Thank you for that part on external control arms senti. The transcript is helpful and does provide some context for the slides.

Not surprising that she is a clinical trial purist, (just like ex ) and was not initially fond of external control arms, but she lays out a pretty strong argument in support of them for GBM and other rare disease trials.

Thanks Dr B

senti, I believe that slide refers to the exact type of hybrid external control arm (matched external control for two-thirds of control arm) that was recommended by the FDA in the Medicenna rGBM trial last fall (which was [no coincidence] 10 days after NW Bio announced the database was locked) :

Thanks for sharing Dr B. There’s more to be gleaned from that presentation than I thought there would be. Did you record an audio or have a transcript?

speaking of patents; did anyone notice the number of new and pending patents in the 10-K ? To refresh your memory:

The first point is that the manual process of producing dendritic cells that Cognate and Northwest Bio optimized for DCVax-L, and used for the clinical trials and compassionate use, is currently being translated into an automated, commercial process. I thought that Northwest Bio might also have Cognate establish a commercial process modifying established automated manufacturing systems, but it appears that Linda wants to own all the intellectual property for both the equipment and commercial process. When the equivalency studies are completed and approved, Northwest Bio will have the only patented, and approved device and process for generating clinically meaningful dendritic cells for commercial production. That seems far more valuable than some previous patents on a manual process that might expire.

Second point, re-read that last sentence and note the plural: "Collectively these patents and patent applications cover key aspects of the design and function of automated cell culture systems."
Flaskworks has patented two automated systems. The other device, the BATON, that seems to be overlooked, is capable of co-culturing two types of cells simultaneously; adherent cells (dendritic cells) and suspension cells (T-cells). Pretty brilliant system in my opinion. In an interview back in 2018, Shashi Murthy describes it:




The BATON is described and pictured here:

Right ski the EDEN culture system is the key. About 90% of the manufacturing process time is spent culturing the cells, and for commercial production this process must be closed and automated to minimize the risk of contamination, and to produce a consistent and cost effective product. They may use the MicroDEN units that have already been produced as an interim step, but I think they will develop an industrial process with the EDEN system when they are preparing for larger-scale commercial production.

While licensing the product or process may be profitable, I think Linda would prefer to keep the exclusive rights, so I highly doubt that will happen.

flip, one more item:

Confidentiality Agreement between Cognate and Charles River signed August 13, 2019.

sukus, it’s been a while, but in the two studies I saw, I think one seeded a little over 100 million, and the other a little under 100 million. And you’re right, “grow” is not really accurate, and a better word would be “differentiate,” but I wasn’t sure that would be understood. In biology, that means the form and function has changed from being general to more specialized or developed.

ski, the MicroDEN system is basically a shoebox-size incubator that cultures dendritic cells. From what I understand, the EDEN is the fluidic part of the MicroDen device, which has a small polystyrene coated container or cartridge (where the patients’s monocytes are loaded and adhere to) and two bottles, one of which contains a colony stimulating factor (CSF) and other growth medium that continually feeds into the cartridge to grow the dendritic cells, and the other is a waste bottle where the depleted media flows from the cartridge to keep the cells free from waste contaminants. The MicroDEN device contains pumps that keep the fluids in the EDEN system flowing. I believe the device also tracks and logs the patient data through those five steps of the manufacturing process, which will be required for commercial production.

So basically, the patient's monocytes are grown for five days in a growth medium into approximately 25 million dendritic cells, and the dendritic cells are exposed to the tumor lysate, then matured for another half day in a maturation media, then harvested, filled into individual doses (of 2.5 million cells), and then cryofrozen.

Without the EDEN culturing system, the expensive manual process of culturing requires an expensive B-class cleanroom per batch, about 15 hours of labor by highly trained, skilled, and paid technicians who use multiple well plates or T-flasks to gather enough cells for a single patient’s batch, and they have to make multiple interventions to replace the depleted differentiation medium during the almost week-long culturing process, which increases the potential for contamination, and produces inconsistent yields.

Lykiri, I agree that is probably the chosen supplier, but I didn’t just pull that out of the air. The Flaskworks’ Agreement actually states this:

sukus, the approved manufacturing process for DCVax-L that was used during the clinical trials and is currently being used for compassionate use in the UK is a manual “open” process in an A or B-class clean room, where the cells are exposed to the outside (aseptic) clean-room environment. Due to potential cross-contamination and patient mix-up concerns, this process only allows a single patient’s batch to be created at a time. Advent can manufacture four or five patient’s batches in a month in their single suite at the Royal Free Hospital in London.

So if Advent is now using that same manual process in two cleanroom suites at Sawston, then it stands to reason that eight to ten batches could be manufactured in a month. Northwest Bio’s recent PR stated that they anticipate manufacturing 40-45 batches per month at Sawston, so i would assume that some MicroDEN systems will be used. That combined with the additional clue in the 10-K that Advent will be performing equivalency studies using the MicroDEN system.

I wouldn’t get too hung up on the 45 per month number though. It’s just an interim number while they evaluate the MicroDEN system and optimize the manufacturing process. With the size of Sawston, they will not be capacity constrained.

Poor Man, I’m not sure how you can determine what value Corning saw from the MicroDen system, or who terminated the supply agreement. Corning was responsible for handling sales of the device, but it was just another product they sold, and I doubt they had dedicated employees to support this. Further, once Northwest Bio bought Flaskworks, Corning wouldn’t have to do ANY sales. They would simply manufacture and supply the disposable plasticware for a soon-to-be commercial product. I agree that there probably wasn’t many MicroDen devices were sold prior to the acquisition, but then how many CAR-T manufacturing systems do you think were sold in 2016 before CAR-T was commercialized? And how many now? It may take a while to ramp production, but when it does, thousands of the single-use cartridges will be needed. I also think that once Northwest Bio commercializes a dendritic cell therapy, there will be many other copycats, just like CAR-T.

