awarded two StarMine Awards (awarded each year by Thomson Reuters and the Financial Times): Number One Stock Picker in the European Pharmaceutical Sector, and Number Two Stock Picker in the U.K. and Ireland Healthcare Sector. Dr. Malik holds a Ph.D. in Drug Delivery within Pharmaceutical Sciences, as well as degrees in Biomedical Sciences Research (M.Sc.) and Biochemistry and Physiology (B.Sc., joint honors). Dr. Malik also holds an MBA in finance from the City University Business School, London. We believe that Dr. Malik’s extensive experience in the life sciences fields and investment banking sector make him well qualified to serve as a Director.
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PROPOSAL NO. 2?—?RATIFICATION OF APPOINTMENT OF INDEPENDENT
REGISTERED PUBLIC ACCOUNTING FIRM
Pursuant to its charter, the Audit Committee of our Board has appointed the firm Cherry Bekaert LLP (“Cherry Bekaert”) to serve as our independent registered public accounting firm for the fiscal year ending December 31, 2024. While the Audit Committee is solely responsible for the appointment, compensation, retention and oversight of the independent registered public accounting firm, the Committee and the Board are requesting that the stockholders ratify this appointment for the fiscal year ending December 31, 2024. If the stockholders ratify this appointment, the Audit Committee, in its discretion, may appoint a different independent registered public accounting firm at any time if it believes that doing so would be in the best interests of our Company. If the stockholders do not ratify this appointment, the Audit Committee may reconsider, but might not change, its appointment. If the stockholders do ratify this appointment, the Audit Committee may nevertheless decide to change our accounting firm.
Vote Required for Ratification
Ratification of the appointment of Cherry Bekaert as our independent registered public accounting firm requires the affirmative vote of a majority of the votes cast with respect to such matter at the Annual Meeting.
Voting by the Proxies
The proxies will vote your shares of common stock in accordance with your instructions. If you are a stockholder of record and you return a signed and dated proxy card, unless you give specific instructions to the contrary, your shares of common stock will be voted for the ratification of the appointment of Cherry Bekaert as our independent registered public accounting firm for the fiscal year ending December 31, 2024.
Recommendation
The Board unanimously recommends that you vote FOR the ratification of the appointment of Cherry Bekaert as our independent registered public accounting firm for the fiscal year ending December 31, 2024.
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PROPOSAL NO. 3?—?RATIFICATION OF THE SAME OPTION AWARDS THAT WERE MADE IN 2020 TO THE NAMED EXECUTIVE OFFICERS AND FOR WHICH THE STOCKHOLDERS ALREADY VOTED IN FAVOR IN AN ADVISORY VOTE AT THE 2021 ANNUAL MEETING AND IN A RATIFICATION VOTE AT THE 2022 ANNUAL MEETING
Executive Summary
The Board of Directors seeks stockholder approval of resolutions ratifying certain option awards which were granted to the Company’s four senior executives in 2020 (the “2020 Executive Options”), reflecting the progress achieved during 2018-2020 and the executives’ roles and contributions. The 2020 Executive Options were awarded to Linda Powers, Les Goldman, Dr. Marnix Bosch and Dr. Alton Boynton.
The 2020 Executive Options were already approved by stockholders in an advisory vote in 2021 and in a ratification vote in 2022, with approval each time by 90% of the votes cast (further details below). In 2022, however, the Plaintiff (defined below) filed a lawsuit challenging the 2020 Executive Options and asserting that the two prior stockholder votes were insufficient. Consequently, the Board of Directors is now seeking, with this Proposal, a third stockholder vote on the same 2020 Executive Options.
No equity awards have been made to the executives in the four years since the 2020 awards. The 2020 Executive Options were already counted in the Company’s capitalization table in 2020.
The Board recommends that, in order to be fully informed, stockholders read in their entirety Proposal No. 3 herein, Proposal No. 4 herein, the Plaintiff’s Amended Complaint (attached as Appendix A), and the Delaware Court’s decision denying the Motion to Dismiss the lawsuit (attached as Appendix B) before voting on Proposal No. 3 or Proposal No. 4.
As set forth in greater detail below, the lawsuit alleges, among other things, that the 2020 Executive Options were not intended as a reward for performance or the milestones that had been achieved in the Company’s programs, but instead were solely to “true up” certain executives to offset the dilutive effects of the Company’s financing transactions. The lawsuit also alleges that the 2020 Options (as defined below) were financially unfair, that the award process and bases were defective because the 2020 Options were evaluated internally by management, the Compensation Committee and the non-executive members of the Board (the Individual Defendants, as defined below) rather than by an external compensation consultant, that approving or accepting the 2020 Options was a breach of fiduciary duties and constituted unjust enrichment, and that the stockholders were not sufficiently informed to be able to cast an effective vote for or against the 2020 Options. The Plaintiff filed the lawsuit against Board members Ambassador J. Cofer Black, Dr. Navid Malik, and Jerry Jasinowski (who has since retired for medical reasons), as well as members of management Linda Powers, Les Goldman and Dr. Al Boynton (the foregoing collectively, the “Individual Defendants”). The descriptions and summary of the lawsuit herein are qualified in their entirety by reference to the proceedings in In re Northwest Biotherapeutics, Inc. Stockholder Litigation, C.A. No. 2022-0193-JTL, pending in the Delaware Court of Chancery (the “Delaware Litigation” or the “Proceedings”).
As also set forth in more detail below, the Individual Defendants dispute the Plaintiff’s allegations for multiple reasons. The Individual Defendants note that equity awards to the Company’s executives have only been made to two of the four senior executives (Ms. Powers and Mr. Goldman) twice in the 13 years since 2011 (in 2018 and in 2020), and have only been made to the other two senior executives (Dr. Bosch and Dr. Boynton) three times in these 13 years (2017, 2018 and 2020), while other biotech companies usually make equity awards every year. The Individual Defendants also note that the Plaintiff’s allegations compare single-year equity compensation at other companies with equity granted only once over multiple years at the Company.
Company management, the Compensation Committee, and the Board routinely discuss compensation, including equity compensation, for employees, directors, and consultants before ultimately implementing the compensation. The Individual Defendants assert that the 2020 Executive Options took account of a number of factors, including the years of service, the executives’ performance, the multiple different roles performed by each of these executives, the progress and milestones achieved by 2020 with an exceptionally small team of just four senior executives (including in the Phase 3 clinical trial program, Sawston facility
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development, negotiations for Flaskworks, expansion of intellectual property and other areas), as well as the need to retain and incentivize these key executives going forward, and the Company’s overall compensation philosophy.
The Individual Defendants note that management had previously evaluated such performance factors for each key executive in 2018. After considering those performance factors along with certain market information from other oncology biotech companies that were developing competing or similar technologies as Northwest Biotherapeutics (dendritic cell therapies or various treatments for brain cancer), that were at the same stage of company development as Northwest Biotherapeutics (in late stage clinical trials, with no product approved or on the market yet), and that management identified as peers of Northwest Biotherapeutics on these bases, management had proposed, and the Compensation Committee and the non-executive Board members had approved, a specific percentage of the equity pool (“Equity Pool Allocation”) for each key executive.
The Individual Defendants note that, in 2020, the Compensation Committee and non-executive Board members reassessed the executives’ roles and performance, and their respective Equity Pool Allocations, based in part on recommendations from management. The Individual Defendants note that the Committee and non-executive Board members approved 2020 Equity Pool Allocations that were substantially the same as in 2018 and that the 2020 Executive Options were issued from the available Equity Pool under the Company’s Equity Compensation Plan in accordance with the respective allocations. Certain Board minutes referred to them internally as true ups that maintained substantially the same Equity Pool Allocations that were determined in 2018?—?and the Individual Defendants assert that they did so in light of the executives’ performance, as evaluated by management, the Compensation Committee and the non-executive Board members, and not as automatic, unearned true-ups as the Plaintiff alleges.
For these reasons and as set forth in greater detail below, the Board of Directors recommends stockholders vote “Yes” on Proposal No. 3.
General
Prior to voting on Proposal No. 3 and to provide stockholders transparency about the Plaintiff’s challenges to the ratification of Proposal No. 3, below is a summary of litigation filed by Plaintiff Glenn F. Schaeffer (the “Plaintiff”), a Company stockholder. This summary is qualified in its entirety by reference to the Proceedings.
Plaintiff has brought derivative1 and direct claims, on an individual and class-wide basis, against the Individual Defendants Ambassador J. Cofer Black, Jerry Jasinowski, Dr. Navid Malik, Dr. Alton L. Boynton, Linda Powers and Leslie J. Goldman and nominal defendant Northwest Biotherapeutics (together with the Individual Defendants, the “Defendants”) challenging the 2020 Executive Options and the 2020 Director Options which are addressed under Proposal No. 4 (the 2020 Executive Options and the 2020 Director Options, collectively the “2020 Options”) and related disclosures.
In the Delaware Litigation, Plaintiff seeks, among other things, to rescind all of the 2020 Executive Options (and all of the 2020 Director Options, which are addressed under Proposal No. 4 below).
On February 22, 2023, the Defendants filed a motion to dismiss the Delaware Litigation following the prior stockholder votes in support of the 2020 Options.
On November 17, 2023, and as explained in greater detail below, the Delaware Court of Chancery denied the Defendants’ motion to dismiss (the “Motion to Dismiss Ruling”) and allowed the litigation to proceed. As a result, the Board is seeking another stockholder vote at this year’s Annual Meeting.
The Plaintiff provided a brokerage statement indicating that as of March 31, 2021 he owned 11,000 shares of the Company’s common stock. The Individual Defendants have served discovery requests on the Plaintiff requesting evidence of the Plaintiff’s shareholding in the Company throughout the period at issue in this case, but to date the Plaintiff has not provided it. As of the Record Date, there were 1,241,178,702
?
1
A derivative action is a lawsuit brought by a stockholder of a corporation on the corporation’s behalf to assert a legal right or claim of the corporation.
?
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shares of common stock outstanding, including the outstanding preferred stock on an as converted basis. If the Plaintiff continued to hold 11,000 shares as of the Record Date, his position represented approximately 0.00089% of the Company’s outstanding shares of stock.
A copy of Plaintiff’s Amended Complaint is attached as Appendix A to this Proxy Statement (the “Amended Complaint”). A copy of the Court of Chancery’s Motion to Dismiss Ruling is attached as Appendix B to this Proxy Statement. As noted above, stockholders should read both the Amended Complaint and the Motion to Dismiss Ruling in their entirety to understand fully Plaintiff’s allegations and the Court of Chancery’s reasoning for allowing the litigation to proceed to trial.
Effects of a “Yes” Vote or “No” Vote on this Proposal No. 3.
“No” Vote
If stockholders vote “No” on Proposal No. 3 and do not ratify the 2020 Executive Options, the Delaware Litigation will proceed and the Individual Defendants will need to prove the “entire fairness” of the 2020 Options.
Further, if the Delaware Litigation proceeds and the Plaintiff prevails at trial, the Individual Defendants anticipate that the Plaintiff will not only ask the Court to rescind and take away the 2020 Executive Options and 2020 Director Options in their entirety, but also that the Plaintiff will ask the Court to approve an award of millions of dollars of fees to the Plaintiff’s attorneys payable by the Company.
The Board believes that the legal fees, distraction and disruption associated with continuation of the Delaware Litigation will have a negative impact on the Company at a time when management’s time and attention, and the Company’s financial resources, would be best spent on pursuing regulatory approval and commercial launch of the Company’s DCVax-L product, pursuing reimbursement coverage, further buildout of the Sawston facility, deployment of the Flaskworks system and manufacturing scale-up, restart of the DCVax-Direct program and expansion of the Company’s pipeline, pursuit of the Company’s lawsuit against certain market makers, and other major milestones.
The Individual Defendants reserve the right to, and plan to, continue to dispute the allegations of the Plaintiff’s Amended Complaint.
“Yes” Vote
If stockholders vote “Yes” on Proposal No. 3 and ratify the 2020 Executive Options, the Individual Defendants intend to seek dismissal of part or all of the Delaware Litigation described below on the grounds that the challenged awards have been ratified by the Company’s stockholders and therefore the Amended Complaint fails as a matter of law.
If the stockholders vote “Yes” on this Proposal No. 3 and ratify the 2020 Executive Options, this ratification will only relate to the same options that were previously approved by the stockholders in the advisory vote in 2021 and the ratification in 2022, and that were already counted in the Company’s capitalization table in 2020.
Vote Required for a “Yes” Vote
Re-approval and ratification of the 2020 Executive Options requires a majority of the votes cast with respect to this Proposal No. 3 at this Annual Meeting by disinterested stockholders.2
Summary of the Delaware Litigation
On June 8, 2022, Plaintiff brought a consolidated stockholder derivative and class action on behalf of the Company (the “Complaint”) against the Board and management as Individual Defendants and the Company as the nominal defendant (collectively, “Defendants”).
?
2
‘Disinterested stockholders’ means parties who own shares of the Company’s stock other than parties who are Company insiders (directors or employees) or related parties. In Northwest Biotherapeutics, such insiders and related parties own mostly options, which have no votes and are not shares?— collectively, the insiders and related parties own only 3.8 percent (3.8%) of the Company’s voting stock.
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This summary of the Delaware Litigation is qualified in its entirety by the Proceedings. Among other things, the Complaint alleged that the 2020 Options were financially unfair and not intended as a reward for performance or milestones achieved in the Company’s operations but instead were solely an unearned true-up to offset the dilutive effects of the Company’s financing transactions. The Complaint alleged that the process and bases for the 2020 Options were defective because the evaluations were done internally and not by an external compensation consultant, and that the 2020 Options were not supported by any peer group analysis. The Complaint further alleged that by approving or accepting the 2020 Options the Individual Defendants breached their fiduciary duties and were unjustly enriched. As detailed below, the 2020 Executive Options and the 2020 Director Options were discussed and considered at length, in numerous Board and Compensation Committee meetings between December 2019 and September 2020, as well as later in 2020, and were not executed and issued until months after the approvals. Nonetheless, the Complaint alleged that the timings of the 2020 Executive Options and the 2020 Director Options were too close together, the approvals should be considered a single transaction in which all members of the Board had a conflict of interest, and consequently all approvals should be rescinded.
Based on these claims, the Plaintiff seeks to rescind all of the 2020 Options. In addition, the Individual Defendants anticipate that the Plaintiff will ask the Court to approve an award of millions of dollars of fees to the Plaintiff’s attorneys payable by the Company if the Plaintiff prevails in having all of the 2020 Options rescinded.
On August 31, 2022, Defendants filed a motion to dismiss the Complaint or, in the alternative, to stay (pause) it. On October 31, 2022, the Plaintiff filed an opposition to Defendants’ motion to dismiss. On December 7, 2022, the Court of Chancery entered a joint stipulation of the parties staying briefing on the motion to dismiss pending the outcome of the stockholder vote on the 2020 Options at the December 2022 Annual Meeting.
At the Annual Meeting on December 30, 2022, above 90% of the Company’s shares voted (representing 56.9% of all eligible votes) were cast to ratify the 2020 Executive Options, and above 90% of the Company’s shares voted (representing 57.6% of all eligible) were cast to approve the 2020 Director Options.
The same day as the stockholders’ approval of the 2020 Options at the December 30, 2022 Annual Meeting, the Plaintiff filed an Amended Complaint asserting new claims of breach of fiduciary duties for alleged deficiencies in the proxy statement for that December 30, 2022 Annual Meeting, and asserting that the stockholder votes at the 2022 Annual Meeting should be disregarded based on these new claims. As noted above, the Amended Complaint is attached as Appendix A hereto.
The Amended Complaint added claims asserting that stockholders may not have known what it meant to vote in favor or against the 2020 Option awards, and that the proxy contained false and misleading information and omissions in describing the 2020 Options awards as being based on considerations of service, performance and market factors, and that the proxy should have said that the awards were solely unearned true-ups. The Amended Complaint also sought a declaratory judgment that the stockholder ratification of the compensation awards to the executive officers was not legally binding because it was structured so that stockholders voted on the Executives’ Options together as a “bundle,” and the Directors’ Options as a separate “bundle,” rather than voting separately on each individual person. The Company’s understanding is that there is no such legal requirement for voting separately on each individual person, and the Company notes that it is not customary practice to do so in compensation votes, such as Say on Pay for executive compensation.
On February 22, 2023, Defendants filed a motion to dismiss the Amended Complaint based upon the stockholder votes at the December 2022 Annual Meeting.
On March 24, 2023, the Plaintiff filed an Opposition to the Motion to Dismiss, again arguing that the stockholder votes should be deemed insufficient.
On September 8, 2023, the Court held a hearing on Defendants’ motion to dismiss.
On November 17, 2023, the Court issued an oral ruling denying the Motion to Dismiss (“Motion to Dismiss Decision,” attached hereto as Appendix B). The Court noted that, at the Motion to Dismiss stage, allegations by the Plaintiff in the Amended Complaint must be viewed by the Court in the light most favorable
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to the Plaintiff and all “reasonably conceivable” allegations must be assumed by the Court to be true. With that perspective, the Court held that the Plaintiff’s allegations were sufficient to survive dismissal. The Court also held, among other things, that the Plaintiff’s allegations were at least “reasonably conceivable” that the stockholder vote was not fully informed in regard to the alleged true-up purpose, the proxy description that the option awards were based on performance and market information, and the effects of a negative vote on the options. This summary is qualified in its entirety by reference to the Proceedings.
On December 20, 2023, the Company answered the Amended Complaint.3 On December 28, 2023, the Individual Defendants answered the Complaint and disputed the Plaintiff’s core allegations.
The parties are now in the discovery stage of the Delaware Litigation. Fact discovery is scheduled to conclude by October 11, 2024; expert discovery is scheduled to occur from October 18, 2024 to January 15, 2025. A nearly week-long trial is scheduled for May 12-15, 2025. Thus, the Delaware Litigation is expected to cost the Company millions of dollars and require hundreds of hours of management’s time, which the Board believes would be better spent achieving the Company’s milestones and pursuing commercialization.
Summary of the Bases Upon Which the Individual Defendants Dispute the Plaintiff’s Allegations
The Individual Defendants dispute the Plaintiff’s allegations in the Delaware Litigation, and believe that the 2020 Executive Options (and 2020 Director Options addressed under Proposal No. 4 below) were properly awarded, and were and are in the best interests of the Company and its stockholders. Among other reasons, they assert the following:
•
The Company has only made equity awards to two of its four senior executives (Ms. Powers and Mr. Goldman) twice in the 13 years since 2011: in 2018 and in 2020, and only made awards to the other two senior executives (Dr. Bosch and Dr. Boynton) three times in these 13 years (2017, 2018 and 2020). No equity awards were made during 2012, 2013, 2014, 2015, 2016, 2019, 2021, 2022, 2023 or 2024 year to date. In contrast, publicly traded biotech companies generally award a combination of equity and cash compensation to their key officers on an annual basis.
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•
In the Delaware Litigation, the Plaintiff’s allegations against the 2020 Executive Options in Northwest Biotherapeutics compare single-year equity compensation in other companies to equity awards made by Northwest Biotherapeutics only once in multiple years.
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At the time of the 2020 Option awards, the Company had 1.2 billion securities outstanding. The 2020 Executive Options were an aggregate total of 135.8 million options, comprising approximately 11.7% of the securities outstanding. The 2020 Director Options were an aggregate total of 26.2 million options, comprising approximately 2.3% of the securities outstanding. For further details see the discussion of Executive Compensation below.
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•
No equity awards have been made to the executives or the non-executive Directors in the four years since the 2020 Options. During this time, and as described in detail below, the Company’s exceptionally small management team has achieved major progress and milestones.
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The 2020 Options were awarded from the securities available within the Equity Pool reserved for employees and directors under the Company’s Equity Compensation Plan, and were awarded in accordance with the Plan.
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The 2020 Executive Options reflected the assessment of each of the executives’ roles and contributions to the Company’s progress and milestones. A particular Equity Pool Allocation was determined for each executive individually. In 2018, the Company’s management and Board determined the Equity Pool Allocations for each executive based on evaluation of roles and contributions, and after comparing the Company with other oncology biotech companies who were developing similar or competing technologies (dendritic cell therapies and/or various brain cancer treatments), and were at a similar stage of company development as the Company (late stage clinical trials; no products approved or on the market yet).
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Company management, the Compensation Committee, and the Board routinely discuss compensation, including equity compensation, for employees, directors, and consultants before ultimately
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3
In derivative litigation, the nominal defendant is considered to be a neutral party.
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implementing the compensation. In 2020, Company management reviewed the executives’ 2018 Equity Pool Allocations and their roles and contributions in the 2018 through 2020 period, and made recommendations regarding 2020 Options to the Compensation Committee. The Compensation Committee (chaired by a biotech industry specialist) then considered the executives’ performance and Equity Pool Allocations, including the management recommendations and determined that the Allocations should remain substantially the same as in 2018. The non-executive Directors further reviewed and considered the executives’ roles and contributions, and their Equity Pool Allocations, and determined that the Allocations should remain substantially the same as in 2018. Portions of the available securities in the Equity Pool corresponding to the Equity Pool Allocations were then awarded as the 2020 Executive Options. The 2020 Executive Options were referred to in certain internal Board minutes as a true-up that maintained the same Equity Pool Allocations as in 2018, but the Individual Defendants assert that the awards reflected the executives’ performance that earned the awards?—?not an automatic unearned true-up as the Plaintiff alleges. Further details are provided in the discussion of the Process and Bases for the 2020 Executive Options below.
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Retaining and incentivizing key executives during the last 13 years overall, and the last six years in particular (2018 to present), has been especially important to the Company. During the last six years, the Company’s exceptionally small management team of only four senior executives, with the assistance of an exceptionally involved Board, has achieved key milestones, including:
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(a)
completion of the DCVax-L Phase 3 trial (one of the largest cell therapy trials ever conducted), Statistical Analysis Plan, data lock and analysis,
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(b)
peer reviewed JAMA Oncology publication,
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(c)
drafting and submission of a Marketing Authorization Application (MAA) for commercial approval of DCVax-L in the United Kingdom (“UK”),
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(d)
Flaskworks acquisition and technology development,
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(e)
Sawston facility development and multi-phase buildout,
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(f)
Sawston licenses including a commercial manufacturing license,
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(g)
expansion of IP and collaborations,
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(h)
defenses against ongoing attacks,
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(i)
successful fundraising of $40-50 million per year in adverse market conditions (including 2023 when biotech company failures reached a 10-year high), and
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(j)
filing and pursuit of a potentially landmark lawsuit against certain market makers.
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Retaining and incentivizing key executives for the foreseeable future remains especially important to the Company as it seeks to achieve further major value milestones, including:
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(a)
completion of the regulatory process and potential approval of the MAA for DCVax-L in the UK,
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(b)
technology assessment and potential reimbursement decision in the UK,
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(c)
applications for regulatory approval of DCVax-L and for reimbursement in other countries
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(d)
completion of development of the GMP version of the Flaskworks system and development of units for commercial operations,
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(e)
further development and buildout of the Sawston facility,
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(f)
launch of combination treatment trials and trials in cancers other than brain cancer,
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(g)
restart of the DCVax-Direct program,
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(h)
prosecution of the lawsuit against the market makers, including extensive discovery if (as the Company anticipates) the case proceeds, and
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(i)
continued major fundraising.
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Further details are provided in the compensation discussion below and in the Summary of the Approval Process and Bases for the Director Options in Proposal No. 4 below.
Summary of the Approval Process and Bases for the Executive Options
The Board granted the 2020 Option awards from the available Equity Pool in accordance with the Company’s Equity Compensation Plan. While the Company was listed on NASDAQ in 2012 through 2016, the Company’s stockholders gave formal approval twice, at two annual meetings, of an equity compensation plan (the “Prior Plan”) under which twenty percent (20%) of the Company’s stock would be reserved in a pool for employees and directors on an ongoing evergreen basis. A copy of the Prior Plan is attached as Exhibit 10.36 to the Company’s Annual Report on Form 10-K for the fiscal year ended December 31, 2019. During the period that the Company has been listed on the OTCQB exchange, from 2016 onward, the Company has continued to operate under a comparable structure and terms and, as previously reported, adopted the Equity Compensation Plan for a new Term with similar structure and terms, including reserving twenty percent (20%) of the Company’s outstanding securities on an evergreen basis in a pool reserved for employees and directors (the “Equity Pool”). A copy of the Equity Compensation Plan is attached as Exhibit 10.81 to the Company’s Annual Report on Form 10-K for the fiscal year ended December 31, 2023. The Company has been advised by a compensation consultant that it is common for pre-commercial biotech companies to reserve a pool of 15-20% for employee and director equity awards.
2018 Review of Executive Compensation
The Company has only made equity awards to two of its four senior executives (Ms. Powers and Mr. Goldman) twice in the 13 years since 2011: in 2018 and in 2020, and only made equity awards to the other two senior executives (Dr. Bosch and Dr. Boynton) three times in these 13 years (2017, 2018 and 2020). In 2018, management identified a comparator group of peer companies from which to obtain comparison information about pay practices. Management considered a number of factors as to the similarity of the business and the stage of development, and did not solely or primarily use just the market capitalization of the other companies. Management identified companies as peers who: (a) were developing medical technologies similar to or competitive with Northwest Biotherapeutics’ DCVax technologies (dendritic cell therapies and/or various treatments for brain cancer), and (b) were at a similar stage of company development as Northwest Biotherapeutics (late stage clinical trials; no products approved or on the market yet).
The companies identified were: Argos Therapeutics (dendritic cell therapy), Bellicum (dendritic cell therapy), Atara (T cell therapy), Agenus (brain cancer immune therapy), and Celldex (brain cancer immune therapy). Management identified these companies as peers of Northwest Biotherapeutics in the same business space and at a comparable stage of clinical development as Northwest Biotherapeutics. Management did not use an external compensation consultant to identify these peer companies.
In addition to reviewing information on compensation in peer companies, management also considered the years of service, roles and contributions of each of the Company’s four key executives, including these executives’ performance of multiple roles, for the 2018 option awards. Based on this information, management made recommendations for consideration by the Compensation Committee about a particular portion (percentage) of the Equity Pool to be awarded to each of the four senior executives (“Equity Pool Allocation”).
The Compensation Committee considered a number of factors in connection with the 2018 option awards to the four executives, including market data from the peer companies that management had identified, each executive’s service, roles and responsibilities, the necessity for these key executives to perform multiple roles due to the exceptionally small executive team, each executive’s contributions to the Company’s progress, and the Company’s progress. This evaluation was done internally by the Committee in light of their knowledge of each executive’s roles and performance, and not by an external compensation consultant. The chair of the Compensation Committee was (and still is) Dr. Navid Malik, a biotech industry specialist who had extensive personal knowledge of the biotech industry generally and the cell therapy and immunotherapy spaces specifically.
Based on the foregoing factors as well as recommendations from management and taking into account that no equity awards had been made for six years, the Compensation Committee determined a particular
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Equity Pool Allocation for each of the four key executives for 2018. The Committee approved the allocations recommended by management. These Allocations were also considered, discussed and approved by the non-executive Board members. These Allocations were then translated into a corresponding number of options which were issued as option awards to the executives in 2018. For details, see the Executive Compensation section below.
2020 Review of Executive Compensation
The 2020 Options were considered extensively, in discussions in Board meetings on December 8, 2019 and on January 14, January 26, March 23, May 23, May 25, May 29, June 28, July 19, August 5, September 2, September 3, October 13, October 18 and December 30, 2020?—?as well as in Compensation Committee meetings on December 8, 2019, May 26, May 29 and August 5, 2020. The Plaintiff alleges that the May 23, 2020 meeting at which the Director Options were re-approved (after having been approved at the January 26 meeting but not executed or issued) and the May 29 meeting at which the Executive Options were approved were in fact part of a single effort to true up the Individual Defendants. The Plaintiff alleges that, even though all of the Board members recused themselves from the votes on their own compensation awards, it was not possible for any of the Board members to be disinterested, and they were inescapably conflicted despite the recusals. The Individual Defendants dispute the Plaintiff’s allegation that the compensation awards were part of a single effort to true up the Individual Defendants, and they dispute the focus on just the two May meetings out of the long series of meetings and discussions of the Options. Among other things, the Individual Defendants assert that the Plaintiff ignores the discussions at many other meetings, and ignores the fact that the Options still were not executed and issued during these May meetings. They were not executed and issued until months later, in July for Executive Options (except for some Executive Options held back for a further two months), and in August for the Directors Options.
For the consideration of potential 2020 Option awards, the Individual Defendants assert that management reviewed the particular Equity Pool Allocation for each key executive that had been determined in 2018, and reviewed the executives’ roles and contributions to the Company’s progress between 2018 and 2020, which included:
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peer reviewed publication of blinded interim Phase 3 trial data in the Journal of Translational Medicine,
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substantial completion of the Phase 3 clinical trial and follow-up,
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substantial completion of the end-of-trial query resolution (including thousands of queries) necessary before data lock, despite severe restrictions and blocking by the hospital trial sites due to the pandemic,
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preparations for data lock,
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substantial completion of work with three separate sets of statisticians to develop the Statistical Analysis Plan,
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successful sale of UK property at a robust price that generated over $45 million of non-dilutive funding for the Company’s operations,
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initial work on development of the Sawston GMP facility under a long-term lease executed in December 2018,
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process and negotiations to acquire Flaskworks from Corning,
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expansion of the Company’s intellectual property (IP) portfolio with addition of certain new IP for enhanced dendritic cells, and
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•
compassionate use program to gain useful real-world experience.
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Company management, the Compensation Committee, and the Board routinely discuss compensation, including equity compensation, for employees, directors, and consultants before ultimately implementing the compensation. For the 2020 Options, management again made recommendations to the Compensation Committee for a particular Equity Pool Allocation for each of the same four key executives as in 2018. Management recommended that these Allocations remain substantially the same in 2020 as in 2018.
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The Individual Defendants assert that the Compensation Committee again reviewed the management recommendations, and again considered the roles and contributions of each of the four executives in the Company’s progress in light of the Committee’s own knowledge of the executives’ activities and performance. The Committee concluded that the Equity Pool Allocations should remain substantially the same as in 2018.
In considering the 2020 Option awards, the Individual Defendants assert that the Compensation Committee recognized the importance of retaining and incentivizing the key executives to continue pushing the Company’s progress forward in the midst of extremely challenging and problematic circumstances in the pandemic. As the Company previously reported in a number of periodic filings, the clinical trial site hospitals were in lockdown, not allowing monitoring visits and making data collection and checking extremely difficult, supply chains were disrupted, the availability of investigators and staff at trial sites was limited, and Institutional Review Board or Ethics Committee meetings and regulatory processes for matters other than COVID-19 were suspended or significantly backlogged.
The non-executive Board members evaluated the Compensation Committee’s recommendations about the Equity Pool Allocations for 2020 as well as the executives’ roles and performance. The non-executive Board members approved the Committee’s recommended Equity Pool Allocations for the key executives, which were substantially the same as the 2018 Equity Pool Allocations. These Allocations of the available securities in the Equity Pool were translated into a corresponding number of options, which were issued as the 2020 Executive Options.
As noted above, the Plaintiff in the Delaware Litigation claims that the 2020 Executive Options were not based on any success in advancing the Company’s business nor any market factors, but were simply unearned true-ups. The Individual Defendants disagree, and assert that, as discussed above, the Compensation Committee’s and non-executive Board members’ determinations of each executive officer’s 2020 Executive Options were made in light of thorough and thoughtful consideration of each executive’s performance and contributions, which were reflected in the respective Equity Pool Allocations determined for each individual executive. Since the Equity Pool Allocations remained substantially the same in 2020 as in 2018, and since the available Equity Pool had grown since 2018, the 2020 Option awards, which certain Board minutes referred to internally as true up awards, did increase the equity held by the key executives up to substantially the same percentage portion of the Equity Pool as they had in 2018. Nevertheless, as explained above, through the determination of Equity Pool Allocations based on the executives’ performances, roles and contributions, the Individual Defendants assert that the Board awarded the 2020 Options based on executive performance that earned them?—?not as unearned windfalls as the Plaintiff alleges.
Summary of the 2020 Executive Options
As previously reported and as previously approved by stockholders twice, the 2020 Executive Options comprise 43,329,153 options awarded to Ms. Linda Powers, 28,544,455 options awarded to Mr. Leslie Goldman, 27,429,455 options awarded to Dr. Marnix Bosch, and 18,794,191 options awarded to Dr. Alton Boynton with an exercise price of $0.35. The 2020 Executive Options also include 11,789,879 options awarded to Ms. Powers and 5,894,939 options awarded to Mr. Goldman with an exercise price of $0.55 per share. Each exercise price was the market price at the time the 2020 Executive Options were awarded in 2020, and was substantially higher than the market price of the Company’s common stock during much of the 2018-2020 periods for which the 2020 Executive Options were awarded as compensation. The exercise period is ten years from the time they become exercisable.
Recommendation
The Board of Directors recommends that, in considering their vote on this Proposal No. 3, stockholders take account of all of the Plaintiff’s allegations.
The Board of Directors unanimously recommends that you vote FOR the ratification of the 2020 Executive Options.
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PROPOSAL NO. 4?—?RATIFICATION OF THE SAME OPTION AWARDS THAT WERE
MADE IN 2020 TO THE NON-EXECUTIVE DIRECTORS ON THE BOARD OF DIRECTORS,
AND THAT WERE PREVIOUSLY REPORTED AND PREVIOUSLY APPROVED BY
STOCKHOLDERS AT THE 2022 ANNUAL MEETING
Executive Summary
The Board of Directors seeks stockholder approval of certain option awards which were granted to Company’s three non-executive Directors in 2020 (the “2020 Director Options,” and with the 2020 Executive Options described above in Proposal No. 3, the “2020 Options”): Ambassador Cofer Black, Dr. Navid Malik and Jerry Jasinowski.
A publicly listed company cannot operate, or continue to be publicly listed, without non-executive directors on its Board of Directors. Attracting and retaining well-qualified non-executive directors is challenging for small, development-stage companies. Serving as a director in such companies can entail extensive time commitments and can involve significant personal risks, including the risk of personal reputational damage from being attacked or criticized by bloggers and other parties who attack the Company, and the risk of being sued personally along with the Company.
At present, three of our five Board members are non-executive Directors, and two are drawn from Company management. The Company considers itself fortunate to have highly accomplished professionals as non-executive Board members, and fortunate to have been able to maintain continuity among its non-executive directors: Dr. Malik has now been serving for over 10 years, Ambassador Black has been serving for 8 years and Mr. Jasinowski served for over 10 years before retiring for medical reasons and being succeeded by Mr. Pat Sarma.
The 2020 Option awards to the Company’s non-executive Directors were expressly conditioned upon stockholder approval, and they were already approved by stockholders in a vote at the 2022 Annual Meeting, with approval by 90% of the votes cast (further details below). However, as described under Proposal No. 3 above, a stockholder plaintiff filed a lawsuit (the “Delaware Litigation”) challenging the 2020 Director Options (as well as the 2020 Executive Options addressed under Proposal No. 3 above), and asserting that the prior stockholder vote was insufficient. Consequently, the Board of Directors is now seeking, with this Proposal No. 4, a second stockholder vote on the same 2020 Director Options.
No equity awards have been made to the non-executive Directors in the four years since the 2020 awards. The 2020 Director Options have already previously been counted in the Company’s capitalization table.
The Board recommends that, in order to be fully informed, stockholders should read in their entirety Proposal No. 3 above, this Proposal No. 4, the Plaintiff’s Amended Complaint (attached as Appendix A), and the Delaware Court’s decision denying the Motion to Dismiss the lawsuit (attached as Appendix B), before voting on this Proposal No. 4. A summary of the lawsuit is also presented for stockholders in Proposal No. 3.
As set forth in greater detail under Proposal No. 3 above, the Delaware Litigation (defined in Proposal No. 3, above) alleges, among other things, that the 2020 Director Options were not intended as a reward for the amount of time and involvement of the non-executive Directors in Northwest Biotherapeutics, and amount of personal risk incurred by the non-executive Directors, but instead were solely to true up the non-executive Directors’ option awards to offset the dilutive effects of the Company’s financing transactions. The lawsuit also alleges that the 2020 Options were financially unfair, that the award process and bases were defective because the evaluations were prepared internally and not by an external compensation consultant, that approving or accepting the 2020 Options was a breach of fiduciary duties and constituted unjust enrichment, and that the stockholders were not sufficiently informed to be able to cast an effective vote for or against the 2020 Options. The lawsuit was filed against Board members Ambassador J. Cofer Black, Dr. Navid Malik, and Jerry Jasinowski (who has since retired for medical reasons), as well as members of management Linda Powers, Les Goldman and Dr. Al Boynton (the foregoing collectively, the “Individual Defendants”). The descriptions and summaries of the lawsuit herein are qualified in their entirety by reference to the Proceedings (defined in Proposal No. 3, above).
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The Plaintiff in the Delaware Litigation has also alleged that the Board, including the non-executive Directors (Ambassador J. Cofer Black, Dr. Navid Malik, and Jerry Jasinowski) and executive Directors (Linda Powers and Dr. Al Boynton), could not impartially consider a demand that the Company bring litigation with respect to the 2020 Options because, although many Board and Committee meetings were held between December 2019 and September 2020, as well as later in 2020, discussing compensation and equity awards, the executive Directors approved the 2020 Director Options (conditional on stockholder approval) and the non-executive Directors approved the 2020 Executive Options. Plaintiff alleges that as a result, all of the directors were inescapably conflicted.
At the Motion to Dismiss stage of the litigation, however, the Court draws inferences in the Plaintiff’s favor and the Court determined, among other things, that the Board could not impartially consider a demand for the Company to bring litigation with respect to the Plaintiff’s claims. The Individual Defendants reserve the right to, and plan to, continue to dispute the allegations of the Amended Complaint, including that the Board believes that the non-executive Directors were independent for the reasons described above and that the respective 2020 Options were approved by Director groups disinterested in the awards they were approving.
As set forth in greater detail below, the Individual Defendants dispute the Plaintiff’s allegations for multiple reasons. The Board believes that accomplished professionals who would be desirable Board candidates simply will not tolerate high levels of personal risk, including litigation risks, especially if such burdens not only occur but persist over the course of years. The Individual Defendants assert that the 2020 Director Options took account of and reflected the exceptional amount of time and involvement of the non-executive Directors as well as the exceptional level of personal risk incurred by the non-executive Directors in Northwest Biotherapeutics?—?burdens and risks that have persisted for years for our Board members. The Individual Defendants note that it is very difficult to find and attract?—?and retain?—?well qualified Board members in such difficult circumstances. The Individual Defendants further note that equity awards have only been made for the non-executive Directors twice in the years since joining the Board in 2012 (Dr. Malik and Mr. Jasinowski) or 2016 (Ambassador Black): in 2018 and 2020.
In light of these significant challenges, the Board believes that it is especially important that the Company’s compensation and benefits policies are effective to attract and retain well qualified non-executive directors necessary for the Company to operate and for support of the Company’s growth and success, both operationally and strategically, to help build stockholder value. The Company’s compensation philosophy is also to take account of individual performance by the directors, including participation in Board and Committee meetings, and roles and contributions. Company management, the Compensation Committee, and the Board routinely discuss compensation, including equity compensation, for employees, directors, and consultants before ultimately implementing the compensation.
For these reasons and as set forth in greater detail below, the Board of Directors recommends that stockholders vote “Yes” on Proposal No. 4.
General
The Company refers stockholders to the General section under Proposal No. 3 above. All summaries and descriptions of the Delaware Litigation are qualified in their entirety by reference to the Proceedings. See also the Amended Complaint attached hereto as Exhibit A, and the Delaware Court’s denial of the Motion to Dismiss the Delaware Litigation attached hereto as Exhibit B.
Effects of a “Yes” Vote or “No” Vote on this Proposal No. 4
“No” Vote
If stockholders vote “No” on Proposal No. 4 and do not ratify the 2020 Director Options, the Delaware Litigation will proceed and the Individual Defendants will need to prove the “entire fairness” of the 2020 Options.
Further, if the Delaware Litigation proceeds and the Plaintiff prevails at trial, the Individual Defendants anticipate that the Plaintiff will not only ask the Court to rescind all of the 2020 Director Options and
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Executive Options, but also that the Plaintiff will ask the Court to approve an award of millions of dollars of fees to the Plaintiff’s attorneys payable by the Company.
The Board believes that the legal fees, distraction and disruption associated with continuation of the Delaware Litigation will have a negative impact on the Company at a time when management’s time and attention, and the Company’s financial resources, would be best spent on pursuing regulatory approval and commercial launch of the Company’s DCVax-L product, pursuing reimbursement coverage, further buildout of the Sawston facility, deployment of the Flaskworks system and manufacturing scale-up, restart of the DCVax-Direct program and expansion of the Company’s pipeline, pursuit of the Company’s lawsuit against certain market makers, and other major milestones.
The Individual Defendants reserve the right to, and plan to, continue to dispute the allegations of the Amended Complaint.
“Yes” Vote
If stockholders vote “Yes” on Proposal No. 4 and ratify the 2020 Director Options, the Individual Defendants intend to seek dismissal of part or all of the Delaware Litigation described above on the grounds that the challenged awards have been ratified by the Company’s stockholders and therefore the Amended Complaint fails as a matter of law.
If the stockholders vote “Yes” on this Proposal No. 4 and ratify the 2020 Director Options, this ratification will only relate to the same options that were previously approved by the stockholders in 2022, and that were already previously counted in the Company’s capitalization table.
Vote Required for a “Yes” Vote
Re-approval and ratification of the 2020 Director Options requires the affirmative vote of a majority of the votes cast in favor of this Proposal 4 at the Annual Meeting by disinterested stockholders.4
Summary of the Delaware Litigation
The Company refers stockholders to the Summary of the Delaware Litigation under Proposal No. 3 above. All summaries and descriptions of the Delaware Litigation are qualified in their entirety by reference to the Proceedings. See also the Amended Complaint attached hereto as Exhibit A, and the Delaware Court’s denial of the Motion to Dismiss the Delaware Litigation attached hereto as Exhibit B.
Summary of the Approval Process and Bases for the Director Options
The Company refers stockholders to the Summary of the Bases Upon Which the Individual Defendants Dispute the Plaintiff’s Allegations and the Summary of the Approval Process and Bases for the Executive Options included in Proposal No. 3 above, which substantially address the process used to determine the 2020 Option awards.
The Company’s non-executive directors are compensated with a combination of cash and equity compensation. Equity awards to the non-executive Directors have only been made twice since they joined the Board in 2012 (Jasinowski and Malik) or 2016 (Black): in 2018 and 2020. Company management, the Compensation Committee, and the Board routinely discuss compensation, including equity compensation, for employees, directors, and consultants before ultimately implementing the compensation.
The Individual Defendants assert that, when approving the option awards made to the non-executive Directors in 2018, the executive Directors considered the amount of time and work devoted by the non-executive Board members as well as the amount of risk exposures, and also considered certain market information from other oncology biotech companies in the same business space as Northwest Biotherapeutics
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4
‘Disinterested stockholders’ means parties who own shares of the Company’s stock other than parties who are Company insiders (directors or employees) or related parties. In Northwest Biotherapeutics, such insiders and related parties own mostly options, which have no votes and are not shares?— collectively, the insiders and related parties own only 3.8 percent (3.8%) of the Company’s voting stock.
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(developing dendritic cell therapies or various treatments for brain cancer), and at the same stage of company development as Northwest Biotherapeutics (in late stage clinical trials, with no product approved or on the market). In light of these considerations, the executive Directors, after considering management recommendations, determined a specific percentage (Equity Pool Allocation) of the Company’s Equity Pool (described above under Proposal No. 3) for each such non-executive Director.
With respect to the 2020 Director Options, the Individual Defendants assert that the executive Directors (Ms. Powers and Dr. Boynton) reassessed the non-executive Directors’ time involvement and workload, roles and risk exposures and kept the non-executive Directors’ respective Equity Pool Allocations substantially the same as in 2018. The reassessment took account of these performance factors and was not based on the market capitalization of peer companies. The executive Directors (Ms. Powers and Dr. Boynton) carried out the reassessment with management input, and not by an external compensation consultant. The 2020 Director Options were issued from the available Equity Pool under the Company’s Equity Compensation Plan in accordance with the respective Allocations. The Individual Defendants assert that they were referred to internally in Board minutes as true-ups as their allocation was informed in part by the Equity Pool Allocations used in 2018. The Individual Defendants assert that the 2020 Director Options were based on the non-executive Directors’ performance reflected in their respective Equity Pool Allocations and were not automatic, unearned true-ups as the Plaintiff alleges.
As noted above, the Individual Defendants assert that the executive Directors determined the 2020 Director Options in light of a number of factors and considerations, including the following. One set of considerations was the extraordinary amount time, effort and support contributed by the non-executive Directors throughout their years of service, including the 2018-2020 period that was covered by the 2020 Option awards. The time and involvement of the non-executive Directors went far beyond the activities typically involved in Board service. The non-executive Directors have continued to devote an extraordinary amount of time to the Company’s business and affairs throughout the four years since the 2020 Option awards, and no further equity awards have been made to the non-executive Directors. For example, while it is typical for a board of directors to meet four to six times a year, our Board meets as much as two dozen times per year, and it holds up to a dozen or more Committee meetings in addition.
Further, the Individual Defendants assert that the non-executive Directors provided, and continue to provide, active support and assistance to management in a variety of areas of the Company’s operations. This active involvement includes, and goes beyond, the oversight role that all Boards are responsible for.
The Individual Defendants assert that another set of considerations for the 2020 Director Options was the extent of personal and professional risk our non-executive Directors have endured in serving on our Board. Our Company has experienced ongoing attacks from short sellers and from bloggers whom the Company believes may be connected with short sellers. The Individual Defendants note that the attacks have also gone beyond the Company itself: aggressive personalized attacks have been made against our directors on social media and message boards. Further, our Company has been subjected to multiple lawsuits which we believe were vexatious and lacked merit, and which we have fought, and continue to fight, vigorously?—?and which have named our directors personally and put them at personal risk.
The Individual Defendants further note that the many years of service provided by the non-executive Directors has afforded valuable continuity for the Company.
As noted above, the Plaintiff in the Delaware Litigation claims that the 2020 Director Options were not based on any success in advancing the Company’s business nor any market factors, but were simply unearned true-ups. The Individual Defendants disagree, and assert that, as discussed above, the executive Directors approved the 2020 Director Options after thoughtful consideration of each non-executive Director’s performance and contributions, which were reflected in the respective Equity Pool Allocations determined for each individual non-executive Director. The 2020 Option awards were referred to in internal Board minutes as true up awards which maintained the same Equity Pool Allocation from the available equity in the pool, but the Equity Pool Allocations were determined in light of the non-executive Directors’ performances, roles and contributions, and the Individual Defendants assert that these awards were based on performance that earned them?—?not unearned windfalls as the Plaintiff alleges.
For all of the above reasons, the 2020 Director Options were approved by the executive directors, expressly subject to stockholder approval, and our management also strongly supports the 2020 Director Options.
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Summary of the 2020 Director Options
As previously reported, the 2020 Director Options, which were conditioned on (and previously received) stockholder approval, comprise 5,710,891 options awarded to Mr. Jerry Jasinowski, 4,769,433 options awarded to Ambassador Cofer Black, and 15,732,288 options awarded to Dr. Navid Malik. The exercise price is $0.34 per share, which was the market price at the time the Options were awarded in 2020, and was substantially higher than the market price of the Company’s common stock during much of the 2018-2020 periods for which the Options were awarded as compensation. The exercise period is ten years from the time they become exercisable.
Recommendation
The Board of Directors recommends that, in considering their vote on this Proposal No. 4, stockholders take account of all of the Plaintiff’s allegations.
The Board of Directors unanimously recommend that you vote FOR the approval of the 2020 stock option awards to the non-executive Directors of the Board of Directors.
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PROPOSAL NO. 5?—?ADVISORY VOTE TO APPROVE EXECUTIVE COMPENSATION
As required under the Dodd-Frank Wall Street Reform and Consumer Protection Act of 2010, or Dodd-Frank Act, the Board of Directors is submitting a “say on pay” proposal for stockholder consideration. While the vote to approve executive compensation is nonbinding and solely advisory in nature, the Board and the Compensation Committee value the opinion of our stockholders and will review and consider the voting results.
Our success is highly dependent on our ability to attract, retain and incentivize executive officers who possess the skills, competencies and passion that are necessary to achieve progress in the Company’s clinical programs and progress toward eventual commercialization, as well as to contend with ongoing challenges to the Company’s progress. To this end, our compensation program has been developed with the following overarching principles in mind:
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the pay of our Named Executive Officers should balance incentivizing performance, ensuring retention and building stockholder value and should be linked to the Named Executive Officers roles and contributions to the Company’s progress.
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the pay of our Named Executive Officers should retain and incentivize individual Named Executive Officers to perform multiple senior executive roles each, at least until such time as the Company’s progress and resources enable expansion of the management team.
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our executive compensation program should enable us to recruit, develop, motivate and retain top talent. This is especially critical in a rapidly evolving field such as immuno-oncology, which requires highly specialized knowledge and experience and for which the talent pool is highly competitive.
?
The Compensation Committee of the Board of Directors, which is composed solely of non-executive directors, is responsible for determining or recommending the overall compensation levels of our executive officers, including our Named Executive Officers, and administering our equity compensation plans.
Our executive officers are compensated based on performance, and in a manner consistent with our strategy, competitive practice, sound corporate governance principles, and Company and stockholder interests. We believe our compensation program is strongly aligned with the long-term interests of the Company and our stockholders.
The compensation of the “Named Executive Officers” ?(as defined in Item 402(a)(3) of Regulation SK) is described on pages 28-36 of this proxy statement.
For 2023 compensation, the Compensation Committee took into account management recommendations and the Committee’s own assessment of the strong progress and major milestones reached in the Company’s programs, with key executives continuing to perform multiple roles. The non-executive Directors took account of the Committee’s assessments and their own assessments in approving the compensation.
In order to approve the executive compensation, stockholders are requested to approve the following resolution:
“RESOLVED, that the stockholders of Northwest Biotherapeutics, Inc. approve, on an advisory basis, the compensation paid to the Named Executive Officers as disclosed pursuant to Item 402 of Regulation SK, including the Summary Compensation Table for fiscal year 2023, and other related tables and disclosures.”
As indicated above, the stockholder vote on this resolution will not be binding on our Company or the Board of Directors, and will not be construed as overruling or determining any decision by us or by the Board. The vote will not be construed to create or imply any change to our Company fiduciary duties or those of the Board, or to create or imply any additional fiduciary duties for our Company or the Board.
Vote Required
Approval, on an advisory basis, of the compensation of our Named Executive Officers, as disclosed in this proxy statement, requires the affirmative vote of a majority of the votes cast with respect to such matter at the Annual Meeting.
Recommendation
The Board of Directors unanimously recommends stockholders vote, on an advisory basis, FOR the Company’s 2023 executive compensation.
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SECURITY OWNERSHIP OF CERTAIN BENEFICIAL OWNERS AND MANAGEMENT
The following table presents information regarding the beneficial ownership of our common stock as of May 9, 2024 by:
•
each person, or group of affiliated persons, who is known by us to beneficially own more than 5% of any class of our equity securities;
?
•
our directors and nominees for director;
?
•
each of our Named Executive Officers, as defined in Item 402(a)(3) of Regulation S-K; and
?
•
our directors and executive officers as a group.
?
Shares of common stock beneficially owned and the respective percentages of beneficial ownership of common stock assume the exercise of all options, warrants and other securities convertible into common stock beneficially owned by such person or entity currently exercisable or exercisable within 60 days of May 9, 2024, and we assume no exercise of any options, warrants and other securities by any other person or entity. Shares issuable pursuant to the exercise of stock options and warrants exercisable on or prior to the date 60 days after May 9, 2024 are deemed outstanding and held by the holder of such options or warrants for computing the percentage of outstanding common stock beneficially owned by such person, but are not deemed outstanding for computing the percentage of outstanding common stock beneficially owned by any other person.
Except as indicated by the footnotes below, we believe, based on the information furnished to us, that the persons and the entities named in the table have sole voting and investment power with respect to all shares of common stock that they beneficially own, subject to applicable community property laws, if any. The table below is based upon the information supplied by our transfer agent, Computershare Trust Company, N.A., the Company’s records and from Schedules 13D and 13G filed with the SEC.
Except as otherwise noted, the address of the individuals in the following table is c/o Northwest Biotherapeutics, Inc., 4800 Montgomery Lane, Suite 800, Bethesda, MD 20814.
Name of Beneficial Owner
? ?
Number of Shares
Beneficially Owned
? ?
Percentage(1)
?
Directors and Officers: ? ? ? ? ? ? ? ? ? ? ? ? ?
Alton L. Boynton, Ph.D.
? ? ? ? 2,979,254 ? ? ? ? ? *% ? ?
Marnix L. Bosch, Ph.D., M.B.A.
? ? ? ? 35,298,794 ? ? ? ? ? 2.8% ? ?
Linda F. Powers(2)
? ? ? ? 29,411,759 ? ? ? ? ? 2.4% ? ?
Leslie J. Goldman(3)
? ? ? ? 172,742 ? ? ? ? ? *% ? ?
Dr. Navid Malik
? ? ? ? 24,007,288 ? ? ? ? ? 1.9% ? ?
Pat Sarma
? ? ? ? 12,535,165 ? ? ? ? ? 1.0% ? ?
J. Cofer Black
? ? ? ? 6,484,433 ? ? ? ? ? *% ? ?
All executive officers and directors as a group (seven persons)
? ? ? ? 110,889,435 ? ? ? ? ? 8.7% ? ?
?
*
Less than 1%
?
(1)
Percentage represents beneficial ownership percentage of common stock calculated in accordance with SEC rules and does not equate to voting percentages. Based upon 1,210,879,427 shares of common stock issued and outstanding as of May 9, 2024. Beneficial ownership is determined in accordance with the rules of the SEC. In computing the number of shares of common stock beneficially owned and the percentage of ownership of such person, we deemed to be outstanding all shares of common stock subject to options and warrants currently exercisable or convertible, or exercisable or convertible within 60 days of May 9, 2024, and we also deemed no shares of common stock to be outstanding pursuant to warrants or options held by any other person. However, we did not deem such shares outstanding for the purpose of computing the percentage ownership of any other person.
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(2)
Consists of 29,411,759 shares of common stock held by Ms. Powers. Ms. Powers also holds 56,992,773 warrants (the majority acquired from a third party and the rest acquired in past years, as previously reported, from the Company in connection with loans by Ms. Powers to the Company when such loans were needed to help enable the Company to survive). Ms. Powers holds 39,200,000 options awarded in 2018 for service during part of that year and a number of preceding years, and 55,119,032 options awarded in 2020 for service during several years. In 2021, Ms. Powers entered into a voluntary blocking agreement with the Company pursuant to which Ms. Powers cannot exercise or convert any options, warrants or other derivative securities, as applicable, to acquire shares of the Company’s common stock, unless Ms. Powers provides the Company at least 61 calendar days’ advance notice and unless certain additional restrictions are satisfied with respect to some of the options. As a result, such options, warrants and other derivative securities are not considered “beneficially owned” within the meaning of Section 13(d) of the Securities Exchange Act of 1934, as amended.
?
(3)
Consists of 172,742 shares of common stock held by Mr. Goldman. Mr. Goldman also holds 643,043 warrants acquired in past years, as previously reported, from the Company in connection with loans by Mr. Goldman to the Company when such loans were needed to help the Company to survive. Mr. Goldman holds 24,500,000 options awarded in 2018 for service during part of that year and a number of preceding years, and 34,449,394 options awarded in 2020 for service during several years. In 2021, Mr. Goldman entered into a voluntary blocking agreement with the Company under which Mr. Goldman cannot exercise or convert of any options, warrants or other derivative securities, as applicable, to acquire shares of the Company’s common stock, unless Mr. Goldman provides the Company at least 61 calendar days’ advance notice and unless certain additional restrictions are satisfied with respect to some of the options. As a result, such options, warrants and other derivative securities are not considered “beneficially owned” within the meaning of Section 13(d) of the Securities Exchange Act of 1934, as amended.
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CORPORATE GOVERNANCE MATTERS
Board Leadership Structure
The Board believes that Ms. Powers’ service as both Chairperson of the Board and Chief Executive Officer is in the Company’s and our stockholders’ best interests. Ms. Powers possesses detailed and in-depth knowledge of the issues, opportunities and challenges facing us, and is thus, we believe, best positioned to develop Company strategies, business plans and priorities, and corresponding Board agendas that ensure that the Board’s time and attention are focused on the most critical matters. The Company has multiple major programs under way, with operations and infrastructure on two continents, which require heightened efficiency and involvement between the Board and management. Ms. Powers’ combined role enables decisive leadership, and, we believe, facilitates this efficiency and involvement. Mr. Jasinowski served as our lead independent director until his retirement in March 2024. The Board’s independent directors will elect a new lead independent director in due course.
Board of Directors’ Role in Risk Oversight
The Board plays an active role in risk oversight of our Company. The Board does not have a formal risk management committee, but administers this oversight function through various standing committees of the Board of Directors and/or through the full Board. The Audit Committee maintains responsibility for oversight of financial reporting-related risks, including those related to our accounting, auditing and financial reporting practices. The Audit Committee also reviews reports and considers any material allegations regarding potential violations of our Company’s Code of Conduct. The Compensation Committee oversees risks arising from our compensation policies and programs and has responsibility for evaluating and approving our executive compensation and benefit plans, policies and programs. The Company also performed an enterprise-wide risk assessment as well as an enterprise-wide fraud risk assessment during 2021 and will continue to update such assessments on an annual basis.
Director Independence
Our Board of Directors has determined that a majority of the Board consists of members who are currently “independent” as that term is defined within the meaning of Section 5605(a)(2) of the Nasdaq Stock Market Rules. The Board of Directors has determined each of Messrs. Malik and Sarma, and Ambassador Black to be independent. In addition, Jerry Jasinowski, who retired as a director on March 8, 2024, was independent during his service on the Board of Directors in 2023.
Audit Committee
The Audit Committee has responsibility for recommending the appointment of our independent accountants, supervising our finance function (which includes, among other matters, our investment activities), reviewing our internal accounting control policies and procedures, and providing the Board such additional information and materials as it may deem necessary to make the Board aware of significant financial matters which require the attention of the Board. The Audit Committee discusses the financial statements with management, approves filings made with the SEC and maintains the necessary discussions with the Company’s independent accountants. The Audit Committee acts under a written charter, which is posted on our website at www.nwbio.com/board-committee-charters/.
The Audit Committee currently consists of Mr. Sarma and Dr. Malik. Our Board of Directors has determined that Mr. Sarma, the Chairman of the Audit Committee, qualifies as an “audit committee financial expert” as defined by the SEC. Our Board has determined that each member of the Audit Committee is “independent” within the meaning of Section 5605(a)(2) of the Nasdaq Stock Market Rules as well as pursuant to the additional test for independence for audit committee members imposed by SEC regulation and Section 5605(c)(2)(A) of the Nasdaq Stock Market Rules. The Audit Committee is established in accordance with Section 3(a)(58)(A) of the Exchange Act.
Compensation Committee
The Compensation Committee is responsible for determining the overall compensation levels of our executive officers and administering our equity compensation plans. The Compensation Committee currently
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consists of Dr. Malik and Mr. Sarma. Dr. Malik is a biotech industry specialist. Our Board of Directors has determined that each member of the Compensation Committee is “independent” under the current listing standards of Nasdaq. The Compensation Committee acts under a written charter, which is posted on our website at www.nwbio.com/board-committee-charters/.
Conflicts Committee
The Conflicts Committee is responsible for review and evaluation of related party matters including related party transactions. The Conflicts Committee currently consists of Ambassador Black, Dr. Malik, and Mr. Sarma. Our Board of Directors has determined that each member of the Conflicts Committee is “independent” within the meaning of Section 5605(a)(2) of the Nasdaq Stock Market Rules. The Conflicts Committee acts under a written charter, which is posted on our website at www.nwbio.com/board-committee-charters/. The Conflicts Committee does not delegate its authority pursuant to its written charter.
Nominations Committee
The Nominations Committee is responsible for assisting the Board of Directors in, among other things, effecting Board organization, membership and function, including: identifying qualified Board nominees; and effecting the organization, membership and function of Board committees, including composition and recommendation of qualified candidates and reviewing the Company’s Corporate Governance Guidelines. The Nominations Committee shall identify and evaluate the qualifications of all candidates for nomination for election as directors. Potential nominees are identified by the Board of Directors based on the criteria, skills and qualifications that have been recognized by the Nominations Committee. While our nomination policy does not prescribe specific diversity standards, the Nominations Committee and its independent members seek to identify nominees who have a variety of perspectives, professional experience, education, difference in viewpoints and skills, and personal qualities that will result in a well-rounded Board of Directors. The Nominations Committee operates under a written charter, which is posted on our website at www.nwbio.com/board-committee-charters/.
The Nominations Committee currently consists of Dr. Malik, as Mr. Jasinowski, who previously served on the Nominations Committee, recently retired for medical reasons. The Board of Directors has determined that each member of the Nominations Committee is “independent” under the current listing standards of Nasdaq. The Board of Directors has adopted a written charter setting forth the authority and responsibilities of the Nominations Committee.
Information Regarding Meetings of the Board and Committees
The business of our Company is under the general oversight of our Board, as provided by the laws of Delaware and our bylaws. During 2023, the Board held 15 meetings. During 2023, the Audit Committee held 4 meetings and the Conflicts Committee held 1 meeting; and the Compensation Committee held 3 meetings. The Nominations Committee did not hold any meetings. Each person who was a director during 2023 attended all of the 15 Board meetings held in 2023, which is consistent with typical practice by our directors. We do not have a formal written policy with respect to Board members’ attendance at our annual meeting of stockholders. All five of our then serving Directors attended our last annual meeting of stockholders.
Code of Conduct
We have an established Code of Conduct applicable to all Board members, executive officers, employees and contractors. Our Code of Conduct is posted on our website at www.nwbio.com.
Recommendation of Director Candidates
The Nominations Committee is responsible for annually reviewing with the Board the requisite skills and criteria for prospective directors and the structure, size and composition of the Board as a whole. Although there are no set criteria considered by the Nominations Committee in evaluating potential director nominees, the committee does consider the skills and expertise that need to be represented on the Board, succession planning and the time commitments required of directors.
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For a stockholder to submit a candidate for the consideration of the Nominations Committee, the stockholder must timely notify our corporate secretary at the address set forth under “Communication with the Board of Directors” below. To make such a recommendation in advance of next year’s Annual Meeting, a stockholder must provide written notification to our corporate secretary not less than 120 days nor more than 150 days in advance of the first anniversary of the date on which the proxy statement in connection with the previous year’s Annual Meeting was first mailed. However, if we do not hold an annual meeting or the date of such annual meeting has been changed by more than 30 days from the date first contemplated by the previous year’s proxy statement, we must receive the stockholder’s notice at least 80 days prior to the date on which we distribute the proxy statement with respect to the upcoming meeting.
The notice must include the information specified in our bylaws, including the following: (a) as to each proposed candidate, (i) such person’s exact name, (ii) such person’s age, principal occupation, business address and telephone number, and residence address and telephone number, (iii) the number of shares (if any) of each class of our capital stock owned directly or indirectly by each such nominee, and (iv) any other information concerning the nominee that must be disclosed as to nominees in proxy solicitations pursuant to Regulation 14A under the Exchange Act (including such person’s notarized written acceptance of such nomination, consent to being named in the proxy statement as a nominee and statement of intention to serve as a director if elected); and (b) as to the stockholder giving the notice, (i) the name and address, as they appear in our records, of such stockholder, (ii) such stockholder’s principal occupation, business address and telephone number, and residence address and telephone number, (iii) the class and number of our shares which are held of record or beneficially owned by such stockholder, and (iv) the dates upon which such stockholder acquired such shares of stock and documentary support for any claims of beneficial ownership. In addition, notices must include a description of all arrangements or understandings between the stockholder giving the notice and each nominee and any other person or persons (naming such person or persons) pursuant to which the nomination or nominations are to be made by such stockholder.
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EXECUTIVE COMPENSATION
Compensation Discussion and Analysis
Overview
This Compensation Discussion and Analysis describes the compensation program for the Company’s principal executive and principal financial officer, and our three most highly compensated executive officers other than our principal executive and financial officer who were serving as executive officers as of December 31, 2023. We refer to these individuals as our “named executive officers” or “NEOs.”
For purposes of this executive compensation discussion, the names and positions of our named executive officers for the 2023 fiscal year were:
•
Linda F. Powers, President and Chief Executive Officer, Chief Financial and Accounting Officer;
?
•
Leslie Goldman, Senior Vice President and General Counsel;
?
•
Marnix L. Bosch, Ph.D., Chief Technical Officer; and
?
•
Alton L. Boynton, Ph.D., Chief Scientific Officer and Secretary.
?
Philosophy and Objectives
Our success is highly dependent on our ability to attract, retain and incentivize executive officers who possess the skills, competencies and passion that are necessary to achieve progress in the Company’s clinical programs and progress toward eventual commercialization, as well as to contend with ongoing challenges to the Company’s progress. To this end, our compensation program has been developed with the following overarching principles in mind:
•
the pay of our NEOs should balance incentivizing performance, ensuring retention and building stockholder value and should be linked to the NEO’s roles and contributions to the Company’s progress.
?
•
the pay of our NEOs should retain and incentivize individual NEOs to perform multiple senior executive roles each, at least until such time as the Company’s progress and resources enable expansion of the management team.
?
•
our executive compensation program should enable us to recruit, develop, motivate and retain top talent. This is especially critical in a rapidly evolving field such as immuno-oncology, which requires highly specialized knowledge and experience and for which the talent pool is highly competitive.
?
Periodically, management makes recommendations to the Compensation Committee and the Compensation Committee reviews the objectives and components of our executive compensation program to assess whether they continue to meet these essential goals. The Compensation Committee Chairman also maintains regular contact with the NEOs to ensure that he not only gets a detailed view of the performance and milestones achieved by the NEOs and the Company, but also so that he has the ability to personally assess and make available to the Committee a detailed summary of performance of the NEOs and employees of the Company for the applicable review period.
To establish compensation parameters for our named executive officers, our Compensation Committee evaluates each element of compensation separately and the total compensation for each named executive officer, as well as the compensation levels at similarly situated companies?—?other oncology biotech companies who are at a comparable stage of company development as the Company, taking account of the stage of the other companies’ clinical programs and whether they have any products approved or on the market. Based on the reviews and analyses to date, our Compensation Committee determined that our process for determining executive compensation is appropriate to attract, and to retain and incentivize, the key senior executives, and is aligned with stockholder interests.
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Risk Management and Mitigation
In reviewing our compensation structure in 2023, the Compensation Committee also considered whether our compensation policies and practices could potentially encourage excessive risk taking by our employees. The Committee determined that this was not the case.
Elements of 2023 Compensation
•
Our 2023 executive compensation program consisted of one primary element?—?base salary.
?
•
The Company anticipates that bonuses will also be awarded to the NEOs in respect of performance during 2023, since the Company believes that 2023 was a year of exceptional progress, including completion and submission to the UK regulatory authority of the Company’s first application for commercial approval of its DCVax®-L immunotherapy, significant progress in the development and optimization of its Flaskworks manufacturing system, approval of a commercial manufacturing license for the Company’s Sawston, UK GMP facility, expansion of the Company’s intellectual property portfolio, and achievement of other major milestones and progress as described in the Management Discussion and Analysis in the Company’s Annual Report on Form 10-K.
?
•
In several prior years, the Company has determined annual bonuses on a delayed basis when additional time was needed for adequate review and determination. Also in multiple prior years, even after executive bonuses have been determined, awarded and reported in the Company’s filings, the payment of such bonuses has been delayed (in some instances for multiple years) based on resource considerations. For 2023, the review and determination will be conducted on a delayed basis.
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Base Salary
Base salary is the fixed portion of an executive’s annual compensation. Base salaries for our NEOs are established based on the individual’s scope of responsibilities, experience, contributions to the Company’s progress, and market factors. The Compensation Committee typically reviews base salaries on an annual basis. The Committee reviews the base salary of our CEO in executive session and recommends her base salary to the non-executive members of the Board for approval, based on the criteria described above.
The Compensation Committee does not use a formulaic approach when setting an executive officer’s base salary. However, taking into account the recommendations of our CEO, the Compensation Committee’s assessment includes factors such as the following when determining (or, in the case of the CEO, recommending to the Board) individual base salary levels:
•
the nature and responsibility of the executive’s position,
?
•
where applicable, the executive’s performance of multiple roles that would typically be held by separate executives (with separate compensation) at other companies,
?
•
competitive considerations for retaining and incentivizing the executive, and
?
•
the executive’s expertise, tenure, responsibilities and performance.
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Our Compensation Committee held a series of meetings to review NEOs’ compensation and determine 2023 base salaries for NEOs. The Compensation Committee considered information about pay practices at a substantial number of other oncology biotech companies at a similar stage of development as Northwest Biotherapeutics (late stage clinical trials, with no products approved or on the market yet), which was gathered by management and provided to the Committee. The Committee considered each NEO’s roles (including performance of multiple roles) and contributions as well as the Company’s strong progress. The Committee also took account of the NEOs’ compensation history, including that base salaries have been the same for three years, in 2020, 2021 and 2022, and that payment of performance based bonuses has tended to be substantially delayed. The Committee also considered management’s recommendations for increases in 2023 base salaries. The Committee conducted these assessments internally and did not engage an external compensation consultant. The Committee deliberated without management present.
In light of the above considerations, the Committee determined that raises in the NEO base salaries recommended by management were appropriate for 2023, as set forth in the Summary Compensation Table
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below. The Committee recommended that the Board approve these raises in base salaries. The Committee noted that bonuses would be addressed separately at another time.
The Board met and considered the factors described above, without management present, and approved the raises in base salaries recommended by the Compensation Committee for Ms. Powers, Mr. Goldman, Dr. Bosch and Dr. Boynton.
Annual Bonus Awards
The Company anticipates making performance based bonus awards in respect of performance during 2023, based on the exceptional milestones and Company progress achieved during the year, as described above, but has not yet determined the bonuses.
Our NEOs are eligible to receive an annual bonus taking into account their individual performance and the performance of the Company. The Company determines Annual Bonus Awards based upon progress achieved in the Company’s programs (including clinical development, manufacturing, intellectual property and finances) and progress toward potential eventual commercialization, as well as the individual’s roles and contributions toward the progress.
Equity Awards
The Company did not make any equity compensation awards to the NEOs in 2023. The Company has made no equity awards in the four years since option awards were last granted in 2020. Overall, the Company has only made equity awards to two of its four senior executives (Ms. Powers and Mr. Goldman) twice in the 13 years since 2011 (in 2018 and in 2020), and has only made equity awards to the other two senior executives (Dr. Bosch and Dr. Boynton) three times in these 13 years (2017, 2018 and 2020).
However, the equity pool reserved for employees and directors established under the Company’s Equity Compensation Plan remains in place. The equity pool includes 20% of the Company’s securities, some of which have been issued to employees and directors and some of which remain available in the pool. The Company has been advised by an independent compensation consultant that it is common for pre-commercial biotech companies to set aside 15-20% of their equity in a pool for employees and directors.
Additional information regarding the stock options granted to our NEOs four years ago, in 2020, is set forth below in the “Summary Compensation Table” and the “Outstanding Equity Awards at 2023 Fiscal-Year End” table.
Other Compensation Plans
401(k) Plan. The NEOs are eligible to participate in employee benefit plans and programs, including long-term disability, to the same extent as the Company’s other full-time employees, subject to the terms and eligibility requirements of those plans. The NEOs also participate in our 401(k) plan, subject to limits imposed by the Internal Revenue Code, to the same extent as the Company’s other full-time employees.
Other Benefits. We do not maintain any defined benefit pension plans or any nonqualified deferred compensation plans.
Limited Perquisites. Perquisites or other personal benefits are not a significant component of the compensation to our NEOs. We provide limited perquisites to our NEOs, such as coverage of phone and internet costs.
Employment Agreements. The Company entered into employment agreements with each of Ms. Powers, Mr. Goldman, Dr. Bosch and Dr. Boynton in 2011. The 2011 agreements have expired. The Company entered into a new employment agreement with Dr. Bosch, which is currently in effect. The Company plans to enter into new employment agreements with Ms. Powers, Mr. Goldman and Dr. Boynton in due course.
Process for Setting Executive Compensation
Compensation Committee Review
Our Compensation Committee reviews the elements of our NEOs’ total compensation during the year, to evaluate whether each element is providing appropriate compensation to retain and incentivize the
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executive, and to be competitive. In making compensation decisions, the Committee relies on its own judgment after considering similarly situated companies, and also considers the factors listed above in connection with base salary determinations and the following factors:
•
the executive’s scope of responsibilities, including whether the executive is performing multiple senior executive roles;
?
•
the executive’s leadership, management and technical expertise, growth potential, and position in our reporting structure;
?
•
overall Company and individual performance;
?
•
retention needs and competitive considerations; and
?
•
the recommendations of our CEO (except with respect to her own compensation).
?
Each year, the Compensation Committee expects to evaluate all elements of executive officer compensation, after reviewing the prior year’s results and the achievement of Company operational and financial objectives. The purpose of this annual evaluation is to determine whether any changes in an officer’s compensation may be appropriate. The CEO does not participate in the Committee’s deliberations regarding her own compensation. At the Committee’s request, the CEO may review with the Committee the performance of the other executive officers. Our Compensation Committee gives substantial weight to the CEO’s evaluations and recommendations because she is particularly able to assess the other executive officers’ performance and contributions.
Independent Compensation Consultant
The evaluations and analyses for the 2023 base salaries for the Company’s NEOs were done internally, and not by a compensation consultant.
Compensation Committee Report
The Compensation Committee has reviewed and discussed the compensation discussion and analysis included in this proxy statement with management and, based on such review and discussions, the compensation committee recommended to our board of directors that the compensation discussion and analysis be included in the Company’s 2024 proxy statement for filing with the SEC.
The foregoing report has been furnished by the Compensation Committee.
Dr. Navid Malik (Chairperson)
Pat Sarma?
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Summary Compensation Table
The following table sets forth certain information concerning compensation paid to or accrued for our executive officers, referred to as our Named Executive Officers, during the years ended December 31, 2023, 2022 and 2021.
Name and Principal Position
? ?
Year
? ?
Salary
($)
? ?
Bonus
($)(1)
? ?
Option
Awards
? ?
Total
($)
?
Linda F. Powers?(2)
Chairperson, President and Chief Executive
Officer, Chief Financial and Accounting Officer
? ? ? ? 2023 ? ? ? ? ? 925,000 ? ? ? ? ? — ? ? ? ? ? — ? ? ? ? ? 925,000 ? ?
? ? ? 2022 ? ? ? ? ? 700,000 ? ? ? ? ? 400,000 ? ? ? ? ? — ? ? ? ? ? 1,100,000 ? ?
? ? ? 2021 ? ? ? ? ? 700,000 ? ? ? ? ? 300,000 ? ? ? ? ? — ? ? ? ? ? 1,000,000 ? ?
Leslie Goldman?(3)
Senior Vice President, General Counsel
? ? ? ? 2023 ? ? ? ? ? 725,000 ? ? ? ? ? — ? ? ? ? ? — ? ? ? ? ? 725,000 ? ?
? ? ? 2022 ? ? ? ? ? 525,000 ? ? ? ? ? 300,000 ? ? ? ? ? — ? ? ? ? ? 825,000 ? ?
? ? ? 2021 ? ? ? ? ? 525,000 ? ? ? ? ? 200,000 ? ? ? ? ? — ? ? ? ? ? 725,000 ? ?
Marnix L. Bosch, Ph.D.?(4)
Chief Technical Officer
? ? ? ? 2023 ? ? ? ? ? 453,600 ? ? ? ? ? — ? ? ? ? ? — ? ? ? ? ? 453,600 ? ?
? ? ? 2022 ? ? ? ? ? 397,500 ? ? ? ? ? 200,000 ? ? ? ? ? — ? ? ? ? ? 597,500 ? ?
? ? ? 2021 ? ? ? ? ? 442,500 ? ? ? ? ? 125,000 ? ? ? ? ? — ? ? ? ? ? 567,500 ? ?
Alton L. Boynton, Ph.D.?(5)
Chief Scientific Officer and Secretary
? ? ? ? 2023 ? ? ? ? ? 375,000 ? ? ? ? ? — ? ? ? ? ? — ? ? ? ? ? 375,000 ? ?
? ? ? 2022 ? ? ? ? ? 350,000 ? ? ? ? ? 100,000 ? ? ? ? ? — ? ? ? ? ? 450,000 ? ?
? ? ? 2021 ? ? ? ? ? 350,000 ? ? ? ? ? 75,000 ? ? ? ? ? — ? ? ? ? ? 425,000 ? ?
?
(1)
The Company plans to award performance bonuses for executives for 2023, in light of the major milestones met and progress made in 2023, but the bonuses have not yet been determined.
?
(2)
The bonuses in 2022 and 2021 were for Ms. Powers’ performance during 2022 and 2021, respectively, which were approved in 2023 and 2022, respectively. The 2021 bonus was paid in March 2023. The 2022 bonus was paid in December 2023.
?
(3)
The bonuses in 2022 and 2021 were for Mr. Goldman’s performance during 2022 and 2021, respectively, which were approved in 2023 and 2022, respectively. The 2021 bonus was paid in March 2023. The 2022 bonus was partially paid as of December 31, 2023.
?
(4)
Dr. Bosch was relocated to our subsidiary in Netherlands effective August 1, 2019. His current annual salary is 420,000 euros, which is equivalent to approximately $454,000. Dr. Bosch’s compensation is paid in Euros and therefore varies based on the exchange rate. The compensation amounts paid to Dr. Bosch presented in the table above are determined by multiplying the amount of euros paid by the average exchange rate of $1.08 per euro for fiscal 2023, of $1.06 per euro for fiscal 2022, and of $1.18 per euro for fiscal 2021.
?
The bonuses in 2022 and 2021 were for Dr. Bosch’s performance during 2022 and 2021, respectively, which were approved in 2023 and 2022, respectively. The 2021 bonus was paid in March 2023. The 2022 bonus has not been paid.
(5)
The bonuses in 2022 and 2021 were for Dr. Boynton’s performance during 2022 and 2021, respectively, which were approved in 2023 and 2022, respectively. The 2021 bonus was paid in March 2023. The 2022 bonus has not been paid.
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Outstanding Equity Awards at Fiscal Year-End
The following table shows outstanding stock option awards classified as exercisable and un-exercisable as of December 31, 2023:
Name
? ?
Number of
Securities
Underlying
Unexercised
Options (#)
Exercisable
? ?
Number of
Securities
Underlying
Unexercised
Options (#)
Unexercisable
? ?
Option
Exercise
Price
($)
? ?
Option
Expiration
Date
?
Linda F. Powers
Chairperson, President and Chief Executive Officer,
Chief Financial and Accounting Officer
? ? ? ? 39,200,000(1) ? ? ? ? ? — ? ? ? ? $ 0.23 ? ? ? ? ? 5/28/2028 ? ?
? ? ? 10,770,429(2) ? ? ? ? ? — ? ? ? ? $ 0.35 ? ? ? ? ? 7/2/2030 ? ?
? ? ? 32,558,724(2) ? ? ? ? ? — ? ? ? ? $ 0.35 ? ? ? ? ? 12/1/2030 ? ?
? ? ? 11,789,879(3) ? ? ? ? ? — ? ? ? ? $ 0.55 ? ? ? ? ? 9/2/2030 ? ?
Leslie J. Goldman
Senior Vice President, General Counsel
? ? ? ? 24,500,000(4) ? ? ? ? ? — ? ? ? ? $ 0.23 ? ? ? ? ? 5/28/2028 ? ?
? ? ? 6,731,518(5) ? ? ? ? ? — ? ? ? ? $ 0.35 ? ? ? ? ? 7/2/2030 ? ?
? ? ? 21,822,937(5) ? ? ? ? ? — ? ? ? ? $ 0.35 ? ? ? ? ? 12/1/2030 ? ?
? ? ? 5,894,939(6) ? ? ? ? ? — ? ? ? ? $ 0.55 ? ? ? ? ? 9/2/2030 ? ?
Marnix L. Bosch, Ph.D.
Chief Technical Officer
? ? ? ? 7,740,182(7) ? ? ? ? ? — ? ? ? ? $ 0.25 ? ? ? ? ? 6/13/2027 ? ?
? ? ? 10,798,729(8) ? ? ? ? ? — ? ? ? ? $ 0.35 ? ? ? ? ? 7/2/2030 ? ?
? ? ? 16,630,726(9) ? ? ? ? ? — ? ? ? ? $ 0.35 ? ? ? ? ? 12/1/2030 ? ?
Alton L. Boynton, Ph.D.
Chief Scientific Officer and Secretary
? ? ? ? 2,967,065(10) ? ? ? ? ? — ? ? ? ? $ 0.23 ? ? ? ? ? 8/31/2028 ? ?
? ? ? 3,096,498(11) ? ? ? ? ? — ? ? ? ? $ 0.35 ? ? ? ? ? 7/2/2030 ? ?
? ? ? 15,697,693(12) ? ? ? ? ? — ? ? ? ? $ 0.35 ? ? ? ? ? 12/1/2030 ? ?
?
(1)
On May 28, 2018, we granted 39,200,000 stock options to Ms. Powers for service during a number of years. The options are exercisable at a price of $0.23 per share, and have a 10-year exercise period. 50% of these options were vested upon grant, and 50% were subject to vesting in monthly installments over two years. Following entry into previous securities suspension agreements in 2021, Ms. Powers entered into a voluntary blocking agreement on an ongoing rolling basis with the Company under which Ms. Powers cannot exercise or convert any of these 2018 options to acquire shares of the Company’s common stock unless Ms. Powers provides the Company at least 61 days’ advance notice. As a result, such derivative securities are not considered “beneficially owned” within the meaning of Section 13(d) of the Securities Exchange Act of 1934, as amended.
?
(2)
On July 2, 2020, we granted 10,770,429 stock options to Ms. Powers for service during several years. The options are exercisable at a price of $0.35 per share, and have a 10-year exercise period. These options were fully vested upon grant. Following entry into previous securities suspension agreements, in 2021 Ms. Powers entered into a voluntary blocking agreement with the Company under which Ms. Powers cannot exercise or convert any of these 2020 options to acquire shares of the Company’s common stock unless Ms. Powers provides the Company at least 61 days’ advance notice and the Company has authorized shares available. As a result, these options are not considered “beneficially owned” within the meaning of Section 13(d) of the Securities Exchange Act of 1934, as amended.
?
On July 2, 2020, we granted 32,558,724 stock options to Ms. Powers for service during several years. These options were subject to certain vesting requirements which have been fulfilled. The options are exercisable at a price of $0.35 per share, and have a 10-year exercise period. 50% of these options were vested upon grant, and 50% were subject to vesting in monthly installments over one year. Following entry into previous securities suspension agreements, in 2021, Ms. Powers entered into a voluntary blocking agreement on an ongoing rolling basis with the Company under which Ms. Powers cannot exercise these 2020 options to acquire shares of the Company’s common stock unless Ms. Powers provides the Company at least 61 days’ advance notice and the Company has authorized shares available. As a result, such derivative securities are not considered “beneficially owned” within the meaning of Section 13(d) of the Securities Exchange Act of 1934, as amended.
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(3)
On September 2, 2020, we granted 11,789,879 stock options to Ms. Powers for service during several years. The options are exercisable at a price of $0.55 per share, and have a 10-year exercise period. These options vested upon the earlier of completion of certain milestones or March 31, 2021. These options were fully vested as of March 31, 2021. Following entry into previous securities suspension agreements, in 2021, Ms. Powers entered into a voluntary blocking agreement on an ongoing rolling basis with the Company under which Ms. Powers cannot exercise these 2020 options to acquire shares of the Company’s common stock unless Ms. Powers provides the Company at least 61 days’ advance notice and the Company has authorized shares available. As a result, such derivative securities are not considered “beneficially owned” within the meaning of Section 13(d) of the Securities Exchange Act of 1934, as amended.
?
(4)
On May 28, 2018, we granted 24,500,000 stock options to Mr. Goldman for service during a number of years. The options are exercisable at a price of $0.23 per share, and have a 10-year exercise period. 50% of these options were vested upon grant, and 50% were subject to vesting in monthly installments over two years. Following entry into previous securities suspension agreements, in 2021, Mr. Goldman entered into a voluntary blocking agreement on an ongoing rolling basis with the Company under which Mr. Goldman cannot exercise these 2018 options to acquire shares of the Company’s common stock, unless Mr. Goldman provides the Company at least 61 days’ advance notice. As a result, such derivative securities are not considered “beneficially owned” within the meaning of Section 13(d) of the Securities Exchange Act of 1934, as amended.
?
(5)
On July 2, 2020, we granted 6,731,518 stock options to Mr. Goldman for service during several years. The options are exercisable at a price of $0.35 per share, and have a 10-year exercise period. These options were fully vested upon grant. Following entry into previous securities suspension agreements, in 2021 Mr. Goldman entered into a voluntary blocking agreement on an ongoing rolling basis with the Company under which Mr. Goldman cannot exercise these 2020 options to acquire shares of the Company’s common stock unless Mr. Goldman provides the Company at least 61 days’ advance notice and the Company has authorized shares available. As a result, such derivative securities are not considered “beneficially owned” within the meaning of Section 13(d) of the Securities Exchange Act of 1934, as amended.
?
On July 2, 2020, we granted 21,822,937 stock options to Mr. Goldman for service during several years. The options are exercisable at a price of $0.35 per share, and have a 10-year exercise period. 50% of these options were vested upon grant, and 50% were subject to vesting in monthly installments over one year. Following entry into previous securities suspension agreements, in 2021 Mr. Goldman entered into a voluntary blocking agreement on an ongoing rolling basis with the Company under which Mr. Goldman cannot exercise these 2020 options to acquire shares of the Company’s common stock unless Mr. Goldman provides the Company at least 61 days’ advance notice and the Company has authorized shares available. As a result, such derivative securities are not considered “beneficially owned” within the meaning of Section 13(d) of the Securities Exchange Act of 1934, as amended.
On January 14, 2021, Mr. Goldman assigned 20,000,000 options that were granted on July 2, 2020 to The Goldman NWBIO GRAT Trust for no consideration. On April 28, 2022, Sue Goldman, Trustee of The Goldman NWBIO GRAT Trust transferred 12,709,287 options to Mr. Goldman in satisfaction of the first annuity amount due to Mr. Goldman. As of December 31, 2023, 7,290,713 options were remaining in The Goldman NWBIO GRAT Trust.
(6)
On September 2, 2020, we granted 5,894,939 stock options to Mr. Goldman for service during several years. The options are exercisable at a price of $0.55 per share, and have a 10-year exercise period. These options vested upon the earlier of completion of certain milestones or March 31, 2021. These options were fully vested as of March 31, 2021. Following entry into previous securities suspension agreements, in 2021 Mr. Goldman entered into a voluntary blocking agreement on an ongoing rolling basis with the Company under which Mr. Goldman cannot exercise these 2020 options to acquire shares of the Company’s common stock unless Mr. Goldman provides the Company at least 61 days’ advance notice and the Company has authorized shares available. As a result, such derivative securities are not considered “beneficially owned” within the meaning of Section 13(d) of the Securities Exchange Act of 1934, as amended.
?
(7)
On June 13, 2017, we awarded 7,940,182 options to Dr. Bosch under the 2007 Stock Plan for service during several years. The options are exercisable at a price of $0.25 per share, and had a 5-year exercise
?
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period. On January 14, 2018, we extended the exercise period of the options from 5-year to 10-year. In 2021, Dr. Bosch entered into a securities suspension agreement with the Company that (i) suspended the exercisability of the vested options and (ii) made no changes to the other terms of such securities. The suspension continued on a monthly basis since then, with respect to 20,429,456 options, until it expired on January 12, 2023.
On March 29, 2023, Dr. Bosch cashless exercised 200,000 options.
(8)
On July 2, 2020, we granted 10,798,729 stock options to Dr. Bosch for service during several years. The options are exercisable at a price of $0.35 per share, and have a 10-year exercise period. These options were fully vested upon grant. Dr. Bosch entered into a securities suspension agreement with the Company that (i) suspended the exercisability of the vested options and (ii) made no changes to the other terms of such securities. The suspension agreement expired on January 12, 2023.
?
(9)
On July 2, 2020, we granted 16,630,726 stock options to Dr. Bosch for service during several years. 50% of these options were vested upon grant, and 50% were subject to vesting in monthly installments over one year. The options are exercisable at a price of $0.35 per share, and have a 10-year exercise period. Dr. Bosch entered into a securities suspension agreement with the Company that (i) suspended the exercisability of 13,165,992 of the vested options and (ii) made no changes to the other terms of such securities. The suspension agreement expired on January 12, 2023.
?
(10)
On August 31, 2018, we granted 2,967,065 stock options to Dr. Boynton for service during several years. The options are exercisable at a price of $0.23 per share, and have a 10-year exercise period. 50% of the options vested on the grant date, and 50% were subject to vesting in monthly installments over two years. Dr. Boynton entered into a securities suspension agreement with the Company that (i) suspended the exercisability of the vested options and (ii) made no changes to the other terms of such securities. The suspension agreement expired on January 12, 2023.
?
(11)
On July 2, 2020, we granted 3,096,498 stock options to Dr. Boynton for service during 2018, 2019 and 2020. The options are exercisable at a price of?$0.35 per share, and have a 10-year exercise period. These options were fully vested upon grant. Dr. Boynton entered into a securities suspension agreement with the Company that (i) suspended the exercisability of the vested options and (ii) made no changes to the other terms of such securities. The suspension agreement expired on January 12, 2023.
?
On April 4, 2023, Dr. Boynton assigned all 3,096,498 of these options to his relatives for no consideration.
(12)
On July 2, 2020, we granted 15,697,693 stock options to Dr. Boynton for service during 2018, 2019 and 2020. The options are exercisable at a price of?$0.35 per share, and have a 10-year exercise period. 50% of these options were vested upon grant, and 50% were subject to vesting in monthly installments over one year. Dr. Boynton entered into a securities suspension agreement with the Company that (i) suspended the exercisability of the vested options and (ii) made no changes to the other terms of such securities. The suspension agreement expired on January 12, 2023.
?
On July 27, 2022, Dr. Boynton assigned 3,000,000 options to his relatives for no consideration. On December 6, 2022, Dr. Boynton assigned 9,000,000 options to his relatives for no consideration. On April 4, 2023, Dr. Boynton assigned the remaining 3,697,693 options to his relatives for no consideration.
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Option Exercises and Stock Vested
The following table shows stock option awards exercised by our Named Executive Officers during the year ended December 31, 2023. No Named Executive Officers vested in any stock awards.
? ? ?
Option Awards
?
Name
? ?
Gross Number of Shares
Acquired on Exercise (#)
? ?
Value Realized on
Exercise ($)
?
Linda F. Powers
? ? ? ? — ? ? ? ? ? — ? ?
Leslie J. Goldman
? ? ? ? — ? ? ? ? ? — ? ?
Marnix L. Bosch, Ph.D.
? ? ? ? 200,000 ? ? ? ? $ 74,000(1) ? ?
Alton L. Boynton, Ph.D.
? ? ? ? — ? ? ? ? ? — ? ?
?
(1)
The value realized upon the exercise of a stock option is calculated by multiplying (i) the number of shares of our common stock to which the exercise of the option related, by (ii) the difference between the per-share closing price of our common stock on the date the stock option was exercised and the per-share exercise price of the options. Represents the gross value realized prior to any applicable tax withholding.
?
Potential Payments on Termination or Change in Control
The Company does not currently have any arrangements that would trigger payments upon termination of a NEO or upon a change in control of the Company. However, the Company plans to enter into employment agreements with Ms. Powers, Mr. Goldman and Dr. Boynton in due course, which may contain such arrangements.
CEO Pay Ratio Disclosure
We are providing the following information about the relationship of the annual total compensation of our employees and the annual total compensation of our CEO. Based on the information for fiscal year 2023, we reasonably estimate that the ratio of our CEO’s annual total compensation to the annual total compensation of our median employee was 6.4:1. Our pay ratio estimate has been calculated in a manner consistent with Item 402(u) of Regulation S-K using the data and assumptions summarized below.
We identified our median compensation employee by examining total compensation paid for fiscal year 2023 to all individuals, excluding Ms. Powers, who were employed by us on December 31, 2023, the last day of our fiscal year, based on payroll records. No assumptions, adjustments or estimates were made in respect of total compensation, except that we annualized the compensation of any employee that was not employed with us for all of fiscal year 2023. We excluded independent contractors who are engaged full time by us. We also excluded independent contractors retained on an as-needed basis, whose compensation is determined by an unaffiliated third party, and who are therefore are not considered our employees for purposes of the pay ratio calculation.
Once we identified our median employee, we calculated such employee’s annual total compensation for 2023 in accordance with the requirements of Item 402(c)(2)(x) of Regulation S-K, resulting in that employee’s annual total compensation of $145,000. The median employee’s annual total compensation includes annualized base salary, annualized bonus during the fiscal year ended December 31, 2023.
With respect to the CEO, we used the amount reported as total compensation in the Summary Compensation Table. Any estimates and assumptions used to calculate total annual compensation are described in footnotes to the Summary Compensation Table.
Pay Versus Performance
As required by Item 402(v) of Regulation S-K, we are providing the following information regarding the relationship between executive compensation and our financial performance for each of the last two completed calendar years. In determining the “compensation actually paid” to our named executive officers
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(“NEOs”), we are required to make various adjustments to amounts that have been previously reported in the Summary Compensation Table in previous years, as the SEC’s valuation methods for this section differ from those required in the Summary Compensation Table.
The following tables and related disclosures provide information about (i) the total compensation (“SCT Total”) of our principal executive officer (“PEO”) and our non-PEO Named Executive Officers (collectively, the “Other NEOs”) as presented in the Summary Compensation Table, (ii) the “compensation actually paid” ?(“CAP”) to our PEO and our Other NEOs, as calculated pursuant to Item 402(v), (iii) certain financial performance measures, and (iv) the relationship of the CAP to those financial performance measures.
Pay Versus Performance Table
The amounts set forth below under the headings “Compensation Actually Paid to PEO” and “Average Compensation Actually Paid to Non-PEO NEOs” have been calculated in a manner consistent with Item 402(v) of Regulation S-K.
Use of the term “compensation actually paid” is required by the SEC’s rules, and as a result of the calculation methodology required by the SEC, such amounts differ from compensation actually received by the individuals for the fiscal years listed below.
In calculating the compensation actually paid amounts reflected in these columns, the fair value or change in fair value, as applicable, of the equity award adjustments included in such calculations were computed in accordance with FASB ASC Topic 718. The valuation assumptions used to calculate such fair values did not materially differ from those disclosed at the time of grant.
Year
? ?
Summary
Compensation
Table Total for
PEO(1)(2)
? ?
Compensation
Actually
Paid to
PEO(3)
? ?
Average
Summary
Compensation
Table Total for
Non-PEO
NEOs(1)(2)
? ?
Average
Compensation
Actually
Paid to
Non-PEO
NEOs(4)
? ?
Value of
Initial
Fixed $100
Investment
Based On
Total
Shareholder
Return(5)
? ?
Value of
Initial
Fixed $100
Investment
Based On
Peer Group
Total
Shareholder
Return(6)
? ?
Net (Loss)
Income
(in thousands)
?
2023
? ? ? $ 925,000 ? ? ? ? $ 925,000 ? ? ? ? $ 518,000 ? ? ? ? $ 518,000 ? ? ? ? $ 170 ? ? ? ? $ 141 ? ? ? ? $ (62,800) ? ?
2022
? ? ? $ 1,100,000 ? ? ? ? $ 1,100,000 ? ? ? ? $ 624,000 ? ? ? ? $ 624,000 ? ? ? ? $ 178 ? ? ? ? $ 136 ? ? ? ? $ (105,032) ? ?
2021
? ? ? $ 1,000,000 ? ? ? ? $ 31,000 ? ? ? ? $ 646,000 ? ? ? ? $ 274,000 ? ? ? ? $ 170 ? ? ? ? $ 158 ? ? ? ? $ 179,026 ? ?
?
(1)
During fiscal years 2023, 2022 and 2021, the PEO was Linda Powers. During fiscal years 2023 and 2022, the non-PEO NEOs were Leslie Goldman, Marnix Bosch, Ph.D. and Alton Boynton, Ph.D. During fiscal year 2021, the non-PEO NEOs were Mr. Goldman and Dr. Bosch.
?
(2)
The dollar amounts reported are the amounts of total compensation reported for Ms. Powers and the average total compensation reported for Non-PEO Named Executive Officers for the applicable fiscal year in the “Total” column of the Summary Compensation Table (SCT).
?
(3)
The following table sets forth the adjustments made to the SCT total for each year represented in the
?
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pay versus performance table to arrive at “compensation actually paid” to our PEO, as computed in accordance with Item 402(v) of Regulation S-K:
SCT Total to CAP Reconciliation
? ?
2023
? ?
2022
? ?
2021
?
SCT Total for PEO
? ? ? $ 925,000 ? ? ? ? $ 1,100,000 ? ? ? ? $ 1,000,000 ? ?
(Less): Aggregate value for stock awards and option awards
included in SCT Total for the covered fiscal year
? ? ? ? — ? ? ? ? ? — ? ? ? ? ? — ? ?
Outstanding and unvested awards: ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?
Add: Fair value at year end of awards granted during the
covered fiscal year that were outstanding and unvested at
the covered fiscal year end
? ? ? ? — ? ? ? ? ? — ? ? ? ? ? — ? ?
Add: Change in fair value as of fiscal year-end, compared to prior fiscal year-end, of awards granted in any prior fiscal year that are outstanding and unvested as of the end of the fiscal year
? ? ? ? — ? ? ? ? ? — ? ? ? ? ? — ? ?