Shashi Murthy has given a number of presentations on automated cell manufacturing systems at Phacilitate, and other venues, some of which Linda Powers was also speaking. I’ve previously posted that I believe it was Linda Powers who approached Shashi Murthy to create the MicroDen product. It was Linda Powers and Northwest Biotherapeutics who needed a closed, automated system to commercialize a dendritic cell therapy. I’m not aware of any other company that is preparing to commercialize a dendritic cell therapy that would need such a system. I believe that Linda wants to be in control of the process and own the intellectual property.

The Flaskworks’ Agreement was interesting to me too Harry. Here’s what I found interesting:

The supply agreement with Corning was terminated, and they were paid ~ $1M cash for their 18.5% ownership. It may be that the wholesale price for the single-use polystyrene flasks, storage bottles, and tubing that Corning supplied was overpriced. (when I requested pricing from the distributor last year, those consumables were nearly $1K, while the MicroDen device itself was $15k.)

Advent evaluated the MicroDen system about a year ago, (according to Lykiri’s research) but it was was tested using Corning’s plastics, and this will no longer be the case going forward. So the first milestone (which was achieved) included the technology transfer of all relevant manufacturing protocols, and a document listing all technical and regulatory specifications for the EDEN system required to manufacture DCVax-L, finding a new supplier (Saint Gobain?) to make the single-use consumables, and then producing a prototype for Advent to test within 90 days of the agreement. (which was Nov 26th)

The second milestone was demonstrating that the EDEN system from the new supplier can replicate the current DCVax-L manufacturing process just as the previous Corning system did. I believe this milestone was likely met as well, but we may need to wait until the next 10-Q.

The third milestone is the completion of comparability studies that demonstrate equivalence of the DCVax-L products manufactured through EDEN and those manufactured through the Company’s current process, and that all applicable data is prepared in a consolidated format sufficient for submission to regulatory agencies in the UK, US, Canada and EU. (note the order that those regions were listed)

The final milestone is approval by a regulator in the US or EU of the comparability of the EDEN process and the Company’s current processes, and the comparability of DCVax-L products manufactured through EDEN and those manufactured through the Company’s current processes, for commercial use.

And yes, Northeastern University was given the option of taking cash or stock in Northwest Bio, but it was only $117K. The former CEO, Jennifer Rossi, was also given that option for her $500K, but what’s interesting is that this option could only be indicated between 90 and 120 days of the closing date. It’s also interesting that Corning wasn’t given the option of receiving Northwest Bio shares, and simply received cash at closing.

Elvisdk

I’m very sorry to hear about your wife, and I know the despair that you are both feeling. I’m sending my positive thoughts and hope to you and your family.

I don’t think it’s possible to get DCVax treatment at this time, but there is another promising personalized cell immunotherapy called TIL (tumor infiltrating lymphocytes) for solid tumors that is recruiting for a clinical trial for non-small cell lung cancer (NSCLC). Not sure where you live, but there’s several locations across the country. It does require a tumor sample to make the treatment, so I’m not sure if it’s possible in your wife’s case.

Some information about this trial here: https://www.iovance.com/clinical/iov-lun-202-non-small-cell-lung-cancer/

A Phase 2 Multicenter Study of Autologous Tumor Infiltrating Lymphocytes (TIL) (LN-145) in Patients with Metastatic Non-Small-Cell Lung Cancer (NSCLC)
 
Immunotherapy For Metastatic Non-Small Cell Lung Cancer (NSCLC)

TUMOR INFILTRATING LYMPHOCYTE (TIL) therapy is derived from a patient’s own immune cells called lymphocytes that have come to the site of tumor to kill the tumor.

The TIL therapy under investigation in this clinical trial, LN-145, is expanded and rejuvenated TIL that was extracted from the patient’s own tumor.

ADDITIONAL INFORMATION ABOUT TIL:

* Data from multiple academic center trials in non-small cell lung cancer (NSCLC) show a positive association between the presence of TIL in NSCLC tumors and patient outcomes. A clinical study run by H. Lee Moffitt Cancer Center showed durable complete responses with Moffitt’s TIL in patients with NSCLC who progressed on nivolumab treatment.1,2

* For more information about clinical results with TIL therapies, please visit our Publication And Scientific Presentations page here.

* To learn more about TIL, please visit our Iovance TIL technology page here.

CLINICAL TRIAL OVERVIEW

IOV-LUN-202 is a Phase 2 clinical trial of Iovance TIL therapy (LN-145), enrolling patients that have been diagnosed with histologically confirmed recurrent or metastatic non-small cell lung cancer (NSCLC) across the following four cohorts:

* Cohort 1: NSCLC patients whose tumors do not express PD-L1, are without a known driver mutation, who have received a single line of approved systemic therapy (combined checkpoint inhibitor (CPI) + chemotherapy ± bevacizumab). Patients must meet study requirements for tumor resection.

* Cohort 2: NSCLC patients whose tumors express PD-L1, are without a known driver mutation, who have received a single line of approved systemic therapy (CPI + chemotherapy ± bevacizumab). Patients must meet study requirements for tumor resection.

* Cohort 3: NSCLC patients whose tumors do not express PD-L1, are without a known driver mutation, who have received a single line of approved systemic therapy (CPI + chemotherapy ± bevacizumab). Patients should not meet study requirements for surgical tumor resection and their TIL will be grown from a tumor biopsy sample instead.

* Cohort 4: LN-145 retreatment in patients who were previously treated in Cohorts 1-3.

YOU MAY QUALIFY FOR THE TRIAL IF:
* You have been diagnosed histologically with locally advanced or metastatic NSCLC
* You are at least 18 years old
* You have documented PD-L1 expression status
* You have received a single line of systemic therapy that included CPI and chemotherapy, with a minimum washout period of 21 days
* You meet specified lab parameters
* You meet the requirements for having a resectable lesion (or aggregate lesions) or qualify for tumor harvest via core biopsy
 
If you satisfy these key eligibility criteria, you may be eligible to participate in this clinical trial. There are other additional eligibility criteria that can only be assessed by a trial physician.
To learn more about the trial, please call: 1-866-565-4410


Here’s the trial information:

Autologous LN-145 in Patients With Metastatic Non-Small-Cell Lung Cancer

https://www.clinicaltrials.gov/ct2/show/NCT04614103

Detailed Description:
LN-145 is a ready-to-infuse, autologous TIL therapy that utilizes an autologous TIL manufacturing process, as originally developed by the NCI and further optimized by Iovance for the treatment of patients with metastatic NSCLC. The cell transfer therapy used in this study involves patients receiving an NMA lymphocyte depleting preparative regimen, followed by infusion of autologous TIL, then finally followed by the administration of IL-2.