Awards granted and vesting in the same year: ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?
Add: Vesting date fair value of awards granted and vested during the covered fiscal year
? ? ? ? — ? ? ? ? ? — ? ? ? ? ? — ? ?
Awards vesting in current fiscal year but granted in a prior fiscal year:
? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?
Add: Change in fair value as of vesting date, compared to
prior fiscal year-end, of awards granted in any prior
fiscal year for which all vesting conditions were satisfied
at fiscal year-end or during the fiscal year
? ? ? ? — ? ? ? ? ? — ? ? ? ? ? (969,000) ? ?
Compensation Actually Paid to PEO
? ? ? $ 925,000 ? ? ? ? $ 1,100,000 ? ? ? ? $ 31,000 ? ?
?
(4)
The following table sets forth the adjustments made to the SCT total for each year represented in the pay versus performance table to arrive at “compensation actually paid” to our non-PEO NEOs, as computed in accordance with Item 402(v) of Regulation S-K:
?
SCT Total to CAP Reconciliation
? ?
2023
? ?
2022
? ?
2021
?
Average SCT Total for Non-PEO NEOs
? ? ? $ 518,000 ? ? ? ? $ 624,000 ? ? ? ? $ 646,000 ? ?
(Less): Aggregate value for stock awards and option awards included in SCT Total for the covered fiscal year
? ? ? ? — ? ? ? ? ? — ? ? ? ? ? — ? ?
Outstanding and unvested awards: ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?
Add: Fair value at year end of awards granted during the covered fiscal year that were outstanding and unvested at the covered fiscal year end
? ? ? ? — ? ? ? ? ? — ? ? ? ? ? — ? ?
Add: Change in fair value as of fiscal year-end, compared to
prior fiscal year-end, of awards granted in any prior fiscal
year that are outstanding and unvested as of the end of the
fiscal year
? ? ? ? — ? ? ? ? ? — ? ? ? ? ? — ? ?
Awards granted and vesting in the same year: ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?
Add: Vesting date fair value of awards granted and vested during the covered fiscal year
? ? ? ? — ? ? ? ? ? — ? ? ? ? ? — ? ?
Awards vesting in current fiscal year but granted in a prior fiscal
year:
? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?
Add: Change in fair value as of vesting date, compared to prior fiscal year-end, of awards granted in any prior fiscal year for which all vesting conditions were satisfied at fiscal year-end or during the fiscal year
? ? ? ? — ? ? ? ? ? — ? ? ? ? ? (372,000) ? ?
Compensation Actually Paid to Non-PEO NEOs
? ? ? $ 518,000 ? ? ? ? $ 624,000 ? ? ? ? $ 274,000 ? ?
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(5)
The amounts reported represent the Total Shareholder Return (“TSR”) for each applicable year calculated based on a fixed investment of $100 in the Company for the period starting December 31, 2020, through the end of the listed year on the same cumulative basis as is used in Item 201(e) of Regulation S-K. Historical stock performance is not necessarily indicative of future stock performance.
?
(6)
The Peer Group TSR used for this calculation is based on the NASDAQ Biotechnology index, which we also use for purposes of our stock performance graph in our most recent annual report on Form 10-K for the fiscal year ended December 31, 2023. The peer group TSR is calculated using the same methodology as describe in footnote 5 above, with the returns of each component company of this group weighted according to the respective company’s stock market capitalization at the beginning of each period for which a return is indicated.
?
Relationship Between CAP Amounts and Performance Measures
The following charts show graphically the relationships over the past two years of the CAP Amounts for the PEO and the Other NEOs as compared to our (i) cumulative total shareholder return and (ii) net income.
While the Compensation Committee makes executive compensation decisions in consideration of a variety of factors, including corporate and individual performance, the decisions of the Compensation Committee and Board of Directors in 2023, 2022 and 2021 were made independently of these disclosure requirements.
[MISSING IMAGE: bc_captsrpeer-4c.jpg]
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[MISSING IMAGE: bc_capvsnet-4c.jpg]
Compensation Committee Interlocks and Insider Participation
None of our officers currently serves, or in the past year has served, as a member of the compensation committee of any entity that has one or more officers serving on our board of directors.
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DIRECTOR COMPENSATION
The following table sets forth certain information concerning compensation paid or accrued to our non-executive directors during the year ended December 31, 2023.
Name(2)
? ?
Year
? ?
Fees
Earned or
Paid in Cash ($)
? ?
Option
Awards ($)
? ?
Total
($)
?
Dr. Navid Malik
? ? ? ? 2023 ? ? ? ? ? 150,000 ? ? ? ? ? — ? ? ? ? ? 150,000 ? ?
Jerry Jasinowski
? ? ? ? 2023 ? ? ? ? ? 150,000 ? ? ? ? ? — ? ? ? ? ? 150,000 ? ?
J. Cofer Black
? ? ? ? 2023 ? ? ? ? ? 150,000 ? ? ? ? ? — ? ? ? ? ? 150,000 ? ?
The non-executive independent directors were compensated on a monthly basis $12,500 ($150,000 annually) for their consistent availability on short notice, participation in the frequent meetings of the board of directors, leadership of at least one board committee, participation on multiple committees of the Board, commitment to corporate governance initiatives, and frequent consultations with management on operational matters. The Company owed Mr. Jasinowski $275,000 as of December 31, 2023.
Mr. Sarma was appointed to the Board as a non-executive director in March 2024, following Mr. Jasinowski’s retirement for medical reasons. As a non-executive director Mr. Sarma is entitled to receive compensation on the same basis as the Company’s other non-executive directors.
Ms. Powers and Dr. Boynton are executives of the Company and do not receive any compensation for their services as a director.
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CERTAIN RELATIONSHIPS AND RELATED TRANSACTIONS
Advent BioServices, Ltd.
Advent BioServices, Ltd. (“Advent”) is a related party based in the U.K. and owned by Toucan Holdings, which is controlled by our Chairperson and Chief Executive Officer, Linda F. Powers. Advent was previously the U.K. branch of Cognate until it was spun off from Cognate in late 2016. Since then, Advent has operated independently of Cognate, providing manufacturing and related services for production of DCVax-L products.
The Company had three operational programs with Advent: (a) an ongoing development and manufacturing program at the GMP facility in London, (b) an ongoing development and manufacturing program at the Sawston GMP facility, and (c) a one-time program for specialized work, organized into ten sets of one-time milestones, which were substantially completed as of December 31, 2023, for the following:
•
Qualifying for and obtaining three required licenses for the Sawston facility: a license from the Human Tissue Authority to collect and process human cells and tissues, a license from the MHRA for manufacturing for clinical trials and compassionate use cases, and a license from the MHRA for commercial manufacturing.
?
•
Six workstreams relating to product matters required for an application for regulatory approval of DCVax-L, including Comparability, Stability, Potency, Product Profile, Mechanism of Action and Fill/?Finish.
?
•
Drafting and submission of key portions of the applications for product approval (MAA).
?
Each of the three operational programs is covered by a separate contract. The ongoing manufacturing in the London facility is covered by a Manufacturing Services Agreement (“MSA”) entered into on May 14, 2018. The development and manufacturing program at the Sawston facility is covered by an Ancillary Services Agreement entered into on November 18, 2019. The specialized work associated with the ten sets of one-time milestones is covered by an SOW 6 entered into under the Ancillary Services Agreement as of April 1, 2022 and amended on September 26, 2022 and September 26, 2023. The 2023 amendment extended the SOW 6 service period for about six months, through March 31, 2024 and it was then further extended to September 30, 2024.
The Ancillary Services Agreement establishes a structure under which the Company and Advent negotiate and agree upon the scope and terms for Statements of Work (“SOWs”) for facility development activities and compassionate use program activities. After an SOW is agreed and approved by the Company, Advent will proceed with, or continue, the applicable services and will invoice the Company pursuant to the SOW. Since both the facility development and the compassionate use program involve pioneering and uncertainties in most aspects, the invoicing under the Ancillary Services Agreement is on the basis of costs incurred plus fifteen percent. The SOWs may involve ongoing activities or specialized one-time projects and related one-time milestone payments. The Ancillary Services Agreement was to end in July 2023, but the Company extended the term by 12 months to July 2024.
SOW 6 provides for ongoing baseline costs for manufacturing at the Sawston facility and one-time milestone incentives for (a) regulatory approval of each of the three licenses required for the Sawston facility, (b) successful completion of each of the six workstreams and (c) completion of drafting key portions of applications for product approval. The milestone incentives are a combination of cash and stock, and are not paid until the milestone is achieved and earned.
During the year ended December 31, 2023, the Company paid an aggregate of $5.0 million in cash, of which $1.0 million was related to two milestones that were completed and fully expensed in 2022, but was unpaid as of December 31, 2022, $4.0 million was payment for four completed one-time milestones (MAA workstream for Mechanism of Action, obtaining a commercial manufacturing license from the MHRA in March 2023 and completion of drafting key portions of the first application for commercial approval and submitting the application to MHRA for product approval). The Company issued 4.5 million common shares as a result of completion of the two one-time milestones (obtaining a commercial manufacturing license from the MHRA and completion of drafting and submitting the MAA application for approval in the U.K.)
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at fair value of $3.2 million, of which $0.6 million was recognized during the year ended December 31, 2023 and $2.6 million had already been recognized (but not paid) in 2022.
As of December 31, 2023, $0.5 million was unpaid and 1.5 million common shares were pending to be issued in regard to the completed milestone (submission of the application to MHRA for product approval).
Related-Party Transaction Approval Policy
Under SEC rules, related-party transactions are those transactions to which we are or may be a party in which the amount involved exceeds the lesser of $120,000 or one percent of the average of our total assets at year-end for the last two completed fiscal years, and in which any of our directors or executive officers or any other related person had or will have a direct or indirect material interest, excluding, among other things, compensation arrangements with respect to employment or board membership. Any transactions with any person who is, or at any time since the beginning of the Company’s fiscal year was, a director or executive officer or a nominee to become a director of the Company, any person who is known to be the beneficial owner of more than 5% of any class of the Company’s voting securities, any immediate family member or person sharing the household of any of the foregoing persons, any firm, corporation or other entity in which any of the foregoing persons is a partner or principal, is subject to approval or ratification in accordance with the procedures of the Company’s Related-Party Transaction Policy. These procedures and practices include Mr. Goldman, the Company’s Senior Vice President and General Counsel, undertaking all negotiations with Advent, briefing the Conflicts Committee and the Board on any contracts, amendments, or issues relating to Advent and on any discussions and votes taken concerning Advent. The procedures further include Ms. Powers being recused from any discussions or votes of the Conflicts Committee and of the Board of Directors on any contractual agreements or business decisions or other matters relating to Advent.
Conflicts Committee
The Conflicts Committee of the Board reviews and decides whether to approve all related-party matters and transactions in light of potential conflicts of interests and reasonableness, as described in the Corporate Governance Matters section above. The Conflicts Committee’s review and approval of any series of similar related-party transactions (such as a series of transactions governed by a single contract) can suffice to satisfy this policy with respect to each transaction in the series.
Report of the Audit Committee
As part of its specific duties, the Audit Committee reviews our Company’s financial reporting process on behalf of the Board; reviews the financial information issued to stockholders and others, including a discussion of the quality, acceptability and clarity of the information, and monitors our systems of internal control and the audit process. Management is responsible for the preparation, presentation and integrity of our financial statements, accounting and financial reporting principles, and disclosure controls and procedures designed to ensure compliance with accounting standards and applicable laws and regulations. Management also is responsible for objectively reviewing and evaluating the adequacy, effectiveness, and quality of our own system of internal control. Our independent registered public accounting firm is responsible for performing an independent audit of the consolidated financial statements and expressing an opinion on the conformity of those financial statements with generally accepted accounting principles.
The Audit Committee has reviewed and discussed with management our audited financial statements for the fiscal year ended December 31, 2023. The Audit Committee has discussed with Cherry Bekaert LLP, our Company’s independent registered public accounting firm for the fiscal year ended December 31, 2023, the matters required to be discussed by the applicable requirements of the Public Company Accounting Oversight Board (the “PCAOB”) and the SEC. The Audit Committee has received the written disclosures and letter from Cherry Bekaert LLP our independent registered public accounting firm required by applicable requirements of the PCAOB regarding the independent registered public accounting firm’s communications with the Audit Committee concerning independence, and has discussed with the independent registered public accounting firm the independent registered public accounting firm’s independence. The Audit Committee has also considered whether the provision of services other than the audit of our financial statements was compatible with maintaining Cherry Bekaert LLP’s independence.
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Based on the review and discussions referred to in the foregoing paragraph, the Audit Committee recommended to the Board of Directors that the audited financial statements be included in our Annual Report on Form 10-K for the fiscal year ended December 31, 2023 for filing with the SEC.
THE AUDIT COMMITTEE
Pat Sarma
Dr. Navid Malik?
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PRINCIPAL ACCOUNTANT FEES AND SERVICES
Fees Paid to Independent Public Accountants
Cherry Bekaert has served as our independent public accounting firm for the fiscal years ended December 31, 2020, 2021, 2022 and 2023 and was engaged to serve in such capacity for 2024.
Audit Fees
The aggregate fees billed for the fiscal years ended December 31, 2023 for professional services rendered by Cherry Bekaert for the audit of our annual financial statements for 2023, an independent audit of the Company’s internal controls for 2023, and the review our financial statements included in our quarterly reports on Form 10-Q for 2023 was $614,000.
The aggregate fees billed in connection with the fiscal year ended December 31, 2022 for professional services rendered by Cherry Bekaert for the audit of our annual financial statement for 2022, including the review of the financial statement information included in our Quarterly Reports on Form 10-Q during 2022, was $550,000.
Audit-Related Fees
There were no fees billed in the fiscal years ended December 31, 2023 and 2022 for assurance and related services rendered by Cherry Bekaert related to the performance of the audit or review of our financial statements.
Tax and Other Non-Audit Professional Services
There were no fees billed in the fiscal years ended December 31, 2023 and 2022 for professional services rendered by Cherry Bekaert for tax related services or other non-audit professional services fees.
Policy on Audit Committee Pre-Approval of Audit and Permissible Non-Audit Services
Consistent with SEC policies and guidelines regarding audit independence, the Audit Committee is responsible for the pre-approval of all audit and permissible non-audit services provided by our principal accountants on a case-by-case basis. Our Audit Committee has established a policy regarding approval of all audit and permissible non-audit services provided by our principal accountants. Our Audit Committee pre-approves these services by category and service. Our Audit Committee pre-approved all of the services provided by our principal accountants during the fiscal years ended December 31, 2023 and 2022.
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OTHER MATTERS
Stockholder Proposals for the Next Annual Meeting of Stockholders
Proposals of stockholders intended to be included in our proxy materials for the next annual meeting of stockholders pursuant to Rule 14a-8 under the Exchange Act must be received by us no later than February [3], 2025 the 120th day prior to the first anniversary of the date on which this proxy statement was first mailed to our stockholders. Proposals should be addressed to Northwest Biotherapeutics, Inc., 4800 Montgomery Lane, Suite 800, Bethesda, Maryland 20814, Attention: Secretary.
In addition, our bylaws require that we be given advance notice of stockholder nominations for election to our Board and of other business that stockholders wish to present for action at an annual meeting of stockholders (other than matters included in our proxy statement in accordance with Rule 14a-8). Our corporate secretary must receive such notice no earlier than January [4], 2025 and no later than February [3], 2025, 150 days and 120 days prior to the first anniversary of the date on which this proxy statement was first mailed to our stockholders, respectively. If the date on which the next annual meeting of stockholders will be held is changed by more than 30 calendar days from the date of the Annual Meeting, we must receive the notice at least 80 days prior to the date on which we intend to distribute the corresponding proxy statement. In addition to giving notice pursuant to the advance notice provisions of the Company’s bylaws, a stockholder who intends to solicit proxies in support of nominees submitted under these advance notice provisions must also provide the notice required Rule 14a-19, the SEC’s universal proxy rule, to our Corporate Secretary regarding such intent no later than April 30, 2025.
The notice for any stockholder proposal must contain certain information set forth in our bylaws. In addition, stockholder proposals made under Rule 14a-8 under the Exchange Act are required to contain certain information. Therefore, we strongly encourage stockholders interested in submitting a proposal to contact legal counsel with regard to the detailed requirements of applicable securities laws. Copies of our bylaws can be obtained without charge from our corporate secretary.
Submitting a stockholder proposal does not guarantee that we will include it in our proxy statement.
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ADDITIONAL INFORMATION
Communication with the Board of Directors
All communications should be in written form and directed to our corporate secretary at the following email address: corpsecretary@nwbio.com.
WHETHER OR NOT YOU PLAN TO ATTEND THE ANNUAL MEETING, YOU ARE URGED TO VOTE BY PHONE, ONLINE, OR COMPLETE, SIGN, DATE AND RETURN THE ENCLOSED PROXY CARD IN THE ACCOMPANYING ENVELOPE. PROMPT RESPONSES WILL GREATLY FACILITATE ARRANGEMENTS FOR THE MEETING AND YOUR COOPERATION IS APPRECIATED.
By Order of the Board of Directors,
/s/ Linda F. Powers
?
Chairperson of the Board of Directors
June [3], 2024
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APPENDIX A: PLAINTIFF’S AMENDED COMPLAINT
IN THE COURT OF CHANCERY OF THE STATE OF DELAWARE
? ? ? ? ) ? ? ? ?
? IN RE NORTHWEST ? ? ) ? ? ? ?
? BIOTHERAPEUTICS, INC. ? ? ) ? ? C.A. No. 2022-0193-JTL ?
? STOCKHOLDER LITIGATION ? ? ) ? ? Consolidated ?
? ? ? ? ) ? ? ? ?
AMENDED AND SUPPLEMENTAL CONSOLIDATED VERIFIED
STOCKHOLDER DERIVATIVE AND CLASS ACTION COMPLAINT
On behalf of Nominal Defendant Northwest Biotherapeutics, Inc. (“Northwest Biotherapeutics” or the “Company”), Plaintiff Glenn F. Schaeffer (“Plaintiff”) asserts claims for breach of fiduciary duty and unjust enrichment against members of the Company’s board of directors (the “Board” or the “Directors” or the “Director Defendants”) and General Counsel (collectively, the “Individual Defendants”).1 On behalf of himself and all other similarly situated stockholders of Northwest Biotherapeutics, Plaintiff also brings a claim against the Director Defendants for breach of the fiduciary duty of candor and a claim against the Company and the Individual Defendants for declaratory relief.
?
1 Plaintiff’s allegations are made upon personal knowledge as to himself and his own acts, and upon information and belief as to all other matters, based upon the investigation conducted by and through his attorneys, which included a review of documents Plaintiff obtained from the Company in connection with a books and records demand under 8 Del. C. § 220 (the “Demand”), documents filed with the U.S. Securities and Exchange Commission (the “SEC”), and various media and analyst reports.
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NATURE AND SUMMARY OF THE ACTION
1. This is a stockholder derivative and class action brought to hold Northwest Biotherapeutics’ insiders accountable for abusing their positions and breaching their fiduciary duties by awarding themselves over $40 million worth of stock options in May 2020 and now belatedly seeking the stockholders’ approval of these awards on the basis of materially false and misleading disclosures.
2. Since 2017, the Board comprised five Directors: (a) non-employee directors J. Cofer Black (“Black”), Jerry Jasinowski (“Jasinowski”), and Navid Malik (“Malik”); and (b) executive directors Linda F. Powers (“Powers”), the Company’s Chief Executive Officer (“CEO”) and Chairperson of the Board, and Alton L. Boynton (“Boynton”), the Company’s co-founder and Chief Scientific Officer.
3. In May 2018, as compensation for their services to the Company, the Directors awarded themselves and Leslie J. Goldman (“Goldman”), the Company’s General Counsel, an aggregate of 84,280,000 stock options worth $14.4 million (the “2018 Option Awards”).
4. Northwest Biotherapeutics is a biotechnology company that has no commercial products and relies primarily on equity issuances in order to raise sufficient capital to fund its operations. During the two years following the 2018 Option Awards, the Company raised tens of million dollars in cash through various equity issuances (the “Financing Transactions”), but as a result saw its outstanding share count increase by approximately 290 million shares, thus diluting all equity holders in the process. That is, with 290 million additional shares outstanding, each equity holder now had a smaller percentage ownership stake in the Company.
5. In May 2020, the Directors (with Goldman attending all meetings) granted themselves (and Goldman) an aggregate of 134,575,229 stock options worth $40.64 million. These awards were not intended as a reward for performance or service. Instead, according to the documents produced in connection with Plaintiff’s Demand, these awards were intended to “true-up” the Individual Defendants to “offset . . . the dilutive effects” of the Financing Transactions on Defendants’ 2018 Option Awards. Stated differently, the Individual Defendants decided to offset their decreased percentage ownership stake occasioned by the Company’s financing needs simply by granting themselves 134,575,229 stock options to bring their percentage ownership stake in the Company back up to their previous levels (the so- called “True-Up” Awards).
6. The True-Up Awards are unprecedented and indefensible. The Individual Defendants do not have the right?—?whether by employment agreement, contract, or otherwise?—?to own a specific percentage of the Company’s common stock. All of the Company’s equity holders?—?public stockholders and Individual Defendants alike?—?suffered dilution as a result of the Financing Transactions. Of course, public stockholders, including Plaintiff, could not simply take more shares from the Company in order to offset the dilution and “true-up” their respective stakes. In a gross abuse of their positions as Company fiduciaries, the Individual Defendants did exactly that.
7. Moreover, the Individual Defendants suffered absolutely no economic harm as a result of the Financing Transactions. While their percentage ownership stake in the Company decreased as a result of the equity issued in the Financing Transactions, Northwest Biotherapeutic’s value increased as a result of the resulting cash inflow. Accordingly, all else being equal, the value of the Individual Defendants’ equity stakes did not change as a result of the Financing Transactions. In other words, the “true-up” rationale is a pretext for what is in reality a windfall of over $40 million that the Individual Defendants secured for themselves in a self- dealing transaction. And it is a pretext that has no logical end point: when the Company issues more shares to raise money going forward, the Individual Defendants apparently will feel entitled to be “trued up” again.
8. The Individual Defendants’ process lacked any semblance of sound corporate governance. They did not retain any consultants or experts to advise them regarding their True-Up Awards, which were never presented to any independent person or entity. Instead, the Individual Defendants handled everything themselves. The manner in which they did so made a mockery of the concept of director “disinterest:” the executive directors (Powers and Boynton) approved the awards for the non-employee directors (Black, Jasinowski, and Malik), while the non-employee directors, in turn, approved the awards for their counterparts, the executive directors and Goldman. Through this “round robin” voting process, the Board attempted to claim that each group was “disinterested” vis-à-vis the other.
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9. It is also notable that the Board originally contemplated seeking, as it had in the past, stockholder approval for the awards made to the non-employee directors, but later abandoned that plan. Instead, as the Company’s internal documents show, the Board proceeded to grant the True-Up Awards to Black, Jasinowski, and Malik in August 2020. More than two years passed without the Board taking any steps towards seeking stockholder approval of these grants.
10. Then, several months after Plaintiff commenced this action, the Board proceeded to schedule a meeting, issue a (materially false and misleading) proxy statement, and seek the “approval” of the Company’s stockholders for these awards, and “ratification” of the True-Up Awards made to Powers, Boynton, and Goldman, as discussed further below.
11. The True-Up Awards are blatantly unfair to the Company and should therefore be rescinded in their entirety.
PARTIES
12. Plaintiff Glenn F. Schaeffer has continuously owned shares of the Company’s common stock since 2019.
13. Nominal Defendant Northwest Biotherapeutics is a Delaware corporation with its principal place of business in Bethesda, Maryland. With respect to Count IV for Declaratory Relief, Northwest Biotherapeutics is being named as a Defendant.
14. Defendant Black has served on the Board since January 2016.
15. Defendant Jasinowski has served on the Board since April 2012.
16. Defendant Malik has served on the Board since April 2012.
17. Defendant Powers has served as Chairperson of the Board since May 2007 and as the Company’s CEO and President since June 2011. As of June 2020, Powers also serves as the Company’s Chief Financial and Accounting Officer.
18. Defendant Boynton co-founded the Company in 1996 and has served as its Chief Scientific Officer and as a director since 1998. Defendant Boynton served as the Company’s CEO from June 2007 to June 2011.
19. Defendant Goldman joined the Company as Senior Vice President, Business Development in June 2011, and became Senior Vice President, General Counsel in 2018.
FURTHER SUBSTANTIVE ALLEGATIONS
Background
20. Northwest Biotherapeutics is a “biotechnology company focused on developing personalized immune therapies for cancer.” Since its inception in 1996, the Company has not brought any product candidates to the commercialization stage of development, i.e., the stage capable of producing meaningful revenues.
21. Northwest Biotherapeutics’ lead product, DCVax®-L, is designed to treat solid tumor cancers in which the tumor can be surgically removed. While the Company recently completed a 331-patient international Phase III trial of DCVax-L for Glioblastoma multiforme brain cancer, a trial that began almost a decade ago, the results of which were announced in November 2022.
The 2018 Option Awards
22. Since July 2017, the Board has comprised the following five directors: non-employee directors Black, Jasinowski, and Malik, and executive directors Boynton and Powers.
23. Since 2015, the Company’s non-employee director compensation program has consisted of an annual cash retainer of $150,000.
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24. As Northwest Biotherapeutics’ CEO and President, Powers received a $502,000 annual salary from 2016 to 2019, and a $700,000 salary in 2020. She also received a $300,000 bonus that was paid in 2020 but approved in 2019 according to the Company’s disclosures.
25. As Chief Scientific Officer, Boynton received a $325,000 salary from 2016 to 2019 (his 2020 salary was not publicly disclosed). Boynton also received a $20,000 bonus in 2019.
26. As the Company’s Senior Vice President, Business Development/General Counsel, Goldman received a $375,000 salary from 2016- 2019, and a $525,000 salary in 2020. Goldman also received a $200,000 bonus that was paid in 2020 but approved in 2019 according to the Company’s disclosures.
27. On January 16, 2018, Northwest Biotherapeutics filed an 8-K with the SEC (the “January 2018 8-K”), which disclosed that, on November 19, 2017, the Board approved stock option awards to various individuals “to take account of employee and director performance over the last approximately 6 years and anticipated performance over the next approximately 2 years.” As further stated in the January 2018 8-K, the Company had begun “undertaking the steps for implementation” of these awards.
28. On April 9, 2018, the Company filed a Schedule 14A Definitive Proxy Statement (the “2018 Proxy”) in connection with a special meeting of stockholders held on April 27, 2018 (the “Special Meeting”). As disclosed in the 2018 Proxy, Powers and Boynton approved the stock option awards designated for Black, Jasinowski, and Malik (the “2018 NED Option Awards”), pursuant to which, subject to stockholder approval, Black would receive 1,715,000 stock options, Jasinowski would receive 4,900,000 stock options, and Malik would receive 9,065,000 stock options.
29. In Proposal No. 3 of the 2018 Proxy, the Board sought stockholder approval of the 2018 NED Option Awards. According to the 2018 Proxy, Powers and Boynton had approved the 2018 NED Option Awards based on a “number of factors and considerations,” including (a) “the extraordinarily long period that the independent directors have been serving without having received any equity compensation, despite the Company’s promises to make such awards”; (b) “the extraordinary amount [of] time, effort and support contributed by the independent directors throughout their respective periods of service, going far beyond the activities typically involved in Board service”; and (c) “the extent of personal and professional risk [the] independent directors have endured in serving on our Board.” At the Special Meeting, stockholders approved Proposal No. 3.
30. On June 1, 2018, the Company filed an 8-K with the SEC (the “June 2018 8-K”), which disclosed that, on May 28, 2018, the Company completed the implementation of the option awards and issued an aggregate of 84,280,000 stock options to the Individual Defendants (i.e., the 2018 Option Awards) in the following amounts:
? ? ? ? ? ?
No. Options
? ? ?
Value2
? ?
? ? Black ? ? ?
1,715,000
? ? ?
$293,000
? ?
? ? Boynton3 ? ? ?
4,900,000
? ? ?
$837,000
? ?
? ? Goldman ? ? ?
24,500,000
? ? ?
$4,186,000
? ?
? ? Jasinowski ? ? ?
4,900,000
? ? ?
$837,000
? ?
? ? Malik ? ? ?
9,065,000
? ? ?
$1,549,000
? ?
? ? Powers ? ? ?
39,200,000
? ? ?
$6,698,000
? ?
? ? Total ? ? ?
84,280,000
? ? ?
$14,400,000
? ?
31. As disclosed in the June 2018 8-K, the stock options issued to Powers, Goldman, and Boynton had an exercise price of $0.23 per share (the closing price of the Company’s common stock on the preceding
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2 The value represents the grant date fair value as disclosed by the Company in its Form 10-K Annual Report filed with the SEC on April 2, 2019.
3 On August 31, 2018, Boynton was granted an additional 2,967,065 stock options with a grant date fair value of approximately $691,000.
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business day, May 25, 2018), and the stock options issued to Black, Jasinowski, and Malik had an exercise price of $0.30 per share.
32. On May 14, 2018, just prior to the issuance of the 2018 Option Awards, Northwest Biotherapeutics had 419,465,016 outstanding shares of common stock.
The Company Issues Equity to Raise Cash and Fund Operations
33. With no commercialized products, Northwest Biotherapeutics relies primarily on equity issuances to raise sufficient capital to fund its operations.4
34. During 2018, the Company received $8.4 million in cash proceeds from the issuance of convertible preferred stock, common stock and warrants, in both public and private offerings. The Company also received $2.6 million in cash proceeds from the exercise of warrants during 2018.
35. During 2019, the Company received $6.9 million from the issuance of convertible preferred stock, common stock and warrants, in both public and private offerings. The Company also received $2.2 million in cash proceeds from the exercise of warrants during 2019.
36. During the six months ended June 30, 2020, the Company received approximately $11.6 million in cash from the issuance of 68.6 million shares of common stock.
37. As a result of these and other equity issuances (i.e., the Financing Transactions), the number of Northwest Biotherapeutics’ shares outstanding increased substantially. As of June 12, 2020, the Company had 710,282,469 outstanding shares?—?nearly 300 million more shares than when the 2018 Option Awards were issued.
The Directors Grant Themselves and Goldman the True-Up Awards
38. On January 26, 2020, the Board convened a meeting attended by all five Directors and Goldman. As described in the minutes of the meeting, the Board “discussed the true-up of options held by certain Board members in accordance with the Company’s outstanding securities and issuances in the past year.” The discussion included “the options at issue, the mechanics of the true-up, and the process for shareholder approval.”
39. On March 23, 2020, the Board convened a meeting attended by all five Directors and Goldman. As stated in the minutes of the meeting, the Board discussed a “true-up of the number of options” held by Black, Jasinowski, and Malik “in accordance with the number of securities issued by the Company.” At the meeting, Powers and Boynton “voted to approve” a proposal seeking “shareholder ratification” of these grants at a special meeting of stockholders before implementing any such “true-up.”
40. On May 23, 2020, the Board again met with all five Directors and Goldman present (the “May 23 Meeting”). According to the minutes, the purportedly “disinterested” directors, Powers and Boynton, “voted unanimously to approve awarding true-up options to the independent directors.” As further stated in the minutes, the “true-up options [would] offset or partially offset the dilutive effects of issuances since the prior option awards to these directors in 2018.”
41. Three days later, on May 26, 2020, Powers emailed the members of the Board’s Compensation Committee (the “Compensation Committee”), Malik and Jasinowski, a list of proposed option awards for various employees and consultants, including Boynton, Goldman, and herself. As described in the email, the list was a joint recommendation from Powers and Goldman, and the proposed options were intended to “true up to new denominator (total securities outstanding at COB on Friday, 5/22/20).”
42. On May 29, 2020, the Board convened a meeting attended by all five Directors and Goldman (the “May 29 Meeting”). As described in the minutes, the Compensation Committee had “met twice this week,” and after “extensive discussions about the potential awards” for employees and certain consultants, the Compensation Committee had “approved the recommendations from Management.” The Board “asked
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4 The Company reported revenues of $2.4 million, $1.3 million, and $1 million, in 2019, 2020, and 2021, respectively.
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questions about the factors used to prepare and to evaluate the proposed allocations,” and following a discussion, the Board?—?with Black, Jasinowski, and Malik voting while Powers and Boynton “recused” themselves?—?approved “the proposed option awards as approved by the [Compensation] Committee.”
43. Thereafter, the Company began implementing the issuance of the “true- up” awards. On July 2, 2020, the Company issued 43,329,153 stock options to Powers, 28,554,455 stock options to Goldman, and 18,794,191 stock options to Boynton. For Powers and Goldman, these options comprised just a portion of their allocated stock options, as explained below. The stock options were originally issued with a $0.25 exercise price, but were later amended to a $0.35 exercise price (which was the closing price of the Company’s common stock on July 2, 2020). The options had certain time-based vesting requirements.
44. On July 19, 2020, the Board convened a meeting attended by all five Directors and Goldman. At the meeting, management and the Board discussed their progress in implementing the previously-approved stock option awards. As described in the minutes of the meeting, the options “for senior management were recently implemented, except that Ms. Powers and Mr. Goldman volunteered to set aside a portion of their option awards until the option awards for staff employees were determined to be sufficient.” Meanwhile, the stock option awards for the non- employee directors were “pending for implementation (subject to shareholder approval at the next meeting, as in the past).”
45. On August 5, 2020, the Board convened another meeting attended by all five Directors and Goldman. At the meeting, the Board approved the stock option awards for staff employees, thus paving the way for Powers and Goldman to receive the rest of their allocated stock options. As described in the minutes of the meeting, the Board, with Powers recusing herself, “voted to approve again the award of the options that were previously set aside for but not yet issued to management (Ms. Powers and Mr. Goldman) while staff options were handled.”
46. Though not explained in the minutes of this meeting, the Board apparently also determined that it would no longer be seeking stockholder approval of the stock option awards to Black, Jasinowski, and Malik. Instead, Powers and Boynton “noted that the implementation of the options previously awarded to the independent Board members should also be completed.”
47. Accordingly, on August 5, 2020, Black received 4,769,433 stock options, Jasinowski received 5,710,891 stock options, and Malik received 15,732,288 stock options. The stock options were issued originally with a $0.25 exercise price, but were later amended to a $0.34 exercise price (which was the closing price of the Company’s common stock on August 5, 2020). Half of the options would vest upon grant and the remaining 50% would vest over the following 12 months.
48. On September 2, 2020, the Board convened a meeting attended by all five Directors and Goldman. As described in the minutes of the meeting, the Board “reaffirmed the issuance” of the stock option awards to Powers and Goldman that had been “set aside until employee options were completed.” Accordingly, on September 2, 2020, Powers received an additional 11,789,879 stock options and Goldman received an additional 5,894,939 stock options. These additional options would vest on March 31, 2021 or upon the achievement of certain performance milestones, whichever was earlier. Accordingly, by March 31, 2021, these options had vested.
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49. In all, the Directors granted themselves and Goldman 134,575,229 stock options worth $40.64 million in the aggregate (i.e., the True-Up Awards):
? ? ? ? ? ?
No. Options
? ? ?
Value5
? ?
? ? Black ? ? ?
4,769,433
? ? ?
$1,250,000
? ?
? ? Boynton ? ? ?
18,794,191
? ? ?
$5,905,000
? ?
? ? Goldman ? ? ?
34,449,394
? ? ?
$10,548,000
? ?
? ? Jasinowski ? ? ?
5,710,891
? ? ?
$1,497,000
? ?
? ? Malik ? ? ?
15,732,288
? ? ?
$4,123,000
? ?
? ? Powers ? ? ?
55,119,032
? ? ?
$17,317,000
? ?
? ? Total ? ? ?
134,575,229
? ? ?
$40,640,000
? ?
The True-Up Awards Unfairly Enrich the Individual Defendants
50. As described above, the Individual Defendants’ stated rationale for the True-Up Awards was to “offset or partially offset the dilutive effects” on the 2018 Option Awards caused by the Financing Transactions. Stock dilution is the decrease in an existing stockholders’ ownership percentage that results from the company issuing new equity. With roughly 419.4 million shares outstanding when the 2018 Option Awards were granted, the Individual Defendants’ 84.28 million stock options represented a 16.7% stake in the Company.6
51. By May 2020, primarily as a result of its Financing Transactions, Northwest Biotherapeutics had approximately 710.3 million outstanding shares, and accordingly the Individual Defendants’ 2018 Option Awards represented a 10.6% stake in the Company.7 Accordingly, the True-Up Awards were intended to offset this decrease in the Individual Defendants’ respective ownership stake by providing them with more stock options and bringing their ownership stake in the Company back up to previous levels.
52. The Individual Defendants were not the only ones who suffered dilution as a result of the Financing Transactions. All of the Company’s equity holders did. But public stockholders, including Plaintiff, could not simply help themselves to more shares to offset the dilution and give themselves a “true-up.” In a gross abuse of their position, the Individual Defendants did exactly that, but only for themselves.
53. The Individual Defendants are not entitled to own a specific percentage of the Company’s common stock. In fact, no one is.
54. Northwest Biotherapeutics’ Seventh Amended and Restated Certificate of Incorporation (the “Certificate of Incorporation”) denies stockholders the preemptive right to participate in a stock offering in order to maintain their level of ownership. Specifically, Section Article IV, Section 1(d) of the Certificate of Incorporation states:
No stockholder of the Corporation shall by reason of his/her/its holding shares of any class of capital stock of the Corporation have any preemptive or preferential right to acquire or subscribe for any additional, unissued or treasury shares (whether now or hereafter acquired) of any class of capital
?
5 This represents the grant date fair value as disclosed by the Company in its Schedule 14A Definitive Proxy Statement filed with the SEC on April 16, 2021 (the “2021 Proxy”). While the value of Boynton’s options was not publicly disclosed, it is calculated based on the assumption that his options had the same per-share value as Powers’ and Goldman’s options.
6 The 419.4 million outstanding shares plus the 84.28 million options equates to approximately 504 million shares. The 84.28 million options represent a 16.7% ownership stake of the 504 million shares.
7 The 710.3 million shares outstanding plus the 84.28 million stock options equates to 794.6 million shares. The 84.28 million options represent a 10.6% ownership interest of the 794.6 million shares. This calculation and the one in the preceding footnote, which do not include any other warrants or options that may have been outstanding at the time, is provided simply to explain the effect of dilution, and not to specifically detail the precise dilutive effect of the Financing Transactions.
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stock of the Corporation now or hereafter to be authorized, or any notes, debentures, bonds or other securities convertible into or carrying any right, option or warrant to subscribe for or acquire shares of any class of capital stock of the Corporation now or hereafter to be authorized, whether or not the issuance of any such shares or such notes, debentures, bonds or other securities would adversely affect the dividends or voting or other rights of that stockholder.
55. The Individual Defendants effectively circumvented this provision and they did so without even paying for their additional shares. Instead, they just gave themselves stock options for no consideration.
56. The True-Up Awards become even more egregious when considering the equity that was being “trued-up”?—?the 2018 Option Awards. While public stockholders had to pay for their shares, the 2018 Option Awards were shares the Individual Defendants granted to themselves. As described above, the 2018 Option Awards were a one-time lucrative award designed to compensate the Defendants for up to six years of past performance and two years going forward. With the True-Up Awards, the Individual Defendants were now using the 2018 Option Awards as a vehicle by which the Individual Defendants could maintain a certain percentage level of ownership in the Company in perpetuity.
57. While the Individual Defendants’ percentage ownership stake in the Company decreased as a result of the equity issued in connection with the Financing Transactions, the Company’s value increased as a result of the cash it received in return. All else being equal, the value of the equity held by the Individual Defendants would not have changed.
58. For example, consider a hypothetical company that has 100 million shares outstanding, which trades at $10.00 per share, and thus has a total market capitalization of $1 billion. A stockholder holding 10 million shares would own 10% of the company and have shares worth $100 million. If the company sold 50 million shares at $10.00 per share and raised gross proceeds of $500 million, the company would now have 150 million shares outstanding, and all else being equal, would be valued at $1.5 billion, with the shares still trading at $10.00 per share. The stockholder with 10 million shares would have been diluted to a 6.66% ownership stake, but because the company was now worth an additional $500 million, her shares, still trading at $10.00 per share, would continue to be worth $100 million.
59. As this hypothetical example illustrates, in reality, the Individual Defendants suffered no economic harm at all as a result of the Financing Transactions, and the True-Up Awards simply provided them with a $40 million windfall.
60. The process the Individual Defendants employed in connection with their True-Up Awards was as defective as their justification for these awards. The Individual Defendants did not retain any consultants or experts to advise them. Nor did they then involve the stockholders. Instead, the Individual Defendants ran the entire process themselves. While the Board minutes indicate that the Individual Defendants’ True-Up Awards were approved by “disinterested” directors, the process the Individual Defendants employed to reach that conclusion was absurd. The executive directors (Powers and Boynton) approved the awards for the non- employee directors (Black, Jasinowski, and Malik), while the non-employee directors, in turn, approved the awards for the executive directors and Goldman. No one was disinterested in approving these awards.
61. For all of these reasons, the True-Up Awards were a blatant abuse of power by the Individual Defendants, and accordingly, should be rescinded in their entirety.
62. Additionally, though not designed to serve as annual compensation, the True-Up Awards would be grossly excessive had that been the Individual Defendants’ intention.
63. With their $150,000 cash retainer and True-Up Awards, the non- employee Directors received the following compensation in 2020:
? ? ? ? ? ?
Cash
? ? ?
Option
Awards
? ? ?
Total
? ?
? ? Malik ? ? ?
$150,000
? ? ?
$4,123,000
? ? ?
$4,273,000
? ?
? ? Jasinowski ? ? ?
$150,000
? ? ?
$1,497,000
? ? ?
$1,647,000
? ?
? ? Black ? ? ?
$150,000
? ? ?
$1,250,000
? ? ?
$1,400,000
? ?
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64. This is facially excessive and unfair to the Company. As described above, Malik, Jasinowski, and Black received $1,549,000, $837,000, and $293,000 respectively, from their 2018 NED Option Awards, which was intended to cover up to eight years of equity compensation (six years going back and two years going forward). Yet in one shot each of the non-employee Directors’ received True-Up Awards the value of which far exceeded what they had received for up to eight years of work.
65. The True-Up Awards were not supported by any peer analysis. Indeed, it does not appear that Northwest Biotherapeutics ever developed a peer group for compensation benchmarking purposes. If the Board had performed any sort of peer analysis, it would have revealed that the True-Up Awards could not possibly be justified from a market perspective.
66. For example, the following three companies recently listed Northwest Biotherapeutics as their peer for compensation purposes: Evoke Pharma, Inc. (“Evoke”), Isoray, Inc. (“Isoray”), and Navidea Biopharmaceuticals, Inc. (“Navidea”). During the 2020 fiscal year, these three companies paid their non- employee directors (who were on their respective boards the full year) average compensation packages valued at $170,960, $52,844, and $69,530, respectively.
67. Similarly, the following three companies recently listed Northwest Biotherapeutics as a competitor: Alaunos Therapeutics, Inc. (“Alaunos”), ImmunityBio, Inc. (“ImmunityBio”), and Kintara Therapeutics, Inc. (“Kintara”). During the 2020 fiscal year, these three companies paid their non-employee directors (who were on their respective boards the full year) average compensation packages valued at $64,752, $560,466, and $94,015, respectively.
68. By way of another example, TD Ameritrade has identified the following four companies, who are also developing cancer therapies, as peers of Northwest Biotherapeutics: Fate Therapeutics, Inc. (“Fate”), Fortress Biotech, Inc. (“Fortress”), Cyclacel Pharmaceuticals, Inc. (“Cyclacel”), and Plus Therapeutics, Inc. (“Plus”). During the 2020 fiscal year, these four companies paid their non- employee directors (who were on their respective boards the full year) average compensation packages valued at $337,641, $260,000, $83,079, and $155,410, respectively.
69. In fact, one would be hard-pressed to find even a handful of publicly- traded companies in the United States where non-employee directors are paid over $1 million each, let alone between $1.4 million and $4.27 million. For example, Frederic W. Cook & Co., Inc. (“F.W. Cook”), an executive and director compensation consulting firm, publishes an annual study of compensation paid to non-employee directors using 300 companies of various sizes and industries. In November 2020, F.W. Cook published its 2020 Director Compensation Report. For “small-cap” companies (those with market capitalization of less than $1 billion) such as Northwest Biotherapeutics, F.W. Cook found that the median, non-employee director compensation was $164,000, and the 75th percentile was $200,000. For “large-cap” companies (companies with a market capitalization greater than $5 billion), F.W. Cook found that the median, non-employee director compensation was $290,000, and the 75th percentile was $323,000.
70. Similarly, Steven Hall & Partners (“Steven Hall”), an independent compensation consulting firm, specializing exclusively in the areas of executive and director compensation, publishes an annual study of compensation to non-employee directors. Its “2020 Director Compensation Study” revealed that the median total compensation paid to non-employee directors at the 200 companies with the largest revenues in fiscal 2019 equaled just $315,000. In other words, with the True-Up Awards, the Company’s non-employee Directors paid themselves more than what many of the largest companies in the world pay their non-employee directors.
71. Powers, Goldman, and Boynton fare no better from a peer analysis perspective. With her $700,000 salary and $17,317,000 stock option award, Powers received total compensation of $18,017,000 in 2020. With his $525,000 salary and $10,548,000 in stock options, Goldman’s compensation package was valued at $11,073,000. And with a $5,950,000 stock option award and a $325,000 salary, Boynton’s compensation package was valued at approximately $6,230,000.
72. Meanwhile, the CEOs of Evoke, Isoray, and Navidea received compensation packages in 2020 valued at $1,171,210, $491,637, and $1,225,051, respectively. The CEOs of Alaunos, ImmunityBio, and Kintara paid their CEOS compensation packages in 2020 valued at $2,090,922, $490,248, and $1,054,476,
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respectively. And the CEOs of Fate, Fortress, Cyclacel, and Plus received 2020 compensation packages valued at $5,600,167, $2,636,602, $1,409,644, and $838,000, respectively.
73. Regardless of which companies are selected as “peers,” it is impossible to justify Powers’s $18 million package, which makes her one of the highest-paid CEOs in the United States. Since 2006, the New York Times, in conjunction with Equilar, has reviewed the largest pay packages awarded to CEOs at U.S. public companies. In June 2021, the New York Times and Equilar published a data set titled “Equilar | New York Times 200 Highest-Paid CEOs,” which listed the 200 highest- paid chief executives at American public companies with revenue of at least $1 billion during the 2020 fiscal year. Of course, with no meaningful revenues to speak of, Northwest Biotherapeutics does not even qualify to make this list. Nonetheless, Powers’ $18 million compensation would place her 133rd on the list:
? ?
Rank
? ? ?
Company
? ? ?
CEO Compensation
? ?
? ?
131
? ? ?
HCA Healthcare, Inc. (“HCA”)
? ? ?
$18,131,223
? ?
? ?
132
? ? ? BioMarin Pharmaceutical Inc. (“BioMarin”) ? ? ?
$18,119,133
? ?
? ?
133
? ? ?
The Allstate Corporation (“Allstate”)
? ? ?
$18,009,544
? ?
? ?
134
? ? ?
Crown Castle International Corp. (“CCI”)
? ? ?
$17,999,135
? ?
? ?
135
? ? ? Fidelity National Information Services, Inc. (“FIS”) ? ? ?
$17,905,009
? ?
74. Incongruously, Powers finds herself in the company of the CEOs of HCA (an $81 billion company with revenues of $51.5 billion in 2020), BioMarin (a $14 billion company with revenues of $1.86 billion in 2020), Allstate (a $35 billion company with revenues of $44.79 billion in 2020), CCI (a $74 billion company with revenues of $5.84 billion in 2020), and FIS (a $55 billion company with revenues of $12.5 billion in 2020). Leading a company with no revenues and that has not brought a product to commercialization during her 15-year tenure at the Company, Powers has no business being on this list at all.
Stockholders Have Not Been Told the Truth About the “True-Up” Awards
75. On April 16, 2021, Northwest Biotherapeutics filed the 2021 Proxy in connection with its 2021 Annual Meeting of Stockholders. SEC rules required the Company to disclose, among other things, the value and nature of any equity awards granted to its non-employee directors and named executive officers during the year ended December 31, 2020.
76. With respect to the non-employee Director awards, the 2021 Proxy provided no information other than the grant date fair value of the awards ($4,123,000 for Malik, $1,497,000 for Jasinowski, and $1,250,000 for Black). These numbers were included in a “Director Compensation” table, as required by SEC rules, showing the amount of “compensation” received by the non-employee directors in 2020. Accordingly, no one reading the 2021 Proxy (or any other public filing for that matter) has any idea what these enormous awards are all about.
77. Meanwhile, the disclosures regarding the awards to Powers and Goldman are affirmatively misleading. In a “Summary Compensation Table” required by SEC rules, the Company disclosed that Powers and Goldman received stock option awards valued at $17,317,000 and $10,548,000, respectively, during 2020.8 In an effort to downplay the amount of these awards, the 2021 Proxy stated that the stock options “were granted for employee performance during 2018, 2019 and 2020.” Of course, this is not true.