Locations

United States, California
City of Hope Recruiting
Duarte, California, United States, 91010

United States, Kentucky
University of Louisville Recruiting
Louisville, Kentucky, United States, 40202

United States, Michigan
Karmanos Cancer Institute Recruiting
Detroit, Michigan, United States, 48201

United States, New Jersey
MD Anderson Cooper Recruiting
Camden, New Jersey, United States, 08103

United States, Ohio
University of Cincinnati Medical Center Recruiting
Cincinnati, Ohio, United States, 45219

Sponsors and Collaborators
Iovance Biotherapeutics, Inc.


Iovance has another clinical trial for NSCLC in combination with various immune checkpoint inhibitors (Keytruda, or Opdivo, or Yervoy)

Study of Autologous Tumor Infiltrating Lymphocytes in Patients With Solid Tumors

https://clinicaltrials.gov/ct2/show/NCT03645928?term=iovance&draw=4&rank=2


A recent article about the treatment:

This Big Leap in Cancer Treatment Could Change the Landscape
TIL therapy looks able to win a large addressable market, and Iovance is the leader of the pack.
Patrick Bafuma Apr 1, 2021 at 6:27AM

https://www.fool.com/investing/2021/04/01/this-big-leap-in-cancer-treatment-could-change-the/

Thanks for the post VuBru, I appreciate your perspective.

Not surprised by your timeline ex, but there is “no way” that it will take until June or July 2022. I will admit that four months was a very optimistic guesstimate, but with 30+ employees on Advent’s payroll now, there’s likely to be some urgency. I also thought there may be a speedier application process after reading this: “Companies applying for a marketing authorisation (also known as a product licence) need to have a manufacturer licence first. The manufacturer licence will be granted first providing the product is in the process of being approved.”

But thinking about it some more, Advent has already missed the first 8-month window (by a year!) and we don’t actually know if the SOW’s included certification. I guessed that the application would be submitted within 6 weeks, and it would be processed in 90 days, but this is Northwest Bio after all, and I double checked and it’s actually 90 “working” days, and further delays due to the recent Covid lockdowns should probably be expected. So upon further reconsideration, I will revise my optimistic guess that Sawston facility will be licensed and certified by September/October.

Basin, not sure that a deal is done, but no doubt there have been on-going discussions. Still think manufacturing needs more time.

On meeting of endpoints; Agree the strength of data is the major factor.

On the value of D; That could the be a sticking point, and why it may be a partnership vs buyout. (maybe resolved with CVR’s)

On a higher pre-approval price based on the probability of approval; LP knows the BP playbook, and she may wait to negotiate from a position of strength.

On the price vs. JUNO and KITE; I think the $21B IMMU buyout set the floor.

Just to finish the thought:

I believe the Statements of Work (SOW’s) were to get Sawston certified by last summer and begin producing a small revenue stream under the UK Specials Program, while establishing commercial processes using the MicroDen system. Eight months from November 2019 was July 2020, but the construction was delayed due to Covid. From the 10-Q, Q2 2020:



These were my thoughts last fall, and I was anticipating certification in March or April this year:



So now my guess is Sawston is certified in June or July, and commercial readiness will be achieved shortly after that.

I believe manufacturing readiness has been the hold up for some time now. Can not receive approval without it, which has always been the goal..

That hasn't gone unnoticed.

Senior Vice President, Business Development Mr. Les Goldman joined us as Senior Vice President, Business Development in June 2011. Prior to joining us, Mr. Goldman was a partner at the law firm of Skadden, Arps for over 30 years, specializing in a wide array of advanced technologies and their commercialization.

What’s the final contingency in Merck’s last buyout?

reminder:

Was the timing of the Charles River acquisition of Cognate just a coincidence?


Charles River Laboratories International, Inc. (CRL)
FORM 8-K | Current report
Feb. 17, 2021 4:03 PM
Entry into a Material Definitive Agreement.

“Confidentiality Agreement” means the Confidentiality Agreement, by and between the Company and Buyer, dated as of August 13, 2019.

https://seekingalpha.com/filing/5376148

Good points Evaluate. It may be difficult for some people to appreciate just how much progress has been made at Sawston because several posters have been suggesting that they were already certified, so this update was a bit of a reality check. What’s even more impressive to me is just how inexpensively this has been accomplished. Recall this Q & A from the Charles River earnings call:

Good catch senti. That’s Flaskworks’ other product, not the MicroDen system. And you’re right, it co-cultures both dendritic cells and T-cells for neoantigen based therapies.

Interesting find Harry. Makes me wonder if this function is new and necessary because this has multiple pumps, or if the MicroDen system also requires this.

anatomy of a Merck buyout:

For those wondering what a partnership or buyout of Northwest Bio might look like, I think it’s interesting and informative to look at the background of recent acquisitions, and observe the modus operandi of a potential suitor, in this case Merck. It seems that they are relentless, and willing to pay up when they want something. As a reminder, Merck is currently in the process of raising $10.5 billion from the Organon spin-off announced last year. Here’s a brief synopsis for those that don’t have time to read the filing.

On February 25, 2021, it was announced that Merck offered to acquire Pandion Therapeutics for $60 a share (a 140%premium), or $1.85 billion. Pandion’s most advanced candidate, PT-101, is an engineered IL-2 mutein fused to a protein backbone which is designed to selectively activate and expand regulatory T cells without activating proinflammatory cells, for the treatment of autoimmune diseases. Pandion just completed a Phase 1a clinical trial for PT-101, which met its primary endpoint of safety and tolerability, and demonstrated proof of mechanism by selectively expanding Tregs in healthy volunteers.

Merck signed a non-disclosure agreement with Pandion back in April 2018, and was following the company’s research for several years, while reviewing various non-public information, then several offers were made over the course of the past year before this final deal was reached. In January of 2020, Merck made their first offer of $65 million up front and up to $425 million in potential milestone payments. This offer was refused as inadequate, since there were many other interested companies. Merck continued informal discussions about the clinical trial progress, Pandion’s other pipeline programs, and potential partnership and acquisition possibilities over the next few months, but no formal offers were made. In June, Pandion began preparing for an IPO, and discussions were put off. In July, Pandion priced an initial public offering of its common stock at $18 per share. Discussions began again in August and continued until a second offer was made in October for $100 million up front, partnering 50/50, and buying a 20% stake in the company, which was also refused. In December, Pandion shared the topline data from the clinical trial with Merck and another interested company, after which Merck expressed their continued interest. Pandion publicly announced the positive topline results of their trial on January 4th, 2021. Later in January, Merck indicated that they were preparing another partnership proposal while it continued due diligence on Pandion’s pipeline candidates. Meanwhile Pandion engaged Centerville Partners to represent them and continued discussions with four other interested companies. Then in the beginning of February, Merck made an offer to acquire the entire company for $40 per share, which was upped to $50 per share two days later after Centerville indicated it was insufficient, and there were other parties interested, and another acquisition offer was on the table. Pandion made a counter offer of $60 per share, which Merck agreed to, contingent on further due diligence, and audits of the two contract manufacturing vendors of Pandion, which was conducted on February 24th. Then the deal was announced on February 25th.

SCHEDULE 14D-9 Pandion Therapeutics, Inc

Confidentiality Agreement
On February 13, 2021, Parent and Pandion entered into an amendment to the Confidential Disclosure-In Agreement, dated April 9, 2018 as amended by Amendment No. 1, dated December 16, 2019, and Amendment No. 2, dated December 18, 2020 (as amended, the “Confidentiality Agreement”), in connection with Parent’s consideration of a potential business combination with Pandion. Under the terms of the Confidentiality Agreement, each party agreed, subject to certain exceptions, to keep confidential certain proprietary or non-public information relating to the other during the term of the Confidentiality Agreement and for a period lasting seven years following the expiration or termination of the Confidentiality Agreement.

Background of the Offer and the Merger
Pandion regularly meets and engages in discussions with other biotechnology and pharmaceutical companies in the ordinary course of business regarding a variety of potential partnerships, licensing arrangements, joint ventures, collaborations and other transactions with respect to Pandion’s product candidates.

During these interactions between 2018 and 2020, Pandion entered into confidentiality agreements with 24 parties that expressed interest in potential partnership or other strategic transactions, including Parent and Parties A through E mentioned below. None of these confidentiality agreements contained standstill provisions. Over the course of 2018 and 2020, Pandion provided non-public due diligence information to all or substantially all of these parties. Only two of the companies receiving non-public due diligence information, Parent and another global biopharmaceutical company, Party A, requested and received access during this period to Pandion’s virtual data room containing regulatory submissions and related supporting study information. Pandion entered into the Confidentiality Agreement with Parent on April 9, 2018 (as subsequently amended by Amendment No. 1, dated December 16, 2019, Amendment No. 2, dated December 18, 2020 and a letter agreement, dated February 13, 2021).

Starting around January 2020, Pandion’s interactions with each of Parent and Party A referenced the possibility of a potential collaboration transaction.
 
15

On January 31, 2020, Parent sent Vikas Goyal, Pandion’s Senior Vice President of Business Development, a non-binding term sheet for the acquisition of Pandion’s IL-2 agonists program, including PT-101, for an upfront cash payment of $65 million and up to $425 million in potential future milestone payments (“Parent’s January 2020 Proposal”).

On the same day, Mr. Goyal informed representatives from Party A that Pandion had received a term sheet from another pharmaceutical company earlier that day.

During February 2020, representatives of Pandion informed Parent that Parent’s January 2020 Proposal did not adequately reflect the value or potential of its program.

On February 14, 2020, Mr. Goyal had a call with representatives from Party A who indicated that Party A would not be able to move forward with a partnership transaction with Pandion at that time, however, Party A continued to be interested in Pandion’s products and wanted to continue to have ongoing discussions with Pandion in the coming months.

During the months leading up to Pandion’s initial public offering, representatives of Pandion engaged with representatives of Parent on several occasions to discuss PT-101’s clinical trial status and other program updates. In these conversations, Parent was informed of Pandion’s plans for an initial public offering, and representatives of Parent expressed potential interest in either an acquisition or a partnership transaction. However, no proposals were made by Parent to Pandion during this period.

On June 11, 2020, Mr. Goyal had a call with a representative from Party A to discuss Party A’s interest in Pandion, updates to Pandion’s clinical programs as well as Pandion’s plans for an initial public offering. The representative from Party A indicated that Party A was still not in a position to restart partnership discussions at that time, but hoped to reconnect with Pandion in August or September for further updates on Pandion’s programs.

On July 16, 2020, Pandion priced an initial public offering of its common stock at $18 per share.

During August and September 2020, representatives of Pandion engaged with representatives of Parent on numerous occasions to discuss updates to PT-101 and Pandion’s other programs and to facilitate due diligence. During these discussions, representatives of Parent reiterated Parent’s strong interest in PT-101 and desire to explore a partnership in the near term and view clinical data for PT-101 when available.

On September 18, 2020, representatives from Pandion had a videoconference with representatives from Party A to discuss Pandion’s programs and discuss business development between the parties, particularly potential partnership transactions.

On September 29, 2020, Drs. Rahul Kakkar, Chief Executive Officer of Pandion, and Jo Viney, President and Chief Scientific Officer of Pandion, Mr. Goyal and Alan Crane, Chairman of the Pandion Board, met with Dr. Roger Perlmutter, Executive Vice President of Parent and President of Merck Research Laboratories, and other representatives of Parent. The parties discussed possible ways to work together on advancing Pandion’s products. Representatives of Parent indicated that the next step would likely be for Parent to provide some potential options for how the parties could work together. Parent’s representatives also reiterated the desire to see Pandion’s Phase 1 data for PT-101.