78. As described above, the 2018 Option Awards were designed to compensate Powers and Goldman for their 2018 and 2019 performance. More importantly, the minutes of the internal Board meetings do not
?
8 Boynton was not considered a “named executive officer,” and was not included in the Summary Compensation Table. Likewise, Boynton was not a “non-employee director,” and is not included in the “Director Compensation” table. Accordingly, the Director Defendants simply chose not to discuss the awards received by Boynton during 2020.
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indicate that there was any discussion of “employee performance during 2018, 2019, and 2020,” much less identify this as the basis for the True-Up Awards. The actual rationale the Individual Defendants used, i.e., the “true-up” nature of these awards, has not been disclosed at all.
79. Finally, another telling lack of “disclosure” is with respect to the Board’s decision not to present the non-employee Directors’ True-Up Awards for stockholder approval, as originally planned. Because the 2018 NED Option Awards were supported by a normal rationale (compensation) and covered a long period of time (eight years), the Board had no problem presenting these awards to the stockholders. But realizing there was no way to justify the True-Up Awards, the Director Defendants granted these awards and disclosed them (as they were required to do), but did not dare initially to seek the stockholders’ approval. After Plaintiff challenged these awards, the Director Defendants apparently changed their mind again.
The Board files a False and Misleading 2022 Proxy
80. On December 5, 2022, roughly two and a half years after the True-Up Awards were issued, the Company filed a Schedule 14A Definitive Proxy Statement (the “2022 Proxy”) in connection with the Company’s 2022 Annual Meeting of Stockholders (the “2022 Annual Meeting”), which is scheduled for December 30, 2022.
81. In Proposal 3 of the 2022 Proxy (“Proposal 3”), the Board is seeking stockholder “ratification” of the True-Up Awards granted to Powers, Goldman, and Boynton. Proposal 3 is titled: “RATIFICATION OF THE SAME OPTION AWARDS THAT WERE MADE IN 2020 TO THE NAMED EXECUTIVE OFFICERS AND FOR WHICH THE STOCKHOLDERS ALREADY VOTED IN FAVOR IN AN ADVISORY VOTE AT LAST YEAR’S ANNUAL MEETING.”
82. In Proposal 5 of the 2022 Proxy (“Proposal 5,” and collectively with Proposal 3, the “Proposals”), the Board is seeking stockholder “approval” of the True-Up Awards granted to Black, Jasinowski, and Malik. Proposal 5 is titled “APPROVAL OF PREVIOUSLY REPORTED 2020 OPTION AWARDS TO THE COMPANY’S INDEPENDENT DIRECTORS OF THE BOARD OF DIRECTORS.”
83. In determining whether to vote in favor or against the Proposals, a reasonable stockholder would need to know the consequences of his or her vote. The 2022 Proxy completely fails in this regard. There is no disclosure as to what will happen if either proposal is approved, nor is there any disclosure as to what will happen if either proposal is rejected. While the Individual Defendants undoubtedly want to preserve their options depending on how the votes turn out, this is not how voting works.
84. In determining whether to vote in favor or against the Proposals, a reasonable stockholder would find it important to know the purpose of the True-Up Awards. As reflected in the Company’s internal documents and as detailed above, the True-Up Awards were granted to the Individual Defendants to “offset the dilutive effects” on the 2018 Option Awards caused by the Financing Transactions in order to bring each of the Individual Defendants’ ownership stake in the Company back up to previous levels. Yet nowhere in the 2022 Proxy is this information disclosed, and for this reason alone the vote on the Proposals is not fully informed.
85. In the Proposals, the Board detailed the “factors and considerations” that were purportedly considered in granting the True-Up Awards. Specifically, with respect to the True-Up Awards to Powers, Goldman, and Boynton, which the 2022 Proxy refers to as the “2020 Executive Options,” the 2022 Proxy states in Proposal 3:
In 2020, as part of its evaluation and determination of the compensation for our executive officers, the Compensation Committee granted the 2020 Executive Options to our executive officers for service to the Company and progress achieved during the years 2018, 2019 and 2020.
Prior to receiving the 2020 Executive Options, our executive officers had not received any equity-based compensation since 2018, and those 2018 options were for service to the Company for years prior to 2018 as well as for 2018.
The 2020 Executive Options awards were based on a number of factors and considerations. These awards were determined after taking account of the years of service by our executive officers, the important progress achieved in the Company’s clinical programs and other operations (including major
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milestones in 2018 related to the Phase III trial of DCVax®-L for Glioblastoma), market factors, the need to retain the executives’ valuable service going forward (including for completion of the Phase III trial program which is key to the Company’s value) and our overall compensation philosophy.
For all of the above reasons, the Compensation Committee (which is composed solely of independent directors), and the independent members of the Board determined that the 2020 Executive Options were in best interests of the Company and our stockholders, and approved the 2020 Executive Options awarded to each of Ms. Powers, Mr. Goldman and Dr. Boynton.
86. With respect to the True-Up Awards for Black, Jasinowski, and Malik, which the 2022 Proxy refers to as the “2020 Director Options,” the 2022 Proxy states in Proposal 5:
The 2020 Director Options were based on a number of factors and considerations. One set of considerations was the extraordinary amount time, effort and support contributed by the independent directors throughout their years of service, including the years 2018, 2019 and 2020 that were covered by the option awards. The time and involvement of the Directors went far beyond the activities typically involved in Board service…
Another set of considerations for the 2020 Director Options was the extent of personal and professional risk our independent Directors have endured in serving on our Board. Our Company has experienced ongoing attacks from short sellers, and from bloggers whom the Company believes may be connected with short sellers… Further, our Company has been subjected to multiple lawsuits which we believe were and are vexatious and without merit, and which we have fought, and continue to fight, vigorously?—?but which have named our Directors personally and put them at personal risk…
Of special note, in addition to undertaking far more activities in support of the Company’s operations than would normally be expected of directors, enduring attacks and lawsuits, our independent Directors have also tolerated long delays in their cash compensation and have waited for as long as 6 years for the Company to implement their equity compensation. Our Directors have also provided personal loans to the Company when needed to help the Company survive, and allowed such loans to remain outstanding and unpaid long after they were due.
Finally, an additional consideration was the long period of years that the independent Directors have been serving and the valuable continuity that has afforded the Company.
For all of the above reasons, the 2020 Director Options were approved by the disinterested directors, subject to stockholder approval, and our management also strongly supports the 2020 Director Options.
87. The above disclosures are materially false and misleading. Each of the above discussions purport to disclose the “factors and considerations” that the True- Up Awards were based upon. The Board thus had a duty to make sure this list was complete and accurate. But missing from the list is, of course, the primary reason the True-Up Awards were approved as reflected in the Company’s internal documents?—?to offset the dilution caused by the Financing Transactions. Notably, each of the reasons provided in the 2022 Proxy were reasons that arguably weighed in favor of the True-Up Awards. But the Board affirmatively left out of this list a reason?—?indeed, the primary reason for the True-Up Awards?—?that undermined the fairness of the True-Up Awards. As a result, the vote on the Proposals is based on a materially misleading 2022 Proxy.
88. According to the above disclosures, one of the primary reasons for the lucrative size of the True-Up Awards was to compensate the Individual Defendants for three years of service?—?2018, 2019, and 2020. Certainly, to the extent this is true, a reasonable stockholder would find this information important in determining whether to approve the Proposals. But this statement is outright false. The minutes of the internal Board meetings produced in connection with the Demand do not indicate that there was any discussion by the Individual Defendants that they had not been adequately compensated for 2018, 2019, and 2020, much less identify this factor as the basis for the True-Up Awards. Moreover, as detailed above, when the Company granted the sizable 2018 Option Awards, it publicly disclosed that those awards were intended to compensate the Individual Defendants for their service “over the next approximately 2 years,” i.e., 2018 and 2019.
89. In a similar vein, the statement that, as of the time the True-Up Awards were granted in 2020, Black, Jasinowski, and Malik had been “waiting for as long as 6 years for the Company to implement their
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equity compensation” is also outright false. Black, Jasinowski, and Malik received the 2018 NED Option Awards just two years earlier in 2018 (which, as described above, were intended to compensate them for the prior six years and the following two years). The similar statement in the 2022 Proxy was simply copied from the 2018 Proxy in connection with the vote on the 2018 NED Option Awards. Indeed, virtually all of the “factors and considerations” detailed in the 2022 Proxy regarding the True-Up Awards to Black, Jasinowski, and Malik?—?including the attacks by short sellers, the personal and professional risk the directors face, and the extraordinary amount of time and effort they supposedly contribute to the Company?—?are copied almost verbatim from the 2018 Proxy in connection with the 2018 NED Option Awards. Rather than comply with their fiduciary duties and tell the stockholders the true purpose of the True-Up Awards, the Director Defendants believe they can simply trick stockholders into going along with approving this largesse by rehashing a laundry list of disclosures that pertained to past awards.
90. The 2022 Proxy also misleads stockholders into believing that the size of the True-Up Awards granted to Black, Jasinowski, and Malik was supported by peer analysis. As stated in Proposal 5: “In determining the independent directors’ compensation, we take into account market data and practices, and we evaluate and compare the nature and scope of responsibilities undertaken and contributions made by our independent directors in helping to support the Company and its operations compared with the typical directors’ roles in other companies.” But this disclosure is materially false. The internal documents produced in the Demand revealed that the Board did not look at any “market data and practices” whatsoever. And as described above, the size of the awards bore no relation to the compensation received by non-employee directors at the Company’s peers. Instead, as the Company’s internal documents revealed, the size of the True-Up Awards was not determined through an analysis of “market data and practices,” but was instead dictated by the amount necessary to satisfy the Individual Defendants’ desire to bring their ownership stake in the Company up to certain levels.
91. In Plaintiff’s Consolidated Verified Stockholder Derivative Complaint filed on June 8, 2022 (the “Complaint”), Plaintiff alleged, among other things, that the True-Up Awards were financially unfair to the Company and its stockholders and were granted through an unfair process in which all of the Directors were interested. Plaintiff is seeking, among other things, the cancellation and/or rescission of the True-Up Awards. In Proposal 3, the Board has asked stockholders to “ratify” the True-Up Awards granted to Powers, Goldman, and Boynton. Proper stockholder “ratification” of interested director action generally shifts the standard of review from entire fairness to the business judgment rule.
92. The “ratification” vote in Proposal 3 is legally deficient for at least three reasons. First, to have legal effect, “ratification” requires a fully informed vote of the stockholders, whereby stockholders are provided with accurate and complete disclosure of material information. And as described above, the 2022 Proxy failed in this regard.
93. Moreover, in addition to the disclosure deficiencies listed above, which are applicable to any stockholder vote, with respect to the concept of “ratification,” stockholders need also to be adequately informed regarding the allegations against the interested directors that the “ratification” vote is seeking to cleanse.
94. In this regard, Proposal 3 contains a single paragraph?—?three sentences long?—?“summar[izing]” this lawsuit.9 As stated in Proposal 3:
Summary of Lawsuit
In June 2022, an alleged stockholder filed a consolidated derivative lawsuit in the Delaware Court of Chancery against the Company, its individual directors and certain executives, seeking to have the 2020 Executive Options revoked and cancelled. Despite acknowledging that the 2020 Executive Options have already been approved by the Company’s Compensation Committee and independent Board members, and for which stockholders already voted in favor (with nearly 90% of the votes) in their advisory Say on Pay vote at last year’s Annual Meeting, the complaint still seeks to dispute the appropriateness of the 2020 Executive Options awarded to Ms. Powers, Mr. Goldman and Dr. Boynton.
?
9 Proposal 5 also relies on this summary as it states: “See Summary of Lawsuit under Proposal No. 3 above.”
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In addition, although the equity compensation to the Directors is subject to stockholder approval and the process for that approval has not yet taken place, the lawsuit also seeks to dispute the 2020 options to the independent directors.
95. To say the least, the Board’s summary of Plaintiff’s allegations?—?that Plaintiff “seeks to dispute” the “appropriateness” of the True-Up Awards?—?is not a complete and accurate disclosure of Plaintiff’s allegations. Indeed, even in this short description, the Board managed to make more materially false and misleading statements than accurate statements. For instance, Plaintiff does not “acknowledg[e]” that the True-Up Awards to Powers, Goldman, and Boynton were approved by “independent Board members.” To the contrary, Plaintiff alleged that the True-Up Awards were approved in a round-robin process in which each director was interested in the other directors’ awards. Nor did Plaintiff “acknowledg[e]” that “stockholders already voted in favor” of the True-Up Awards to Powers, Goldman, and Boynton. Given the advisory nature of the Say-on-Pay-Vote, Plaintiff’s position is that it has no bearing on what stockholders thought about the True-Up Awards. Nor did Plaintiff seek to challenge the True-Up Awards to Black, Jasinowski, and Malik despite the awards having been “subject to stockholder approval” all along. As the Complaint specifically alleged on the basis of the documents produced in connection with the Demand, the Individual Defendants had long abandoned that plan. To the extent the Individual Defendants wish to state their viewpoint on the True-Up Awards, they are of course free to do so. But in attributing these viewpoints to Plaintiff and describing them as having been alleged in the Complaint, the 2022 Proxy is materially false and misleading.
96. Second, under Delaware law, stockholder “ratification” will have legal effect only if stockholders are specifically told the consequences of their vote. As it applies here, the “consequences” of a favorable vote on Proposal 3 would be to provide business judgment rule protection for the True-Up Awards granted to Powers, Goldman, and Boynton, thus effectively extinguishing Plaintiff’s claims on these awards. Yet, the 2022 Proxy fails to disclose this consequence (or any consequences of a favorable vote). Nor does the 2022 Proxy disclose the “consequences” if the stockholders reject Proposal 3?—?for example, whether Powers, Goldman, and Boynton will return their True-Up Awards if Proposal 3 is rejected.
97. Third, stockholder “ratification” will have legal effect only if it is approved in a fully informed vote of disinterested stockholders. However, each of the Directors are being permitted to vote the shares of Northwest Biotherapeutics common stock they currently own on Proposal 3. As stated in the 2022 Proxy, approval of Proposal 3 “requires the affirmative vote of a majority of the votes cast at [the 2022] Annual Meeting.” And as further stated in the 2022 Proxy, all 1,052,853,960 shares of common stock outstanding as of October 31, 2022 will be “entitled to vote” at the 2022 Annual Meeting.
98. Finally, Proposal 3 is improperly structured, as it “bundles” together what should be separate proposals for Powers, Boynton, and Goldman. Stockholders may well have different views on the compensation awarded to Powers, Boynton, and Goldman, who are dissimilarly situated with respect to the True-Up Awards. Because stockholders are not being permitted to vote separately on these distinct matters, the vote on Proposal 3 is structurally unsound and no ratification effect can be achieved.
DEMAND FUTILITY ALLEGATIONS
99. Plaintiff realleges each allegation contained above as if set forth herein.
100. Plaintiff brings this action derivatively on behalf of Northwest Biotherapeutics to redress injuries suffered, and to be suffered, by the Company as a direct and proximate result of the Individual Defendants’ misconduct.
101. Plaintiff has owned Northwest Biotherapeutics stock continuously throughout the course of wrongful conduct and continues to hold Northwest Biotherapeutics common stock.
102. Plaintiff will adequately and fairly represent the interests of Northwest Biotherapeutics in enforcing and prosecuting its rights, and has retained counsel with substantial experience in stockholder derivative litigation.
103. At the time of this filing there are five directors on the Board: Black, Boynton, Jasinowski, Malik, and Powers (the “Current Board”). Each member of the Current Board has been named as a defendant in this action.
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104. Plaintiff did not make a demand on the Current Board prior to instituting this action because such a demand would be futile.
105. Each member of the Current Board, and therefore a majority of the Current Board, received the True-Up Awards. Each Current Board member thus has a strong financial incentive to refuse to authorize any corrective action that would involve the rescission, cancellation, or disgorgement of the True-Up Awards. Accordingly, because each member of the Current Board is interested in the True- Up Awards, none of them would be able to impartially consider a demand. Demand is therefore excused.
106. The True-Up Award that each Individual Defendant received cannot be separated for demand futility purposes from the True-Up Awards received by the other Individual Defendants. This is notwithstanding the Individual Defendants’ transparent attempt to separate the transaction by having the non-employee directors approve the awards for the executive directors and the executive directors approve the awards for the non-employee directors.
107. As described above, the True-Up Awards were, among other things, developed in the same tainted process, based on the same improper rationale, approved within days of each other (May 23rd and May 29th, 2020), and effectively constitute one transaction. Because each Individual Defendant received a True-Up Award, none of them would be able to impartially consider a demand seeking the rescission of another Individual Defendant’s True-Up Awards, as any attempt to do so would require them to question the fairness of their own award.
108. Moreover, as executives of the Company and with their principal source of income based on their employment with the Company, Powers and Boynton lack independence from the Company’s non-employee Directors (who are responsible for establishing the executive compensation program). In its 2021 Proxy, the Company acknowledges that Powers and Boynton are not independent. Accordingly, demand is excused as to Powers and Boynton for this reason as well.
CLASS ACTION ALLEGATIONS
109. Pursuant to Court of Chancery Rule 23, Plaintiff brings this action on his own behalf and as a class action on behalf of those who held Northwest Biotherapeutics stock as of the close of business on October 31, 2022, which is the record date for stockholders entitled to vote at the 2022 Annual Meeting, and who continue to hold shares through the present (the “Class”). The Individual Defendants are excluded from the Class, as are the Individual Defendants’ affiliates, immediate families, legal representatives, heirs, successors or assigns, and any entity in which the Individual Defendants have or had a controlling interest.
110. The action is properly maintainable as a class action.
111. The Class is so numerous that joinder of all members is impracticable. The Company had 1,052,853,970 shares of common stock outstanding and 972,700 shares of preferred stock outstanding as of October 31, 2022. While the exact number of Class members is unknown to Plaintiff at this time and can only be ascertained through discovery, there likely are thousands of members in the Class.
112. Questions of law and fact are common to the Class, including, inter alia, the following:
(i)
Whether the 2022 Proxy omits material information and/or includes materially false and misleading information in connection with the Proposals;
?
(ii)
Whether the Director Defendants breached their fiduciary duties by failing to disclose all material information and/or by presenting false and misleading information in connection with the Proposals;
?
(iii)
Whether the vote on Proposal 3 constitutes proper stockholder “ratification” under Delaware law; and
?
(iv)
Whether Plaintiff and other members of the Class have been or will be harmed by the wrongs complained of herein and, if so, what is the proper remedy.
?
113. Plaintiff is committed to prosecuting this action and has retained competent counsel experienced in litigation of this nature. Plaintiff’s claims are typical of the claims of other members of the Class and
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Plaintiff has the same interests as other members of the Class. Plaintiff is an adequate representative of the Class and will fairly and adequately protect the interests of the Class.
114. The prosecution of separate actions by individuals members of the Class would create the risk of inconsistent or varying adjudications with respect to individual members of the Class that would establish incompatible standards of conduct for the Director Defendants, or adjudications with respect to individual members of the Class that would as a practical matter be dispositive of the interests of the other members not parties to the adjudications or substantially impair their ability to protect their interests.
115. The Director Defendants have acted, or refused to act, on grounds that apply generally to the Class, and caused injury to the Class, such that final injunctive or declaratory relief is appropriate on behalf of the Class as a whole.
116. The questions of law and fact common to the members of the Class predominate over any questions affecting only its individual members, such that a class action is superior to any other available method for fairly and efficiently adjudicating the controversy.
COUNT I
Breach of Fiduciary Duty
(Derivative Claim Against the Individual Defendants)
117. Plaintiff re-alleges each allegation contained above as if set forth herein.
118. As directors and officers of the Company, each Individual Defendant owes fiduciary duties to the Company and its stockholders.
119. The Individual Defendants must prove the entire fairness of the True- Up Awards, which they awarded themselves in a conflicted transaction.
120. Defendants Black, Boynton, Jasinowski, Malik, and Powers breached their fiduciary duty of loyalty by granting themselves the improper and unfair True- Up Awards.
121. Defendant Goldman breached his fiduciary duty of loyalty by accepting the improper and unfair True-Up Awards.
122. As a result of the Individual Defendants’ actions, the Company has been and will be damaged.
123. Plaintiff, on behalf of the Company, has no adequate remedy at law.
COUNT II
Unjust Enrichment
(Derivative Claim Against the Individual Defendants)
124. Plaintiff re-alleges each allegation contained above as if set forth herein.
125. Each Individual Defendant received improper and unfair financial benefits as a result of the True-Up Awards.
126. It would be unconscionable and against fundamental principles of justice and equity for the Individual Defendants to retain the benefits of the improper and unfair True-Up Awards.
127. Plaintiff, on behalf of the Company, has no adequate remedy at law.
COUNT IIII
Breach of Fiduciary Duty
(Individual and Class Claim against the Director Defendants)
128. Plaintiff re-alleges each allegation contained above as if set forth herein.
129. The Director Defendants owe fiduciary duties to the Company’s stockholders, including the duty to speak truthfully when seeking stockholder action.
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130. The Director Defendants breached their fiduciary duty by causing the Company to issue the 2022 Proxy that omitted material information and contained materially false and misleading representations in connection with the vote on the Proposals.
131. As a result of the Directors Defendants’ breaches of fiduciary duty, Plaintiff and the Class are being, and will continue to be, harmed.
132. Plaintiff and the Class have no adequate remedy at law.
COUNT IV
(Individual and Class Claim Against the Company and the
Director Defendants for Declaratory Relief)
133. Plaintiff re-alleges each allegation above as if set forth in full herein.
134. In Proposal 3, the Director Defendants are seeking stockholder “ratification” of the True-Up Awards granted to Powers, Boynton, and Goldman.
135. To constitute legally binding “ratification,” the stockholder vote must, among other things, be a fully informed vote based on complete and accurate disclosures, stockholders must be told of the consequences of the “ratification,” and only disinterested stockholders may be permitted to vote. The vote on Proposal 3 fails in all three respects.
136. In addition, Proposal 3 is improperly structured, as it “bundles” together what should be separate proposals for Powers, Boynton, and Goldman. Stockholders may well have different views on the compensation awarded to Powers, Boynton, and Goldman, who are dissimilarly situated with respect to the True-Up Awards. Because stockholders are not being permitted to vote separately on these distinct matters, the vote on Proposal 3 is structurally unsound and no ratification effect can be achieved.
137. Plaintiff and the Class are entitled to a declaration that the vote on Proposal 3 does not constitute a legally binding “ratification” under Delaware law.
138. Plaintiff and the Class have no adequate remedy at law.
PRAYER FOR RELIEF
WHEREFORE, Plaintiff requests entry of an order of judgment as follows:
A. Finding that any demand upon the Current Board concerning the wrongdoing complained of herein would be futile;
B. Declaring this action, as to Counts III and IV, to be a properly maintained class action, and certifying Plaintiff as the Class representative and his counsel as Class counsel;
C. Finding that Defendants breached their fiduciary duty to the Company’s stockholders;
D. Rescinding, cancelling, and/or ordering disgorgement of the True-Up Awards, including all shares of Northwest Biotherapeutics common stock issued through any exercise of the True-Up Awards;
E. Finding that the 2022 Proxy omitted material information and contained materially false and misleading information in connection with the Proposals;
F. Declaring that the purported “ratification” vote on Proposal 3 does not constitute legally binding stockholder ratification under Delaware law;
G. Declaring the stockholder votes on the Proposals to be ineffective and invalid;
H. Awarding restitution and damages, including rescissory damages, against all Defendants in favor of the Company as a result of Defendants’ breaches of fiduciary duties, plus pre-judgment and post-judgment interest;
I. Awarding Plaintiff the costs and disbursements of this action, including reasonable allowance of fees and costs for Plaintiff’s attorneys, experts, and accountants; and
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J. Granting Plaintiff such other and further relief as the Court may deem just and proper.
A-18
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Dated: December 30, 2022
? ? ? ? SMITH, KATZENSTEIN & JENKINS LLP ?
? ? ? ?
/s/ David A. Jenkins
?
David A. Jenkins (No. 932)
Neal C. Belgam (No. 2721)
Jason Z. Miller (No. 6310)
1000 North West Street, Suite 1501
P.O. Box 410
Wilmington, DE 19899 (courier 19801)
daj@skjlaw.com
ncb@skjlaw.com
jzm@skjlaw.com
?
? ? ? ? Attorneys for Lead Plaintiff Glenn F. Schaeffer ?
Of Counsel:
Steven J. Purcell
Robert H. Lefkowitz
Anisha Mirchandani
PURCELL & LEFKOWITZ LLP
369 Lexington Avenue, Third Floor
New York, New York 10017
212-725-1000
A-19
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01 - Dr. Alton L. BoyntonFor Withhold1 U P X02 - Ambassador J. Cofer BlackNorthwest Biotherapeutics, Inc.Using a black ink pen, mark your votes with an X as shown in this example.Please do not write outside the designated areas.0404KD++Company Proposals — The Board of Directors recommends a vote FOR the nominees listed in Proposal A 1, and FOR Proposals 2 - 5.1. To elect two members to our Board of Directors to serve as Class I Directors for a term of three years:Please sign exactly as name(s) appears hereon. Joint owners should each sign. When signing as attorney, executor, administrator, corporate officer, trustee, guardian, or custodian, please give full title.Date (mm/dd/yyyy) — Please print date below. Signature 1 — Please keep signature within the box. Signature 2 — Please keep signature within the box.B Authorized Signatures — This section must be completed for your vote to be counted. — Date and Sign BelowqIF VOTING BY MAIL, SIGN, DETACH AND RETURN THE BOTTOM PORTION IN THE ENCLOSED ENVELOPE.qAnnual Meeting Proxy Card2. To ratify the appointment of Cherry Bekaert LLP as ourindependent registered public accounting firm for thefiscal year ending December 31, 2024;4. To ratify the same option awards that were made in 2020 tothe non-executive Directors on the Board of Directors, and thatwere previously reported and previously approved bystockholders at the 2022 Annual Meeting;For Against AbstainFor Against Abstain3. To ratify the same option awards that were made in 2020 tothe named executive officers and for which the stockholdersalready voted in favor in an advisory vote at the 2021 AnnualMeeting and in a ratification vote at the 2022 Annual Meeting;5. To approve, on an advisory basis, the Company’s executivecompensation; and6. To act upon such other matters as may properly come beforethe meeting or any adjournments or postponements thereof.For Against AbstainFor Against AbstainPRELIMINARY PROXY CARD - SUBJECT TO COMPLETION1234 5678 9012 345MMMMMMMMM 594836MR A SAMPLE (THIS AREA IS SET UP TO ACCOMMODATE140 CHARACTERS) MR A SAMPLE AND MR A SAMPLE ANDMR A SAMPLE AND MR A SAMPLE AND MR A SAMPLE ANDMR A SAMPLE AND MR A SAMPLE AND MR A SAMPLE ANDC 1234567890 J N TMMMMMMMMMMMMMMMMMMMIf no electronic voting,delete QR code and control #? ˜000001MR A SAMPLEDESIGNATION (IF ANY)ADD 1ADD 2ADD 3ADD 4ADD 5ADD 6ENDORSEMENT_LINE______________ SACKPACK_____________MMMMMMMMMMMMMMM C123456789000000000.000000 ext000000000.000000 ext000000000.000000 ext000000000.000000 ext000000000.000000 ext000000000.000000 extSave paper, time and money!Sign up for electronic delivery atwww.investorvote.com/NWBOPhoneCall toll free 1-800-652-VOTE (8683) withinthe USA, US territories and CanadaOnlineBefore the Meeting vote at www.investorvote.com/NWBO orscan the QR code - login details are located in the shadedbar below.You may vote online or by phone instead of mailing this card.Votes submitted electronically must bereceived by 1:00 AM Eastern Time, onJune 29, 2024.Your vote matters – here’s how to vote!
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Small steps make an impact.Help the environment by consenting to receive electronicdelivery, sign up at www.investorvote.com/NWBONotice of Annual Meeting of StockholdersSaturday, June 29, 2024 at 1:30 p.m. Eastern TimeProxy Solicited by Board of Directors for Annual MeetingLinda F. Powers and Leslie J. Goldman (the “Named Proxies”), or any of them, each with the power of substitution, are hereby authorized to represent andvote the shares of the undersigned, with all the powers which the undersigned would possess if personally present, at the Annual Meeting of Stockholdersof Northwest Biotherapeutics, Inc. to be held at 1:30 p.m. Eastern Time on Saturday, June 29, 2024 at the offices of Gibson, Dunn & Crutcher LLP,1050 Connecticut Avenue NW, 2nd floor, Washington, DC 20036, or at any postponement or adjournment thereof (including, if applicable, on any matter whichthe Board of Directors did not know would be presented at the Annual Meeting by a reasonable time before the proxy solicitation was made or for the electionof a person to the Board of Directors if any nominees named in Proposal 1 becomes unable or unavailable to serve).Shares represented by this proxy, when properly executed, will be voted in the manner directed herein. If a properly executed proxy is returned and no suchdirections are indicated, the Proxies will have authority to vote FOR the Class I Director nominees listed in Proposal 1, and FOR Proposals 2 - 5. In their discretion,the Named Proxies are authorized to vote upon such other matters that may properly come before the meeting or any adjournment or postponement thereof.(Items to be voted appear on reverse side.)Proxy — Northwest Biotherapeutics, Inc.qIF VOTING BY MAIL, SIGN, DETACH AND RETURN THE BOTTOM PORTION IN THE ENCLOSED ENVELOPE.qC Non-Voting Items++Change of Address — Please print new address below. Comments — Please print your comments below. Meeting AttendanceMark box to the right if youplan to attend the AnnualMeeting.The Annual Meeting of Stockholders of Northwest Biotherapeutics, Inc. will be held onSaturday, June 29, 2024 at 1:30 p.m. Eastern Time at the offices ofGibson, Dunn & Crutcher LLP, 1050 Connecticut Avenue NW, 2nd floor, Washington, DC 20036
Lykiri:
Sunday, May 26, 2024 8:10:22 AM
Les Goldman says "they are on track for accelerated approval (150- day assessment)" witch is new information.
We know that Northwest Biotherapeutics has requested the MHRA to allow the 150-day assessment route.
December 21, 2023
The MAA seeks approval for commercialization of DCVax-L for both newly diagnosed and recurrent glioblastoma (GBM). The application also requests to be considered under the MHRA’s rapid 150-day review pathway, which the agency has established for new medicines for serious unmet medical needs.
https://nwbio.com/northwest-biotherapeutics-announces-marketing-authorization-applications-submitted-uk-mhra-dcvax-l-glioblastoma/
The MHRA offers only a 150-day assessment timeline for all high-quality marketing authorisation applications (MAAs).
https://www.gov.uk/guidance/guidance-on-150-day-assessment-for-national-applications-for-medicines
I believe that Northwest Biotherapeutics' MAA is well-qualified as a high-quality market authorization application.
October 13, 2023
“The Company strongly believes that after so many years of work on the DCVax-L program, taking some additional time to help ensure that the full MAA package is as strong as it can be is especially important since the Company plans to submit applications to multiple regulators.
https://nwbio.com/northwest-biotherapeutics-provides-update-on-near-term-plans-for-submission-of-marketing-authorization-application/
+ Les Goldman comment regarding accelerated approval in the UK. (Summer 2020)
CHATgpt
The criteria for qualifying for the 150-day assessment route in the UK are designed to ensure that the applications submitted to the MHRA meet specific standards of quality, safety, and efficacy. Here are some key criteria that pharmaceutical companies typically need to fulfill in order to qualify for this expedited review route:
1. **Comprehensive Data:** Applicants must provide a thorough and well-documented set of data on the quality, safety, and efficacy of the drug. This includes results from preclinical studies, clinical trials, manufacturing processes, and stability testing.
2. **Adherence to Good Manufacturing Practices (GMP):** The drug manufacturing facilities must adhere to Good Manufacturing Practices to ensure the quality and consistency of the product. The MHRA may conduct inspections to verify compliance with GMP standards.
3. **Compliance with Regulatory Guidelines:** The MA application should demonstrate compliance with relevant regulatory guidelines and requirements set forth by the MHRA and the European Medicines Agency (EMA), where applicable. This includes submitting all necessary documentation and following standardized procedures.
4. **Innovative or High Medical Need:** Drugs that offer significant therapeutic benefits for patients or address unmet medical needs are often prioritized for the 150-day assessment route. Innovative therapies or those targeting rare diseases may qualify for expedited review.
5. **Early Engagement with the MHRA:** It is advisable for applicants to engage with the MHRA early in the drug development process to discuss regulatory requirements, potential challenges, and any specific considerations for the application. This proactive approach can help streamline the review process.
6. **Risk Management Plan:** The application should include a comprehensive risk management plan to identify, evaluate, and mitigate potential risks associated with the drug, including pharmacovigilance strategies for monitoring safety post-approval.
7. **Benefit-Risk Assessment:** The applicant must provide a detailed benefit-risk assessment that weighs the therapeutic benefits of the drug against potential risks to patient safety. This assessment is crucial for the MHRA to evaluate the overall suitability of the drug for marketing authorization.
By meeting these criteria and submitting a high-quality MA application that aligns with the requirements set by the MHRA, pharmaceutical companies can increase their chances of qualifying for the 150-day assessment route and benefit from the expedited regulatory review process. This pathway aims to facilitate timely access to safe and effective medicines for patients while upholding rigorous regulatory standards.
I believe that Northwest Biotherapeutics' MAA is well-qualified and received confirmation as a high-quality market authorization application. Additionally, on March 7, the Company received confirmation that they were allowed to pursue the 150-day accelerated route. IMO
CHATgpt
The timeline for receiving confirmation that your Marketing Authorization Application (MAA) qualifies for the 150-day assessment route after submission to the Medicines and Healthcare products Regulatory Agency (MHRA) can vary depending on various factors. However, in general, the process typically unfolds as follows:
1. **Validation of MAA:** Upon submission of the MAA to the MHRA, the initial step is the validation process. During validation, the MHRA reviews the application to ensure that it contains all the necessary information and documentation required for assessment. This step typically aims to confirm that the application is complete and meets the basic regulatory requirements.
2. **Notification of Validation:** Once the validation process is complete, the MHRA will notify the applicant that the MAA has been validated. This notification typically confirms that the application has met the initial validation requirements and is proceeding to the next stage of assessment.
3. **Qualification for the 150-Day Assessment Route:** Following validation, the MHRA will then assess the application to determine if it qualifies for the 150-day assessment route. This assessment involves evaluating whether the application meets the specific criteria for expedited review under the 150-day pathway, as discussed in the previous responses.
4. **Confirmation of Qualification:** If the MAA meets the criteria for the 150-day assessment route, the MHRA will inform the applicant that their application has been qualified for expedited review. This notification typically confirms that the application will be subject to the accelerated 150-day timeline for regulatory assessment.
The time between the initial validation of the MAA and confirmation of qualification for the 150-day assessment route can vary, but applicants can generally expect to receive communication from the MHRA within a few weeks to a couple of months, depending on the complexity of the application and the workload of the regulatory authority.
It is important for applicants to engage proactively with the MHRA during the submission process, seek clarification on any requirements or issues that may arise during validation, and maintain open communication to ensure a smooth transition to the expedited review pathway if the application qualifies for the 150-day assessment route.
Overall, while the specific timing of notifications may vary, the MHRA strives to provide timely and transparent communication throughout the regulatory review process to support efficient evaluation of MA applications and expedite access to new medicines for patients in the UK.
NWBO
Northwest Biotherapeutics Inc (QB)
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Form PRE 14A - Other preliminary proxy statements • Edgar (US Regulatory) • 05/22/2024 08:13:36 PM
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Form 8-K - Current report • Edgahyperopia
Re: Lykiri post# 694029
Sunday, May 26, 2024 8:09:30 PM
Post#
694185
of 694244
Lykiri, thanks for the thoughtful post. I agree that it’s likely that Northwest Bio’s marketing application was high quality, and did not require additional information to be requested from the MHRA, as stated in the 1st quarter report. I also agree that it is highly likely that the application has received priority review.
I personally don’t believe that we can deduce the exact timing of the final decision by the timing of the ASM, or anything that Les said, since the company will only have a general idea of where the MHRA is in the process (and because Les has not exactly been reliable about timing). It appears to me that they have passed the first assessment phase and are now somewhere in the second phase, but it is difficult to know how long this phase will take with the backlog of inspections, and understaffed inspectors at the MHRA. I say this because Les said that no negative disclosures were required in the quarterly report, and he was talking about scheduling site visits, which generally occur after the initial scientific assessment. The company may also be able to deduce where the MHRA is in the process, if their questions change from questions about the application itself, to questions about defining the label, (whether enough evidence was presented for the label to be broad - for all gliomas, or simply for nGBM and rGBM) and post-approval risk management plans, etc.
It seems somewhat irrelevant (to me) to be trying to determine exactly when the assessment started, and counting days in the 150-day assessment timeline when the MHRA hasn’t been close to completing a single assessment in this timeline that was established four years ago. Having said that - I personally don’t know what the second validation date of March 7th means, but I believe that it was determined on or by that date, that the application was complete, and of high quality, so no further information will be officially requested by the MHRA, and the application is entitled and “confirmed” to receive priority review.
I think that, for the purposes of the MHRA’s own timeline, (since they track this) the official assessment (and timeclock) started at the first MHRA validation date of January 24th. I believe that they intend to complete the assessment as soon as they can, but with backlogs, it may take more than 150 days. However, I’ve always hoped the MHRA could pull a rabbit out of its hat for Northwest Bio.
dstock07734
https://investorshub.advfn.com/boards/read_msg.aspx?message_id=174493875
Last year 42% of Merck's revenue came from Keytruda. Merck mentioned in its 10Q last August with one sentence about its subcutaneous keytruda, the one Merck will use to overcome the patent cliff issue.
KEYNOTE-A86, a study evaluating pembrolizumab subcutaneous versus pembrolizumab intravenous administered with platinum doublet chemotherapy in patients with metastatic squamous or nonsquamous NSCLC, met its dual primary endpoints and Merck anticipates disclosing details in the future.
According to the information on clinicltrials.gov, Merch finished its Study Protocol and Statistical Analysis Plan last July already. What could possibly make Merck slow in releasing PR on the p3 trial, having presentations at ACSO next week? I bet Merck investors will ask critical questions about SC keytruda given that two of its competitors already have PDUFA date assigned by FDA.
Keytruda’s sales accounted for 41.6% of Merck’s revenue in 2023 and 45% of its sales in the fourth quarter.
Who's No. 1? With $25B in sales, Merck's Keytruda looks to be the top-selling drug of 2023
https://www.fiercepharma.com/pharma/whos-no-1-25b-sales-mercks-keytruda-appears-set-be-top-selling-drug-2023
Study of Pembrolizumab (MK-3475) Subcutaneous (SC) Versus Pembrolizumab Intravenous (IV) Administered With Platinum Doublet Chemotherapy in Participants With Metastatic Squamous or Nonsquamous Non-Small Cell Lung Cancer (NSCLC) (MK-3475-A86)
https://classic.clinicaltrials.gov/ct2/show/NCT04956692?term=subcutaneous&lead=Merck&draw=2&rank=6
https://www.sec.gov/ix?doc=/Archives/edgar/data/310158/000162828023027770/mrk-20230630.htm
biosectinvestor
Re: dstock07734 post# 694195
Monday, May 27, 2024 7:34:42 AM
Thai doc, ChatGPT explaining it:
This document is an announcement from the Academic Services Center of Chulalongkorn University regarding the winner of a procurement bid. The announcement details the purchase of Hiltonol (Poly-IL) Injection for supporting a project focused on developing technology for producing Biosimilar Therapeutic Antibodies targeting the PD-1/PD-L1 Pathway for cancer immunotherapy. The project code is 962013, and the procurement was done through a specific method. The selected supplier is Oncovir, Inc., with a total bid price of 321,499.04 Thai Baht (321,499.04 Baht), subject to changes based on the exchange rate on the purchase date. The announcement was made on December 20, 2019.
dstock07734
Re: None
Sunday, May 26, 2024 9:43:26 PM
Post#
694195
of 694236
Mr. Vandermast, the president of Oncovir said the following.
“We have a drug master file with the FDA, and we have been in front of many of the world’s tier 1 regulatory agencies including the European Union Countries including France and Switzerland, in addition to Canada, Japan, Brazil and Thailand. Our product is going to be able to be used around the world. Our big push is to get funding so that we can support the development of Hiltonol with our partners and get commercialized in one therapeutic area.”
Found a document from Thailand which is related to poly-iclc. Can someone on this board read Thai?
MarauderWarlock33
Re: None
Sunday, May 26, 2024 2:18:23 PM
Post#
694151
of 694162
NWBO submitted MAA on DEC 20, 2023 to meet the CHM meeting on March 14,2024,
NWBO received MAA Validation Notice on Jan 20, 2024,
The Phase I 80 day review end on April 9, 2024,
If we don't receive RFI by then, Phase II will start from April 10, 2024 since RFI is issue in between Phases,
Phase II 70 day ends on June 20, 2024.
The assessment timetable will begin after validation of the application.
iii) Assessment process and expert advice
The assessment process includes consultation with the Commission on Human Medicines (CHM) on fixed dates each month.
The submission slots will be linked to the dates of CHM meetings.
The MHRA may additionally wish to seek advice/input from therapy area experts (specialty expert groups) during the assessment process.
The phases of the assessment process
The assessment process will run in two phases totalling 150 days
There will be an intervening clock-off period between phase I and phase II, if required.
Assessment phase I
This phase will be completed 80 days after the clock starts.
Issues arising/requiring clarification from the initial assessment will be raised with the applicant as a letter requesting further information (RFI) and should be addressed within the clock off period of 60 days.
Requests for extension of the clock off period for up to another 60 days may be granted exceptionally.
Applicants may contact the assessment team for discussing issues raised in the RFI letter.
Assessment in phase-I will also address eligibility for grant of orphan status.
Assessment phase II
This will commence on receipt of the applicant’s responses fro phase I.
Applicants are recommended to contact the MHRA Assessment Team in advance of the intended date of submission of response to align with CHM meetings.
Based on the assessment, the MHRA will provide a decision on approvability of the product by day 150.
iv) Appealing a decision to refuse
If the MHRA proposes to refuse to grant the MA based on advice from CHM, there is an opportunity for the applicant to request a review of the decision.
The procedure for such review is set out in Schedule 5, and paragraph 11 of Schedule 11, to the Human Medicines Regulations.
The MHRA decision letter will detail the appeal process and timelines.
The orphan status will be determined at the time of MA grant. If orphan status is not agreed and the company wishes to appeal this decision, the grant of a marketing authorisation will only be possible when the appeal process is completed.
v) Publication
Conclusion of the assessment will lead to the publication of a UK Public Assessment Report for the product.
MarauderWarlock33
Re: MarauderWarlock33 post# 694151
Sunday, May 26, 2024 3:56:22 PM
Post#
694162
of 694164
Base on this MHRA 150 day approval process guide line, RFI is generated during the CHM meeting. If no issues and concerns by the CHM board members during the meeting no RFI is need. Then MHRA can confirm the company that their MAA will be assess in 150 day approval process; therefore, in the last 10Q the company said there were no question, communication from MHRA which I take that as no RFI. By now MHRA should know if they can process the MAA in 150 days or not and should have been relay to the company. With this information, the company can set the date for ASM, maybe sign a licensing deal or two. AMO.
flipper44
Member Level
Re: ATLnsider post# 694104
Sunday, May 26, 2024 1:40:23 PM
Post#
694143
of 694164
I think lyriki is wrong on this, but I’m waiting for MHRA to get back to me.
What starts the clock?
1. Receipt of valid maa.
2. Notification maa passing review.
3. Confirmation of maa validation.
I lean towards #2.
Lykiri:Then is the MAA approval date 150 calendar days from 1/24/24, or 150 business days from 1/24/24? Thanks.A.E.K.
Re: None
Sunday, May 26, 2024 8:10:22 AM
Post#
694029
of 694129
May 9, 2024
Lykiri
Re: ATLnsider post# 694104
Sunday, May 26, 2024 1:19:32 PM
Post#
694137
of 694139
I don't believe that March 7th marked the end of the phase1 assessment process
It seems logical that the 150-day assessment period began on January 24, 2024, when the initial validation was confirmed. The March 7, 2024, confirmation likely served as an additional administrative check within the ongoing Phase 1 review process to ensure all documentation was in place and that the application was qualified for the 150-day assessment route.
Les Goldman says "they are on track for accelerated approval (150- day assessment)" witch is new information.
We know that Northwest Biotherapeutics has requested the MHRA to allow the 150-day assessment route.
December 21, 2023
The MAA seeks approval for commercialization of DCVax-L for both newly diagnosed and recurrent glioblastoma (GBM). The application also requests to be considered under the MHRA’s rapid 150-day review pathway, which the agency has established for new medicines for serious unmet medical needs.
https://nwbio.com/northwest-biotherapeutics-announces-marketing-authorization-applications-submitted-uk-mhra-dcvax-l-glioblastoma/
The MHRA offers only a 150-day assessment timeline for all high-quality marketing authorisation applications (MAAs).
https://www.gov.uk/guidance/guidance-on-150-day-assessment-for-national-applications-for-medicines
I believe that Northwest Biotherapeutics' MAA is well-qualified as a high-quality market authorization application.
October 13, 2023
“The Company strongly believes that after so many years of work on the DCVax-L program, taking some additional time to help ensure that the full MAA package is as strong as it can be is especially important since the Company plans to submit applications to multiple regulators.
https://nwbio.com/northwest-biotherapeutics-provides-update-on-near-term-plans-for-submission-of-marketing-authorization-application/
+ Les Goldman comment regarding accelerated approval in the UK. (Summer 2020)
CHATgpt
The criteria for qualifying for the 150-day assessment route in the UK are designed to ensure that the applications submitted to the MHRA meet specific standards of quality, safety, and efficacy. Here are some key criteria that pharmaceutical companies typically need to fulfill in order to qualify for this expedited review route:
1. **Comprehensive Data:** Applicants must provide a thorough and well-documented set of data on the quality, safety, and efficacy of the drug. This includes results from preclinical studies, clinical trials, manufacturing processes, and stability testing.
2. **Adherence to Good Manufacturing Practices (GMP):** The drug manufacturing facilities must adhere to Good Manufacturing Practices to ensure the quality and consistency of the product. The MHRA may conduct inspections to verify compliance with GMP standards.
3. **Compliance with Regulatory Guidelines:** The MA application should demonstrate compliance with relevant regulatory guidelines and requirements set forth by the MHRA and the European Medicines Agency (EMA), where applicable. This includes submitting all necessary documentation and following standardized procedures.
4. **Innovative or High Medical Need:** Drugs that offer significant therapeutic benefits for patients or address unmet medical needs are often prioritized for the 150-day assessment route. Innovative therapies or those targeting rare diseases may qualify for expedited review.
5. **Early Engagement with the MHRA:** It is advisable for applicants to engage with the MHRA early in the drug development process to discuss regulatory requirements, potential challenges, and any specific considerations for the application. This proactive approach can help streamline the review process.
6. **Risk Management Plan:** The application should include a comprehensive risk management plan to identify, evaluate, and mitigate potential risks associated with the drug, including pharmacovigilance strategies for monitoring safety post-approval.
7. **Benefit-Risk Assessment:** The applicant must provide a detailed benefit-risk assessment that weighs the therapeutic benefits of the drug against potential risks to patient safety. This assessment is crucial for the MHRA to evaluate the overall suitability of the drug for marketing authorization.
By meeting these criteria and submitting a high-quality MA application that aligns with the requirements set by the MHRA, pharmaceutical companies can increase their chances of qualifying for the 150-day assessment route and benefit from the expedited regulatory review process. This pathway aims to facilitate timely access to safe and effective medicines for patients while upholding rigorous regulatory standards.
I believe that Northwest Biotherapeutics' MAA is well-qualified and received confirmation as a high-quality market authorization application. Additionally, on March 7, the Company received confirmation that they were allowed to pursue the 150-day accelerated route. IMO
CHATgpt
The timeline for receiving confirmation that your Marketing Authorization Application (MAA) qualifies for the 150-day assessment route after submission to the Medicines and Healthcare products Regulatory Agency (MHRA) can vary depending on various factors. However, in general, the process typically unfolds as follows:
1. **Validation of MAA:** Upon submission of the MAA to the MHRA, the initial step is the validation process. During validation, the MHRA reviews the application to ensure that it contains all the necessary information and documentation required for assessment. This step typically aims to confirm that the application is complete and meets the basic regulatory requirements.
2. **Notification of Validation:** Once the validation process is complete, the MHRA will notify the applicant that the MAA has been validated. This notification typically confirms that the application has met the initial validation requirements and is proceeding to the next stage of assessment.
3. **Qualification for the 150-Day Assessment Route:** Following validation, the MHRA will then assess the application to determine if it qualifies for the 150-day assessment route. This assessment involves evaluating whether the application meets the specific criteria for expedited review under the 150-day pathway, as discussed in the previous responses.