On October 2, 2020, Parent announced the retirement of Dr. Perlmutter and the appointment of Dr. Dean Li as President of Merck Research Laboratories. On the same day, Mr. Goyal spoke with a representative of Parent to discuss the announcement and its effect on the discussions between Parent and Pandion. During this conversation, the representative of Parent indicated that Parent intended to propose a few different possible transaction structures to Pandion within the coming week.
 
16

On October 12, 2020, Mr. Goyal spoke with a representative of Parent, who indicated that Parent was planning to submit a proposal for Pandion’s consideration within the next 24 hours and would expect Pandion’s feedback by October 16.

Later that day, Parent submitted to Pandion a non-binding proposal for a 50-50 partnership arrangement between Parent and Pandion in Pandion’s IL-2 agonists program, for an upfront cash payment of $100 million and the purchase of newly-issued common stock of Pandion to give Parent a 19.9% equity stake in Pandion at the closing of such transaction at an unspecified price (“Parent’s October 2020 Proposal”).

On October 16, 2020, Dr. Kakkar spoke with a representative of Parent, indicating that Parent’s October 2020 Proposal was viewed as not reflecting Pandion’s value. The representative of Parent communicated that Parent would need to review Pandion’s Phase 1 data for PT-101 in order to consider a revised proposal.

On October 26, 2020, Pandion received a non-binding offer from a global pharmaceutical company, Party B, for a collaboration arrangement between the parties on Pandion’s skin-tethered assets that were in early discovery stage. The non-binding offer from Party B provided a $7 million upfront payment for an exclusive license to compounds in the skin-tether program, up to $276 million in milestone payments and additional royalties payable as a percentage of net sales.

On October 28, 2020, Party A sent Mr. Goyal a list of follow-up diligence questions with respect to PT-101 and Pandion’s other pipeline products.

On November 10, 2020, representatives of Pandion met with representatives of Party A via videoconference to discuss Party A’s diligence questions and timelines for Pandion’s products.
Also in November 2020, Mr. Goyal responded to Party B that Pandion would be interested in pursuing a collaboration for the relevant Pandion assets but not for less than a $50 million upfront payment, and as a result Party B ceased further discussions.

On November 30 and December 1, 2020, representatives of Pandion met with representatives of Parent via videoconference to discuss updates regarding PT-101 and to discuss Pandion’s pre-clinical pipeline.

In December 2020, representatives of Pandion met separately with representatives of Parent, representatives of Party A and representatives of another large international pharmaceutical company (Party C) to present topline data from PT-101’s Phase 1a trial. Representatives of two other large international pharmaceutical companies (Parties D and E) received this presentation by Pandion in the first two weeks of January 2021.

After the presentation in December 2020, a representative of Parent called Mr. Goyal to indicate that Parent was still very interested in Pandion and PT-101.
On January 4, 2021, Pandion publicly announced positive topline data from its Phase 1a single-dose, healthy volunteer clinical trial for PT-101.

On that same day, a representative of Centerview Partners LLC (“Centerview”) contacted Dr. Kakkar to discuss industry perspectives and views on various potential parties that might be interested in a transaction with Pandion in light of the strength of the recently announced data. Members of the Pandion Board were informed by Dr. Kakkar of his discussions with Centerview during routine director updates over subsequent weeks.

On January 11, 2021, a representative of Party A indicated to a representative of Pandion that Party A expected to potentially submit a proposal with respect to a partnership transaction, although the submission of such a proposal remained subject to further internal review and approval by Party A. Party A also indicated a desire to continue due diligence, which Pandion facilitated.
 
17

During January and February 2021, Parent continued to conduct due diligence on Pandion. None of Party C, Party D or Party E sought additional information beyond the Phase 1a topline data presentation provided by Pandion. Although on January 20, 2021, Party C indicated possible interest in submitting a proposal for a partnership transaction, Party C subsequently did not engage further with Pandion after follow-up by Pandion representatives prior to the exclusivity period with Parent. Party C was viewed by Pandion as unlikely to engage in a transaction given other strategic priorities and as unlikely to move quickly if informed of a bid from another interested party. Prior to the exclusivity period with Parent, Party D expressed interest in potentially co-funding certain studies for PT-101 (but indicated that it was not interested in further development work around ulcerative colitis, which was viewed by Pandion as an important value contributor to the program). Party E was viewed by Pandion as not having a strong interest in the Phase 1a topline data presentation based on historical interactions and Party E’s lack of follow-up. Other than the interactions with Parent and Party B, and Pandion’s publicly disclosed collaboration with Astellas Pharma, Inc., none of the parties with whom Pandion entered into a confidentiality agreement (including Party A, Party C, Party D and Party E) made any proposal for an acquisition of Pandion, partnership or other strategic transaction.

On February 7, 2021, Parent submitted a non-binding proposal to acquire all of the fully-diluted common stock of Pandion for $40.00 per share in cash (the “February 7 Proposal”). In the February 7 Proposal, Parent indicated that it had substantially completed scientific and regulatory due diligence with respect to assessing PT-101 and the proposal was subject to the completion of corporate due diligence, which Parent was prepared to do expeditiously while the parties contemporaneously negotiated a definitive acquisition agreement. Parent also expressed its desire to execute a definitive acquisition agreement on February 16, 2021.

On February 8, 2021, the Pandion Board held a meeting by teleconference, which included senior management and representatives from Centerview, Skadden, Arps, Slate, Meagher & Flom LLP, transactional counsel to Pandion (“Skadden”), and Wilmer Cutler Pickering Hale and Dorr LLP, corporate counsel to Pandion (“WilmerHale”). Representatives of Skadden discussed with the Pandion Board its fiduciary obligations. Representatives of Centerview provided an overview of the February 7 Proposal, including a comparison of the proposal to certain of Pandion’s trading metrics and discussed with the Pandion Board the preliminary valuation presentation provided by Centerview and the projections prepared by Pandion management for the Pandion Board during January and February 2021. See “ — Certain Financial Projections” below for a discussion of the management projections utilized by Centerview. Representatives from Centerview then discussed with the Pandion Board possible negotiation strategies in responding to the February 7 Proposal in order to obtain the highest possible offer from Parent in the event the Pandion Board desired to further explore a sale of the company, taking into consideration Parent’s request to move quickly in order to enter into a definitive agreement and announce as early as February 16, 2021. The Pandion Board also discussed with representatives of Centerview and management their perspectives on other potentially interested parties, considering the history of interactions with such parties, the fact that Pandion’s data from its Phase 1a single-dose, healthy volunteer clinical trial of PT-101 had been publicly announced, and the risk that contacting additional parties could result in leaks that would be disruptive to Pandion’s business and would likely cause Parent to disengage.

After discussion, the Pandion Board instructed Centerview to respond to Parent that the February 7 Proposal was insufficient and Parent needed to significantly increase its offer, in particular if Pandion were to proceed on the timeframe requested by Parent. The Pandion Board also instructed Centerview to concurrently communicate to Party A that Pandion had received an acquisition proposal from a large international pharmaceutical company looking to pursue a transaction that would announce as early as February 16, 2021. The Pandion Board also directed management to continue to work with representatives of Centerview to enable Centerview to complete financial analyses of the February 7 Proposal and Pandion on a standalone basis. Representatives of Centerview conveyed the respective messages as directed by the Pandion Board to a representative of Parent, and to a member of senior management of Party A, while the Pandion Board meeting was ongoing.

Also at the meeting on February 8, 2021, the Pandion Board, with the representatives of Centerview absent from the meeting, discussed the considerations associated with engaging a financial advisor, like Centerview, that had
 
18

existing relationships with Parent and Party A, including that a senior member of the Centerview deal team for Pandion is part of the team engaged by Parent on matters unrelated to Pandion. Following this discussion, the Pandion Board approved the entry into an engagement letter with Centerview to serve as financial advisor to Pandion. Later in the day, Pandion and Centerview entered into the engagement letter.

Also at the meeting on February 8, 2021, the Pandion Board conducted an executive session and approved the 2020 annual target bonuses and compensation.

On the morning of February 9, 2021, through a telephone conversation, a representative of Parent delivered to representatives of Centerview a revised offer to acquire all of the fully-diluted common stock of Pandion for a price of $50.00 per share in cash (the “February 9 Proposal”), which was conditioned on immediate entry into an exclusivity agreement between Parent and Pandion.

At 11:00 a.m. Eastern time on February 9, 2021, the Pandion Board held a meeting by teleconference, which included senior management and representatives from Centerview, Skadden and WilmerHale. The Pandion Board discussed the February 9 Proposal, including the possibility of obtaining a higher offer from Parent and the risk that Parent would refuse to proceed without immediate exclusivity. Representatives of Centerview then updated the Pandion Board on its discussion with Party A, and explained that Party A was discussing internally whether it would be submitting an acquisition proposal and would revert promptly.

The Pandion Board then discussed with representatives of Centerview and Skadden the potential exclusivity agreement required by Parent and the ability of Party A to make an unsolicited bid during the exclusivity period if Party A wished to submit an acquisition proposal. Representatives from Skadden discussed the anticipated fiduciary out provisions of a merger agreement and the circumstances under which the Pandion Board may consider or accept a competing acquisition proposal even after entering into a definitive agreement with Parent.

Following further discussion, the Pandion Board directed representatives of Centerview to convey to Parent a counterproposal of $60.00 per share in cash (the “February 9 Counterproposal”) and that Pandion would be willing to enter into a short-term exclusivity agreement only on the basis of such counterproposal, which representatives of Centerview communicated to a representative of Parent following the meeting.

At 8:00 p.m. Eastern time on February 9, 2021, the Pandion Board held a meeting by teleconference, which included senior management and representatives of Centerview, Skadden and WilmerHale. Prior to representatives of Centerview joining the meeting, representatives of Skadden discussed with the Pandion Board its fiduciary obligations. Representatives of Skadden also discussed with the Pandion Board information provided by Centerview with respect to its previous and ongoing work for or on behalf of Parent and Party A, including the fact (as the Pandion Board was already aware) that a senior member of the Centerview deal team for Pandion is part of the team engaged by Parent on matters unrelated to Pandion, which information provided by Centerview is summarized in “ —Opinion of Pandion’s Financial Advisor”. The Pandion Board considered the relationship disclosures provided by Centerview and its experience in dealing with Parent and Party A, and the Pandion Board determined that such relationships did not interfere with Centerview’s ability to provide financial advisory services to Pandion in connection with its consideration of the acquisition proposal by Parent or other strategic alternatives.

Representatives of Centerview then joined the meeting and updated the Pandion Board that the February 9 Counterproposal was acceptable to Parent, contingent on the entry into an exclusivity agreement between Parent and Pandion. Representatives of Centerview also updated that Parent’s legal counsel were expected to send the initial draft of a definitive acquisition agreement in the near future, and that Parent continued to target public announcement of a transaction on February 16, 2021. Representatives of Skadden then discussed with the Pandion Board the terms and duration of the proposed exclusivity agreement received from Parent, providing for an initial exclusivity period ending on February 19, 2021 followed by an automatic 10-day extension if, at the end of the initial exclusivity period, Parent was working in good faith toward finalizing the proposed transaction.
 
19

Representatives of Centerview also updated the Pandion Board that Party A had not provided a further update on whether it would in fact submit an acquisition proposal or its timing for making such a decision.

Following discussion, the Pandion Board authorized Pandion’s entry into the exclusivity agreement with Parent, instructing management to discontinue Party A’s access to the virtual data room containing regulatory submissions and related supporting study information, and directed management of Pandion, with the assistance of Skadden and Centerview, to facilitate Parent’s confirmatory due diligence and negotiate the terms of the definitive acquisition agreement with Parent on the basis of the proposed price of $60.00 per share in cash.