4. **Confirmation of Qualification:** If the MAA meets the criteria for the 150-day assessment route, the MHRA will inform the applicant that their application has been qualified for expedited review. This notification typically confirms that the application will be subject to the accelerated 150-day timeline for regulatory assessment.
The time between the initial validation of the MAA and confirmation of qualification for the 150-day assessment route can vary, but applicants can generally expect to receive communication from the MHRA within a few weeks to a couple of months, depending on the complexity of the application and the workload of the regulatory authority.
It is important for applicants to engage proactively with the MHRA during the submission process, seek clarification on any requirements or issues that may arise during validation, and maintain open communication to ensure a smooth transition to the expedited review pathway if the application qualifies for the 150-day assessment route.
Overall, while the specific timing of notifications may vary, the MHRA strives to provide timely and transparent communication throughout the regulatory review process to support efficient evaluation of MA applications and expedite access to new medicines for patients in the UK.
ATLnsider
Re: Lykiri post# 694029
Sunday, May 26, 2024 12:11:53 PM
Post#
694104
of 694139
Thanks Lykiri! Do you also believe that March 7th marked the end of the DCVax-L MAA Phase 1 assessment period, and the start of the 80-Day Phase 2 assessment period?
Bullish
BULLISH
NWBO
Northwest Biotherapeutics Inc (QB)
Re: None
Sunday, May 26, 2024 8:10:22 AM
Post#
694029
of 694139
May 9, 2024
Les Goldman says "they are on track for accelerated approval (150- day assessment)" witch is new information.
We know that Northwest Biotherapeutics has requested the MHRA to allow the 150-day assessment route.
December 21, 2023
The MAA seeks approval for commercialization of DCVax-L for both newly diagnosed and recurrent glioblastoma (GBM). The application also requests to be considered under the MHRA’s rapid 150-day review pathway, which the agency has established for new medicines for serious unmet medical needs.
https://nwbio.com/northwest-biotherapeutics-announces-marketing-authorization-applications-submitted-uk-mhra-dcvax-l-glioblastoma/
The MHRA offers only a 150-day assessment timeline for all high-quality marketing authorisation applications (MAAs).
https://www.gov.uk/guidance/guidance-on-150-day-assessment-for-national-applications-for-medicines
I believe that Northwest Biotherapeutics' MAA is well-qualified as a high-quality market authorization application.
October 13, 2023
“The Company strongly believes that after so many years of work on the DCVax-L program, taking some additional time to help ensure that the full MAA package is as strong as it can be is especially important since the Company plans to submit applications to multiple regulators.
https://nwbio.com/northwest-biotherapeutics-provides-update-on-near-term-plans-for-submission-of-marketing-authorization-application/
+ Les Goldman comment regarding accelerated approval in the UK. (Summer 2020)
CHATgpt
The criteria for qualifying for the 150-day assessment route in the UK are designed to ensure that the applications submitted to the MHRA meet specific standards of quality, safety, and efficacy. Here are some key criteria that pharmaceutical companies typically need to fulfill in order to qualify for this expedited review route:
1. **Comprehensive Data:** Applicants must provide a thorough and well-documented set of data on the quality, safety, and efficacy of the drug. This includes results from preclinical studies, clinical trials, manufacturing processes, and stability testing.
2. **Adherence to Good Manufacturing Practices (GMP):** The drug manufacturing facilities must adhere to Good Manufacturing Practices to ensure the quality and consistency of the product. The MHRA may conduct inspections to verify compliance with GMP standards.
3. **Compliance with Regulatory Guidelines:** The MA application should demonstrate compliance with relevant regulatory guidelines and requirements set forth by the MHRA and the European Medicines Agency (EMA), where applicable. This includes submitting all necessary documentation and following standardized procedures.
4. **Innovative or High Medical Need:** Drugs that offer significant therapeutic benefits for patients or address unmet medical needs are often prioritized for the 150-day assessment route. Innovative therapies or those targeting rare diseases may qualify for expedited review.
5. **Early Engagement with the MHRA:** It is advisable for applicants to engage with the MHRA early in the drug development process to discuss regulatory requirements, potential challenges, and any specific considerations for the application. This proactive approach can help streamline the review process.
6. **Risk Management Plan:** The application should include a comprehensive risk management plan to identify, evaluate, and mitigate potential risks associated with the drug, including pharmacovigilance strategies for monitoring safety post-approval.
7. **Benefit-Risk Assessment:** The applicant must provide a detailed benefit-risk assessment that weighs the therapeutic benefits of the drug against potential risks to patient safety. This assessment is crucial for the MHRA to evaluate the overall suitability of the drug for marketing authorization.
By meeting these criteria and submitting a high-quality MA application that aligns with the requirements set by the MHRA, pharmaceutical companies can increase their chances of qualifying for the 150-day assessment route and benefit from the expedited regulatory review process. This pathway aims to facilitate timely access to safe and effective medicines for patients while upholding rigorous regulatory standards.
I believe that Northwest Biotherapeutics' MAA is well-qualified and received confirmation as a high-quality market authorization application. Additionally, on March 7, the Company received confirmation that they were allowed to pursue the 150-day accelerated route. IMO
CHATgpt
The timeline for receiving confirmation that your Marketing Authorization Application (MAA) qualifies for the 150-day assessment route after submission to the Medicines and Healthcare products Regulatory Agency (MHRA) can vary depending on various factors. However, in general, the process typically unfolds as follows:
1. **Validation of MAA:** Upon submission of the MAA to the MHRA, the initial step is the validation process. During validation, the MHRA reviews the application to ensure that it contains all the necessary information and documentation required for assessment. This step typically aims to confirm that the application is complete and meets the basic regulatory requirements.
2. **Notification of Validation:** Once the validation process is complete, the MHRA will notify the applicant that the MAA has been validated. This notification typically confirms that the application has met the initial validation requirements and is proceeding to the next stage of assessment.
3. **Qualification for the 150-Day Assessment Route:** Following validation, the MHRA will then assess the application to determine if it qualifies for the 150-day assessment route. This assessment involves evaluating whether the application meets the specific criteria for expedited review under the 150-day pathway, as discussed in the previous responses.
4. **Confirmation of Qualification:** If the MAA meets the criteria for the 150-day assessment route, the MHRA will inform the applicant that their application has been qualified for expedited review. This notification typically confirms that the application will be subject to the accelerated 150-day timeline for regulatory assessment.
The time between the initial validation of the MAA and confirmation of qualification for the 150-day assessment route can vary, but applicants can generally expect to receive communication from the MHRA within a few weeks to a couple of months, depending on the complexity of the application and the workload of the regulatory authority.
It is important for applicants to engage proactively with the MHRA during the submission process, seek clarification on any requirements or issues that may arise during validation, and maintain open communication to ensure a smooth transition to the expedited review pathway if the application qualifies for the 150-day assessment route.
Overall, while the specific timing of notifications may vary, the MHRA strives to provide timely and transparent communication throughout the regulatory review process to support efficient evaluation of MA applications and expedite access to new medicines for patients in the UK.
Roman516 : Thanks for your important post on Memorial Day weekend.Below are three links which I posted on my family blog this morning. jhpratt@alphavestcapital.com .A.E.K.
sentiment_stocks: Since everybody knows from multiple Twitter postings that the MHRA considers the MAA to be perfect, and that inspections began before 5/1/24, where does that put your estimate of final MAA approval ? Sorry, I have seen no Twitter postings as to how long the inspection process takes.
A.E.K.
Member Level
Re: manibiotech post# 694051
Sunday, May 26, 2024 10:49:49 AM
Post#
694063
of 694085
Lykiri has indicated in a more recent post (that I hadn’t read yet) that he thinks the process began on 1/24. So doesn’t 150 days (without a clock off) take us sometime into later June?
So perhaps we’ll have an MHRA answer before the ASM… and if there was an RFI given after the Q, perhaps instead they’ll be in clock off. I would think, then, that we’ll at least get an update of the application assessment (where it is in the process) by the company at the ASM.
Lykiri
Re: StonkMaster post# 694035
Sunday, May 26, 2024 10:00:29 AM
Post#
694046
of 694093
StonkMaster,
I believe the 150-day assessment begane on Jan.24
IMO, it doesn't make sense to suggest that the 150-day assessment would begin on March 7, given that the standard process typically takes 210 days. Starting the rapid assessment 43 days after the validation confirmation would unnecessarily delay the process. It is logical to conclude that the 150-day assessment began on January 24, when the MAA initially passed validation.
CHATgpt:
The 150-day assessment route for Northwest Biotherapeutics' Marketing Authorization Application (MAA) for DCVax-L would start after the application passes validation. According to the information you provided:
- The MAA was filed on December 20, 2023.
- The company received notification on January 24, 2024, that the MAA had passed validation.
- On March 7, 2024, the company received confirmation of this validation.
The critical date here is January 24, 2024, when the company was first notified that the MAA had passed validation. This is typically when the regulatory review period, including any expedited assessment routes like the 150-day assessment, would begin. Therefore, the 150-day assessment route would start from January 24, 2024.
Re: StonkMaster post# 694035
Sunday, May 26, 2024 10:00:29 AM
Post#
694046
of 694079
StonkMaster,
I believe the 150-day assessment begane on Jan.24
IMO, it doesn't make sense to suggest that the 150-day assessment would begin on March 7, given that the standard process typically takes 210 days. Starting the rapid assessment 43 days after the validation confirmation would unnecessarily delay the process. It is logical to conclude that the 150-day assessment began on January 24, when the MAA initially passed validation.
CHATgpt:
The 150-day assessment route for Northwest Biotherapeutics' Marketing Authorization Application (MAA) for DCVax-L would start after the application passes validation. According to the information you provided:
- The MAA was filed on December 20, 2023.
- The company received notification on January 24, 2024, that the MAA had passed validation.
- On March 7, 2024, the company received confirmation of this validation.
The critical date here is January 24, 2024, when the company was first notified that the MAA had passed validation. This is typically when the regulatory review period, including any expedited assessment routes like the 150-day assessment, would begin. Therefore, the 150-day assessment route would start from January 24, 2024.
JFR161162
Re: alphapuppy post# 693510
Thursday, May 23, 2024 10:01:38 AM
Post#
693513
of 694077
I’m quite certain we’ll have big news soon.
The impact of the news on the stock price may change my opinion.
If I’m wrong and they don’t make announcement(s), it’s a NO for sure.
Here what ChapGPT says about the proxy
“In the United States, public companies are required to distribute proxy materials to shareholders ahead of the annual shareholder meeting (ASM). According to the rules set by the Securities and Exchange Commission (SEC), companies must send proxy statements at least 40 calendar days before the meeting date if the proxy materials are being delivered electronically (under the Notice and Access model). This model allows companies to provide shareholders with a notice of availability of the proxy materials online, rather than sending the full set of materials by mail immediately.
If a company chooses not to use the Notice and Access model and instead sends the full set of proxy materials by mail, they typically need to do so at least 30 days before the meeting.
These timelines ensure that shareholders have adequate time to review the materials and make informed voting decisions on the matters to be addressed at the ASM.”
Re: JFR161162 post# 693505
Thursday, May 23, 2024 9:55:38 AM
Post#
693510
of 694076
Yes, I agree. It’s a vote no for me. It’s just when I look at the numbers they are so enormous.
I know Linda is very knowledgeable and very valuable and has indeed saved the company but she does make $1 million a year and that’s a lot of money; but you look at these option warrants and I added them all up and it was something like 150 million shares or about 10% of the company. Doesn’t look like as much at these price levels but if we get any appreciation literally it’s $1 billion stock option award. Kind of like Musk.
So in the end, I think that’s a little much quite a little too much. I did like that. There was a price on them that they weren’t free. I just don’t like how many they’re getting. I think they’re do some however it’s just who decided that it was this enormous number?
IS THIS THE ONLY RECRUITNG TRIAL IN THE US WHERE ONE CAN GET DC VAX L,KEYTRUDA,AND POLY IC LC?
RECRUITING
Pembrolizumab and a Vaccine (ATL-DC) for the Treatment of Surgically Accessible Recurrent Glioblastoma
ClinicalTrials.gov ID NCT04201873
Sponsor Jonsson Comprehensive Cancer Center
Information provided by Jonsson Comprehensive Cancer Center (Responsible Party)
Last Update Posted 2024-05-02
This phase I trial studies the side effects and how well of pembrolizumab and a vaccine therapy (ATL-DC vaccine) work in treating patients with glioblastoma that has come back (recurrent) and can be removed by surgery (surgically accessible). Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Vaccines, such as ATL-DC vaccine, may help the body build an effective immune response to kill tumor cells. Giving pembrolizumab and ATL-DC vaccine may work better in treating patients with glioblastoma compared to ATL-DC alone.
Detailed Description
PRIMARY OBJECTIVES:
I. To evaluate the influence of pembrolizumab on the cell cycle-related genetic signature within the tumor microenvironment of progressive/recurrent glioblastoma.
II. To evaluate the influence of adjuvant autologous tumor lysatepulsed dendritic cell (ATL-DC) vaccination on peripheral T cell responses.
III. To evaluate the safety and tolerability of pembrolizumab and ATL-DC vaccination in progressive/recurrent glioblastoma.
SECONDARY OBJECTIVES:
I. To estimate the 6 month progression-free survival (PFS6) based on Response Assessment in Neuro-Oncology (RANO) criteria in patients treated on both arms of the clinical trial.
II. To calculate the overall survival of recurrent glioblastoma patients treated on both arms of the clinical trial.
EXPLORATORY OBJECTIVES:
I. To evaluate the associations between exploratory biomarkers, clinical outcomes, and adverse events which include:
Ia. Estimating the correlation of quantitative assessments of tumor infiltrating lymphocyte (TIL) density or the interferon (IFN) gamma-associated genetic signature with clinical responses to pembrolizumab and ATL-DC in recurrent glioblastoma patients.
Ib. Estimating the efficacy of pembrolizumab and ATL-DC through PFS6, PFS and overall survival (OS) as defined by RANO.
Ic. Estimating the efficacy of pembrolizumab and ATL-DC through PFS6, PFS, and OS as defined by immunotherapy RANO (iRANO).
Id. Exploring whether oligoclonal T cell populations within tumor tissue are similarly expanded in peripheral blood after ATL-DC vaccination and/or pembrolizumab, and correlating with clinical responses.
Ie. Exploring whether changes in specific magnetic resonance imaging (MRI) parameters correlate with tumor and peripheral blood immune responses.
OUTLINE: Patients are randomized to 1 of 2 groups.
GROUP A: Beginning 14 days prior to scheduled surgery, patients receive pembrolizumab intravenously (IV) over 30 minutes. After surgery, patients receive pembrolizumab IV over 30 minutes on day 1. Cycle repeats every 3 weeks in the absence of disease progression or unacceptable toxicity. Patients also receive ATL-DC intradermally (ID) with poly ICLC intramuscularly (IM) every 2 weeks for up to 3 doses in the absence of disease progression or unacceptable toxicity.
GROUP B: Beginning 14 days prior to scheduled surgery, patients receive placebo IV. After surgery, patients receive placebo IV on day 1. Cycle repeats every 3 weeks in the absence of disease progression or unacceptable toxicity. Patients also receive ATL-DC ID with poly ICLC IM every 2 weeks for up to 3 doses in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days and then every 3 months thereafter.
Show more
Official Title
Phase I Surgical Trial to Evaluate Early Immunologic Pharmacodynamic Parameters for the PD-1 Antibody Pembrolizumab With Autologous Tumor Lysate-Pulsed Dendritic Cell Vaccination in Patients With Surgically Accessible Recurrent/Progressive Glioblastoma
Conditions
Recurrent Glioblastoma
Intervention / Treatment
Biological: Dendritic Cell Tumor Cell Lysate Vaccine
Biological: Pembrolizumab
Other: Placebo Administration
Drug: Poly ICLC
Other Study ID Numbers
19-001090
NCI-2019-07994 ( Registry Identifier ) (REGISTRY: CTRP (Clinical Trial Reporting Program))
19-001090 ( Other Identifier ) (OTHER: UCLA / Jonsson Comprehensive Cancer Center)
Study Start (Actual)
2020-01-08
Primary Completion (Estimated)
2024-08-01
Study Completion (Estimated)
2025-08-01
Enrollment (Estimated)
40
Study Type
Interventional
Phase
Phase 1
Resource links provided by the National Library of Medicine
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Contact
Name: Quan Li, Ph.D.
Phone Number:
310 825-1416
Email: quanli@mednet.ucla.edu
Study Contact Backup
Name: Emese Filka
Phone Number:
3107943521
Email: efilka@mednet.ucla.edu
United States
California Locations
Los Angeles, California, United States, 90095
RecruitingQuan
Contact:
Quan li, Ph.D.
310-825-1416 quanli@mednet.ucla.edu
Contact:
Emese Filka
3107943521 efilka@mednet.ucla.edu
Principal Investigator:
Timothy F. Cloughesy
Click to view interactive map
Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
For general information about clinical research, read Learn About Studies.
Eligibility Criteria
Description
Inclusion Criteria:
Participants with histologically confirmed diagnosis of surgically accessible recurrent/progressive glioblastoma will be enrolled in this study
Be at first or second relapse (Note: relapse is defined as progression following initial therapy, i.e., radiation +/- chemotherapy. For participants who had prior therapy for a low-grade glioma, the surgical diagnosis of a high-grade glioma will be considered the first relapse)
Must be undergoing surgery that is clinically indicated, and eligible for resection with the expectation that the surgeon is able to resect at least 2 gram of tumor for lysate and research with low risk of inducing neurological injury
A male participant must agree to use a contraception during the treatment period and for at least 120 days after the last dose of study treatment and refrain from donating sperm during this period
A female participant who has childbearing potential must have negative urine or serum pregnancy test 72 hrs prior to the first dose and be willing to use adequate method of contraception for course of study and 120 days after last dose
The participant (or legally acceptable representative if applicable) provides written informed consent for the trial
Have unequivocal evidence for contrast enhancing tumor progression by RANO criteria based on MRI scan within 14 days prior to randomization
Have a minimum tumor size of 2 x 2 cm^2 based on MRI scan prior to surgery
An interval of the following durations prior to randomization:
At least 28 days from prior surgical resection
At least 7 days from prior stereotactic biopsy
At least 12 weeks from prior radiotherapy, unless there is unequivocal histologic confirmation of tumor progression
At least 23 days from prior chemotherapy
At least 42 days from nitrosureas
Have sufficient archival tumor tissue confirming glioblastoma or variants for submission following registration. The following amount of tissue is required: 1 formalin-fixed, paraffin embedded (FFPE) tissue block (preferred) or 10 FFPE ,unstained slides (5um thick)
Have a Karnofsky performance status (KPS) >= 70
Absolute neutrophil count (ANC) >= 1500/uL (uL=microliter) (collected within 14 days prior to the start of study treatment)
Platelets >= 100 000/uL (collected within 14 days prior to the start of study treatment)
Hemoglobin >= 9.0 g/dL or >= 5.6 mmol/L (collected within 14 days prior to the start of study treatment)
Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks
Creatinine =< 1.5 x upper limit of normal (ULN) OR measured or calculated creatinine clearance >= 30 mL/min for participant with creatinine levels > 1.5 x institutional ULN (collected within 14 days prior to the start of study treatment) (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl])
Creatinine clearance (CrCl) should be calculated per institutional standard
Total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for participants with total bilirubin levels > 1.5 x ULN (collected within 14 days prior to the start of study treatment)
Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT[) =< 2.5 x ULN (=< 5 x ULN for participants with liver metastases) (collected within 14 days prior to the start of study treatment)
International normalized ratio (INR) OR prothrombin time (PT) =< 1.5 x ULN unless participant is receiving anticoagulant therapy as long as PT or activated partial thromboplastin time (aPTT) is within therapeutic range of intended use of anticoagulants (collected within 14 days prior to the start of study treatment)
aPTT =< 1.5 x ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants (collected within 14 days prior to the start of study treatment)
Exclusion Criteria:
A woman of childbearing potential (WOCBP) who has a positive urine pregnancy test within 72 hours prior to randomization. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX-40, CD137)
Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to randomization
Note: Participants must have recovered from all adverse events (AEs) due to previous therapies to =< grade 1 or baseline. Participants with =< grade 2 neuropathy may be eligible
Note: If participant received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment
Has received prior radiotherapy within 2 weeks of start of study treatment. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (=< 2 weeks of radiotherapy) to non-central nervous system (CNS) disease
Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus calmette-guerin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist) are live attenuated vaccines and are not allowed
Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment
Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent
Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug
Has a known additional malignancy that is progressing or has required active treatment within the past 3 years
Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g. breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded
Has known tumor primarily localized to the brainstem or spinal cord
Has severe hypersensitivity (>= grade 3) to pembrolizumab and/or any of its excipients
Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
Has an active infection requiring systemic therapy
Has a known history of human immunodeficiency virus (HIV)
Has a known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known active hepatitis C virus (defined as hepatitis C virus [HCV] ribonucleic acid [RNA] is detected) infection. Note: no testing for hepatitis B and hepatitis C is required unless mandated by local health authority
Has a known history of active TB (Bacillus tuberculosis)
Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment
Show more
Ages Eligible for Study
18 Years and older (Adult, Older Adult )
Sexes Eligible for Study
All
Accepts Healthy Volunteers
No
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
Expand all / Collapse all
How is the study designed?
What is the study measuring?
Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Sponsor
Jonsson Comprehensive Cancer Center
Collaborators
National Cancer Institute (NCI)
Merck Sharp & Dohme LLC
Phase One Foundation
Oncovir, Inc.
Investigators
Principal Investigator:Timothy F Cloughesy,UCLA / Jonsson Comprehensive Cancer Center
Publications
The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.
General Publications
No publications available
* Find Publications about Study Results and related Pubmed Publications in the “Results” section of the study record.
Study Record Dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Registration Dates
First Submitted
2019-12-12
First Submitted that Met QC Criteria
2019-12-13
First Posted
2019-12-17
Study Record Updates
Last Update Submitted that met QC Criteria
2024-05-01
Last Update Posted
2024-05-02
Last Verified
2024-05
dstock07734
Friday, May 24, 2024 10:49:31 PM
693897
I agree with you.
Recall that some powerful players forced Al Musella to take down Dr. Liau's webinar video twice. A NWBO investor uploaded the video to Youtube and the video has been shadow blocked. Given that Merck spent $2.3b on advertising last year, I always have suspicion that Merck could be the one which forced Musella to take down the video and Merck could also be the one which has been colluding with the dark forces to suppress the sp. Think about this. With the publication of the Nature article in which it was specifically mentioned that the trial used the vaccine licensed by NWBO, everyone would know that the results presented by Dr. Liau were from the technology licensed by NWBO too if the video were visible to the public, which certainly brings more competitors.
Now two of Merck's competitors already filed for the approval of subcutaneous checking point inhibitors. I tend to believe that Merck's results are not as good as those of the two competitors. Otherwise Merck would have been singing like a canary quite a while ago. I suspect Merck should be under pressure now to show its investors that there is no such issue as patent cliff.
The following is about the PDUFA for BMY and Roche on their subcutaneous checking point inhibitors.
FDA moved the PDUFA date of BMY subcutaneous Opdivo from February 28, 2025 to December 29, 2024. Roche subcutaneous PDUFA is September 15, 2024.
Bristol Myers Squibb (NYSE: BMY) today announced that the U.S. Food and Drug Administration (FDA) has reassigned the previously announced Prescription Drug User Fee Act (PDUFA) goal date of the Biologics License Application (BLA) for the subcutaneous formulation of Opdivo ® (nivolumab) co-formulated with Halozyme’s proprietary recombinant human hyaluronidase (rHuPH20) (herein referred to as “subcutaneous nivolumab”) across all previously approved adult, solid tumor Opdivo indications as monotherapy, monotherapy maintenance following completion of Opdivo plus Yervoy (ipilimumab) combination therapy, or in combination with chemotherapy or cabozantinib. The updated goal date is December 29, 2024.
https://news.bms.com/news/details/2024/Bristol-Myers-Squibb-Announces-Updated-Action-Date-by-the-U.S.-Food-and-Drug-Administration-for-Subcutaneous-Nivolumab-nivolumab-and-hyaluronidase/default.aspx
https://news.bms.com/news/corporate-financial/2024/U.S.-Food-and-Drug-Administration-Accepts-Bristol-Myers-Squibbs-Application-for-Subcutaneous-Nivolumab-nivolumab-and-hyaluronidase/default.aspx
https://www.reddit.com/r/NWBO/comments/1cr272z/big_news_week_in_review_nwbo/
There has been a lot of new information in the last two weeks. There have been three SEC filings and a publication of the UCLA ran Phase II trial on Nature.com.
Lets start with the Phase II study. https://www.nature.com/articles/s41467-024-48073-y
“TLR agonists polarize interferon responses in conjunction with dendritic cell vaccination in malignant glioma: a randomized phase II Trial”
This study was performed by the UCLA team (Linda Liau and Robert Prinz et al) from September 2010 to August 2024. I will post the abstract here, and emphasis is mine.
“In this randomized phase II clinical trial, we evaluated the effectiveness of adding the TLR agonists, poly-ICLC or resiquimod, to autologous tumor lysate-pulsed dendritic cell (ATL-DC) vaccination in patients with newly-diagnosed or recurrent WHO Grade III-IV malignant gliomas. ~The primary endpoints were to assess the most effective combination of vaccine and adjuvant in order to enhance the immune potency, along with safety.~ The combination of ATL-DC vaccination and TLR agonist was safe and found to enhance systemic immune responses, as indicated by increased interferon gene expression and changes in immune cell activation. Specifically, PD-1 expression increases on CD4+?T-cells, while CD38 and CD39 expression are reduced on CD8+?T cells, alongside an increase in monocytes. Poly-ICLC treatment amplifies the induction of interferon-induced genes in monocytes and T lymphocytes. Patients that exhibit higher interferon response gene expression demonstrate prolonged survival and delayed disease progression. These findings suggest that combining ATL-DC with poly-ICLC can induce a polarized interferon response in circulating monocytes and CD8+?T cells, which may represent an important blood biomarker for immunotherapy in this patient population.”
The purpose of the study was to measure if combinations worked AND if they were safe. There was however an added bonus.
“Median follow-up of patients treated on this clinical trial was 2.2 years after surgery, although the long-term survivors have now been followed for over 10 years. Median progression-free survival (PFS) was 8.1 months; and median overall survival (OS) was 26.6 months~. Although this clinical trial was not designed or powered to detect effects of these treatments on survival between the treatment groups, there were noticeable differences in median survival between the treatments groups for both OS (placebo: 7.7 months, poly-ICLC: 52.5 months, and resiquimod: 16.7 months; log-rank~ ~P~?~=?0.017) and PFS (placebo: 5.5 months, poly-ICLC: 31.4 months and resiquimod: 8.1 months; log-rank~ ~P~?~=?0.0012)”~
To put it bluntly, this stuff in combination is working really well and provides significant overall survival to GBM sufferers. There were 23 patients in this trial (very small sample size) and 4 WERE STILL ALIVE AT THE END OF THIS STUDY in 2023!! (Supplementary Data 1A) There also may be an error in box N22 fwiw.
The article has been peer reviewed before being published.
~April 29 Amended 10K form for year end 2023.~
There was not a whole lot of new information but I did take a dive on Exhibit 10.90 Which is the loan agreement with Streeterville Capital from November 2023. As one of the debt covenants (If you take my money you agree to my rules) it reads, “(ii) the Common Stock shall be listed or quoted for trading on any of (a) NYSE, (b) NASDAQ, (c) OTCQX, (d) OTCQB, or (e) OTC Pink Current Information; and (iii) trading in Borrower’s Common Stock will not be suspended, halted, chilled, frozen, reach zero bid or otherwise cease on Borrower’s principal trading market.”
~May 2 SEC 8K Form~
NWBO Raised $11 Million from Steeterville Capital (again). Payments begin in December. This money will be used to build out the Sawston facility (in anticipation of MHRA approval) which lead us to the main event!
~May 10~****~th~ ~SEC 10Q Form~
Long story short, the company is burning through cash but is fortunate enough to pay creditors with stock in lieu of cash.
Spending on the Sawston facility has almost doubled. (Page 17)
There are several takeaways on page 23. A 40-Patient Phase I trial was completed using the DCVax-Direct. This was tested on “OVER A DOZEN TYPES OF CANCERS.” This foundation is being set to build an extensive pipeline.
~MAA APPLICATION UPDATE~
MAA was submitted on Dec 20, 2023. On Jan 24, 2024 the company was notified by MHRA that MAA passed validation. On March 7, 2024 the company was notified by MHRA that the validation was confirmed. There were no requested updates for clarification in that time period. (Page 23) This is where the confusion begins however as to where the clock started ticking.
I made a post 2 months ago “MHRA Timeline/Phase I completed”.
The company statements appear to align with my own projections. I feel the clock started upon the submission date. It sounds like the March 7th communication was to inform them that Phase I was completed, and that NO RFI WAS NECESSARY.
I may be wrong, but I expect MAA approval this week.
The company has stated that they will be going media silent until a decision has been made.
The Company also continued discussions and negotiations during the first quarter of 2024 relating to collaborations which the Company believes will help it build a ~broad franchise in dendritic cell-based immunotherapies.~ (Page 24)
“Annual Shareholder Meeting**. The Company plans to conduct its Annual Shareholder Meeting before the end of June 2024.”** To my knowledge they have never had a shareholder meeting.
~Lawsuit Updates~
There is a lawsuit against the board members over a dispute about their compensation. The board members motion to dismiss was denied and that lawsuit is now in the discovery phase.
~Manipulation lawsuit~
So basically the court told NWBO that they pleaded their case effectively, however, their calculations for losses was improper. They granted the motion to dismiss WITHOUT prejudice (They can refile with proper calculations AND THEY DID).
On May 1, the Market Manipulators (alleged) filed a new Motion to Dismiss. NWBO has 30 days to file a response (and is working on that now).
~Tl;DR~
MAA decision is imminent.
Groundwork is being laid for an extensive pipeline.
Lawsuits are going well (for investors at least).
As always, my sources:
~https://www.sec.gov/edgar/browse/?CIK=1072379&owner=exclude~
https://www.nature.com/articles/s41467-024-48073-y
~https://www.reddit.com/r/NWBO/comments/1bot5hz/mhra_timeline_phase_i_completed_nwbo/~
I added 20K shares to my position today. I am very bullish.
Thanks for your insights. But my thinking re the MAA approval date is late June: the timing confusion stems from whether or not to count every calendar day vs. work days (also when the clock started, which seems to be more clear now). Not sure it's valid to count every calendar day since the board isn't likely working on weekends. Secondly, expectations - especially w/MHRA approval hanging in the balance - often disappoint.
Having said that, I wouldn't mind being wrong.
HOW MANY DENDRITIC CELL CANCER VACCINES ARE IN THE MAA APPLICATON QUEUE ?
https://braintumourresearch.org/en-us/blogs/research-campaigning-news/whats-the-plan
"...the need to get the dendritic cell therapies currently in development actually licensed..."
1 ), At Westminster this week a question from Alistair Strathern (Labour Mid Bedfordshire ) was answered. He asked the Secretary of State for Health and Social Care, "whether NHS England plans to provide dendric cell therapy for glioma".
2) "With the news of trial opportunities being missed, barriers for our research sector and the need to get the dendritic cell therapies currently in development actually licensed, then it is clear our manifesto could not be more timely or more needed and that we must, and we will, push on on with our plans to have the commitments realised. Your role as brain tumour campaigner in this is critical now and in the build up to the General Election."
3)“Currently, only 5% of brain tumour patients enter the limited number of trials available, so any route to improvement must be listened to. In our new manifesto, we are calling on the Government to commit to increased participation of adult and paediatric brain tumour patients in clinical trials because equity of access is crucial if we are to find better treatments and, ultimately, a cure.
TheFollower
Saturday, May 25, 2024
"Brain Tumour Research has contributed to a new paper which highlights the barriers and opportunities for the brain tumour research sector in the UK to accelerate progress for adult patients across the world.
Dr Karen Noble, our Director of Research, Policy and Innovation, is a named author of the position paper, which reviews the current landscape and identifies three cross-cutting themes and seven research priorities in order to improve outcomes for brain tumour patients.
Dr Noble said: “Despite the funding announcements in 2018, there remain a number of challenges and bottlenecks, spanning basic research to patient experience, that are slowing down our progress to find a cure for all types of brain tumours. The UK continues to have relatively fewer clinical trials compared to other countries and patient survival has not significantly improved in decades.”
Members of the UK National Cancer Research Institute (NCRI) Brain Group investigated the current brain tumour research landscape using information from expert panel sessions, reports published by Cancer Research UK (CRUK), the National Institute for Health and Care Research (NIHR) and the All-Party Parliamentary Group on Brain Tumours (APPGBT).
The resulting paper identified three cross-cutting themes including collaborative networks and initiatives, funding and training; and seven research priorities, encompassing prompter diagnosis, development of accessible, innovative and evidence-based clinical trials, treating every patient as a research patient, and the facilitation of living beyond a brain tumour.
“The recommendations made in this position paper are designed to inspire UK reform and provide focal points for future funding calls and partnerships, to accelerate progress towards better and longer life for adult brain tumour patients across the world.”
At Westminster this week a question from Alistair Strathern (Labour Mid Bedfordshire ) was answered. He asked the Secretary of State for Health and Social Care, "whether NHS England plans to provide dendric cell therapy for glioma".
Health Minister Stephenson Conservative answered that: "The National Institute for Health and Care Excellence (NICE) evaluates all new licensed medicines, including medicines for glioma, to determine whether they represent a clinically and cost-effective use of resources. The NICE aims to publish guidance on new medicines as close as possible to licensing. Any medicine for glioma, recommended in draft NICE guidance, will be eligible for funding through the Cancer Drugs Fund from the point a positive draft guidance is published, in line with the standard arrangements for cancer medicines.
"On 24 April 2024, the NICE published draft guidance recommending a new treatment for glioma in children and young people that will be available to eligible patients once supply of the treatment is available (we reported on this in last week's update).
"There are currently no licensed dendritic cell therapies for glioma. A number of dendritic cell therapies are in development for the treatment of glioma, and any new licensed and NICE recommended treatments would be funded by NHS England, in line with NICE’s recommendations."
A new report published by the Teenage Cancer Trust warns that too many young people aged 13–24 are missing out on the chance to take part in clinical trials, leaving them unable to access innovative new treatments that could increase their chances of survival.
The report, which was developed after a year of consultation with young people the charity supports plus clinicians, academics, charities, and other experts, identifies the main barriers to participation and makes recommendations on how policymakers, the NHS, pharmaceutical industry, and researchers can help overcome these.
In the report, key stakeholders identified a lack of available trials as the key barrier. A lack of open trials impacts patients of all ages, but young people are uniquely disadvantaged because they are more likely to experience rare cancers or find themselves too old to take part in paediatric trials and too young for adult trials.
Other barriers identified include a lack of reliable easily searchable information about current trials for clinicians, and a lack of age-appropriate information for young people to aid their decision making. The report also highlights the need for trial participants to often travel long distances to take part, and the associated expense.
The Teenage Cancer Trust says the unique needs of young people are consistently overlooked in national efforts to increase access to trials – for example last year’s O’Shaughnessy Review on commercial clinical trials – and is calling for their views and experiences to be addressed as recommendations are developed and put into action.
To effectively measure reductions in inequality, the Teenage Cancer Trust is calling for data around the numbers of young people who are offered and participate in trials – and those for whom no trial is available – be consistently collected and transparently available.
Thomas said: “Access to clinical trials is a huge issue for the brain tumour community and we welcome this report from the Teenage Cancer Trust which highlights the barriers facing young people.
“Currently, only 5% of brain tumour patients enter the limited number of trials available, so any route to improvement must be listened to. In our new manifesto, we are calling on the Government to commit to increased participation of adult and paediatric brain tumour patients in clinical trials because equity of access is crucial if we are to find better treatments and, ultimately, a cure.”
This week Thomas attended Cancer52’s Members’ Meeting, which had a special Q&A with Professor Peter Johnson, National Clinical Director for Cancer. Cancer52 represents nearly 100 cancer charities, including Brain Tumour Research, united by their vision of seeing a better future for everyone affected by the rare and less common cancers, which account for more than half of all cancer deaths in the UK.
Professor Johnson said it was his aim to ensure that the NHS is as innovative possible. He spoke about the importance of lowering the barriers to the investigative process of cancers but noted that rare and less common cancers are still a challenge for the system. There are particular problems with brain cancer where the early diagnosis rates are quite low.
In terms of access to treatments, Professor Johnson said that the “NHS does reasonably well to gain access to drugs that have a good evidence base”. He said that the NHS was aware it needed to ensure value for taxpayers' money is maximised and that treatments are deemed effective.
With the news of trial opportunities being missed, barriers for our research sector and the need to get the dendritic cell therapies currently in development actually licensed, then it is clear our manifesto could not be more timely or more needed and that we must, and we will, push on on with our plans to have the commitments realised. Your role as brain tumour campaigner in this is critical now and in the build up to the General Election.
That is it for this week.
Although there has been the policy emphasis this week I am still going horseracing this week - this time at Newmarket. Please keep an eye on our social media to see the fantastic fundraising opportunities presented to us by our partnerships with The Jockey Club and The British Hat Guild - you may decide it is time to invest in that new hat!
Wishing you all a peaceful time until next Friday when we will be back with another campaigning update.
Hugh and Thomas"
braintumourresearch.org
https://braintumourresearch.org/en-us/blogs/research-campaigning-news/whats-the-plan
"With the news of trial opportunities being missed, barriers for our research sector and the need to get the dendritic cell therapies currently in development actually licensed, then it is clear our manifesto could not be more timely or more needed and that we must, and we will, push on on with our plans to have the commitments realised. Your role as brain tumour campaigner in this is critical now and in the build up to the General Election."
dstock07734
Re: sukus post# 693929
Saturday, May 25, 2024 10:52:56 AM
Post#
693930
of 693932
Sorry to say there is no way that Merck can come up with an alternative before the expiration of the patent. Even Merck starts a trial today on the possible alternative, Merck cannot even file for FDA approval on that alternative before the patent expiration.
Let's see what Merck will say on the Oncology Investor Event. On May 5, BMY was informed by FDA that the PDUFA of its SC Opdivo was February 28, 2025. This week, FDA informed BMY that the PDUFA was reassigned as December 28, 2024. I suspect it should be through Project Orbis too. Merck investors are going to ask critical questions such as where is the hell of our SC keytruda?
dstock07734
Re: Horseb4CarT post# 693892
Friday, May 24, 2024 10:49:31 PM
Post#
693897
of 693933
Horse,
I agree with you.
Recall that some powerful players forced Al Musella to take down Dr. Liau's webinar video twice. A NWBO investor uploaded the video to Youtube and the video has been shadow blocked. Given that Merck spent $2.3b on advertising last year, I always have suspicion that Merck could be the one which forced Musella to take down the video and Merck could also be the one which has been colluding with the dark forces to suppress the sp. Think about this. With the publication of the Nature article in which it was specifically mentioned that the trial used the vaccine licensed by NWBO, everyone would know that the results presented by Dr. Liau were from the technology licensed by NWBO too if the video were visible to the public, which certainly brings more competitors.
Now two of Merck's competitors already filed for the approval of subcutaneous checking point inhibitors. I tend to believe that Merck's results are not as good as those of the two competitors. Otherwise Merck would have been singing like a canary quite a while ago. I suspect Merck should be under pressure now to show its investors that there is no such issue as patent cliff.
The following is about the PDUFA for BMY and Roche on their subcutaneous checking point inhibitors.
FDA moved the PDUFA date of BMY subcutaneous Opdivo from February 28, 2025 to December 29, 2024. Roche subcutaneous PDUFA is September 15, 2024.
Bristol Myers Squibb (NYSE: BMY) today announced that the U.S. Food and Drug Administration (FDA) has reassigned the previously announced Prescription Drug User Fee Act (PDUFA) goal date of the Biologics License Application (BLA) for the subcutaneous formulation of Opdivo ® (nivolumab) co-formulated with Halozyme’s proprietary recombinant human hyaluronidase (rHuPH20) (herein referred to as “subcutaneous nivolumab”) across all previously approved adult, solid tumor Opdivo indications as monotherapy, monotherapy maintenance following completion of Opdivo plus Yervoy (ipilimumab) combination therapy, or in combination with chemotherapy or cabozantinib. The updated goal date is December 29, 2024.
https://news.bms.com/news/details/2024/Bristol-Myers-Squibb-Announces-Updated-Action-Date-by-the-U.S.-Food-and-Drug-Administration-for-Subcutaneous-Nivolumab-nivolumab-and-hyaluronidase/default.aspx
https://news.bms.com/news/corporate-financial/2024/U.S.-Food-and-Drug-Administration-Accepts-Bristol-Myers-Squibbs-Application-for-Subcutaneous-Nivolumab-nivolumab-and-hyaluronidase/default.aspx
d_stock07734:
: In order to start Dr.Liau's next combo trial idea,("We have planned a series of novel pre-clinical studies to re-polarize myeloid cells, to optimize how the timing and sequence of immunotherapy can influence ant-tumor immunity, and a new clinical trial to test the first-in-human combination of a new brain penetrant CSF-1R inhibitor (CSF-1Ri; PLX3397, Daiichi-Sankyo) with DC vaccination and PD-1 mAb blockade (Pembrolizumab, Merck") in patients with newly diagnosed GBM.), did the trials below (1,2,3) , and maybe others , need to be completed and published beforehand ?
Are there any other trials that need to be completed before Dr.Liau' s next combo idea (dc vax L, Keytruda, poly iclc, CSF-Daisshi) starts?
1)https://x.com/d_stock07734/status/1794104024293114018…
2)https://x.com/d_stock07734/status/1794106934380933586…
3)
From Dr. Liau's paper and presentation, without doubt CSF1R-I plays a key role in tackling immunosuppressive issue due to tumor-associated macrophage. https://t.co/tQrFrh5Wso
— d_stock (@d_stock07734) May 24, 2024
It is interesting to see that in collaboration with LifeMax Laboratories, Amgen is trying to develop… pic.twitter.com/oeQVbeW2rH
The Danish Dude
https://investorshub.advfn.com/boards/read_msg.aspx?message_id=174342925
Because looking at the share price over the years I've been invested, boy how we long retailers have had any influence on the share price. Maybe (lol) you can kid exwannabe, iclight, inquiriq, theorysuit, legend431, learningcurve2020, manibiotech et al .... the creme de la creme of due diligencers on Ihub of that.
Any sane person knows, pumping is not an option in this stock, unless it is as part of an expression in a fud narrative, from the usual fudspects, being immune to due diligence and factual circumstances regarding NWBO.
"If the mountain won't come to Muhammad, then Muhammad must go to the mountain".
So what is it about the art of due diligence and enhancing retailer awareness with factual insights, some of you are so obviously afraid of, that you need to dismiss it firsthand as pump? Easier, than to actually refute the insights with real arguments supported by evidence? Are you against, that I refute the bullshit from fudders continously? That I - and others - have successfully proven, again and again, that ATL-DC in the combo trials at UCLA with poly-iclc and Keytruda IS DCvax-L?
Everything below are facts
Data lock happened
MIA approval happened
Advent has ramped up from 14 to around 100 employees
A production unit of Flaskworks Eden is now being made
NWBO has filed for MAA approval
MHRA has been extraordinary funded with $10M for 2 years, with the purpose of also getting cancer vaccines faster to patients
British politicians have urged MHRA to approve and NICE to reimburse in the Pathway to a Cure report
Two combo trials are being run at UCLA, with DCvax-L and poly-iclc and Keytruda. Another one in preparation that will also include DCVax + Keytruda + CSF-1R Inhibitor Pexidartinib (PLX-3397)
ATL-DC in the two UCLA combo trial ARE beyond all doubt - DCVax-L
There's a lawsuit against 7 market makers. No deal announced. No costs shown in SEC filings. Cohen and Milstein usually take these cases on contingency. Thus, it is rational to assume it HAS been taken on contingency, since this is a HUGE lawsuit.
"In January 2016 Black became an independent director of NWBO to investigate the market manipulation of the company's stock by the hedge fund "wolfpack". The wolfpack and others use naked shorting of stock to drive promising young biotechs toward bankruptcy or to the point where they need to raise capital at extremely low valuations from the wolfpack themselves", as was stated in an Alchetron news article.
NWBO stated in a PR
"It is exciting to see the potential of the DCVax personalized immune therapies being developed by NW Bio for a wide range of cancers. I look forward to utilizing my expertise in helping the Company protect its technology and operations."
So when the lawsuit came 2022, and the plaintiff say they have +6 years of evidence against MM and their spoofing, it is rational to believe, THAT was Cofer Blacks job.
A Nature journal preprint is on its way regarding the results of the DCvax-L and poly-iclc trial.
MHRA stated about confirmatory efficacy trial
Although each biosimilar development needs to be evaluated on a case by case basis, it is considered that, in most cases, a comparative efficacy trial may not be necessary if sound scientific rationale supports this approach.
FDA states in its guidance documents outline how biosimilars may be approved based on pharmacokinetic (PK) data and PD biomarker data without a comparative clinical efficacy study. Reliance on PK and PD data allows for shorter and less costly clinical studies that can often be conducted in healthy participants
Let's look at facts about companies Revimmune SAS, Ltd, Inc
Linda Powers director in US and UK and in full control. Revimmune trials with Interleukin-7 back more than a decade gets PR'ed as Revimmune Inc. http://Revimmune.com say Maryland Bethesda is head office. Head office address is same address as Northwest Bio Inc and Toucan Capital. Revimmune is assignee on combo patent from 2014. Interleukin-7 also called IL-7 is in many claims on the combo patent. Before 2012 it was called CYT-107 after the company Cytheris. Mac Cheever was working with it. He joined NWBO SAB in 2016.
Revimmune Ltd dormant company but just been confirmed, that "its intended future activities are lawful" meaning ...
Industry Codes used
$NWBO is in control of NWBO Limited since January 19th. 2024. Linda Powers ASSIGNED control to NWBO Inc.
3 months ago!!!
Northwest Biotherapeutics Limited and Revimmune Inc shares a funny same address.
J Kelly Ganjei from AmplifyBio and being on the combo patent and Philippe Pire from Advent Bioservices are "attached".
Linda Powers and Mark Lowdell ownes a company called Novamune LTD.
On April 2 a compulsory strike-off was sent and supposedly Novamune had two months to respond. On April 25, the government issued a formal notice already on discontinuing the strike-off notice.
Mark Lowdell is a consultant to Inmune Bio. Turns out he is ALSO on the SAB board of NWBO.
But NWBO have not disclosed him being so!
J Kelly Ganjei, the guy having worked for Linda Powers at Toucan, who is on the combo patent, who is CEO of AmplifyBio is also on the board of Inmune Bio
Phil Parry who have been head of engineering at Roche and Autolomous just hired at Advent Bioservice. A step down or step up?
To Chatgbt
Can you ponder over the info below and come up with theories what the Revimmune Inc and Revimmune Ltd are meant for?
1) Northwest Biotherapeutics have a combination patent with DCVax-L and checkpoint inhibitors and Interleukin-7
2) Linda Powers is CEO of Northwest Biotherapeutics
3) Linda Powers owns Toucan Capital
4) Linda Powers is CEO of Advent Bioservices
5) Linda Powers is Director of Revimmune SAS
6) Linda Powers is Director of Revimmune Limited
7) Linda Powers was CEO of Cognate
8) Philippe Pire is CFO of Advent Bioservices
9) Philippe Pire is listed as employee at Revimmune Limited
10) J. Kelly Ganjei is CEO of AmplifyBio
11) J. Kelly Ganjei was at Cognate
12) J. Kelly Ganjei was at Toucan Capital
13) Revimmune SAS is former Cytheris and changed its name in 2014 and is situated in France
14) Revimmune Limited is registered as a "dormant company" in the UK in 2020, one share for £1
15) The registration address of Revimmune Inc is Toucan Capitals company address
16) Revimmune SAS developed CYT-107 (Interleukin-7) when it was Cytheris
17) Mac Cheever was oo-inventor of CYT-107 at Cytheris
18) Mac Cheever joined NWBO SAB 2016
19) Mac Cheever is co-inventor of combination patent with DCvax-L and checkpoint inhibitors and Interleukin-7
20) J. Kelly Ganjei is co-inventor of combination patent with DCvax-L and checkpoint inhibitors and Interleukin-7
CHATGBT
Considering the information provided, here are some theories regarding the purposes of Revimmune Inc and Revimmune Ltd:
Strategic Patent Holding and Licensing: Revimmune Inc and Revimmune Ltd might be structured to hold and manage patents, particularly the combination patent involving DCVax-L, checkpoint inhibitors, and Interleukin-7. This setup could be designed to optimize intellectual property protection and licensing opportunities within different legal frameworks (U.S. vs. EU).
Biotechnology Research and Development: Given their connection with IL-7 (CYT-107) development and the combination therapies, these entities could be focused on advancing specific biotechnological research areas. Revimmune SAS's history as Cytheris, which developed IL-7, suggests a continued interest in immunotherapy and its applications.
Operational and Financial Flexibility: By having multiple entities in different jurisdictions (Revimmune Inc, Revimmune Ltd, and Revimmune SAS), the network can potentially leverage various regulatory and financial environments. This flexibility can aid in fundraising, minimizing taxes, or meeting specific regulatory criteria.
Holding and Managing Assets: Revimmune Ltd's status as a dormant company might be strategic for holding certain assets or intellectual property without active business operations, possibly to be activated when needed, such as in response to strategic shifts in the market or pending the outcomes of clinical trials.
Collaborative Networks: The overlapping roles of key personnel (Linda Powers and J. Kelly Ganjei) across different organizations hint at a tightly knit network aimed at fostering collaboration across different segments of drug development and commercialization.
These entities, therefore, seem to be strategically positioned to facilitate innovative drug development, manage intellectual property efficiently, and enhance the operational scope of their interconnected networks.
ME
Could Revimmune Ltd be used in a strategic Merger and acquisition maneouver of Northwest Biotherapeutics who have been victim of spoofing and naked shorting and found its share price suppressed artiificially, thus planning to "overtake" NWBO and list at a stock exchange? Would that force naked short positions to cover?
CHATGBT
Using Revimmune Ltd in a strategic merger or acquisition maneuver by Northwest Biotherapeutics (NWBO) could indeed be a tactic in the complex financial and strategic landscape of biotech. If NWBO has been experiencing issues like spoofing and naked short selling, leading to a suppressed share price, orchestrating a merger or acquisition with Revimmune Ltd could potentially help in several ways:
Reorganization and Valuation: Merging with or acquiring a company like Revimmune Ltd could allow NWBO to reorganize its assets and potentially reset its market valuation.
Market Impact: Such a strategic move could draw market attention and potentially impact stock prices, which might force those holding naked short positions to cover, thereby driving up the share price due to a sudden increase in buy demands.
Access to New Markets: Listing Revimmune Ltd on a stock exchange could provide NWBO with access to additional capital markets or different investor bases, offering financial benefits and broader exposure.
This scenario would require careful regulatory navigation and clear strategic planning to ensure that it aligns with legal frameworks and effectively addresses the underlying financial challenges.
And on and on it goes.
Thanks for dstock, Peter Davis and other for DD provided in the above.
So where is my "pumping" in the above FeMike?
Are you gonna dismiss it all? Some?
I have OPINIONS when I deliver due diligence and this is MY TAKE on, what is the POTENTIAL and PROBABILITIES of stuff happening.
Regarding Revimmune, Novamune, NWBO ltd, Advent Bioservices setup, the entities, who is in control, where are the entities registered wrt addresses, which persons are involved, are there activities going on, are there relations to patents.
That kind of info has impact on my opinions whether a BO will happen, whether it gives LP and NWBO other possibilities to maneouver wrt merging and acquisitions possibilities and thus having other possibilities countering the market makers spoofing NWBO.
Call it pump, but it is well argued POSSIBILITIES founded in factual proven circumstances.They might not happen. They might. It is leverage for how NWBO MIGHT be able to act going forward.
My one post for the day.
You can go back to your "pump" uttering again.
What a great and easy way to disregard due diligence.
https://www.griproom.com/fun/10-signs-your-stock-is-being-manipulated
Bullish
BULLISH
ATL-DC is DCVax-L
https://www.ajmc.com/view/an-overview-of-the-specialty-therapy-pipeline-in-
2023May 2, 2023
An Overview of the Specialty Therapy Pipeline in 2023
Author(s):
Hayden E. Klein
Conference|Asembia
At the first business session of Asembia 2023, Ray Tancredi, divisional vice president at Walgreens, provided updates to the 2023 specialty therapy pipeline.
To kick off the first business session of Asembia 2023, Ray Tancredi, divisional vice president at Walgreens, noted 6 major trends in the 2023 specialty therapy pipeline:
Innovation
Gene and cell therapy
Oncology
Patient centricity
Biosimilars
Rare disease
Tancredi noted that specialty pharmacies grew by 315% between 2015 and 2021, with hospital or health system-owned specialty pharmacies accounting for about a third of this total growth—and that the specialty drug pipeline is projected to grow by another 8% each year through 2025.
“Specialty pharmacy continues to carry the FDA pipeline year over year,” Tancredi said. “What I saw was about 39 more drugs that could potentially be approved by the end of 2023, and of those 39, I think 28 of them could be considered specialty.”
He first listed 8 major recent specialty drug approvals that “have the potential to change the standard of care in a given disease and/or have a large economic impact to payer.” These were:
Spesolimab-sbzo injection (Spevigo) for pustular psoriasis flares
Efgartigimod alfa-fcab (Vyvgart) for myasthenia gravis
Olipudase alfa-rpcp (Xenpozyme) for non-central nervous system manifestations of acid sphingomyelinase deficiency
Deucravacitinib (Sotyktu) for moderate-to-severe plaque psoriasis
Fam-trastuzumab deruxtecan-nxki (Enhertu) for unresectable or metastatic HER2-low breast cancer
Mavacamten (Camzyos) for class II or III obstructive hypertrophic cardiomyopathy
Lecanemab-irmb (Leqembi) for Alzheimer disease
Zanubrutinib (Brukinsa) for chronic lymphocytic leukemia or small lymphocytic lymphoma
Looking to the rest of 2023, there are several more specialty drugs anticipated to receive FDA approval. Here is a wrapped-up version of these anticipated approvals.
Rare and Orphan Disease
Tancredi focused on 23 drugs in the pipeline to treat a large variety of rare and orphan diseases. There are more than 7000 rare diseases, which affect fewer than 200,000 individuals per condition and 30 million Americans overall. Since the Orphan Drug Act was signed into law in 1983, the FDA has approved hundreds of treatments for rare diseases, though most rare diseases still do not have FDA-approved treatments.
This list included 11 oral drugs and 12 drugs delivered via injection. All drugs are in phase 2 or 3 of research and development, or filed for FDA approval.
The orally administrated drugs on this list include:
Mavorixafor for WHIM syndrome
Nirogacestat for desmoid tumors
Sodium oxybate for narcolepsy
Alvelestat for alpha 1 antitrypsin congenital deficiency
Vamorolone for Duchenne muscular dystrophy
Govorestat for galactosemia
Elafibranor for primary biliary cirrhosis
Sparsentan for IgA nephropathy
Paltusotine for acromegaly
Leniolisib for activated phosphoinositide 3-kinase delta syndrome
Trofinetide for Rett syndrome
The drugs delivered via injection on this list include:
Concizumab for hemophilia A and B
Tilavonemab for Alzheimer disease
Cendakimab for eosinophilic esophagitis
Magrolimab for myelodysplastic syndrome
Acaziolcept for systemic lupus erythematosus
Tegoprubart for amyotrophic lateral sclerosis (ALS)
Fitusiran for hemophilia A and B
Tofersen sodium for ALS
Sotatercept for pulmonary arterial hypertension
Narsoplimab for thrombosis
Diazoxide choline for Prader-Will syndrome
Nipocalimab for hemolytic disease of the fetus and newborn
Specialty Drugs
Tancredi focused on 19 traditional specialty drugs in the pipeline for FDA approval, including 10 oral drugs, 8 drugs delivered via injection, and 1 delivered via inhalation.
The orally-administrated drugs on this list include:
Resmetirom for nonalcoholic steatohepatitis
Ritlecitinib for alopecia
Danicopan for paroxysmal nocturnal hemoglobinuria
Islatravir hydrate for HIV
Tolebrutinib for relapsing remitting multiple sclerosis, with potential indication for myasthenia gravis
Etrasimod arginine for ulcerative colitis
Remibrutinib for chronic spontaneous urticaria
Bemnofosbuvir for hepatitis C
Omecamtiv mecarbil for chronic heart failure
Evobrutinib for multiple sclerosis
The drugs delivered via injection on this list include:
Ziltivekimab for cardiovascular disease
Nirsevimab for respiratory syncytial virus
Mirikizumab for ulcerative colitis
Brazikumab for Crohn’s disease
Itepekimab for chronic obstructive pulmonary disease
Lebrikizumab for eczema and atopic dermatitis
Avacincaptad pegol for geographic atrophy
Donanemab for Alzheimer disease
Additionally, treprostinil sodium was the only drug on this list delivered via inhalation.
Oncology
Tancredi noted that about 13 oncology drugs are approved each year. In 2023, there are 16 oral drugs and 6 drugs delivered via injection in the pipeline, with 6 drugs in the pipeline for breast cancer and 3 for non-small cell lung cancer (NSCLC).
The orally-administrated drugs on this list include:
Veliparib for breast cancer
Tovorafenib for breast cancer
Ipatasertib for prostate cancer
Giredestrant for breast cancer
Momelotinib for myelofibrosis
Repotrectinib for NSCLC
Imlunestrant for breast cancer
Navitoclax dihydrochloride for myelofibrosis
Elacestrant for breast cancer
Bezuclastinib for gastrointestinal stromal tumors
Capivasertib for breast cancer
Milademetan for soft tissue sarcoma
Bemcentinib for myelodysplastic syndrome
Pirtobrutinib for non-Hodgkin lymphoma
Sitravatinib for NSCLC
Xl092 for colorectal cancer
The drugs delivered via injection on this list include:
Vusolimogene oderparepvec for cutaneous squamous cell carcinoma
Talquetamab for multiple myeloma
Sabatolimab for chronic myelomonocytic leukemia
Epcoritamab for non-Hodgkin lymphoma
Tiragolumab for esophageal cancer
Tusamitamab ravtansine for NSCLC
Gene and Cell Therapies
There are 13 injectable gene and cell therapies in the pipeline, with 1 drug delivered topically.
The gene and cell therapies delivered via injection on this list include:
Tabelecleucel for Epstein-Barr virus
Factor VIII for hemophilia A, developed by Bayer
Dcvax-L for glioblastoma
Valoctocogene roxaparvovec for hemophilia A
Delandistrogene moxeparvovec for Duchenne muscular dystrophy
Fidanacogene elaparvovec for hemophilia B
FCR001 for scleroderma
DTX401 for glycogen storage disease type 1a
Posoleucel for Epsteinn-Barr virus
Exagamglogene autotemcel for sickle cell disease
Fordadistrogene movaparvovec for Duchenne muscular dystrophy
Aglatimagene besadenovec for prostate cancer
Factor VIII for hemophilia A, developed by Roche
Beremagene geperpavec is also in the pipeline for topical treatment of dystrophic epidermolysis bullosa.
Ken Griffin Gave the Commencement Speech at Harvard
— kristen shaughnessy (@kshaughnessy2) May 23, 2024
"...Live a life for others. Seek to make tangible differences in the lives of those around you by tutoring youth in the inner city, building a business that creates jobs, or running for public office..."… pic.twitter.com/PBYvQqhmX9
$nwbo @alphavestcap TRIFECTA, AND MAYBE MORE.
— alphavestcapital.com (@alphavestcap) May 24, 2024
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georgebailey
Re: Bright Boy post# 693547
Thursday, May 23, 2024 11:44:19 AM
Post#
693555
of 693729
BB- I plan to vote for the additional comp to help make the litigation as you described go away. I don’t want any distractions for this management team.
Second, hoping the NDA has expired, I anticipate an extremely positive ASM with at least one material milestone announced near the ASM. I expect bullish discussion of the franchise model, Eden’s, partnering, new trials and touching on uplist and Direct.
If MHRA has not yet green lighted L, then I expect they’ll do the best they can to describe approval timing.
Best ASM yet is 5 weeks away and very much looking forward to it.
exwannabe
Re: georgebailey post# 693555
Friday, May 24, 2024 8:41:57 AM
Post#
693728
of 693728
BB- I plan to vote for the additional comp to help make the litigation as you described go away.
A Yes vote does not make the lawsuit go away.
First, as already ruled by the Court wrt the 2022 vote, failing to disclose that the award was actually a true-up nullifies it. The Court must accept plaintiffs argument on the true-up nature as valid at this time (can be reviewed after discovery). And if true, then NWBO should clearly disclose that the award was at least partially to make up for dilution.
Second, even NWBO does not even state the case goes away., They state they will seek dismissal of part or all of the case. That is a far cry from saying it will go away.
Excellent posts by sukus:
Walgreens’ annual revenues are currently plateaued at about $135 Billions. So having expected $24 Billions additional revenues annually from Cell and Gene therapies lines certainly give Walgreens quite a big boost.
https://macrotrends.net/stocks/charts/WBA/walgreens/revenue
https://investorshub.advfn.com/boards/read_msg.aspx?message_id=174482139
Bio9999’s excellent write up gave a prelude what this collaboration could transpire.
https://reddit.com/r/NWBO/s/5DjXvhYnpB
https://investorshub.advfn.com/boards/read_msg.aspx?message_id=174482148
The Danish Dude
Re: iclight post# 693262
Thursday, May 23, 2024 2:16:33 AM
Post#
693451
of 693526
It's yet again ... welcome to the "REFUTE FUD HAPPY HOUR SHOW".
A month out from the ASM and fudders are out in droves working overtime on anything that moves ... and it is NOT brain cells.
Trial halt ... 2015 on the table again ... REALLY!!!
Facts about trial halt in 2015
In 2015, the clinical trial of DCVax-L, a promising immunotherapy for glioblastoma, faced a temporary halt. This interruption primarily resulted from regulatory scrutiny and compliance issues. Northwest Biotherapeutics, the company behind DCVax-L, had to temporarily suspend new patient screening while they submitted trial data for regulatory review. This regulatory review was crucial to ensure the ongoing safety and efficacy of the trial and to address any concerns raised by regulatory bodies? (Fierce Biotech)?? (Northwest Biotherapeutics)?.
The company also faced issues with the EudraCT trials database in Europe, which inaccurately listed the trial as halted in Germany. In reality, the trial continued as per protocol, but new patient enrollment was paused. This discrepancy was due to limitations in the database's categorization, which did not have an option to reflect a temporary suspension of new screenings while the trial itself continued? (Fierce Biotech)?.
The temporary halt was not due to any specific adverse events or issues with the drug itself but was more about ensuring compliance with regulatory requirements and providing necessary data to authorities? (Northwest Biotherapeutics)
The Data Safety Monitoring Board (DSMB) plays a critical role in the oversight of clinical trials. Here’s a breakdown of their responsibilities and the decision-making process related to trial continuation or halting:
DSMB Role and Recommendations:
The DSMB is an independent group of experts that monitors patient safety and treatment efficacy data while a clinical trial is ongoing.
They review interim data and can recommend continuing the trial without changes, modifying the trial, or halting the trial based on their findings.
Reasons for Halting Trials:
Safety Concerns: If the DSMB identifies significant safety issues, they report these to both the sponsor and the FDA. If the concerns are severe, they can recommend a trial halt for patient safety.
Efficacy and Futility: The DSMB also evaluates the trial for efficacy (whether the treatment is working as expected) and futility (whether it is unlikely to achieve its goals). They report these findings to the sponsor. If the trial is deemed futile, the sponsor may decide to halt it to avoid unnecessary exposure of patients to ineffective treatments.
Decision Process:
For Safety: If the DSMB recommends halting the trial due to safety issues, the FDA may mandate a halt based on the DSMB’s findings.
For Efficacy or Futility: The DSMB’s recommendation for halting due to efficacy (if the treatment is proven effective early) or futility (if the treatment is unlikely to be effective) is reported to the sponsor. The sponsor then decides whether to continue or halt the trial based on these recommendations.
Specific Case of DCVax-L Trial:
In the case of the DCVax-L trial, the DSMB did not recommend a halt for safety, efficacy, or futility. Instead, the temporary suspension was related to regulatory review processes rather than safety or efficacy concerns raised by the DSMB? (Northwest Biotherapeutics)?? (Fierce Biotech)?.
To summarize, the DSMB monitors clinical trials and can recommend halting for safety, efficacy, or futility. They report safety concerns to the FDA and other issues to the trial sponsor, who then decides on the trial’s future. The 2015 DCVax-L trial halt was due to regulatory compliance rather than a DSMB recommendation based on trial data.
So is this statement right or wrong?
"That the DSMB chose to continue the trial, NOT HALT it."
ChatGBT
Yes, it is correct to say that the DSMB chose to continue the trial and did not halt it.
In 2015, the DSMB for the DCVax-L Phase III trial reviewed the trial data and decided to continue the trial without recommending a halt. The temporary suspension of new patient screening was due to regulatory review processes rather than a DSMB recommendation based on safety, efficacy, or futility concerns. The DSMB's role involves ongoing monitoring and they would report any significant safety issues to the FDA and efficacy or futility concerns to the trial sponsor. In this case, the DSMB did not find any issues warranting a halt, and the trial continued as per their guidance? (Northwest Biotherapeutics)?? (Fierce Biotech)?.
Due diligence ic ... you might have heard about it! LOL
The usual non invested fudspects, that have so enrichened retailers lives, by dedicating theirs to ours ... as people do for years in an OTC stock ... will be doing their worst the coming month, to keep sentiment at bay.
What does reason and logic tells us about the proxy, and management wanting to ratify award options?
We must assume they will NOT get a quorum, if substantial good news have NOT materialized beforehand.
HINT: So ... do you think NWBO would allow for this to happen?
"The only limit to our realization of tomorrow is our doubts of today." – Franklin D. Roosevelt
What does reason and logic tells us about situations, where retailers find themselves wishing for the same thing as fudspects?
Let's take an example. If the favourite fud narrative is WE WANT GOVERNANCE AND GUIDANCE, should we assume that THAT is because of their empathical minds, as learningcurve2020 states it .... "poor retailers", which is why this corps of Florence Nightingales have worried so insanely for years on our behalf?
Love Thy Neighbour ... and boy ... do they love us!
Logic and reason tells us, that disinformation, misusing, abusing and distortion WILL follow after NWBO have brought forward any kind of information, if possible, instigating lawsuits and complaints or any kind of event, that could take away precious time, effort, money and ressources from the main goals.
Thus ... if in doubt ... don't.
If not in doubt ... don't.
Don't throw bones at fudders.
But we do expect a bone thrown retailers way, before June 29th.
ATL-DC is DCVax-L
NWBO
Northwest Biotherapeutics Inc (QB)
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Last Trade Time: 10:09:00 AM EDT
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Chart for Northwest Biotherapeutics Inc (QB)
NWBO Detailed Quote
dstock07734
Re: None
Thursday, September 28, 2023 10:53:29 PM
Post#
636069
of 693463
In the 2024 NCI budget proposed by Dr. Monica Bertagnolli, she mentioned the following specifically about brain caner.
https://www.cancer.gov/about-nci/budget/congressional-justification/fy2024-nci-congressional-justification.pdf
New Treatments for Brain Cancer
Despite substantial public and private investment, the survival rate for adult glioblastoma (GBM) remains dismal and new treatment approaches are needed. GBM presents substantial biological challenges to be addressed in preclinical studies that support testing of therapies in the clinic. In 2021, NCI launched the Glioblastoma Therapeutics Network (GTN), a national multi-institutional collaborative effort with the goal of taking novel therapeutic agents from preclinical studies in models of GBM into pilot clinical studies that include biomarkers of effects. GTN grantees are currently conducting collaborative pilot projects and initiating clinical studies. This research advances the Cancer Moonshot goal of speeding progress against the deadliest cancers.
What intrigues me the most is the part about "pilot clinical studies that include biomarkers of effects". As a way of investigation, I went through all the clinical trials on Glioblastoma sponsored by NCI including the ones in which NIC was the collaborator. Here are all the trials started late 2019 until late 2022. Note that I didn't include the DCVax-L combo trial here. I searched each trial trying to see which one includes the biomarkers of effects in its primary or second ending points. None could I find! I mean zero!
Sonobiopsy for Noninvasive and Sensitive Detection of Glioblastoma
https://classic.clinicaltrials.gov/ct2/show/NCT05281731?cond=NCT05281731&draw=2&rank=1
Partial Brain RT, Temozolomide, Chloroquine, and TTF Therapy for the Treatment of Newly Diagnosed Glioblastoma
https://classic.clinicaltrials.gov/ct2/show/NCT04397679?cond=NCT04397679&draw=2&rank=1
Verteporfin for the Treatment of Recurrent High Grade EGFR-Mutated Glioblastoma
https://classic.clinicaltrials.gov/ct2/show/NCT04590664?cond=NCT04590664&draw=2&rank=1
Testing the Addition of the Chemotherapy Drug Lomustine (Gleostine®) to the Usual Treatment (Temozolomide and Radiation Therapy) for Newly Diagnosed MGMT Methylated Glioblastoma
https://classic.clinicaltrials.gov/ct2/show/NCT05095376?cond=NCT05095376&draw=2&rank=1
Neuro-pharmacological Properties of Repurposed Posaconazole in Glioblastoma: A Phase 0 Clinical Trial
https://classic.clinicaltrials.gov/ct2/show/NCT04825275?cond=NCT04825275&draw=2&rank=1
Mycophenolate Mofetil in Combination With Standard of Care for the Treatment of Glioblastoma
https://classic.clinicaltrials.gov/ct2/show/NCT05236036?cond=NCT05236036&draw=2&rank=1
AB154 Combined With AB122 for Recurrent Glioblastoma
https://classic.clinicaltrials.gov/ct2/show/NCT04656535?cond=NCT04656535&draw=2&rank=1
Natural Progesterone for the Treatment of Recurrent Glioblastoma
https://classic.clinicaltrials.gov/ct2/show/NCT05091866?cond=NCT05091866&draw=2&rank=1
Trial of Anti-PD-1 Immunotherapy and Stereotactic Radiation in Patients With Recurrent Glioblastoma
https://classic.clinicaltrials.gov/ct2/show/NCT04977375?cond=NCT04977375&draw=2&rank=1
Brain Tumor-Specific Immune Cells (IL13Ralpha2-CAR T Cells) for the Treatment of Leptomeningeal Glioblastoma, Ependymoma, or Medulloblastoma
https://classic.clinicaltrials.gov/ct2/show/NCT04661384?cond=NCT04661384&draw=2&rank=1
Selinexor (KPT-330) in Combination With Temozolomide and Radiation Therapy in Patients With Newly Diagnosed Glioblastoma
https://classic.clinicaltrials.gov/ct2/show/NCT04216329?cond=NCT04216329&draw=2&rank=1
Association of Peripheral Blood Immunologic Response to Therapeutic Response to Adjuvant Treatment With Immune Checkpoint Inhibition (ICI) in Patients With Newly Diagnosed Glioblastoma or Gliosarcoma
https://classic.clinicaltrials.gov/ct2/show/NCT04817254?cond=NCT04817254&draw=2&rank=1
Testing the Addition of an Anti-cancer Drug, Selinexor, to the Usual Chemotherapy Treatment (Temozolomide) for Brain Tumors That Have Returned After Previous Treatment
https://classic.clinicaltrials.gov/ct2/show/NCT05432804?cond=NCT05432804&draw=2&rank=1
A Study Testing the Effect of Immunotherapy (Ipilimumab and Nivolumab) in Patients With Recurrent Glioma With Elevated Mutational Burden
https://classic.clinicaltrials.gov/ct2/show/NCT04145115?cond=NCT04145115&draw=2&rank=1
A Study of the Drug Selinexor With Radiation Therapy in Patients With Newly-Diagnosed Diffuse Intrinsic Pontine (DIPG) Glioma and High-Grade Glioma (HGG)
https://classic.clinicaltrials.gov/ct2/show/NCT05099003?cond=NCT05099003&draw=2&rank=1
Now take a look at the current combo trial. I can find biomarker related measures everywhere. I even find the exact word "Biomarker analysis"
The association between biomarkers and clinical outcomes (PFS and OS) will be evaluated using Cox regression. Changes in markers pre- and post- treatment will be assessed using paired t-tests.
https://classic.clinicaltrials.gov/ct2/show/NCT04201873?cond=atl-dc&draw=2&rank=1
The writing on the wall couldn't be more clear. If DCVax-L is not the cornerstone of the Moonshot program, at least DCVax-L is going to be an important part of the Moonshot program.
The transient window of opportunity is going to be gone. Anyone who has dry powder should seize the opportunity.
Again the above is purely my speculation. Take it for fun if you don't like it.
dennisdave
Re: Margin Buu post# 693092
Wednesday, May 22, 2024 7:02:38 AM
Post#
693144
of 693209
Normally I would have told you that it is NWBO that is warning shareholders about their lack of marketing sales and patient support and not me
From NWBO's 10K
Our product candidates will require different marketing and sales methods and personnel than conventional therapeutic products. Also, we lack sales and marketing experience. These factors may result in significant difficulties in commercializing our product candidates. The commercial success of any of our product candidates will depend upon the strength of our sales and marketing efforts. We do not have a marketing or sales force and have no experience in marketing or sales of products like our lead product, DCVax-L for GBM, or our additional product, DCVax-Direct. To fully commercialize our product candidates, we will need to recruit and train marketing staff and a sales force with technical expertise and ability to manage the distribution of our DCVax-L for GBM. As an alternative, we could seek assistance from a corporate partner or a third-party services firm with a large distribution system and a large direct sales force. However, since our DCVax products are living cell, immune therapy products, and these are a fundamentally new and different type of product than are on the market today, we would still have to train such partner’s or such services firm’s personnel about our products and would have to make changes in their distribution processes and systems to handle our products. We may be unable to recruit and train effective sales and marketing forces or our own, or of a partner or a services firm, and/or doing so may be more costly and difficult than anticipated. Such factors may result in significant difficulties in commercializing our product candidates, and we may be unable to generate significant revenues.
And NO this is NOT standard boilerplate meaningless text, as some simpletons here have suggested.
However, what is VERY VERY interesting is that text has been removed from the last 10Q..... In my view, that means that NWBO has now removed the lack of sales and marketing experience without adding anyone to their staff.... in my opinion, that is because NWBO has arranged for a third party prepared to sell DCVAXL under a license.
Step 1 to a buy out after UK approval
dstock07734
Wednesday, May 22, 2024 2:05:57 AM
Hi Dstock and thanks for what you do. Regarding Hiltonol the original patent recently expired and if you google polyicl the drug is available for sale through many compounding pharmacies. The company has applied for a patent for a more potent variation with manufacturing improvements.
I would bet the new version of hiltonol has been used in the specials program and also trials started in last few years.
A partnership between nwbo and hiltonol would pretty much put a nail in the coffin of the pharce that big pharma actually has cancer immunotherapy treatments that work for many and have low side effects.Member Level
Re: dstock07734 post# 693094
Wednesday, May 22, 2024 2:05:57 AM
Post#
693132
of 693156
Hi Dstock and thanks for what you do. Regarding Hiltonol the original patent recently expired and if you google polyicl the drug is available for sale through many compounding pharmacies. The company has applied for a patent for a more potent variation with manufacturing improvements.
I would bet the new version of hiltonol has been used in the specials program and also trials started in last few years.
A partnership between nwbo and hiltonol would pretty much put a nail in the coffin of the pharce that big pharma actually has cancer immunotherapy treatments that work for many and have low side effects.
dstock07734
Re: newman2021 post# 692969
Tuesday, May 21, 2024 11:42:50 AM
Post#
692974
of 692985
Even more interesting part is that Kelly Ganjei has been the board member of INmune Bio Inc since 2016. The other director of Novamune is Mark Lowdell who happens to be the CSO/CMO of INmune Bio Inc.
dstock07734
Re: newman2021 post# 692969
Tuesday, May 21, 2024 11:42:50 AM
Post#
692974
of 692985
Even more interesting part is that Kelly Ganjei has been the board member of INmune Bio Inc since 2016. The other director of Novamune is Mark Lowdell who happens to be the CSO/CMO of INmune Bio Inc.
attilathehunt : what would cause a NWBO CUSIP change ?
Re: skitahoe post# 692860
Tuesday, May 21, 2024 9:35:55 AM
Post#
692919
of 692921
With the upcoming CUSIP change (and it is coming) I wouldn't want to be oaning out any shares. It may take a while for the new shares to show up...
Loaners beware!!
hyperopia: me apologize to you.A.E.K.
Re: biosectinvestor post# 692689
Tuesday, May 21, 2024 1:05:44 AM
Post#
692874
of 692902
Really bio? You respond to ae kusterer, but not to my original post?
Poly-ICLC is a different company's DRUG. Not part of any natural dendritic cell
maturation process. It works by pretending to be a VIRUS and stimulating other processes in the body when DCVax-L is injected. The entire notion is incorrect, and as I said, it is not in that particular patent that was referenced in the post to which I just previously referred. It's not included in any version of DCVax, either Direct or DCVax-L It's another company's carefully created, manufactured, drug and NWBO did not have a patent to make it any more than they had a patent to make Keytruda. They also have never claimed they make it nor that they sourced it from Uncover for their manufacturing.
I too, hope they coordinate and present trials with the combination in the future. The results are wonderful. But sometimes people make things up because they want to believe something. They get it in their head. Poly-ICLC is an adjuvant treatment in all of the trials. It is injected separately in an intramuscular injection. The UCLA formula for ATL-DC and DCVax-L are the same. There is no disconnection, as has been claimed by some shorts and so there is no need to further promote this false theory that will only create confusion as there is simply no basis to it.
No basis to this false theory huh? Okay, I’ll show you one of Northwest Bio’s patents for DCVax-Direct, and the part that states that poly I:C can be used as a maturation agent, and I won’t waste any more of my time on this:
OPTIMALLY ACTIVATED DENDRITIC CELLS THAT INDUCE AN IMPROVED OR INCREASED ANTI-TUMOR IMMUNE RESPONSE
One method to overcome this down regulation has been disclosed in WO 2004/053072 (incorporated herein by reference) where it was found that down regulation can be avoided through partial maturation of the DCs prior to administration. In this method dendritic cell precursors (bone marrow cells following red cell lysis or monocytic dendritic cell precursors) were induced in vitro to differentiate into immature dendritic cells and the immature dendritic cells were induced to begin maturation by culturing the cells with a dendritic cell maturation agent, such as BCG and IFN?, lipopolysaccharide (LPS), tumor necrosis factor a (TNFa), an imidazoquinoline compound, a synthetic double stranded polyribonucleotide, a agonist of a Toll-like receptor (TLR), a sequence of nucleic acids containing unmethylated CpG motifs known to induce the maturation of DC, or any combination thereof. The immature dendritic cells were allowed to continue maturation for a time period less than what had previously been determined for the immature dendritic cells to fully mature. If the dendritic cells were allowed to fully mature in vitro the cells would be unable to uptake and process antigen subsequent to administration to the patient. The inventors disclosed that the dendritic cells should be allowed to mature for 1 to about 10 hours for optimal activation prior to isolation of the partially mature dendritic cells and formulation for administration to a patient.
In the methods the dendritic cell maturation agent can be inactivated Bacillus Calmette-Guerin (BCG), interferon ? (IFN?), lipopolysaccharide (LPS), tumor necrosis factor a (TNFa), an imidazoquinoline compound, a synthetic double stranded polyribonucleotide, for example, poly I:C, a agonist of a Toll-like receptor (TLR), a sequence of nucleic acids containing unmethylated CpG motifs known to induce the maturation of dendritic cells, or any combination thereof. The inactivated BCG can comprise whole BCG, cell wall constituents of BCG, BCG-derived lipoarabidomannans, or BCG components and the inactivated BCG can be heat-inactivated, formalin-treated, heat-inactivated and formalin treated, and the like.
Claims
8. The method according to any one of claims 1 and 2, wherein the dendritic cell maturation agent is inactivated Bacillus Calmette-Guerin (BCG), interferon ? (IFN?), lipopolysaccharide (LPS), tumor necrosis factor a (TNFa), an imidazoquinoline compound, a synthetic double stranded polyribonucleotide, a agonist of a Toll-like receptor (TLR), a sequence of nucleic acids containing unmethylated CpG motifs known to induce the maturation of dendritic cells, or any combination thereof.
14. The method according to claim 8, wherein the synthetic double stranded polyribonucleotide is poly I:C.
https://patents.justia.com/patent/20180187145
Re: biosectinvestor post# 692875
Tuesday, May 21, 2024 2:18:24 AM
Post#
692879
of 692904
bio, the poster that you responded to was ae kusterer, who we all know, reposts other people posts without good reference. It was my post that he reposted, which I also put in my response to you as reference. You basically claimed in your response to him that part of my theory, which states that poly I:C could be used as a maturation /activation agent for DCVax-Direct was a false theory with no basis.
In the part of your post that I bolded, you said that poly-ICLC can’t be used as a maturation agent, or used in the manufacture of any DCVax product including Direct, and that it can only be administered separately as an adjuvant. That is false and you are wrong, as I just showed in Northwest Bio’s patent. I’ve seen you twist an argument, and go off on tangents, to make it seem like you were not wrong many times, just as you are doing here. This is exactly why I said that I don’t want to waste my time on this.
dstock07734
Re: skitahoe post# 692812
Monday, May 20, 2024 6:02:06 PM
Post#
692835
of 692864
Gary,
My post is about the way Merck is handling its p3 trial results on SC keytruda is quite different from what BMS and Roche were doing on their SC checking point inhibitors. Since Merck and NWBO are highly correlated with each other, I was wondering if there is any special reason that Merck chose to submit the study results without any PR, poster, presentation.
Here is something funny. Merck put May 20, 2024 at the results updated date on last Friday. Today they corrected the date.
dstock07734
Re: skitahoe post# 692786
Monday, May 20, 2024 3:48:54 PM
Post#
692801
of 692863
Gary,
If it is not today, we can expect something before ASCO.
Here is something interesting and I am not sure if it has special meaning.
Roche had PR on its p3 trial of subcutaneous Tecentriq on August 02, 2022 and later some presentations and publications
https://www.roche.com/media/releases/med-cor-2022-08-02
https://www.sciencedirect.com/science/article/pii/S0923753423006944
https://medically.gene.com/content/dam/pdmahub/restricted/oncology/hopa-2023/HOPA-2023-poster-burotto-IMscin001-part-2-randomized-phase-iii-pharmacokinetics.pdf
Then in January 2023 Roche filed for FDA approval as mentioned in 10Q from Halozyme .
In November 2022, Roche submitted a Biologics License Application (“BLA”) to the FDA and a Marketing Authorization Application (“MAA”) to the EMA for SC formulation of Tecentriq (atezolizumab) with ENHANZE across all approved indications of IV Tecentriq. In January 2023, FDA accepted the BLA for the SC formulation of Tecentriq with the official PDUFA goal date of September 15, 2023.
https://www.sec.gov/Archives/edgar/data/1159036/000115903623000012/halo-20221231.htm
According to the webpage of its p3 trial, the study results were submitted to clinicaltrials.gov in April 2023. I want to emphasize the study results were uploaded to the website after Roche submitted the filing package.
https://clinicaltrials.gov/study/NCT03735121?cond=NCT03735121&rank=1&tab=results
Now take a look at what BMS did for its subcutaneous Opdivo. BMS released PR on its subcutaneous Nivolumab on October, 19, 2023 and later had presentations and publications just like what Roche did on its SC Tecentriq.
https://news.bms.com/news/corporate-financial/2023/Phase-3-CheckMate--67T-Trial-of-Subcutaneous-Nivolumab-nivolumab-and-hyaluronidase-Meets-Co-Primary-Endpoints-in-Advanced-or-Metastatic-Clear-Cell-Renal-Cell-Carcinoma/default.aspx
https://ascopubs.org/doi/10.1200/JCO.2024.42.4_suppl.LBA360
Then the company released PR on May 6, 2024 saying that FDA accepted the BLA and set February 28, 2025 as PDUFA date.
https://news.bms.com/news/corporate-financial/2024/U.S.-Food-and-Drug-Administration-Accepts-Bristol-Myers-Squibbs-Application-for-Subcutaneous-Nivolumab-nivolumab-and-hyaluronidase/default.aspx
But if we check clinicaltrials.gov, BMS hasn't submitted the study results yet.
https://clinicaltrials.gov/study/NCT04810078?tab=results
Here comes the interesting part. Merck submitted study results on the p3 trial of SC keytruda to clinicaltrial.gov without releasing any PR or publication before hand. I didn't see Merck would present anything related to SC keytruda from the latest news. It would be fun to see what Merck is going to say on the Oncology Investor Event at ASCO.
https://classic.clinicaltrials.gov/ct2/show/results/NCT04956692?term=subcutaneous&lead=Merck&draw=2&rank=6
ATLnsider
Re: ae kusterer post# 692780
Monday, May 20, 2024 3:28:39 PM
Post#
692795
of 692832
Thanks ae kusterer, one thing that a lot of NWBO longs are failing to grasp or understand, is that now when Dr. Linda Liau speaks about DCVax-L (DC Vaccine) alone, she actually means DCVax-L along with poly-ICLC.
This is because poly-ICLC has been added as a component to the DCVax-L formulation as an in vivo maturation agent, that will maturate and hyperactivate the dendritic cells in situ.
There are no current DCVax-L clinical trials, or future planned DCVax-L clinical trials, that does not include poly-ICLC as an in vivo maturation agent.
The 2 (DCVax-L and poly-ICLC) are not mixed together into 1 vaccine, but are co-administered, at the same time. The DCVax-L is administered intradermally, and the poly-ICLC is administered intramuscarly, at the same time. Poly-ICLC is not referred to as an adjuvant treatment. The 2 shots work together, and are collectively referrred to as DCVax:
ae kusterer https://investorshub.advfn.com/boards/read_msg.aspx?message_id=174455169
Re: None
Monday, May 20, 2024 2:40:06 PM
Post#
692780
of 692833
Dr.Liau: "We have planned .... and a new clinical trial to test the first-in-human combination of a new brain penetrant CSF-1R inhibitor (CSF-1Ri; PLX3397, Daiichi-Sankyo) with DC vaccination and PD-1 mAb blockade (Pembrolizumab, Merck) in patients with newly diagnosed GBM."
https://trp.cancer.gov/spores/abstracts/ucla_brain.htm
Linda Liau, MD, PhD, MBA
Project 1: Targeting immunotherapy-induced resistance with DC vaccination and immune modulation
Project 2: Overcoming drug-induced resistance to intrinsic apoptosis in glioblastoma
Project 3: Strategies against radiation-induced cellular plasticity in glioblastoma
Administrative Core
Biospecimen and Pathology Core (BiPC)
Neuro-Imaging Core (NIC)
Biostatistics and Bioinformatics Core (BBC)
Developmental Research Program
Career Enhancement Program
Institutional SPORE Website
Principal Investigator Contact Information
Linda Liau MD, PhD, MBA
Professor and W. Eugene Stern Chair
Department of Neurosurgery
University of California, Los Angeles
300 Stein Plaza, Suite 564
Los Angeles, California 90095-6901
Tel: (310) 267-9449
Overview
The objectives of the UCLA SPORE in Brain Cancer are to contribute significantly to progress in the diagnosis, prognosis, and treatment of brain cancer with a particular focus on developing novel strategies to overcome the problem of treatment-induced resistance. In order to achieve these translational research goals of our program, we propose three main projects involving:
Project 1: Targeting immunotherapy-induced resistance with DC vaccination and immune modulation
Project 2: Overcoming drug-induced resistance to intrinsic apoptosis in glioblastoma
Project 3: Strategies against radiation-induced cellular plasticity in glioblastoma
These translational research projects will be supported by shared resource cores in administration, biospecimen/pathology, neuroimaging, and biostatistics/bioinformatics. Our program will also be responsive to SPORE themes by incorporating Developmental Research and Career Enhancement Programs in order to foster new approaches for assessing and treating brain cancer.
^ Back to Top
Project 1: Targeting immunotherapy-induced resistance with DC vaccination and immune modulation
Project Co-Leaders:
Robert M. Prins, PhD (Basic Science Leader)
Linda M. Liau, MD, PhD, MBA (Clinical Science Leader)
The overall goals of this project are to investigate mechanisms of immune evasion following treatment with dendritic cell (DC) vaccines, and to develop rational combinations of immunotherapeutic strategies to overcome the immunosuppressive milieu of the brain tumor microenvironment. We previously found that, in addition to inducing T-cell infiltration into brain tumors, DC vaccination + anti-PD1 blockade may also create a pro-inflammatory environment within the tumor that induces the immigration of immunosuppressive myeloid cells (TIM). TIM are phenotypically similar to the myeloid cells that attenuate the T-cell response to chronic viral infections, and may counteract the anti-tumor T-cell responses induced by DC vaccination. Therapies that target myeloid cells within the tumor microenvironment represent a promising new strategy. As such, inhibition of these myeloid cells using a CSF-1R inhibitor, in conjunction with autologous tumor lysate-pulsed DC vaccination (ATL-DC) and PD-1 mAb blockade, resulted in significantly prolonged survival in tumor-bearing animals with large, well-established intracranial gliomas. Our hypothesis is that myeloid cells mediate adaptive immune resistance in response to T-cell activation induced by immunotherapy. We have planned a series of novel pre-clinical studies to re-polarize myeloid cells, to optimize how the timing and sequence of immunotherapy can influence ant-tumor immunity, and a new clinical trial to test the first-in-human combination of a new brain penetrant CSF-1R inhibitor (CSF-1Ri; PLX3397, Daiichi-Sankyo) with DC vaccination and PD-1 mAb blockade (Pembrolizumab, Merck) in patients with newly diagnosed GBM. A better understanding of the biology of these cellular interactions will provide insight into more effective ways to induce therapeutic anti-tumor immune responses for this deadly type of brain tumor.
Aim 1: To identify the optimal timing and sequence by which immunotherapy alters the local tumor-infiltrating immune response in syngeneic murine glioma models and in recurrent glioblastoma patients.
Aim 2: To conduct a new first-in-human Phase I clinical trial of ATL-DC vaccination in conjunction with CSF-1R inhibitor (PLX3397) and PD-1 mAb (Pembrolizumab) blockade, and develop predictive immunological and imaging biomarkers.
Aim 3: To elucidate the immunotherapy-induced resistance mechanisms by which immuno-suppressive myeloid cells inhibit anti-tumor immune responses in pre-clinical animal models and in newly diagnosed glioblastoma patients.
Figure for Project 1. Depiction of the critical immune components that regulate effective anti-tumor immune responses for malignant gliomas.
Figure for Project 1. Depiction of the critical immune components that regulate effective anti-tumor immune responses for malignant gliomas.
^ Back to Top
Project 2: Overcoming drug-induced resistance to intrinsic apoptosis in glioblastoma
Project Co-Leaders:
David Nathanson, PhD (Basic Science Leader)
Timothy Cloughesy, MD (Clinical Science Leader)
Glioblastoma (GBM) tumors are defined by high resistance to therapy-induced cell death. Through a combination of molecular and functional profiling of the intrinsic apoptotic machinery, we have identified that all GBM are comprised of two molecular intrinsic apoptotic blocks — MCL-1 and BCL-xL — to prevent tumor cell death. The goal of Project 2 is to translate rationally-designed drug combinations, consisting of new and pre-existing clinical agents, that selectively ablate the GBM dual apoptotic barrier to promote tumor cell death and induce durable clinical responses in patients.
Aim 1: To investigate whether a novel, antibody drug conjugate with a potent warhead against an essential apoptotic block has anti-tumor effects when combined with TMZ/radiation or a new, clinical brain penetrant EGFR TKI in pre-clinical GBM models.
Aim 2: To conduct a “window of opportunity” clinical trial to explore whether these new clinical drugs can ablate the two intrinsic apoptotic blocks in recurrent GBM patients.
Aim 3: To identify potential mechanisms of resistance to targeting the intrinsic apoptotic machinery in diverse pre-clinical GBM samples.
Together, the studies proposed in this application present a new therapeutic paradigm through specific manipulation of intrinsic apoptotic pathways in malignant glioma and have the long-term potential to shift current approaches in glioma therapy.
Figure for Project 2. All GBM have a dual apoptotic barrier — MCL1 and BCL-xL. Drug perturbations remove the MCL1 block in a genotype specific manner, creating an exclusive dependency on BCL-xL for survival. For EGFR TKI, changes in FDG uptake is a surrogate for ablation of MCL1
Figure for Project 2. All GBM have a dual apoptotic barrier — MCL1 and BCL-xL. Drug perturbations remove the MCL1 block in a genotype specific manner, creating an exclusive dependency on BCL-xL for survival. For EGFR TKI, changes in FDG uptake is a surrogate for ablation of MCL1
^ Back to Top
Project 3: Inhibition of radiation-induced phenotype conversion in glioblastoma
Project Co-Leaders:
Frank Pajonk, MD, PhD (Basic Science Leader)
Leia Nghiemphu, MD (Clinical Science Co-Leader)
Albert Lai, MD, PhD (Clinical Science Co-Leader)
The overarching goal of Project 3 is to improve radiotherapy (RT) outcome for patients suffering from glioblastoma (GBM). In our last SPORE funding period, we used patient-derived glioblastoma cell lines, patient-derived orthotopic xenografts (PDOXs), and dopamine receptor antagonists (DRAs) to understand how glioma cells react to the combination of radiation and dopamine receptor inhibition. We found that the combination of RT with DRAs upregulated the fatty acid/cholesterol biosynthesis pathway, and that blocking this pathway led to markedly increased survival in tumor-bearing mice. We therefore hypothesize that blocking the radiation-induced phenotype conversion of non-stem GBM cells into radiation-resistant glioma-initiating cells using the dopamine receptor antagonist quetiapine (QTP) and statins improves radiation responses, generates an exploitable metabolic vulnerability, and can be safely applied in patients with recurrent glioblastoma.
Aim 1: To optimize the timing, sequence, and bioavailability of combination treatment with RT/QTP and statins that induces alterations in lipid metabolism and extends survival in tumor-bearing animal models
Aim 2: To test if RT/QTP induces changes in lipid metabolism that can lead to a vulnerability to be targeted for therapeutic gain in a first-in-human combination Phase I clinical trial of RT/QTP +/- statins
Aim 3: To determine the mechanisms by which RT/QTP-induced changes in lipid metabolism may be reversed by statins and prolong survival
Figure for Project 3. Compared to radiation treatment alone, a combination of radiation and the dopamine receptor antagonist quetiapine significantly improves the median survival in mouse models of glioblastoma. At the same time, this combination treatment up-regulates gene expression of key enzymes in the mevalonate pathway with subsequent up-regulation of cholesterol biosynthesis. Targeting the rate-limiting enzyme in the mevalonate pathway, HMGCR (3-hydroxy-3-methylglutaryl-CoA reductase), using the statin simvatstain down-regulates cholesterol biosynthesis in glioma cells. A triple combination of radiation, quetiapine and simvastatin further improves median survival in mouse models of glioblastoma.
Figure for Project 3. Compared to radiation treatment alone, a combination of radiation and the dopamine receptor antagonist quetiapine significantly improves the median survival in mouse models of glioblastoma. At the same time, this combination treatment up-regulates gene expression of key enzymes in the mevalonate pathway with subsequent up-regulation of cholesterol biosynthesis. Targeting the rate-limiting enzyme in the mevalonate pathway, HMGCR (3-hydroxy-3-methylglutaryl-CoA reductase), using the statin simvatstain down-regulates cholesterol biosynthesis in glioma cells. A triple combination of radiation, quetiapine and simvastatin further improves median survival in mouse models of glioblastoma.
^ Back to Top
Administrative Core
Core Directors:
Linda M. Liau, MD, PhD, MBA (Core Director)
Timothy Cloughesy, MD (Core Co-Director)
Robert M. Prins, PhD (Core Co-Director)
The Administrative Core is responsible for the oversight and daily functions of the SPORE and provides organizational leadership for the overall successful conduct of the program. It provides organizational leadership and administrative support for all of the aspects of the SPORE, including coordination and communication between all investigators and committee members. It provides scientific management, including ongoing management and scientific review of all projects and cores to ensure that the stated scientific goals of the SPORE are met.
^ Back to Top
Biospecimen and Pathology Core (BiPC)
Core Directors:
Fausto J. Rodriguez, MD (Core Director)
Harley I. Kornblum, MD, PhD (Core Co-Director)
David A. Nathanson, PhD (Core Co-Director)
The Biospecimen and Pathology Core (BiPC), a biorepository and multifaceted research resource, provides critical support for the translational and diagnostic/therapeutic studies of the three major UCLA Brain SPORE projects, which are directed at understanding glioma biology and developing novel therapeutic approaches for brain cancer. In addition, the BiPC supports various developmental research projects and career enhancement programs. The SPORE projects have a critical need for high-quality brain tumor biospecimens, associated clinical and molecular annotations, histology, tissue microdissection, immunohistochemistry and characterization of models systems including neurospheres and xenografts. Neuropathology and biobanking expertise exist to accomplish the research aims and tightly interacts with the other cores.
Aim 1: To optimally collect, store, and distribute high-quality brain tumor biospecimens with detailed clinical and molecular annotations (tumor tissue, blood, urine, and cerebrospinal fluid) and implement biobanking best practices.
Aim 2: To perform molecular characterization of patient-derived tumor tissue and specific project models using histologic analysis, immunohistochemistry and genomic tools, including characterization of the tumor microenvironment and apoptotic machinery and single-cell RNA sequencing.
Aim 3: To create, provide, and characterize novel human biospecimen derivatives, gliomaspheres, patient-derived orthotopic xenografts (PDOX), and organoids that represent the molecular diversity of glioblastoma.