Later that evening, Covington & Burling LLP, Parent’s legal advisor (“Covington”), provided Skadden with an initial draft of the Merger Agreement prepared by Covington, which contemplated tender and support agreements from all directors and officers of Pandion and their respective affiliates and retention agreements with unidentified key employees. Parent later identified these employees as Drs. Jo Viney and John Sundy, Chief Medical Officer of Pandion.

On February 9, 2021, Pandion provided Parent and its legal and financial advisors access to additional diligence materials through a virtual data room to enable Parent and its representatives to perform their confirmatory due diligence investigation of Pandion. In addition to a review of the virtual data room, Parent and its advisors subsequently participated in calls with senior management and representatives of Pandion as part of Parent’s due diligence investigation. During the confirmatory due diligence process, Parent indicated that completion of site audits of two of Pandion’s contract manufacturing vendors would be important to Parent’s ability to proceed with a transaction, and the parties worked to enter into confidentiality agreements with such vendors and schedule these audits with third parties as promptly as possible.

On February 10, 2021, the Pandion Board held a meeting by teleconference, which included senior management and representatives of Centerview, Skadden and WilmerHale. The Pandion Board discussed potential compensation changes and programs proposed by Pandion management for the purpose of aligning the interests of management and the rest of Pandion’s employees with the interests of stockholders in the completion of the proposed transaction with Parent. At the Pandion Board’s direction, Pandion management conveyed such proposals to Parent as authorized by the Pandion Board. During the period from February 10 through February 15, 2021, Parent’s and Pandion’s respective representatives and legal counsel engaged in discussions as to the proposals authorized by the Pandion Board, ultimately resulting in the incentives described in “Item 3. Past Contacts, Transactions, Negotiations and Agreements — Arrangements with Parent and Purchaser and Their Affiliates” for the implementation of the severance benefits for Pandion employees who are not otherwise entitled to contractual severance protection and the Cash Incentive Pool.

On February 13, 2021, Parent and Pandion amended the Confidentiality Agreement, expanding the information disclosed under the Confidentiality Agreement to include a possible business combination and imposing mutual confidentiality obligations on Pandion with respect to information disclosed by Parent under the Confidentiality Agreement.

Between February 9 and February 15, 2021, Skadden and Covington conducted a number of conference calls and exchanged drafts of the Merger Agreement, the form of Tender and Support Agreement, the confidential disclosure schedule and other transaction documents. Among other items, the parties negotiated the scope of the conditions to closing (including the definition of a material adverse effect) and termination provisions, the amount of Pandion’s termination fee in the event Pandion terminated the Merger Agreement to accept a Superior Proposal (as defined in the Merger Agreement) and other circumstances in which such fee would be payable, the ability of the Pandion Board to engage with third parties interested in pursuing an acquisition proposal under various circumstances, the percentage of the outstanding shares of common stock that would be subject to Tender and Support Agreements to be sought from Pandion shareholders, the conditions to Parent’s obligations to complete the transaction, the obligations of Parent to extend the tender offer in order to permit the satisfaction of offer conditions, and the provisions relevant to obtaining regulatory approvals for the transaction. On
 
20

February 15, 2021, the parties resolved all outstanding material issues under the proposed merger agreement and other transaction documents. However, representatives of Parent also informed representatives of Pandion and Centerview that same day that Parent was not prepared to proceed with the transaction until after completion of site audits with two of Pandion’s contract manufacturing vendors, which were anticipated to be completed on or about February 24, 2021.

Later on February 15, 2021, the Pandion Board held a meeting by teleconference, which included senior management and representatives of Centerview, Skadden and WilmerHale.

Representatives of Pandion management updated the Pandion Board regarding the anticipated site audits by Parent of two of Pandion’s contract manufacturing vendors and the fact that Parent would not be able to complete its confirmatory due diligence and was unwilling to enter into a definitive agreement until such audits were completed to its satisfaction, which was expected to occur on or about February 24, 2021. In response to questions from the Pandion Board, representatives of Centerview confirmed that Centerview had not received any inquiries from or had any interactions with Party A since February 9, 2021, when Centerview had informed Party A that Pandion had entered into an exclusivity agreement with the party that had submitted an acquisition proposal. Representatives of Skadden updated the Pandion Board on the resolution of material terms of the proposed merger agreement and other transaction documents.

On February 24, 2021, Parent completed its site audits of the two contract manufacturing vendors of Pandion.

Later that evening, the Pandion Board held a meeting by teleconference, which included senior management and representatives of Centerview, Skadden and WilmerHale. Representatives of Centerview reviewed with the Pandion Board Centerview’s financial analyses of the Offer Price and the Merger Consideration, and rendered to the Pandion Board an oral opinion, which was subsequently confirmed by delivery of a written opinion dated February 24, 2021 that, as of such date and based upon and subject to various assumptions made, procedures followed, matters considered, and qualifications and limitations upon the review undertaken in preparing its opinion, the Offer Price and the Merger Consideration proposed to be paid to the holders of Shares (other than as specified in such opinion) pursuant to the Merger Agreement were fair, from a financial point of view, to such holders. See “— Certain Financial Projections” below for a discussion of the management projections utilized by Centerview; see “— Opinion of Pandion’s Financial Advisor” below for a discussion of Centerview’s opinion. The opinion delivered by Centerview is attached to this Schedule 14D-9 as Annex I.

Representatives of Skadden discussed with the Pandion Board the material terms of the Merger Agreement, the form of Tender and Support Agreement, the retention agreements with Drs. Jo Viney and John Sundy, and the compensation arrangements as agreed between Parent and Pandion, including the severance benefits for Pandion employees who are not otherwise entitled to contractual severance protection and the Cash Incentive Pool.