Figure for Biospecimen and Pathology Core. This figure shows the workflow of the Core with respect to tissue collection, and the development and characterization of relevant models
Figure for Biospecimen and Pathology Core. This figure shows the workflow of the Core with respect to tissue collection, and the development and characterization of relevant models.
^ Back to Top
Neuro-Imaging Core (NIC)
Core Director(s):
Benjamin M. Ellingson, PhD (Core Director)
Johannes Czernin, MD (Core Co-Director)
The goal of the Neuro-Imaging Core (NIC) is to provide advanced MRI and PET imaging support with established reliability and consistency to SPORE project investigators for their respective projects. The NIC uses quantitative µMRI and µPET for pre-clinical imaging (Aim 1), state-of-the-art MR and PET imaging acquisition, advanced post-processing, and novel analysis tools for clinical imaging of patients in novel clinical trials (Aim 2), and professional expertise and resources for traditional and enhanced radiographic response assessment for the clinical trials (Aim 3).
For Project 1, we theorize that tumors treated with DC vaccination and immune modulation will result in significantly higher uptake on immunoPET (89Zr-IAB22M2C Anti-CD8+ Minibody PET) and a significant decrease in tumor T2* on TAM-sensitive ferumoxytol MRI.
NIC strategy for Project 1.
For Project 2, we theorize that a combined imaging biomarker — simultaneous 18F-FDG PET and pH-weighted CEST-EPI — may be a valuable imaging biomarker for glycolytic flux, which can be perturbed using EGFR inhibition (in EGFR altered GBM) or chemoradiation (in p53 wild type GBM).
NIC strategy for Project 2.
For Project 3, we theorize that radiation therapy changes the microstructure of the subventricular zone (SVZ), known to harbor adult neural stem cells, as measured via diffusion MRI.
NIC strategy for Project 3.
^ Back to Top
Biostatistics and Bioinformatics Core (BBC)
Core Directors:
Gang Li, PhD (Core Director)
Thomas Graeber, PhD (Core Co-Director)
The overarching goal of the Biostatistics and Bioinformatics Core of the UCLA Brain SPORE is to provide comprehensive support in the areas of biostatistics and bioinformatics for all research projects, developmental research and career enhancement programs, and other cores of the UCLA SPORE in Brain Cancer. This Core has two specific aims:
Aim 1: Biostatistics Support: Provide SPORE investigators broad-based statistical support for the individual SPORE projects. This includes statistical advice on study design, analysis and interpretation of experimental results, preparation of manuscripts, development and submission of new grant applications, data management, and the design, analysis, conduct, and monitoring of SPORE investigator-initiated clinical trials. Core 3 also develops relevant innovative methodologies and analytical tools that address specific needs from SPORE projects.
Aim 2: Bioinformatics Support: Provide infrastructure and bioinformatics leadership to design and carry out projects using high-throughput technologies, such as genomic, transcriptomic, and/or lipidomic data from tumors and/or immune cells, from bulk tissue and/or single cell next generation sequencing (NGS), and from patient tumors involved in clinical trials and from preclinical xenograft and immunocompetent mouse models. Up-to-date bioinformatics software and pipelines are provided.
^ Back to Top
Developmental Research Program
Program Director:
Robert M. Prins, PhD
The goal of the UCLA SPORE in Brain Cancer Developmental Research Program (DRP) is to foster the exploration of innovative research ideas through the funding of pilot developmental research projects in the field of brain cancer. This program will identify new, innovative projects for funding that will constantly renew the vigor of our Brain SPORE research portfolio and add to, augment, or replace current major research projects. We expect to select three highly innovative proposals for funding each year.
^ Back to Top
Career Enhancement Program
Program Director:
Linda M. Liau, MD, PhD, MBA
A central mission of the UCLA SPORE in Brain Cancer is to stimulate, recruit, develop, and retain new investigators in the field of brain tumor research, with particular focus on translation of scientific discoveries to novel clinical applications. The UCLA SPORE in Brain Cancer Career Enhancement Program (CEP) provides a research support resource that allows junior faculty to transition to independent investigator status with adequate peer-reviewed funding, and helps established investigators to focus or redirect their research to the area of brain cancer. Each year, we anticipate supporting two to three highly innovative candidates with CEP funds.
^ Back to Top
Institutional SPORE Website
https://cancer.ucla.edu/research/ucla-brain-spore
Back to California SPOREs
Back to Brain SPOREs
^ Back to Top
TRP Home Contact TRP Site Map Accessibility Disclaimer Policy FOIA HHS Vulnerability Disclosure
U.S. Department of Health and Human Services National Institutes of Health National Cancer Institute USA.gov
NIH… Turning Discovery Into Health®
Re: None
Monday, May 20, 2024 10:57:58 AM
Post#
692731
of 692833
dstock07734
Re: biosectinvestor post# 692720
Monday, May 20, 2024 10:53:11 AM
Post#
692727
of 692729
bio,
I bookmarked this post. Let's see what will happen soon.
BTW, when you write post, don't make it effusively verbose in a way to show you have deep insight. As illustration, no one has patience to read your long post on CSF1R-I. You just need to say one line: CSF1R-I can deplete tumor associated macrophages that suppress t-cells loaded with tumor-associated antigens. That's all we need to know. Next time make it concise and simple. This way can save your time and readers' time too.
Dr.Liau: "We have planned .... and a new clinical trial to test the first-in-human combination of a new brain penetrant CSF-1R inhibitor (CSF-1Ri; PLX3397, Daiichi-Sankyo) with DC vaccination and PD-1 mAb blockade (Pembrolizumab, Merck) in patients with newly diagnosed GBM."
https://trp.cancer.gov/spores/abstracts/ucla_brain.htm
Linda Liau, MD, PhD, MBA
Project 1: Targeting immunotherapy-induced resistance with DC vaccination and immune modulation
Project 2: Overcoming drug-induced resistance to intrinsic apoptosis in glioblastoma
Project 3: Strategies against radiation-induced cellular plasticity in glioblastoma
Administrative Core
Biospecimen and Pathology Core (BiPC)
Neuro-Imaging Core (NIC)
Biostatistics and Bioinformatics Core (BBC)
Developmental Research Program
Career Enhancement Program
Institutional SPORE Website
Principal Investigator Contact Information
Linda Liau MD, PhD, MBA
Professor and W. Eugene Stern Chair
Department of Neurosurgery
University of California, Los Angeles
300 Stein Plaza, Suite 564
Los Angeles, California 90095-6901
Tel: (310) 267-9449
Overview
The objectives of the UCLA SPORE in Brain Cancer are to contribute significantly to progress in the diagnosis, prognosis, and treatment of brain cancer with a particular focus on developing novel strategies to overcome the problem of treatment-induced resistance. In order to achieve these translational research goals of our program, we propose three main projects involving:
Project 1: Targeting immunotherapy-induced resistance with DC vaccination and immune modulation
Project 2: Overcoming drug-induced resistance to intrinsic apoptosis in glioblastoma
Project 3: Strategies against radiation-induced cellular plasticity in glioblastoma
These translational research projects will be supported by shared resource cores in administration, biospecimen/pathology, neuroimaging, and biostatistics/bioinformatics. Our program will also be responsive to SPORE themes by incorporating Developmental Research and Career Enhancement Programs in order to foster new approaches for assessing and treating brain cancer.
^ Back to Top
Project 1: Targeting immunotherapy-induced resistance with DC vaccination and immune modulation
Project Co-Leaders:
Robert M. Prins, PhD (Basic Science Leader)
Linda M. Liau, MD, PhD, MBA (Clinical Science Leader)
The overall goals of this project are to investigate mechanisms of immune evasion following treatment with dendritic cell (DC) vaccines, and to develop rational combinations of immunotherapeutic strategies to overcome the immunosuppressive milieu of the brain tumor microenvironment. We previously found that, in addition to inducing T-cell infiltration into brain tumors, DC vaccination + anti-PD1 blockade may also create a pro-inflammatory environment within the tumor that induces the immigration of immunosuppressive myeloid cells (TIM). TIM are phenotypically similar to the myeloid cells that attenuate the T-cell response to chronic viral infections, and may counteract the anti-tumor T-cell responses induced by DC vaccination. Therapies that target myeloid cells within the tumor microenvironment represent a promising new strategy. As such, inhibition of these myeloid cells using a CSF-1R inhibitor, in conjunction with autologous tumor lysate-pulsed DC vaccination (ATL-DC) and PD-1 mAb blockade, resulted in significantly prolonged survival in tumor-bearing animals with large, well-established intracranial gliomas. Our hypothesis is that myeloid cells mediate adaptive immune resistance in response to T-cell activation induced by immunotherapy. We have planned a series of novel pre-clinical studies to re-polarize myeloid cells, to optimize how the timing and sequence of immunotherapy can influence ant-tumor immunity, and a new clinical trial to test the first-in-human combination of a new brain penetrant CSF-1R inhibitor (CSF-1Ri; PLX3397, Daiichi-Sankyo) with DC vaccination and PD-1 mAb blockade (Pembrolizumab, Merck) in patients with newly diagnosed GBM. A better understanding of the biology of these cellular interactions will provide insight into more effective ways to induce therapeutic anti-tumor immune responses for this deadly type of brain tumor.
Aim 1: To identify the optimal timing and sequence by which immunotherapy alters the local tumor-infiltrating immune response in syngeneic murine glioma models and in recurrent glioblastoma patients.
Aim 2: To conduct a new first-in-human Phase I clinical trial of ATL-DC vaccination in conjunction with CSF-1R inhibitor (PLX3397) and PD-1 mAb (Pembrolizumab) blockade, and develop predictive immunological and imaging biomarkers.
Aim 3: To elucidate the immunotherapy-induced resistance mechanisms by which immuno-suppressive myeloid cells inhibit anti-tumor immune responses in pre-clinical animal models and in newly diagnosed glioblastoma patients.
Figure for Project 1. Depiction of the critical immune components that regulate effective anti-tumor immune responses for malignant gliomas.
Figure for Project 1. Depiction of the critical immune components that regulate effective anti-tumor immune responses for malignant gliomas.
^ Back to Top
Project 2: Overcoming drug-induced resistance to intrinsic apoptosis in glioblastoma
Project Co-Leaders:
David Nathanson, PhD (Basic Science Leader)
Timothy Cloughesy, MD (Clinical Science Leader)
Glioblastoma (GBM) tumors are defined by high resistance to therapy-induced cell death. Through a combination of molecular and functional profiling of the intrinsic apoptotic machinery, we have identified that all GBM are comprised of two molecular intrinsic apoptotic blocks — MCL-1 and BCL-xL — to prevent tumor cell death. The goal of Project 2 is to translate rationally-designed drug combinations, consisting of new and pre-existing clinical agents, that selectively ablate the GBM dual apoptotic barrier to promote tumor cell death and induce durable clinical responses in patients.
Aim 1: To investigate whether a novel, antibody drug conjugate with a potent warhead against an essential apoptotic block has anti-tumor effects when combined with TMZ/radiation or a new, clinical brain penetrant EGFR TKI in pre-clinical GBM models.
Aim 2: To conduct a “window of opportunity” clinical trial to explore whether these new clinical drugs can ablate the two intrinsic apoptotic blocks in recurrent GBM patients.
Aim 3: To identify potential mechanisms of resistance to targeting the intrinsic apoptotic machinery in diverse pre-clinical GBM samples.
Together, the studies proposed in this application present a new therapeutic paradigm through specific manipulation of intrinsic apoptotic pathways in malignant glioma and have the long-term potential to shift current approaches in glioma therapy.
Figure for Project 2. All GBM have a dual apoptotic barrier — MCL1 and BCL-xL. Drug perturbations remove the MCL1 block in a genotype specific manner, creating an exclusive dependency on BCL-xL for survival. For EGFR TKI, changes in FDG uptake is a surrogate for ablation of MCL1
Figure for Project 2. All GBM have a dual apoptotic barrier — MCL1 and BCL-xL. Drug perturbations remove the MCL1 block in a genotype specific manner, creating an exclusive dependency on BCL-xL for survival. For EGFR TKI, changes in FDG uptake is a surrogate for ablation of MCL1
^ Back to Top
Project 3: Inhibition of radiation-induced phenotype conversion in glioblastoma
Project Co-Leaders:
Frank Pajonk, MD, PhD (Basic Science Leader)
Leia Nghiemphu, MD (Clinical Science Co-Leader)
Albert Lai, MD, PhD (Clinical Science Co-Leader)
The overarching goal of Project 3 is to improve radiotherapy (RT) outcome for patients suffering from glioblastoma (GBM). In our last SPORE funding period, we used patient-derived glioblastoma cell lines, patient-derived orthotopic xenografts (PDOXs), and dopamine receptor antagonists (DRAs) to understand how glioma cells react to the combination of radiation and dopamine receptor inhibition. We found that the combination of RT with DRAs upregulated the fatty acid/cholesterol biosynthesis pathway, and that blocking this pathway led to markedly increased survival in tumor-bearing mice. We therefore hypothesize that blocking the radiation-induced phenotype conversion of non-stem GBM cells into radiation-resistant glioma-initiating cells using the dopamine receptor antagonist quetiapine (QTP) and statins improves radiation responses, generates an exploitable metabolic vulnerability, and can be safely applied in patients with recurrent glioblastoma.
Aim 1: To optimize the timing, sequence, and bioavailability of combination treatment with RT/QTP and statins that induces alterations in lipid metabolism and extends survival in tumor-bearing animal models
Aim 2: To test if RT/QTP induces changes in lipid metabolism that can lead to a vulnerability to be targeted for therapeutic gain in a first-in-human combination Phase I clinical trial of RT/QTP +/- statins
Aim 3: To determine the mechanisms by which RT/QTP-induced changes in lipid metabolism may be reversed by statins and prolong survival
Figure for Project 3. Compared to radiation treatment alone, a combination of radiation and the dopamine receptor antagonist quetiapine significantly improves the median survival in mouse models of glioblastoma. At the same time, this combination treatment up-regulates gene expression of key enzymes in the mevalonate pathway with subsequent up-regulation of cholesterol biosynthesis. Targeting the rate-limiting enzyme in the mevalonate pathway, HMGCR (3-hydroxy-3-methylglutaryl-CoA reductase), using the statin simvatstain down-regulates cholesterol biosynthesis in glioma cells. A triple combination of radiation, quetiapine and simvastatin further improves median survival in mouse models of glioblastoma.
Figure for Project 3. Compared to radiation treatment alone, a combination of radiation and the dopamine receptor antagonist quetiapine significantly improves the median survival in mouse models of glioblastoma. At the same time, this combination treatment up-regulates gene expression of key enzymes in the mevalonate pathway with subsequent up-regulation of cholesterol biosynthesis. Targeting the rate-limiting enzyme in the mevalonate pathway, HMGCR (3-hydroxy-3-methylglutaryl-CoA reductase), using the statin simvatstain down-regulates cholesterol biosynthesis in glioma cells. A triple combination of radiation, quetiapine and simvastatin further improves median survival in mouse models of glioblastoma.
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Administrative Core
Core Directors:
Linda M. Liau, MD, PhD, MBA (Core Director)
Timothy Cloughesy, MD (Core Co-Director)
Robert M. Prins, PhD (Core Co-Director)
The Administrative Core is responsible for the oversight and daily functions of the SPORE and provides organizational leadership for the overall successful conduct of the program. It provides organizational leadership and administrative support for all of the aspects of the SPORE, including coordination and communication between all investigators and committee members. It provides scientific management, including ongoing management and scientific review of all projects and cores to ensure that the stated scientific goals of the SPORE are met.
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Biospecimen and Pathology Core (BiPC)
Core Directors:
Fausto J. Rodriguez, MD (Core Director)
Harley I. Kornblum, MD, PhD (Core Co-Director)
David A. Nathanson, PhD (Core Co-Director)
The Biospecimen and Pathology Core (BiPC), a biorepository and multifaceted research resource, provides critical support for the translational and diagnostic/therapeutic studies of the three major UCLA Brain SPORE projects, which are directed at understanding glioma biology and developing novel therapeutic approaches for brain cancer. In addition, the BiPC supports various developmental research projects and career enhancement programs. The SPORE projects have a critical need for high-quality brain tumor biospecimens, associated clinical and molecular annotations, histology, tissue microdissection, immunohistochemistry and characterization of models systems including neurospheres and xenografts. Neuropathology and biobanking expertise exist to accomplish the research aims and tightly interacts with the other cores.
Aim 1: To optimally collect, store, and distribute high-quality brain tumor biospecimens with detailed clinical and molecular annotations (tumor tissue, blood, urine, and cerebrospinal fluid) and implement biobanking best practices.
Aim 2: To perform molecular characterization of patient-derived tumor tissue and specific project models using histologic analysis, immunohistochemistry and genomic tools, including characterization of the tumor microenvironment and apoptotic machinery and single-cell RNA sequencing.
Aim 3: To create, provide, and characterize novel human biospecimen derivatives, gliomaspheres, patient-derived orthotopic xenografts (PDOX), and organoids that represent the molecular diversity of glioblastoma.
Figure for Biospecimen and Pathology Core. This figure shows the workflow of the Core with respect to tissue collection, and the development and characterization of relevant models
Figure for Biospecimen and Pathology Core. This figure shows the workflow of the Core with respect to tissue collection, and the development and characterization of relevant models.
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Neuro-Imaging Core (NIC)
Core Director(s):
Benjamin M. Ellingson, PhD (Core Director)
Johannes Czernin, MD (Core Co-Director)
The goal of the Neuro-Imaging Core (NIC) is to provide advanced MRI and PET imaging support with established reliability and consistency to SPORE project investigators for their respective projects. The NIC uses quantitative µMRI and µPET for pre-clinical imaging (Aim 1), state-of-the-art MR and PET imaging acquisition, advanced post-processing, and novel analysis tools for clinical imaging of patients in novel clinical trials (Aim 2), and professional expertise and resources for traditional and enhanced radiographic response assessment for the clinical trials (Aim 3).
For Project 1, we theorize that tumors treated with DC vaccination and immune modulation will result in significantly higher uptake on immunoPET (89Zr-IAB22M2C Anti-CD8+ Minibody PET) and a significant decrease in tumor T2* on TAM-sensitive ferumoxytol MRI.
NIC strategy for Project 1.
For Project 2, we theorize that a combined imaging biomarker — simultaneous 18F-FDG PET and pH-weighted CEST-EPI — may be a valuable imaging biomarker for glycolytic flux, which can be perturbed using EGFR inhibition (in EGFR altered GBM) or chemoradiation (in p53 wild type GBM).
NIC strategy for Project 2.
For Project 3, we theorize that radiation therapy changes the microstructure of the subventricular zone (SVZ), known to harbor adult neural stem cells, as measured via diffusion MRI.
NIC strategy for Project 3.
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Biostatistics and Bioinformatics Core (BBC)
Core Directors:
Gang Li, PhD (Core Director)
Thomas Graeber, PhD (Core Co-Director)
The overarching goal of the Biostatistics and Bioinformatics Core of the UCLA Brain SPORE is to provide comprehensive support in the areas of biostatistics and bioinformatics for all research projects, developmental research and career enhancement programs, and other cores of the UCLA SPORE in Brain Cancer. This Core has two specific aims:
Aim 1: Biostatistics Support: Provide SPORE investigators broad-based statistical support for the individual SPORE projects. This includes statistical advice on study design, analysis and interpretation of experimental results, preparation of manuscripts, development and submission of new grant applications, data management, and the design, analysis, conduct, and monitoring of SPORE investigator-initiated clinical trials. Core 3 also develops relevant innovative methodologies and analytical tools that address specific needs from SPORE projects.
Aim 2: Bioinformatics Support: Provide infrastructure and bioinformatics leadership to design and carry out projects using high-throughput technologies, such as genomic, transcriptomic, and/or lipidomic data from tumors and/or immune cells, from bulk tissue and/or single cell next generation sequencing (NGS), and from patient tumors involved in clinical trials and from preclinical xenograft and immunocompetent mouse models. Up-to-date bioinformatics software and pipelines are provided.
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Developmental Research Program
Program Director:
Robert M. Prins, PhD
The goal of the UCLA SPORE in Brain Cancer Developmental Research Program (DRP) is to foster the exploration of innovative research ideas through the funding of pilot developmental research projects in the field of brain cancer. This program will identify new, innovative projects for funding that will constantly renew the vigor of our Brain SPORE research portfolio and add to, augment, or replace current major research projects. We expect to select three highly innovative proposals for funding each year.
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Career Enhancement Program
Program Director:
Linda M. Liau, MD, PhD, MBA
A central mission of the UCLA SPORE in Brain Cancer is to stimulate, recruit, develop, and retain new investigators in the field of brain tumor research, with particular focus on translation of scientific discoveries to novel clinical applications. The UCLA SPORE in Brain Cancer Career Enhancement Program (CEP) provides a research support resource that allows junior faculty to transition to independent investigator status with adequate peer-reviewed funding, and helps established investigators to focus or redirect their research to the area of brain cancer. Each year, we anticipate supporting two to three highly innovative candidates with CEP funds.
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Institutional SPORE Website
https://cancer.ucla.edu/research/ucla-brain-spore
Back to California SPOREs
Back to Brain SPOREs
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TRP Home Contact TRP Site Map Accessibility Disclaimer Policy FOIA HHS Vulnerability Disclosure
U.S. Department of Health and Human Services National Institutes of Health National Cancer Institute USA.gov
NIH… Turning Discovery Into Health®
dstock07734
Re: biosectinvestor post# 692720
Monday, May 20, 2024 10:53:11 AM
Post#
692727
of 692729
bio,
I bookmarked this post. Let's see what will happen soon.
BTW, when you write post, don't make it effusively verbose in a way to show you have deep insight. As illustration, no one has patience to read your long post on CSF1R-I. You just need to say one line: CSF1R-I can deplete tumor associated macrophages that suppress t-cells loaded with tumor-associated antigens. That's all we need to know. Next time make it concise and simple. This way can save your time and readers' time too.
"Merck will hold an Oncology Investor Event to coincide with the 2024 ASCO Annual Meeting on Monday, June 3, 2024, 6 p.m. CT, at which senior management will provide an update on the company’s oncology strategy and program. The event will take place in Chicago, Ill., and will be accessible via webcast. Investors, analysts, members of the media and the general public are invited to listen to a webcast of the presentation via this weblink."
https://www.merck.com/news/merck-to-present-new-data-at-2024-asco-annual-meeting-demonstrating-advancements-in-novel-oncology-treatment-approaches-across-broad-portfolio-and-diverse-pipeline/
Merck to Present New Data at 2024 ASCO Annual Meeting Demonstrating Advancements in Novel Oncology Treatment Approaches Across Broad Portfolio and Diverse Pipeline
May 15, 2024 6:45 am ET
New Phase 3 data evaluating sacituzumab tirumotecan (sac-TMT), an investigational TROP2-directed antibody-drug conjugate, in previously treated locally recurrent or metastatic triple-negative breast cancer
First presentation of Phase 2b three-year follow-up data evaluating mRNA-4157 (V940), an investigational individualized neoantigen therapy, in combination with KEYTRUDA® (pembrolizumab) in patients with high-risk stage III/IV melanoma following complete resection
RAHWAY, N.J.--(BUSINESS WIRE)-- Merck (NYSE: MRK), known as MSD outside of the United States and Canada, today announced that new data for four approved oncology medicines and four pipeline candidates in more than 25 types of cancer will be presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago from May 31-June 4. New data being shared at the meeting showcase the company’s continued progress to advance clinical research for Merck’s broad portfolio and diverse pipeline of investigational candidates.
“At ASCO, the breadth of data across multiple types of cancer and stages of disease underscores our efforts to drive innovations that have potential to shape the future of oncology,” said Dr. Marjorie Green, senior vice president and head of oncology, global clinical development, Merck Research Laboratories. “This year’s ASCO is also particularly meaningful as we approach 10 years since KEYTRUDA was first approved in the U.S. Reflecting back, it is remarkable to see just how much the oncology treatment landscape has transformed, thanks to the significant contributions from patients, researchers and physicians around the world.”
For KEYTRUDA, key presentations include updated and long-term follow-up data in certain advanced gastrointestinal cancers and advanced melanoma, as well as new quality of life and patient-reported outcomes data in metastatic bladder and earlier stage non-small cell lung cancer.
Key data for KEYTRUDA to be presented at ASCO 2024:
Three-year follow-up data from the Phase 3 KEYNOTE-966 study evaluating KEYTRUDA plus chemotherapy versus chemotherapy alone for patients with advanced biliary tract cancer (BTC) (Abstract #4093; Gastrointestinal Cancer—Gastroesophageal, Pancreatic, and Hepatobiliary Poster Session).
Longer-term follow-up results from the Phase 3 KEYNOTE-859 study evaluating KEYTRUDA plus chemotherapy versus chemotherapy alone for advanced human epidermal growth factor receptor 2 (HER2)-negative gastric or gastroesophageal junction cancer (Abstract #4045; Gastrointestinal Cancer—Gastroesophageal, Pancreatic, and Hepatobiliary Poster Session).
Patient-reported outcomes (PROs) from the Phase 3 KEYNOTE-A39/EV-302 trial evaluating KEYTRUDA plus enfortumab vedotin versus chemotherapy in patients with previously untreated locally advanced or metastatic urothelial cancer (la/mUC) (Abstract #4502; Genitourinary Cancer—Kidney and Bladder Oral Abstract Session).1
Health-related quality of life (HRQoL) data from the Phase 3 KEYNOTE-671 study evaluating perioperative KEYTRUDA (neoadjuvant KEYTRUDA plus chemotherapy followed by resection and adjuvant KEYTRUDA as a single agent) versus pre-operative chemotherapy for resectable stage II, IIIA or IIIB non-small cell lung cancer (NSCLC) (Abstract #8012; Lung Cancer—Non-Small Cell Local-Regional/Small Cell/Other Thoracic Cancers Rapid Oral Abstract Session).
Updated efficacy and safety data from both cohorts of the Phase 2 KEYNOTE-224 study evaluating KEYTRUDA monotherapy in patients with sorafenib-treated and treatment- naïve advanced hepatocellular carcinoma (HCC) (Abstract #4100; Gastrointestinal Cancer—Gastroesophageal, Pancreatic, and Hepatobiliary Poster Session).
Long-term data from the Phase 2 KEYNOTE-629 study evaluating KEYTRUDA for recurrent/metastatic or locally advanced cutaneous squamous cell carcinoma (cSCC) that is not curable by surgery or radiation (Abstract #9554; Melanoma/Skin Cancers Poster Session).
As Merck continues to build its broad oncology portfolio, the company will also present data at ASCO from its diverse pipeline of investigational candidates, many being evaluated in combination with KEYTRUDA. This includes mRNA-4157 (V940), an investigational individualized neoantigen therapy (INT) being developed in collaboration with Moderna, in combination with KEYTRUDA; vibostolimab/pembrolizumab, an investigational coformulation of vibostolimab, an anti-TIGIT therapy, and KEYTRUDA; sacituzumab tirumotecan (sac-TMT; formerly MK-2870/SKB264), an investigational anti-TROP2 antibody-drug conjugate (ADC) being developed in collaboration with Kelun-Biotech; and patritumab deruxtecan (HER3-DXd), a HER3-directed ADC being developed in collaboration with Daiichi Sankyo.
Key data from Merck’s pipeline to be presented at ASCO 2024:
First presentation of three-year follow-up data from the Phase 2b KEYNOTE-942/mRNA-4157-P201 trial evaluating mRNA-4157 (V940) in combination with KEYTRUDA as adjuvant treatment for resected high-risk melanoma (Abstract #LBA9512; Melanoma/Skin Cancers Rapid Oral Abstract Session).2
Data from a Phase 3 study conducted in China, independently led by Kelun-Biotech, evaluating sac-TMT versus chemotherapy as treatment for previously treated locally recurrent or metastatic TNBC (Abstract #104; Next-Generation Antibody–Drug Conjugates: The Revolution Continues Clinical Science Symposium Session).3
First-time data from a Phase 2 study conducted in China, independently led by Kelun-Biotech, evaluating sac-TMT in combination with KL-A167 (a PD-L1 antibody) as first-line treatment for advanced NSCLC (Abstract #8502; Lung Cancer—Non-Small Cell Metastatic Oral Abstract Session).3
Data from cohort B1 of the Phase 2 KeyVibe-005 study evaluating vibostolimab/pembrolizumab in patients with previously treated advanced mismatch repair-deficient (dMMR) endometrial cancer (Abstract #5502; Gynecologic Cancer Oral Abstract Session).
Merck investor event
Merck will hold an Oncology Investor Event to coincide with the 2024 ASCO Annual Meeting on Monday, June 3, 2024, 6 p.m. CT, at which senior management will provide an update on the company’s oncology strategy and program. The event will take place in Chicago, Ill., and will be accessible via webcast. Investors, analysts, members of the media and the general public are invited to listen to a webcast of the presentation via this weblink.
Details on abstracts listed above and additional key abstracts for Merck
Breast cancer
Sacituzumab tirumotecan (SKB264/MK-2870) in patients (pts) with previously treated locally recurrent or metastatic triple-negative breast cancer (TNBC): Results from the phase III OptiTROP-Breast01 study. B. Xu.3
Abstract #104, Next-Generation Antibody–Drug Conjugates: The Revolution Continues Clinical Science Symposium
Gastrointestinal cancers
Three-year follow-up data from KEYNOTE-966: Pembrolizumab (pembro) plus gemcitabine and cisplatin (gem/cis) compared with gem/cis alone for patients (pts) with advanced biliary tract cancer (BTC). R. Finn.
Abstract #4093, Gastrointestinal Cancer—Gastroesophageal, Pancreatic, and Hepatobiliary Poster Session
Pembrolizumab (pembro) + chemotherapy (chemo) for advanced HER2-negative gastric or gastroesophageal junction (G/GEJ) cancer: Updated results from the KEYNOTE-859 study. S. Rha.
Abstract #4045, Gastrointestinal Cancer—Gastroesophageal, Pancreatic, and Hepatobiliary Poster Session
Pembrolizumab (pembro) in patients (pts) with sorafenib-treated (cohort 1) and treatment (tx)-naive (cohort 2) advanced hepatocellular carcinoma (aHCC) after additional follow-up in the phase 2 KEYNOTE-224 study. R. Finn.
Abstract #4100, Gastrointestinal Cancer—Gastroesophageal, Pancreatic, and Hepatobiliary Poster Session
Phase II trial of BXCL701 and pembrolizumab in patients with metastatic pancreatic ductal adenocarcinoma (EXPEL-PANC): Preliminary findings. B. Weinberg.4
Abstract #LBA4132, Gastrointestinal Cancer—Gastroesophageal, Pancreatic, and Hepatobiliary Poster Session
NEOPRISM-CRC: Neoadjuvant pembrolizumab stratified to tumour mutation burden for high risk stage 2 or stage 3 deficient-MMR/MSI-high colorectal cancer. K. Shiu.
Abstract #LBA3504, Gastrointestinal Cancer—Colorectal and Anal
Oral Abstract Session
Genitourinary cancers
Patient-reported outcomes (PROs) from a randomized, phase 3 trial of enfortumab vedotin plus pembrolizumab (EV+P) versus platinum-based chemotherapy (PBC) in previously untreated locally advanced or metastatic urothelial cancer (la/mUC). S. Gupta.1
Abstract #4502, Genitourinary Cancer—Kidney and Bladder Oral Abstract Session
Gynecologic cancers
Vibostolimab coformulated with pembrolizumab (vibo/pembro) for previously treated advanced mismatch repair–deficient (dMMR) endometrial cancer: Results from cohort B1 of the phase 2 KeyVibe-005 study. C. Rojas.
Abstract #5502, Gynecologic Cancer Oral Abstract Session
Lung cancer
Health-related quality of life (HRQoL) outcomes from the randomized, double-blind phase 3 KEYNOTE-671 study of perioperative pembrolizumab for early-stage non-small-cell lung cancer (NSCLC). M. Garrassino.
Abstract #8012, Lung Cancer—Non-Small Cell Local-Regional/Small Cell/Other Thoracic Cancers Rapid Oral Abstract Session
Sacituzumab tirumotecan (SKB264/MK-2870) in combination with KL-A167 (anti-PD-L1) as first-line treatment for patients with advanced NSCLC from the phase II OptiTROP-Lung01 study. W. Fang.3
Abstract #8502, Lung Cancer—Non-Small Cell Metastatic Oral Abstract Session
Melanoma
Individualized neoantigen therapy mRNA-4157 (V940) plus pembrolizumab in resected melanoma: 3-year update from the mRNA-4157-P201 (KEYNOTE-942) trial. J. Weber.2
Abstract #LBA9512, Melanoma/Skin Cancers Rapid Oral Abstract Session
Pembrolizumab (pembro) for locally advanced (LA) or recurrent/metastatic (R/M) cutaneous squamous cell carcinoma (cSCC): Long-term results of the phase 2 KEYNOTE-629 study. E. Muñoz.
Abstract #9554, Melanoma/Skin Cancers Poster Session
Lenvatinib (len) plus pembrolizumab (pembro) in patients with advanced melanoma that progressed on anti–PD-(L)1 therapy: Over 4 years of follow-up from the phase 2 LEAP-004 study. A. Arance.5
Abstract #9559, Melanoma/Skin Cancers Poster Session
1 In collaboration with Pfizer and Astellas 2 Led by Moderna 3 Independent study led by Kelun-Biotech 4 Sponsored by Georgetown University, in collaboration with BioXcel Therapeutics, Inc. 5 In collaboration with Eisai
About Merck’s early-stage cancer clinical program
Finding cancer at an earlier stage may give patients a greater chance of long-term survival. Many cancers are considered most treatable and potentially curable in their earliest stage of disease. Building on the strong understanding of the role of KEYTRUDA in later-stage cancers, Merck is studying KEYTRUDA in earlier disease states, with more than 25 ongoing registrational studies across multiple types of cancer.
About KEYTRUDA® (pembrolizumab) injection, 100 mg
KEYTRUDA is an anti-programmed death receptor-1 (PD-1) therapy that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD- L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.
Merck has the industry’s largest immuno-oncology clinical research program. There are currently more than 1,600 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient's likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.
Selected KEYTRUDA® (pembrolizumab) Indications in the U.S.
Melanoma
KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.
KEYTRUDA is indicated for the adjuvant treatment of adult and pediatric (12 years and older) patients with stage IIB, IIC, or III melanoma following complete resection.
Non-Small Cell Lung Cancer
KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.
KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.
KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [tumor proportion score (TPS) =1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is:
stage III where patients are not candidates for surgical resection or definitive chemoradiation, or
metastatic.
KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS =1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.
KEYTRUDA is indicated for the treatment of patients with resectable (tumors =4 cm or node positive) NSCLC in combination with platinum-containing chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery.
KEYTRUDA, as a single agent, is indicated as adjuvant treatment following resection and platinum-based chemotherapy for adult patients with Stage IB (T2a =4 cm), II, or IIIA NSCLC.
Urothelial Carcinoma
KEYTRUDA, in combination with enfortumab vedotin, is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer.
KEYTRUDA, as a single agent, is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma:
who are not eligible for any platinum-containing chemotherapy, or
who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
KEYTRUDA, as a single agent, is indicated for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.
Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer
KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC) as determined by an FDA-approved test.
Gastric Cancer
KEYTRUDA, in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS =1) as determined by an FDA-approved test.
This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval of this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
KEYTRUDA, in combination with fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma.
Hepatocellular Carcinoma
KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) secondary to hepatitis B who have received prior systemic therapy other than a PD-1/PD-L1-containing regimen.
Biliary Tract Cancer
KEYTRUDA, in combination with gemcitabine and cisplatin, is indicated for the treatment of patients with locally advanced unresectable or metastatic biliary tract carcinoma (BTC).
Endometrial Carcinoma
KEYTRUDA, in combination with LENVIMA, is indicated for the treatment of patients with advanced endometrial carcinoma that is mismatch repair proficient (pMMR) as determined by an FDA-approved test or not MSI-H, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation.
KEYTRUDA, as a single agent, is indicated for the treatment of patients with advanced endometrial carcinoma that is MSI-H or dMMR, as determined by an FDA-approved test, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation.
Cutaneous Squamous Cell Carcinoma
KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) or locally advanced cSCC that is not curable by surgery or radiation.
Triple-Negative Breast Cancer
KEYTRUDA is indicated for the treatment of patients with high-risk early-stage triple-negative breast cancer (TNBC) in combination with chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery.
KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS =10) as determined by an FDA-approved test.
See additional selected KEYTRUDA indications in the U.S. after the Selected Important Safety Information.
Selected Important Safety Information for KEYTRUDA
Severe and Fatal Immune-Mediated Adverse Reactions
KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death receptor-1 (PD-1) or the programmed death ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, can affect more than one body system simultaneously, and can occur at any time after starting treatment or after discontinuation of treatment. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions.
Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Early identification and management are essential to ensure safe use of anti–PD-1/PD-L1 treatments. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. For patients with TNBC treated with KEYTRUDA in the neoadjuvant setting, monitor blood cortisol at baseline, prior to surgery, and as clinically indicated. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.
Withhold or permanently discontinue KEYTRUDA depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose adverse reactions are not controlled with corticosteroid therapy.
Immune-Mediated Pneumonitis
KEYTRUDA can cause immune-mediated pneumonitis. The incidence is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Pneumonitis resolved in 59% of the 94 patients.
Pneumonitis occurred in 8% (31/389) of adult patients with cHL receiving KEYTRUDA as a single agent, including Grades 3-4 in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 5.4% (21) of patients. Of the patients who developed pneumonitis, 42% interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution.
Pneumonitis occurred in 7% (41/580) of adult patients with resected NSCLC who received KEYTRUDA as a single agent for adjuvant treatment of NSCLC, including fatal (0.2%), Grade 4 (0.3%), and Grade 3 (1%) adverse reactions. Patients received high-dose corticosteroids for a median duration of 10 days (range: 1 day to 2.3 months). Pneumonitis led to discontinuation of KEYTRUDA in 26 (4.5%) of patients. Of the patients who developed pneumonitis, 54% interrupted KEYTRUDA, 63% discontinued KEYTRUDA, and 71% had resolution.
Immune-Mediated Colitis
KEYTRUDA can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (1.1%), and Grade 2 (0.4%) reactions. Systemic corticosteroids were required in 69% (33/48); additional immunosuppressant therapy was required in 4.2% of patients. Colitis led to permanent discontinuation of KEYTRUDA in 0.5% (15) and withholding in 0.5% (13) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Colitis resolved in 85% of the 48 patients.
Hepatotoxicity and Immune-Mediated Hepatitis
KEYTRUDA as a Single Agent
KEYTRUDA can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.4%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 68% (13/19) of patients; additional immunosuppressant therapy was required in 11% of patients. Hepatitis led to permanent discontinuation of KEYTRUDA in 0.2% (6) and withholding in 0.3% (9) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Hepatitis resolved in 79% of the 19 patients.
KEYTRUDA With Axitinib
KEYTRUDA in combination with axitinib can cause hepatic toxicity. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider monitoring more frequently as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased alanine aminotransferase (ALT) (20%) and increased aspartate aminotransferase (AST) (13%) were seen at a higher frequency compared to KEYTRUDA alone. Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT =3 times upper limit of normal (ULN) (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%. Among the 92 patients who were rechallenged with either KEYTRUDA (n=3) or axitinib (n=34) administered as a single agent or with both (n=55), recurrence of ALT =3 times ULN was observed in 1 patient receiving KEYTRUDA, 16 patients receiving axitinib, and 24 patients receiving both. All patients with a recurrence of ALT =3 ULN subsequently recovered from the event.
Immune-Mediated Endocrinopathies
Adrenal Insufficiency
KEYTRUDA can cause primary or secondary adrenal insufficiency. For Grade 2 or higher, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA depending on severity. Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.3%) reactions. Systemic corticosteroids were required in 77% (17/22) of patients; of these, the majority remained on systemic corticosteroids. Adrenal insufficiency led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.3% (8) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.
Hypophysitis
KEYTRUDA can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Hypophysitis occurred in 0.6% (17/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.2%) reactions. Systemic corticosteroids were required in 94% (16/17) of patients; of these, the majority remained on systemic corticosteroids. Hypophysitis led to permanent discontinuation of KEYTRUDA in 0.1% (4) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.
Thyroid Disorders
KEYTRUDA can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Thyroiditis occurred in 0.6% (16/2799) of patients receiving KEYTRUDA, including Grade 2 (0.3%). None discontinued, but KEYTRUDA was withheld in <0.1% (1) of patients.
Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (0.8%). It led to permanent discontinuation of KEYTRUDA in <0.1% (2) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Hypothyroidism occurred in 8% (237/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (6.2%). It led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.5% (14) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. The majority of patients with hypothyroidism required long-term thyroid hormone replacement. The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC, occurring in 16% of patients receiving KEYTRUDA as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. The incidence of new or worsening hypothyroidism was higher in 389 adult patients with cHL (17%) receiving KEYTRUDA as a single agent, including Grade 1 (6.2%) and Grade 2 (10.8%) hypothyroidism. The incidence of new or worsening hyperthyroidism was higher in 580 patients with resected NSCLC, occurring in 11% of patients receiving KEYTRUDA as a single agent as adjuvant treatment, including Grade 3 (0.2%) hyperthyroidism. The incidence of new or worsening hypothyroidism was higher in 580 patients with resected NSCLC, occurring in 22% of patients receiving KEYTRUDA as a single agent as adjuvant treatment (KEYNOTE-091), including Grade 3 (0.3%) hypothyroidism.
Type 1 Diabetes Mellitus (DM), Which Can Present With Diabetic Ketoacidosis
Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold KEYTRUDA depending on severity. Type 1 DM occurred in 0.2% (6/2799) of patients receiving KEYTRUDA. It led to permanent discontinuation in <0.1% (1) and withholding of KEYTRUDA in <0.1% (1) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.
Immune-Mediated Nephritis With Renal Dysfunction
KEYTRUDA can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.1%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 89% (8/9) of patients. Nephritis led to permanent discontinuation of KEYTRUDA in 0.1% (3) and withholding in 0.1% (3) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Nephritis resolved in 56% of the 9 patients.
Immune-Mediated Dermatologic Adverse Reactions
KEYTRUDA can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms, and toxic epidermal necrolysis, has occurred with anti–PD-1/PD-L1 treatments. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes. Withhold or permanently discontinue KEYTRUDA depending on severity. Immune-mediated dermatologic adverse reactions occurred in 1.4% (38/2799) of patients receiving KEYTRUDA, including Grade 3 (1%) and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 40% (15/38) of patients. These reactions led to permanent discontinuation in 0.1% (2) and withholding of KEYTRUDA in 0.6% (16) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 6% had recurrence. The reactions resolved in 79% of the 38 patients.
Other Immune-Mediated Adverse Reactions
The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received KEYTRUDA or were reported with the use of other anti–PD-1/PD-L1 treatments. Severe or fatal cases have been reported for some of these adverse reactions. Cardiac/Vascular: Myocarditis, pericarditis, vasculitis; Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy; Ocular: Uveitis, iritis and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss; Gastrointestinal: Pancreatitis, to include increases in serum amylase and lipase levels, gastritis, duodenitis; Musculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis (and associated sequelae, including renal failure), arthritis (1.5%), polymyalgia rheumatica; Endocrine: Hypoparathyroidism; Hematologic/Immune: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection, other transplant (including corneal graft) rejection.
Infusion-Related Reactions
KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% of 2799 patients receiving KEYTRUDA. Monitor for signs and symptoms of infusion-related reactions. Interrupt or slow the rate of infusion for Grade 1 or Grade 2 reactions. For Grade 3 or Grade 4 reactions, stop infusion and permanently discontinue KEYTRUDA.
Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)
Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after anti–PD-1/PD-L1 treatments. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute and chronic GVHD, hepatic veno-occlusive disease after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between anti–PD-1/PD-L1 treatments and allogeneic HSCT. Follow patients closely for evidence of these complications and intervene promptly. Consider the benefit vs risks of using anti–PD-1/PD-L1 treatments prior to or after an allogeneic HSCT.
Increased Mortality in Patients With Multiple Myeloma
In trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of these patients with an anti–PD-1/PD-L1 treatment in this combination is not recommended outside of controlled trials.
Embryofetal Toxicity
Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. Advise women of this potential risk. In females of reproductive potential, verify pregnancy status prior to initiating KEYTRUDA and advise them to use effective contraception during treatment and for 4 months after the last dose.
Adverse Reactions
In KEYNOTE-006, KEYTRUDA was discontinued due to adverse reactions in 9% of 555 patients with advanced melanoma; adverse reactions leading to permanent discontinuation in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). The most common adverse reactions (=20%) with KEYTRUDA were fatigue (28%), diarrhea (26%), rash (24%), and nausea (21%).
In KEYNOTE-054, when KEYTRUDA was administered as a single agent to patients with stage III melanoma, KEYTRUDA was permanently discontinued due to adverse reactions in 14% of 509 patients; the most common (=1%) were pneumonitis (1.4%), colitis (1.2%), and diarrhea (1%). Serious adverse reactions occurred in 25% of patients receiving KEYTRUDA. The most common adverse reaction (=20%) with KEYTRUDA was diarrhea (28%). In KEYNOTE-716, when KEYTRUDA was administered as a single agent to patients with stage IIB or IIC melanoma, adverse reactions occurring in patients with stage IIB or IIC melanoma were similar to those occurring in 1011 patients with stage III melanoma from KEYNOTE-054.
In KEYNOTE-189, when KEYTRUDA was administered with pemetrexed and platinum chemotherapy in metastatic nonsquamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 20% of 405 patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney injury (2%). The most common adverse reactions (=20%) with KEYTRUDA were nausea (56%), fatigue (56%), constipation (35%), diarrhea (31%), decreased appetite (28%), rash (25%), vomiting (24%), cough (21%), dyspnea (21%), and pyrexia (20%).
In KEYNOTE-407, when KEYTRUDA was administered with carboplatin and either paclitaxel or paclitaxel protein-bound in metastatic squamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 15% of 101 patients. The most frequent serious adverse reactions reported in at least 2% of patients were febrile neutropenia, pneumonia, and urinary tract infection. Adverse reactions observed in KEYNOTE-407 were similar to those observed in KEYNOTE-189 with the exception that increased incidences of alopecia (47% vs 36%) and peripheral neuropathy (31% vs 25%) were observed in the KEYTRUDA and chemotherapy arm compared to the placebo and chemotherapy arm in KEYNOTE-407.
In KEYNOTE-042, KEYTRUDA was discontinued due to adverse reactions in 19% of 636 patients with advanced NSCLC; the most common were pneumonitis (3%), death due to unknown cause (1.6%), and pneumonia (1.4%). The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia (7%), pneumonitis (3.9%), pulmonary embolism (2.4%), and pleural effusion (2.2%). The most common adverse reaction (=20%) was fatigue (25%).
In KEYNOTE-010, KEYTRUDA monotherapy was discontinued due to adverse reactions in 8% of 682 patients with metastatic NSCLC; the most common was pneumonitis (1.8%). The most common adverse reactions (=20%) were decreased appetite (25%), fatigue (25%), dyspnea (23%), and nausea (20%).
In KEYNOTE-671, adverse reactions occurring in patients with resectable NSCLC receiving KEYTRUDA in combination with platinum-containing chemotherapy, given as neoadjuvant treatment and continued as single-agent adjuvant treatment, were generally similar to those occurring in patients in other clinical trials across tumor types receiving KEYTRUDA in combination with chemotherapy.
The most common adverse reactions (reported in =20%) in patients receiving KEYTRUDA in combination with chemotherapy were fatigue/asthenia, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, dyspnea, pyrexia, alopecia, peripheral neuropathy, mucosal inflammation, stomatitis, headache, weight loss, abdominal pain, arthralgia, myalgia, insomnia, palmar-plantar erythrodysesthesia, urinary tract infection, and hypothyroidism.
In the neoadjuvant phase of KEYNOTE-671, when KEYTRUDA was administered in combination with platinum-containing chemotherapy as neoadjuvant treatment, serious adverse reactions occurred in 34% of 396 patients. The most frequent (=2%) serious adverse reactions were pneumonia (4.8%), venous thromboembolism (3.3%), and anemia (2%). Fatal adverse reactions occurred in 1.3% of patients, including death due to unknown cause (0.8%), sepsis (0.3%), and immune-mediated lung disease (0.3%). Permanent discontinuation of any study drug due to an adverse reaction occurred in 18% of patients who received KEYTRUDA in combination with platinum-containing chemotherapy; the most frequent adverse reactions (=1%) that led to permanent discontinuation of any study drug were acute kidney injury (1.8%), interstitial lung disease (1.8%), anemia (1.5%), neutropenia (1.5%), and pneumonia (1.3%).
Of the KEYTRUDA-treated patients who received neoadjuvant treatment, 6% of 396 patients did not receive surgery due to adverse reactions. The most frequent (=1%) adverse reaction that led to cancellation of surgery in the KEYTRUDA arm was interstitial lung disease (1%).
In the adjuvant phase of KEYNOTE-671, when KEYTRUDA was administered as a single agent as adjuvant treatment, serious adverse reactions occurred in 14% of 290 patients. The most frequent serious adverse reaction was pneumonia (3.4%). One fatal adverse reaction of pulmonary hemorrhage occurred. Permanent discontinuation of KEYTRUDA due to an adverse reaction occurred in 12% of patients who received KEYTRUDA as a single agent, given as adjuvant treatment; the most frequent adverse reactions (=1%) that led to permanent discontinuation of KEYTRUDA were diarrhea (1.7%), interstitial lung disease (1.4%), increased aspartate aminotransferase (1%), and musculoskeletal pain (1%).
Adverse reactions observed in KEYNOTE-091 were generally similar to those occurring in other patients with NSCLC receiving KEYTRUDA as a single agent, with the exception of hypothyroidism (22%), hyperthyroidism (11%), and pneumonitis (7%). Two fatal adverse reactions of myocarditis occurred.
In KEYNOTE-048, KEYTRUDA monotherapy was discontinued due to adverse events in 12% of 300 patients with HNSCC; the most common adverse reactions leading to permanent discontinuation were sepsis (1.7%) and pneumonia (1.3%). The most common adverse reactions (=20%) were fatigue (33%), constipation (20%), and rash (20%).
In KEYNOTE-048, when KEYTRUDA was administered in combination with platinum (cisplatin or carboplatin) and FU chemotherapy, KEYTRUDA was discontinued due to adverse reactions in 16% of 276 patients with HNSCC. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonia (2.5%), pneumonitis (1.8%), and septic shock (1.4%). The most common adverse reactions (=20%) were nausea (51%), fatigue (49%), constipation (37%), vomiting (32%), mucosal inflammation (31%), diarrhea (29%), decreased appetite (29%), stomatitis (26%), and cough (22%).
In KEYNOTE-012, KEYTRUDA was discontinued due to adverse reactions in 17% of 192 patients with HNSCC. Serious adverse reactions occurred in 45% of patients. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. The most common adverse reactions (=20%) were fatigue, decreased appetite, and dyspnea. Adverse reactions occurring in patients with HNSCC were generally similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy, with the exception of increased incidences of facial edema and new or worsening hypothyroidism.
In KEYNOTE-204, KEYTRUDA was discontinued due to adverse reactions in 14% of 148 patients with cHL. Serious adverse reactions occurred in 30% of patients receiving KEYTRUDA; those =1% were pneumonitis, pneumonia, pyrexia, myocarditis, acute kidney injury, febrile neutropenia, and sepsis. Three patients died from causes other than disease progression: 2 from complications after allogeneic HSCT and 1 from unknown cause. The most common adverse reactions (=20%) were upper respiratory tract infection (41%), musculoskeletal pain (32%), diarrhea (22%), and pyrexia, fatigue, rash, and cough (20% each).
In KEYNOTE-087, KEYTRUDA was discontinued due to adverse reactions in 5% of 210 patients with cHL. Serious adverse reactions occurred in 16% of patients; those =1% were pneumonia, pneumonitis, pyrexia, dyspnea, GVHD, and herpes zoster. Two patients died from causes other than disease progression: 1 from GVHD after subsequent allogeneic HSCT and 1 from septic shock. The most common adverse reactions (=20%) were fatigue (26%), pyrexia (24%), cough (24%), musculoskeletal pain (21%), diarrhea (20%), and rash (20%).
In KEYNOTE-170, KEYTRUDA was discontinued due to adverse reactions in 8% of 53 patients with PMBCL. Serious adverse reactions occurred in 26% of patients and included arrhythmia (4%), cardiac tamponade (2%), myocardial infarction (2%), pericardial effusion (2%), and pericarditis (2%). Six (11%) patients died within 30 days of start of treatment. The most common adverse reactions (=20%) were musculoskeletal pain (30%), upper respiratory tract infection and pyrexia (28% each), cough (26%), fatigue (23%), and dyspnea (21%).
In KEYNOTE-A39, when KEYTRUDA was administered in combination with enfortumab vedotin to patients with locally advanced or metastatic urothelial cancer (n=440), fatal adverse reactions occurred in 3.9% of patients, including acute respiratory failure (0.7%), pneumonia (0.5%), and pneumonitis/ILD (0.2%). Serious adverse reactions occurred in 50% of patients receiving KEYTRUDA in combination with enfortumab vedotin; the serious adverse reactions in =2% of patients were rash (6%), acute kidney injury (5%), pneumonitis/ILD (4.5%), urinary tract infection (3.6%), diarrhea (3.2%), pneumonia (2.3%), pyrexia (2%), and hyperglycemia (2%). Permanent discontinuation of KEYTRUDA occurred in 27% of patients. The most common adverse reactions (=2%) resulting in permanent discontinuation of KEYTRUDA were pneumonitis/ILD (4.8%) and rash (3.4%). The most common adverse reactions (=20%) occurring in patients treated with KEYTRUDA in combination with enfortumab vedotin were rash (68%), peripheral neuropathy (67%), fatigue (51%), pruritus (41%), diarrhea (38%), alopecia (35%), weight loss (33%), decreased appetite (33%), nausea (26%), constipation (26%), dry eye (24%), dysgeusia (21%), and urinary tract infection (21%).
In KEYNOTE-052, KEYTRUDA was discontinued due to adverse reactions in 11% of 370 patients with locally advanced or metastatic urothelial carcinoma. Serious adverse reactions occurred in 42% of patients; those =2% were urinary tract infection, hematuria, acute kidney injury, pneumonia, and urosepsis. The most common adverse reactions (=20%) were fatigue (38%), musculoskeletal pain (24%), decreased appetite (22%), constipation (21%), rash (21%), and diarrhea (20%).
In KEYNOTE-045, KEYTRUDA was discontinued due to adverse reactions in 8% of 266 patients with locally advanced or metastatic urothelial carcinoma. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.9%). Serious adverse reactions occurred in 39% of KEYTRUDA-treated patients; those =2% were urinary tract infection, pneumonia, anemia, and pneumonitis. The most common adverse reactions (=20%) in patients who received KEYTRUDA were fatigue (38%), musculoskeletal pain (32%), pruritus (23%), decreased appetite (21%), nausea (21%), and rash (20%).
In KEYNOTE-057, KEYTRUDA was discontinued due to adverse reactions in 11% of 148 patients with high-risk NMIBC. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.4%). Serious adverse reactions occurred in 28% of patients; those =2% were pneumonia (3%), cardiac ischemia (2%), colitis (2%), pulmonary embolism (2%), sepsis (2%), and urinary tract infection (2%). The most common adverse reactions (=20%) were fatigue (29%), diarrhea (24%), and rash (24%).
Adverse reactions occurring in patients with MSI-H or dMMR CRC were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy.
In KEYNOTE-158 and KEYNOTE-164, adverse reactions occurring in patients with MSI-H or dMMR cancer were similar to those occurring in patients with other solid tumors who received KEYTRUDA as a single agent.
In KEYNOTE-811, when KEYTRUDA was administered in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, KEYTRUDA was discontinued due to adverse reactions in 6% of 217 patients with locally advanced unresectable or metastatic HER2+ gastric or GEJ adenocarcinoma. The most common adverse reaction resulting in permanent discontinuation was pneumonitis (1.4%). In the KEYTRUDA arm vs placebo, there was a difference of =5% incidence between patients treated with KEYTRUDA vs standard of care for diarrhea (53% vs 44%) and nausea (49% vs 44%).
The most common adverse reactions (reported in =20%) of patients receiving KEYTRUDA in combination with chemotherapy were fatigue/asthenia, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, dyspnea, pyrexia, alopecia, peripheral neuropathy, mucosal inflammation, stomatitis, headache, weight loss, abdominal pain, arthralgia, myalgia, insomnia, palmar-plantar erythrodysesthesia, urinary tract infection, and hypothyroidism.
In KEYNOTE-859, when KEYTRUDA was administered in combination with fluoropyrimidine- and platinum-containing chemotherapy, serious adverse reactions occurred in 45% of 785 patients. Serious adverse reactions in >2% of patients included pneumonia (4.1%), diarrhea (3.9%), hemorrhage (3.9%), and vomiting (2.4%). Fatal adverse reactions occurred in 8% of patients who received KEYTRUDA including infection (2.3%) and thromboembolism (1.3%). KEYTRUDA was discontinued due to adverse reactions in 15% of patients. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA (=1%) were infections (1.8%) and diarrhea (1%). The most common adverse reactions (reported in =20%) in patients receiving KEYTRUDA in combination with chemotherapy were peripheral neuropathy (47%), nausea (46%), fatigue (40%), diarrhea (36%), vomiting (34%), decreased appetite (29%), abdominal pain (26%), palmar-plantar erythrodysesthesia syndrome (25%), constipation (22%), and weight loss (20%).
In KEYNOTE-590, when KEYTRUDA was administered with cisplatin and fluorouracil to patients with metastatic or locally advanced esophageal or GEJ (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma who were not candidates for surgical resection or definitive chemoradiation, KEYTRUDA was discontinued due to adverse reactions in 15% of 370 patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA (=1%) were pneumonitis (1.6%), acute kidney injury (1.1%), and pneumonia (1.1%). The most common adverse reactions (=20%) with KEYTRUDA in combination with chemotherapy were nausea (67%), fatigue (57%), decreased appetite (44%), constipation (40%), diarrhea (36%), vomiting (34%), stomatitis (27%), and weight loss (24%).
Adverse reactions occurring in patients with esophageal cancer who received KEYTRUDA as a monotherapy were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy.
In KEYNOTE-A18, when KEYTRUDA was administered with CRT (cisplatin plus external beam radiation therapy [EBRT] followed by brachytherapy [BT]) to patients with FIGO 2014 Stage III-IVA cervical cancer, fatal adverse reactions occurred in 1.4% of 292 patients, including 1 case each (0.3%) of large intestinal perforation, urosepsis, sepsis, and vaginal hemorrhage. Serious adverse reactions occurred in 30% of patients; those =1% included urinary tract infection (2.7%), urosepsis (1.4%), and sepsis (1%). KEYTRUDA was discontinued for adverse reactions in 7% of patients. The most common adverse reaction (=1%) resulting in permanent discontinuation was diarrhea (1%). For patients treated with KEYTRUDA in combination with CRT, the most common adverse reactions (=10%) were nausea (56%), diarrhea (50%), vomiting (33%), urinary tract infection (32%), fatigue (26%), hypothyroidism (20%), constipation (18%), decreased appetite and weight loss (17% each), abdominal pain and pyrexia (12% each), hyperthyroidism, dysuria, rash (11% each), and pelvic pain (10%).
In KEYNOTE-826, when KEYTRUDA was administered in combination with paclitaxel and cisplatin or paclitaxel and carboplatin, with or without bevacizumab (n=307), to patients with persistent, recurrent, or first-line metastatic cervical cancer regardless of tumor PD-L1 expression who had not been treated with chemotherapy except when used concurrently as a radio-sensitizing agent, fatal adverse reactions occurred in 4.6% of patients, including 3 cases of hemorrhage, 2 cases each of sepsis and due to unknown causes, and 1 case each of acute myocardial infarction, autoimmune encephalitis, cardiac arrest, cerebrovascular accident, femur fracture with perioperative pulmonary embolus, intestinal perforation, and pelvic infection. Serious adverse reactions occurred in 50% of patients receiving KEYTRUDA in combination with chemotherapy with or without bevacizumab; those =3% were febrile neutropenia (6.8%), urinary tract infection (5.2%), anemia (4.6%), and acute kidney injury and sepsis (3.3% each).
KEYTRUDA was discontinued in 15% of patients due to adverse reactions. The most common adverse reaction resulting in permanent discontinuation (=1%) was colitis (1%).
For patients treated with KEYTRUDA, chemotherapy, and bevacizumab (n=196), the most common adverse reactions (=20%) were peripheral neuropathy (62%), alopecia (58%), anemia (55%), fatigue/asthenia (53%), nausea and neutropenia (41% each), diarrhea (39%), hypertension and thrombocytopenia (35% each), constipation and arthralgia (31% each), vomiting (30%), urinary tract infection (27%), rash (26%), leukopenia (24%), hypothyroidism (22%), and decreased appetite (21%).
For patients treated with KEYTRUDA in combination with chemotherapy with or without bevacizumab, the most common adverse reactions (=20%) were peripheral neuropathy (58%), alopecia (56%), fatigue (47%), nausea (40%), diarrhea (36%), constipation (28%), arthralgia (27%), vomiting (26%), hypertension and urinary tract infection (24% each), and rash (22%).
In KEYNOTE-158, KEYTRUDA was discontinued due to adverse reactions in 8% of 98 patients with previously treated recurrent or metastatic cervical cancer. Serious adverse reactions occurred in 39% of patients receiving KEYTRUDA; the most frequent included anemia (7%), fistula, hemorrhage, and infections [except urinary tract infections] (4.1% each). The most common adverse reactions (=20%) were fatigue (43%), musculoskeletal pain (27%), diarrhea (23%), pain and abdominal pain (22% each), and decreased appetite (21%).
In KEYNOTE-394, KEYTRUDA was discontinued due to adverse reactions in 13% of 299 patients with previously treated hepatocellular carcinoma. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was ascites (2.3%). The most common adverse reactions in patients receiving KEYTRUDA (=10%) were pyrexia (18%), rash (18%), diarrhea (16%), decreased appetite (15%), pruritis (12%), upper respiratory tract infection (11%), cough (11%), and hypothyroidism (10%).
In KEYNOTE-966, when KEYTRUDA was administered in combination with gemcitabine and cisplatin, KEYTRUDA was discontinued for adverse reactions in 15% of 529 patients with locally advanced unresectable or metastatic biliary tract cancer. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA (=1%) was pneumonitis (1.3%). Adverse reactions leading to the interruption of KEYTRUDA occurred in 55% of patients. The most common adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA (=2%) were decreased neutrophil count (18%), decreased platelet count (10%), anemia (6%), decreased white blood cell count (4%), pyrexia (3.8%), fatigue (3.0%), cholangitis (2.8%), increased ALT (2.6%), increased AST (2.5%), and biliary obstruction (2.3%).
The most common adverse reactions (reported in =20%) in patients receiving KEYTRUDA in combination with chemotherapy were fatigue/asthenia, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, dyspnea, pyrexia, alopecia, peripheral neuropathy, mucosal inflammation, stomatitis, headache, weight loss, abdominal pain, arthralgia, myalgia, insomnia, palmar-plantar erythrodysesthesia, urinary tract infection, and hypothyroidism.
In KEYNOTE-017 and KEYNOTE-913, adverse reactions occurring in patients with MCC (n=105) were generally similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a single agent.
In KEYNOTE-426, when KEYTRUDA was administered in combination with axitinib, fatal adverse reactions occurred in 3.3% of 429 patients. Serious adverse reactions occurred in 40% of patients, the most frequent (=1%) were hepatotoxicity (7%), diarrhea (4.2%), acute kidney injury (2.3%), dehydration (1%), and pneumonitis (1%). Permanent discontinuation due to an adverse reaction occurred in 31% of patients; KEYTRUDA only (13%), axitinib only (13%), and the combination (8%); the most common were hepatotoxicity (13%), diarrhea/colitis (1.9%), acute kidney injury (1.6%), and cerebrovascular accident (1.2%). The most common adverse reactions (=20%) were diarrhea (56%), fatigue/asthenia (52%), hypertension (48%), hepatotoxicity (39%), hypothyroidism (35%), decreased appetite (30%), palmar-plantar erythrodysesthesia (28%), nausea (28%), stomatitis/mucosal inflammation (27%), dysphonia (25%), rash (25%), cough (21%), and constipation (21%).
In KEYNOTE-581, when KEYTRUDA was administered in combination with LENVIMA to patients with advanced renal cell carcinoma (n=352), fatal adverse reactions occurred in 4.3% of patients. Serious adverse reactions occurred in 51% of patients; the most common (=2%) were hemorrhagic events (5%), diarrhea (4%), hypertension, myocardial infarction, pneumonitis, and vomiting (3% each), acute kidney injury, adrenal insufficiency, dyspnea, and pneumonia (2% each).
Permanent discontinuation of KEYTRUDA, LENVIMA, or both due to an adverse reaction occurred in 37% of patients; 29% KEYTRUDA only, 26% LENVIMA only, and 13% both. The most common adverse reactions (=2%) resulting in permanent discontinuation of KEYTRUDA, LENVIMA, or the combination were pneumonitis, myocardial infarction, hepatotoxicity, acute kidney injury, rash (3% each), and diarrhea (2%).
The most common adverse reactions (=20%) observed with KEYTRUDA in combination with LENVIMA were fatigue (63%), diarrhea (62%), musculoskeletal disorders (58%), hypothyroidism (57%), hypertension (56%), stomatitis (43%), decreased appetite (41%), rash (37%), nausea (36%), weight loss, dysphonia and proteinuria (30% each), palmar-plantar erythrodysesthesia syndrome (29%), abdominal pain and hemorrhagic events (27% each), vomiting (26%), constipation and hepatotoxicity (25% each), headache (23%), and acute kidney injury (21%).
In KEYNOTE-564, when KEYTRUDA was administered as a single agent for the adjuvant treatment of renal cell carcinoma, serious adverse reactions occurred in 20% of patients receiving KEYTRUDA; the serious adverse reactions (=1%) were acute kidney injury, adrenal insufficiency, pneumonia, colitis, and diabetic ketoacidosis (1% each). Fatal adverse reactions occurred in 0.2% including 1 case of pneumonia. Discontinuation of KEYTRUDA due to adverse reactions occurred in 21% of 488 patients; the most common (=1%) were increased ALT (1.6%), colitis (1%), and adrenal insufficiency (1%). The most common adverse reactions (=20%) were musculoskeletal pain (41%), fatigue (40%), rash (30%), diarrhea (27%), pruritus (23%), and hypothyroidism (21%).
In KEYNOTE-775, when KEYTRUDA was administered in combination with LENVIMA to patients with advanced endometrial carcinoma that was pMMR or not MSI-H (n=342), fatal adverse reactions occurred in 4.7% of patients. Serious adverse reactions occurred in 50% of these patients; the most common (=3%) were hypertension (4.4%) and urinary tract infections (3.2%).
Discontinuation of KEYTRUDA due to an adverse reaction occurred in 15% of these patients. The most common adverse reaction leading to discontinuation of KEYTRUDA (=1%) was increased ALT (1.2%).
The most common adverse reactions for KEYTRUDA in combination with LENVIMA (reported in =20% patients) were hypothyroidism and hypertension (67% each), fatigue (58%), diarrhea (55%), musculoskeletal disorders (53%), nausea (49%), decreased appetite (44%), vomiting (37%), stomatitis (35%), abdominal pain and weight loss (34% each), urinary tract infections (31%), proteinuria (29%), constipation (27%), headache (26%), hemorrhagic events (25%), palmar-plantar erythrodysesthesia (23%), dysphonia (22%), and rash (20%).
Adverse reactions occurring in patients with MSI-H or dMMR endometrial carcinoma who received KEYTRUDA as a single agent were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a single agent.
Adverse reactions occurring in patients with TMB-H cancer were similar to those occurring in patients with other solid tumors who received KEYTRUDA as a single agent.
Adverse reactions occurring in patients with recurrent or metastatic cSCC or locally advanced cSCC were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy.
In KEYNOTE-522, when KEYTRUDA was administered with neoadjuvant chemotherapy (carboplatin and paclitaxel followed by doxorubicin or epirubicin and cyclophosphamide) followed by surgery and continued adjuvant treatment with KEYTRUDA as a single agent (n=778) to patients with newly diagnosed, previously untreated, high-risk early-stage TNBC, fatal adverse reactions occurred in 0.9% of patients, including 1 each of adrenal crisis, autoimmune encephalitis, hepatitis, pneumonia, pneumonitis, pulmonary embolism, and sepsis in association with multiple organ dysfunction syndrome and myocardial infarction. Serious adverse reactions occurred in 44% of patients receiving KEYTRUDA; those =2% were febrile neutropenia (15%), pyrexia (3.7%), anemia (2.6%), and neutropenia (2.2%). KEYTRUDA was discontinued in 20% of patients due to adverse reactions. The most common reactions (=1%) resulting in permanent discontinuation were increased ALT (2.7%), increased AST (1.5%), and rash (1%). The most common adverse reactions (=20%) in patients receiving KEYTRUDA were fatigue (70%), nausea (67%), alopecia (61%), rash (52%), constipation (42%), diarrhea and peripheral neuropathy (41% each), stomatitis (34%), vomiting (31%), headache (30%), arthralgia (29%), pyrexia (28%), cough (26%), abdominal pain (24%), decreased appetite (23%), insomnia (21%), and myalgia (20%).
In KEYNOTE-355, when KEYTRUDA and chemotherapy (paclitaxel, paclitaxel protein-bound, or gemcitabine and carboplatin) were administered to patients with locally recurrent unresectable or metastatic TNBC who had not been previously treated with chemotherapy in the metastatic setting (n=596), fatal adverse reactions occurred in 2.5% of patients, including cardio-respiratory arrest (0.7%) and septic shock (0.3%). Serious adverse reactions occurred in 30% of patients receiving KEYTRUDA in combination with chemotherapy; the serious reactions in =2% were pneumonia (2.9%), anemia (2.2%), and thrombocytopenia (2%). KEYTRUDA was discontinued in 11% of patients due to adverse reactions. The most common reactions resulting in permanent discontinuation (=1%) were increased ALT (2.2%), increased AST (1.5%), and pneumonitis (1.2%). The most common adverse reactions (=20%) in patients receiving KEYTRUDA in combination with chemotherapy were fatigue (48%), nausea (44%), alopecia (34%), diarrhea and constipation (28% each), vomiting and rash (26% each), cough (23%), decreased appetite (21%), and headache (20%).
Lactation
Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment and for 4 months after the last dose.
Pediatric Use
In KEYNOTE-051, 173 pediatric patients (65 pediatric patients aged 6 months to younger than 12 years and 108 pediatric patients aged 12 years to 17 years) were administered KEYTRUDA 2 mg/kg every 3 weeks. The median duration of exposure was 2.1 months (range: 1 day to 25 months).
Adverse reactions that occurred at a =10% higher rate in pediatric patients when compared to adults were pyrexia (33%), leukopenia (31%), vomiting (29%), neutropenia (28%), headache (25%), abdominal pain (23%), thrombocytopenia (22%), Grade 3 anemia (17%), decreased lymphocyte count (13%), and decreased white blood cell count (11%).
Geriatric Use
Of the 564 patients with locally advanced or metastatic urothelial cancer treated with KEYTRUDA in combination with enfortumab vedotin, 44% (n=247) were 65-74 years and 26% (n=144) were 75 years or older. No overall differences in safety or effectiveness were observed between patients 65 years of age or older and younger patients. Patients 75 years of age or older treated with KEYTRUDA in combination with enfortumab vedotin experienced a higher incidence of fatal adverse reactions than younger patients. The incidence of fatal adverse reactions was 4% in patients younger than 75 and 7% in patients 75 years or older.
Additional Selected KEYTRUDA Indications in the U.S.
Head and Neck Squamous Cell Cancer
KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).
KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [Combined Positive Score (CPS) =1] as determined by an FDA-approved test.
KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy.
Classical Hodgkin Lymphoma
KEYTRUDA is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL).
KEYTRUDA is indicated for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy.
Primary Mediastinal Large B-Cell Lymphoma
KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy.
KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.
Microsatellite Instability-High or Mismatch Repair Deficient Cancer
KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options.
Esophageal Cancer
KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic esophageal or gastroesophageal junction (GEJ) (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either:
in combination with platinum- and fluoropyrimidine-based chemotherapy, or
as a single agent after one or more prior lines of systemic therapy for patients with tumors of squamous cell histology that express PD-L1 (CPS =10) as determined by an FDA-approved test.
Cervical Cancer
KEYTRUDA, in combination with chemoradiotherapy (CRT), is indicated for the treatment of patients with FIGO 2014 Stage III-IVA cervical cancer.
KEYTRUDA, in combination with chemotherapy, with or without bevacizumab, is indicated for the treatment of patients with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1 (CPS =1) as determined by an FDA-approved test.
KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS =1) as determined by an FDA-approved test.
Merkel Cell Carcinoma
KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC).
Renal Cell Carcinoma
KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC).
KEYTRUDA, in combination with LENVIMA, is indicated for the first-line treatment of adult patients with advanced RCC.
KEYTRUDA is indicated for the adjuvant treatment of patients with RCC at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions.
Tumor Mutational Burden-High Cancer
KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [=10 mutations/megabase (mut/Mb)] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options.
This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
The safety and effectiveness of KEYTRUDA in pediatric patients with TMB-H central nervous system cancers have not been established.
Please see Prescribing Information for KEYTRUDA (pembrolizumab) at http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf and Medication Guide for KEYTRUDA at http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_mg.pdf .
About LENVIMA® (lenvatinib); available as 10 mg and 4 mg capsules
LENVIMA, discovered and developed by Eisai, is an orally available multiple receptor tyrosine kinase inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). LENVIMA inhibits other kinases that have been implicated in pathogenic angiogenesis, tumor growth, and cancer progression in addition to their normal cellular functions, including fibroblast growth factor (FGF) receptors FGFR1-4, the platelet derived growth factor receptor alpha (PDGFRa), KIT, and RET. In syngeneic mouse tumor models, LENVIMA decreased tumor-associated macrophages, increased activated cytotoxic T cells, and demonstrated greater antitumor activity in combination with an anti-PD-1 monoclonal antibody compared to either treatment alone.
LENVIMA® (lenvatinib) Indications in the U.S.
For the treatment of adult patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC)
In combination with pembrolizumab, for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC)
In combination with everolimus, for the treatment of adult patients with advanced renal cell carcinoma (RCC) following one prior anti-angiogenic therapy
For the first-line treatment of patients with unresectable hepatocellular carcinoma (HCC)
In combination with pembrolizumab, for the treatment of patients with advanced endometrial carcinoma (EC) that is mismatch repair proficient (pMMR), as determined by an FDA-approved test, or not microsatellite instability-high (MSI-H), who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation.
Selected Safety Information for LENVIMA
Warnings and Precautions
Hypertension. In differentiated thyroid cancer (DTC), hypertension occurred in 73% of patients on LENVIMA (44% grade 3-4). In advanced renal cell carcinoma (RCC), hypertension occurred in 42% of patients on LENVIMA + everolimus (13% grade 3). Systolic blood pressure =160 mmHg occurred in 29% of patients, and 21% had diastolic blood pressure =100 mmHg. In unresectable hepatocellular carcinoma (HCC), hypertension occurred in 45% of LENVIMA-treated patients (24% grade 3). Grade 4 hypertension was not reported in HCC.
Serious complications of poorly controlled hypertension have been reported. Control blood pressure prior to initiation. Monitor blood pressure after 1 week, then every 2 weeks for the first 2 months, and then at least monthly thereafter during treatment. Withhold and resume at reduced dose when hypertension is controlled or permanently discontinue based on severity.
Cardiac Dysfunction. Serious and fatal cardiac dysfunction can occur with LENVIMA. Across clinical trials in 799 patients with DTC, RCC, and HCC, grade 3 or higher cardiac dysfunction occurred in 3% of LENVIMA-treated patients. Monitor for clinical symptoms or signs of cardiac dysfunction. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.
Arterial Thromboembolic Events. Among patients receiving LENVIMA or LENVIMA + everolimus, arterial thromboembolic events of any severity occurred in 2% of patients in RCC and HCC and 5% in DTC. Grade 3-5 arterial thromboembolic events ranged from 2% to 3% across all clinical trials.
Among patients receiving LENVIMA with KEYTRUDA, arterial thrombotic events of any severity occurred in 5% of patients in CLEAR, including myocardial infarction (3.4%) and cerebrovascular accident (2.3%).
Permanently discontinue following an arterial thrombotic event. The safety of resuming after an arterial thromboembolic event has not been established, and LENVIMA has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months.
Hepatotoxicity. Across clinical studies enrolling 1,327 LENVIMA-treated patients with malignancies other than HCC, serious hepatic adverse reactions occurred in 1.4% of patients. Fatal events, including hepatic failure, acute hepatitis and hepatorenal syndrome, occurred in 0.5% of patients. In HCC, hepatic encephalopathy occurred in 8% of LENVIMA-treated patients (5% grade 3-5). Grade 3-5 hepatic failure occurred in 3% of LENVIMA-treated patients. 2% of patients discontinued LENVIMA due to hepatic encephalopathy, and 1% discontinued due to hepatic failure.
Monitor liver function prior to initiation, then every 2 weeks for the first 2 months, and at least monthly thereafter during treatment. Monitor patients with HCC closely for signs of hepatic failure, including hepatic encephalopathy. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.
Renal Failure or Impairment. Serious including fatal renal failure or impairment can occur with LENVIMA. Renal impairment was reported in 14% and 7% of LENVIMA-treated patients in DTC and HCC, respectively. Grade 3-5 renal failure or impairment occurred in 3% of patients with DTC and 2% of patients with HCC, including 1 fatal event in each study. In RCC, renal impairment or renal failure was reported in 18% of LENVIMA + everolimus–treated patients (10% grade 3).
Initiate prompt management of diarrhea or dehydration/hypovolemia. Withhold and resume at reduced dose upon recovery or permanently discontinue for renal failure or impairment based on severity.
Proteinuria. In DTC and HCC, proteinuria was reported in 34% and 26% of LENVIMA-treated patients, respectively. Grade 3 proteinuria occurred in 11% and 6% in DTC and HCC, respectively. In RCC, proteinuria occurred in 31% of patients receiving LENVIMA + everolimus (8% grade 3). Monitor for proteinuria prior to initiation and periodically during treatment. If urine dipstick proteinuria =2+ is detected, obtain a 24-hour urine protein. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.
Diarrhea. Of the 737 LENVIMA-treated patients in DTC and HCC, diarrhea occurred in 49% (6% grade 3). In RCC, diarrhea occurred in 81% of LENVIMA + everolimus–treated patients (19% grade 3). Diarrhea was the most frequent cause of dose interruption/reduction, and diarrhea recurred despite dose reduction. Promptly initiate management of diarrhea. Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.
Fistula Formation and Gastrointestinal Perforation. Of the 799 patients treated with LENVIMA or LENVIMA + everolimus in DTC, RCC, and HCC, fistula or gastrointestinal perforation occurred in 2%. Permanently discontinue in patients who develop gastrointestinal perforation of any severity or grade 3-4 fistula.
QT Interval Prolongation. In DTC, QT/QTc interval prolongation occurred in 9% of LENVIMA-treated patients and QT interval prolongation of >500 ms occurred in 2%. In RCC, QTc interval increases of >60 ms occurred in 11% of patients receiving LENVIMA + everolimus and QTc interval >500 ms occurred in 6%. In HCC, QTc interval increases of >60 ms occurred in 8% of LENVIMA-treated patients and QTc interval >500 ms occurred in 2%.
Monitor and correct electrolyte abnormalities at baseline and periodically during treatment. Monitor electrocardiograms in patients with congenital long QT syndrome, congestive heart failure, bradyarrhythmias, or those who are taking drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics. Withhold and resume at reduced dose upon recovery based on severity.
Hypocalcemia. In DTC, grade 3-4 hypocalcemia occurred in 9% of LENVIMA-treated patients. In 65% of cases, hypocalcemia improved or resolved following calcium supplementation with or without dose interruption or dose reduction. In RCC, grade 3-4 hypocalcemia occurred in 6% of LENVIMA + everolimus–treated patients. In HCC, grade 3 hypocalcemia occurred in 0.8% of LENVIMA-treated patients. Monitor blood calcium levels at least monthly and replace calcium as necessary during treatment. Withhold and resume at reduced dose upon recovery or permanently discontinue depending on severity.
Reversible Posterior Leukoencephalopathy Syndrome (RPLS). Across clinical studies of 1,823 patients who received LENVIMA as a single agent, RPLS occurred in 0.3%. Confirm diagnosis of RPLS with MRI. Withhold and resume at reduced dose upon recovery or permanently discontinue depending on severity and persistence of neurologic symptoms.
Hemorrhagic Events. Serious including fatal hemorrhagic events can occur with LENVIMA. In DTC, RCC, and HCC clinical trials, hemorrhagic events, of any grade, occurred in 29% of the 799 patients treated with LENVIMA as a single agent or in combination with everolimus. The most frequently reported hemorrhagic events (all grades and occurring in at least 5% of patients) were epistaxis and hematuria. In DTC, grade 3-5 hemorrhage occurred in 2% of LENVIMA-treated patients, including 1 fatal intracranial hemorrhage among 16 patients who received LENVIMA and had CNS metastases at baseline. In RCC, grade 3-5 hemorrhage occurred in 8% of LENVIMA + everolimus–treated patients, including 1 fatal cerebral hemorrhage. In HCC, grade 3-5 hemorrhage occurred in 5% of LENVIMA-treated patients, including 7 fatal hemorrhagic events. Serious tumor-related bleeds, including fatal hemorrhagic events, occurred in LENVIMA-treated patients in clinical trials and in the postmarketing setting. In postmarketing surveillance, serious and fatal carotid artery hemorrhages were seen more frequently in patients with anaplastic thyroid carcinoma (ATC) than other tumors. Safety and effectiveness of LENVIMA in patients with ATC have not been demonstrated in clinical trials.
Consider the risk of severe or fatal hemorrhage associated with tumor invasion or infiltration of major blood vessels (eg, carotid artery). Withhold and resume at reduced dose upon recovery or permanently discontinue based on severity.
Impairment of Thyroid Stimulating Hormone Suppression/Thyroid Dysfunction. LENVIMA impairs exogenous thyroid suppression. In DTC, 88% of patients had baseline thyroid stimulating hormone (TSH) level =0.5 mU/L. In patients with normal TSH at baseline, elevation of TSH level >0.5 mU/L was observed post baseline in 57% of LENVIMA-treated patients. In RCC and HCC, grade 1 or 2 hypothyroidism occurred in 24% of LENVIMA + everolimus–treated patients and 21% of LENVIMA-treated patients, respectively. In patients with normal or low TSH at baseline, elevation of TSH was observed post baseline in 70% of LENVIMA-treated patients in HCC and 60% of LENVIMA + everolimus–treated patients in RCC.
Monitor thyroid function prior to initiation and at least monthly during treatment. Treat hypothyroidism according to standard medical practice.
Impaired Wound Healing. Impaired wound healing has been reported in patients who received LENVIMA. Withhold LENVIMA for at least 1 week prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of LENVIMA after resolution of wound healing complications has not been established.
Osteonecrosis of the Jaw (ONJ). ONJ has been reported in patients receiving LENVIMA. Concomitant exposure to other risk factors, such as bisphosphonates, denosumab, dental disease or invasive dental procedures, may increase the risk of ONJ.
Perform an oral examination prior to treatment with LENVIMA and periodically during LENVIMA treatment. Advise patients regarding good oral hygiene practices and to consider having preventive dentistry performed prior to treatment with LENVIMA and throughout treatment with LENVIMA.
Avoid invasive dental procedures, if possible, while on LENVIMA treatment, particularly in patients at higher risk. Withhold LENVIMA for at least 1 week prior to scheduled dental surgery or invasive dental procedures, if possible. For patients requiring invasive dental procedures, discontinuation of bisphosphonate treatment may reduce the risk of ONJ.
Withhold LENVIMA if ONJ develops and restart based on clinical judgement of adequate resolution.
Embryo-Fetal Toxicity. Based on its mechanism of action and data from animal reproduction studies, LENVIMA can cause fetal harm when administered to pregnant women. In animal reproduction studies, oral administration of LENVIMA during organogenesis at doses below the recommended clinical doses resulted in embryotoxicity, fetotoxicity, and teratogenicity in rats and rabbits. Advise pregnant women of the potential risk to a fetus; and advise females of reproductive potential to use effective contraception during treatment with LENVIMA and for 30 days after the last dose.
Adverse Reactions
In DTC, the most common adverse reactions (=30%) observed in LENVIMA-treated patients were hypertension (73%), fatigue (67%), diarrhea (67%), arthralgia/myalgia (62%), decreased appetite (54%), decreased weight (51%), nausea (47%), stomatitis (41%), headache (38%), vomiting (36%), proteinuria (34%), palmar-plantar erythrodysesthesia syndrome (32%), abdominal pain (31%), and dysphonia (31%). The most common serious adverse reactions (=2%) were pneumonia (4%), hypertension (3%), and dehydration (3%).
Adverse reactions led to dose reductions in 68% of LENVIMA-treated patients; 18% discontinued LENVIMA. The most common adverse reactions (=10%) resulting in dose reductions were hypertension (13%), proteinuria (11%), decreased appetite (10%), and diarrhea (10%); the most common adverse reactions (=1%) resulting in discontinuation of LENVIMA were hypertension (1%) and asthenia (1%).
In RCC, the most common adverse reactions (=20%) observed in LENVIMA + KEYTRUDA-treated patients were fatigue (63%), diarrhea (62%), musculoskeletal pain (58%), hypothyroidism (57%), hypertension (56%), stomatitis (43%), decreased appetite (41%), rash (37%), nausea (36%), decreased weight (30%), dysphonia (30%), proteinuria (30%), palmar-plantar erythrodysesthesia syndrome (29%), abdominal pain (27%), hemorrhagic events (27%), vomiting (26%), constipation (25%), hepatotoxicity (25%), headache (23%), and acute kidney injury (21%).
Fatal adverse reactions occurred in 4.3% of patients receiving LENVIMA in combination with KEYTRUDA, including cardio-respiratory arrest (0.9%), sepsis (0.9%), and one case (0.3%) each of arrhythmia, autoimmune hepatitis, dyspnea, hypertensive crisis, increased blood creatinine, multiple organ dysfunction syndrome, myasthenic syndrome, myocarditis, nephritis, pneumonitis, ruptured aneurysm and subarachnoid hemorrhage.
Serious adverse reactions occurred in 51% of patients receiving LENVIMA and KEYTRUDA. Serious adverse reactions in =2% of patients were hemorrhagic events (5%), diarrhea (4%), hypertension (3%), myocardial infarction (3%), pneumonitis (3%), vomiting (3%), acute kidney injury (2%), adrenal insufficiency (2%), dyspnea (2%), and pneumonia (2%).
Permanent discontinuation of LENVIMA, KEYTRUDA, or both due to an adverse reaction occurred in 37% of patients; 26% LENVIMA only, 29% KEYTRUDA only, and 13% both drugs. The most common adverse reactions (=2%) leading to permanent discontinuation of LENVIMA, KEYTRUDA, or both were pneumonitis (3%), myocardial infarction (3%), hepatotoxicity (3%), acute kidney injury (3%), rash (3%), and diarrhea (2%).
Dose interruptions of LENVIMA, KEYTRUDA, or both due to an adverse reaction occurred in 78% of patients receiving LENVIMA in combination with KEYTRUDA. LENVIMA was interrupted in 73% of patients and both drugs were interrupted in 39% of patients. LENVIMA was dose reduced in 69% of patients. The most common adverse reactions (=5%) resulting in dose reduction or interruption of LENVIMA were diarrhea (26%), fatigue (18%), hypertension (17%), proteinuria (13%), decreased appetite (12%), palmar-plantar erythrodysesthesia (11%), nausea (9%), stomatitis (9%), musculoskeletal pain (8%), rash (8%), increased lipase (7%), abdominal pain (6%), and vomiting (6%), increased ALT (5%), and increased amylase (5%).
In RCC, the most common adverse reactions (=30%) observed in LENVIMA + everolimus–treated patients were diarrhea (81%), fatigue (73%), arthralgia/myalgia (55%), decreased appetite (53%), vomiting (48%), nausea (45%), stomatitis (44%), hypertension (42%), peripheral edema (42%), cough (37%), abdominal pain (37%), dyspnea (35%), rash (35%), decreased weight (34%), hemorrhagic events (32%), and proteinuria (31%). The most common serious adverse reactions (=5%) were renal failure (11%), dehydration (10%), anemia (6%), thrombocytopenia (5%), diarrhea (5%), vomiting (5%), and dyspnea (5%). Adverse reactions led to dose reductions or interruption in 89% of patients. The most common adverse reactions (=5%) resulting in dose reductions were diarrhea (21%), fatigue (8%), thrombocytopenia (6%), vomiting (6%), nausea (5%), and proteinuria (5%). Treatment discontinuation due to an adverse reaction occurred in 29% of patients.
In HCC, the most common adverse reactions (=20%) observed in LENVIMA-treated patients were hypertension (45%), fatigue (44%), diarrhea (39%), decreased appetite (34%), arthralgia/myalgia (31%), decreased weight (31%), abdominal pain (30%), palmar-plantar erythrodysesthesia syndrome (27%), proteinuria (26%), dysphonia (24%), hemorrhagic events (23%), hypothyroidism (21%), and nausea (20%). The most common serious adverse reactions (=2%) were hepatic encephalopathy (5%), hepatic failure (3%), ascites (3%), and decreased appetite (2%). Adverse reactions led to dose reductions or interruption in 62% of patients. The most common adverse reactions (=5%) resulting in dose reductions were fatigue (9%), decreased appetite (8%), diarrhea (8%), proteinuria (7%), hypertension (6%), and palmar-plantar erythrodysesthesia syndrome (5%). Treatment discontinuation due to an adverse reaction occurred in 20% of patients. The most common adverse reactions (=1%) resulting in discontinuation of LENVIMA were fatigue (1%), hepatic encephalopathy (2%), hyperbilirubinemia (1%), and hepatic failure (1%).
In endometrial carcinoma, the most common adverse reactions (=20%) observed in LENVIMA + KEYTRUDA-treated patients were hypothyroidism (67%), hypertension (67%), fatigue (58%), diarrhea (55%), musculoskeletal disorders (53%), nausea (49%), decreased appetite (44%), vomiting (37%), stomatitis (35%), decreased weight (34%), abdominal pain (34%), urinary tract infection (31%), proteinuria (29%), constipation (27%), headache (26%), hemorrhagic events (25%), palmar-plantar erythrodysesthesia (23%), dysphonia (22%), and rash (20%).
Fatal adverse reactions occurred in 4.7% of those treated with LENVIMA and KEYTRUDA, including 2 cases of pneumonia, and 1 case of the following: acute kidney injury, acute myocardial infarction, colitis, decreased appetite, intestinal perforation, lower gastrointestinal hemorrhage, malignant gastrointestinal obstruction, multiple organ dysfunction syndrome, myelodysplastic syndrome, pulmonary embolism, and right ventricular dysfunction.
Serious adverse reactions occurred in 50% of patients receiving LENVIMA and KEYTRUDA. Serious adverse reactions with frequency =3% were hypertension (4.4%), and urinary tract infection (3.2%).
Discontinuation of LENVIMA due to an adverse reaction occurred in 26% of patients. The most common (=1%) adverse reactions leading to discontinuation of LENVIMA were hypertension (2%), asthenia (1.8%), diarrhea (1.2%), decreased appetite (1.2%), proteinuria (1.2%), and vomiting (1.2%).
Dose reductions of LENVIMA due to adverse reactions occurred in 67% of patients. The most common (=5%) adverse reactions resulting in dose reduction of LENVIMA were hypertension (18%), diarrhea (11%), palmar-plantar erythrodysesthesia syndrome (9%), proteinuria (7%), fatigue (7%), decreased appetite (6%), asthenia (5%), and weight decreased (5%).
Dose interruptions of LENVIMA due to an adverse reaction occurred in 58% of these patients. The most common (=2%) adverse reactions leading to interruption of LENVIMA were hypertension (11%), diarrhea (11%), proteinuria (6%), decreased appetite (5%), vomiting (5%), increased alanine aminotransferase (3.5%), fatigue (3.5%), nausea (3.5%), abdominal pain (2.9%), weight decreased (2.6%), urinary tract infection (2.6%), increased aspartate aminotransferase (2.3%), asthenia (2.3%), and palmar-plantar erythrodysesthesia (2%).
Use in Specific Populations
Because of the potential for serious adverse reactions in breastfed children, advise women to discontinue breastfeeding during treatment and for 1 week after the last dose. LENVIMA may impair fertility in males and females of reproductive potential.
No dose adjustment is recommended for patients with mild (creatine clearance [CLcr] 60-89 mL/min) or moderate (CLcr 30-59 mL/min) renal impairment. LENVIMA concentrations may increase in patients with DTC, RCC, or EC and severe (CLcr 15-29 mL/min) renal impairment. Reduce the dose for patients with DTC, RCC, or endometrial carcinoma and severe renal impairment. There is no recommended dose for patients with HCC and severe renal impairment. LENVIMA has not been studied in patients with end stage renal disease.
No dose adjustment is recommended for patients with HCC and mild hepatic impairment (Child-Pugh A). There is no recommended dose for patients with HCC with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment. No dose adjustment is recommended for patients with DTC, RCC, or endometrial carcinoma and mild or moderate hepatic impairment. LENVIMA concentrations may increase in patients with DTC, RCC, or endometrial carcinoma and severe hepatic impairment. Reduce the dose for patients with DTC, RCC, or endometrial carcinoma and severe hepatic impairment.
Please see Prescribing Information for LENVIMA (lenvatinib) at http://www.lenvima.com/pdfs/prescribing-information.pdf .
About the Merck and Eisai strategic collaboration
In March 2018, Eisai and Merck, known as MSD outside the United States and Canada, through an affiliate, entered into a strategic collaboration for the worldwide co-development and co-commercialization of LENVIMA. Under the agreement, the companies jointly develop, manufacture and commercialize LENVIMA, both as monotherapy and in combination with Merck’s anti-PD-1 therapy, KEYTRUDA. Eisai and Merck are studying the KEYTRUDA plus LENVIMA combination through the LEAP (LEnvatinib And Pembrolizumab) clinical program in various tumor types across multiple clinical trials.
About the Astellas, Seagen and Merck collaboration
Astellas and Seagen entered a clinical collaboration agreement with Merck to evaluate the combination of Astellas’ and Seagen’s Padcev® (enfortumab vedotin-ejfv) and Merck’s KEYTRUDA® (pembrolizumab) in patients with previously untreated metastatic urothelial cancer. Padcev® and the Padcev device are trademarks jointly owned by Agensys, Inc., and Seagen Inc. Pfizer Inc. completed its acquisition of Seagen on December 14, 2023.
About the Daiichi Sankyo and Merck collaboration
Daiichi Sankyo and Merck (known as MSD outside of the United States and Canada) entered into a global collaboration in October 2023 to jointly develop and commercialize patritumab deruxtecan (HER3-DXd), ifinatamab deruxtecan (I-DXd) and raludotatug deruxtecan (R-DXd), except in Japan where Daiichi Sankyo will maintain exclusive rights. Daiichi Sankyo will be solely responsible for manufacturing and supply.
Merck’s focus on cancer
Every day, we follow the science as we work to discover innovations that can help patients, no matter what stage of cancer they have. As a leading oncology company, we are pursuing research where scientific opportunity and medical need converge, underpinned by our diverse pipeline of more than 25 novel mechanisms. With one of the largest clinical development programs across more than 30 tumor types, we strive to advance breakthrough science that will shape the future of oncology. By addressing barriers to clinical trial participation, screening and treatment, we work with urgency to reduce disparities and help ensure patients have access to high-quality cancer care. Our unwavering commitment is what will bring us closer to our goal of bringing life to more patients with cancer. For more information, visit https://www.merck.com/research/oncology/.
About Merck
At Merck, known as MSD outside of the United States and Canada, we are unified around our purpose: We use the power of leading-edge science to save and improve lives around the world. For more than 130 years, we have brought hope to humanity through the development of important medicines and vaccines. We aspire to be the premier research-intensive biopharmaceutical company in the world – and today, we are at the forefront of research to deliver innovative health solutions that advance the prevention and treatment of diseases in people and animals. We foster a diverse and inclusive global workforce and operate responsibly every day to enable a safe, sustainable and healthy future for all people and communities. For more information, visit www.merck.com and connect with us on X (formerly Twitter), Facebook, Instagram, YouTube and LinkedIn.
Forward-Looking Statement of Merck & Co., Inc., Rahway, N.J., USA
This news release of Merck & Co., Inc., Rahway, N.J., USA (the “company”) includes “forward-looking statements” within the meaning of the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995. These statements are based upon the current beliefs and expectations of the company’s management and are subject to significant risks and uncertainties. There can be no guarantees with respect to pipeline candidates that the candidates will receive the necessary regulatory approvals or that they will prove to be commercially successful. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements.
Risks and uncertainties include but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; global trends toward health care cost containment; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approval; the company’s ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of the company’s patents and other protections for innovative products; and the exposure to litigation, including patent litigation, and/or regulatory actions.
The company undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in the company’s Annual Report on Form 10-K for the year ended December 31, 2023 and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site (www.sec.gov).
Media:
Julie Cunningham
(617) 519-6264
Kristen Drake
(908) 740-1679
Investor:
Peter Dannenbaum
(732) 594-1579
Damini Chokshi
(732) 594-1577
Source: Merck & Co., Inc.
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https://nwbio.com/video-dr-marnix-bosch-speaks-at-asco-2023/
trying to locate the nwbo video that showed Sawston production rate goal of 1000 doses per month. thanks for the help.