After further discussion, the Pandion Board unanimously (i) determined that the Merger Agreement and the transactions contemplated thereby, including the Offer and the Merger, are fair to, and in the best interest of, Pandion and its stockholders; (ii) declared that it is advisable for Pandion to enter into the Merger Agreement; (iii) approved the execution, delivery and performance by Pandion of the Merger Agreement and the consummation of the transactions contemplated by the Merger Agreement, including the Offer and the Merger; (iv) agreed that the Merger will be effected under Section 251(h) of the DGCL; (v) resolved to recommend that Pandion’s stockholders accept the Offer and tender their Shares pursuant to the Offer; and (v) declared that the Chief Executive Officer, the President and Chief Scientific Officer, and the Chief Operating Officer of the Corporation are each authorized to execute and deliver the Merger Agreement in the form presented to the Pandion Board.

Following the Pandion Board meeting, at approximately 10:45 p.m. Eastern time on February 24, 2021, Parent, Purchaser and Pandion executed and delivered the Merger Agreement.
 
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On February 25, 2021 and prior to the start of trading on Nasdaq, Pandion and Parent issued a joint press release announcing the execution of the Merger Agreement and the forthcoming commencement of the Offer, and Pandion filed a Current Report on Form 8-K.

On March 4, 2021, Purchaser commenced the Offer and Pandion filed this Schedule 14D-9.

https://www.sec.gov/Archives/edgar/data/1807901/000119312521069722/d112288dsc14d9.htm



Merck in talks for jumbo debt for spin-off
https://www.nasdaq.com/articles/merck-in-talks-for-jumbo-debt-for-spin-off-2021-03-12

Thank you sentiment_stocks.

Great DD Jerry!

(eyeroll)

senti, I would think that the data from the largest and longest clinical trial in Glioblastoma, and which demonstrates a huge advancement in the treatment of Glioblastoma, would be published in a medical journal prior to regulatory approval. However for some accelerated approvals, you may be interested to read this:

Disconnect Between FDA Approval of Oncology Drugs and Publication of Results of Registration Trials
May 31, 2020 Susan Moench, PhD, PA-C

During 2000 to 2019, no peer-reviewed publication of registration trial results was available for nearly half of oncology drugs granted accelerated approval by the US Food and Drug Administration (FDA) at the time of authorization, according to findings of a retrospective study released as part of the ASCO20 Virtual Scientific Program.1

No systematic investigations have evaluated the timing of oncology drug registration trial publication relative to the approval of these drugs by the FDA.

Although package inserts include data from these studies, “FDA labels can be highly variable in the amount of information that they provide, and they rarely contain the information that is found in published manuscripts, in particular details such as the study protocol [and] inclusion and exclusion criteria,” noted Jeremy L. Warner, an associate professor of medicine and biomedical informatics at Vanderbilt-Ingram Cancer Center in Nashville, Tennessee, and the study’s senior author.

In the analysis, information on the type of FDA approval (standard review for regular/full approval or expedited review for accelerated approval), whether a new or expanded FDA approval was involved, and the date, if any, of the first full publication of results of the corresponding registration trial were collected from FDA drug labels, as well as from HemOnc.org, a free hematology/oncology reference resource,2 for oncology drugs receiving FDA approval during the period from 2000 to 2019.

Excluded from the study were biosimilar drugs, drugs with non-oncology indications, and label revisions not supported by any associated evidence.

Of the 378 oncology drug approvals considered in this analysis, slightly more than one-third (37%) did not have prior publication of corresponding results from the registration trial, with a median overall time from approval to publication of findings from the corresponding registration trial of 140 days. For the remaining 63% of drugs with registration trial publication prior to FDA approval, there was a median of 157 days between trial publication and FDA approval.

Although the absolute number of FDA approvals of oncology drugs in the absence of prior registration trial publication increased by 27% from the earliest study time interval of 2000 to 2005 to the most recent study time interval covered by 2016 to 2019, the percentage of overall FDA approvals in oncology without prior registration trial publication was shown to have successively decreased over time. The rates of these types of approvals were 67%, 55%, 37%, and 22% during the time periods corresponding to 2000 to 2005, 2006 to 2010, 2011 to 2015, and 2016 to 2019, respectively.

Regarding oncology drugs receiving accelerated approval, 46% received this designation from the FDA prior to the publication of results for their associated registration trials. However, no clear trend was observed during the period of 2000 to 2019 regarding the percentages of oncology drugs receiving accelerated FDA approval without prior publication of registration trial results, which were determined to be 67% (2000 to 2005), 36% (2006 to 2010), 54% (2011 to 2015), and 34% (2016 and 2019).

Overall, compared with drugs approved by the FDA through the regular/full pathway, those receiving accelerated FDA approval during the study period were more likely to be approved prior to publication of registration trial results (odds ratio [OR], 1.66 95% CI, 1.03-2.70; P =0.04).

A similar comparison of new FDA approvals with expanded FDA approvals of oncology drugs revealed that 45% of the former and 32% of the latter did not have prior publication of the results of their registration trials (OR, 1.76; 95% CI, 1.15-2.70; P =.01 for drugs with new vs expanded approval).

“I think that companies pursuing expanded approval for a drug have more incentive to have these trials published than to pursue timely FDA approval,” stated Ali Raza Khaki from the University of Washington in Seattle, Washington, who is first author of the study. “Once a trial is published, [the drug] may be incorporated into the [National Comprehensive Cancer Network] guidelines and clinicians may start using [it] off label. However, for new [drug approvals], patients and clinicians will not have access to drugs until the drug is approved by the FDA, so in this setting the FDA approval would probably be of greater priority than the publication.”

In their concluding remarks, the study authors noted that because “trial publications help with adoption of new treatments and mitigation of adverse effects … efforts are needed to ensure trial results are published in a timely manner.”

Disclosure: This study was funded by the US National Institutes of Health. For a full list of disclosures, please refer to the abstract.
Editor’s Note: This article was updated on June 17, 2020.

https://www.cancertherapyadvisor.com/home/news/conference-coverage/american-society-of-clinical-oncology-asco/asco-2020/fda-approval-oncology-cancer-drugs-disconnect-between-publication-results-trial/

Yep ATLnsider, I’m also convinced of the Project Orbis route (which starts with the FDA), and potential simultaneous approvals. I wonder if the construction delays at Sawston held up the actual submission a few months while the company submitted preliminary data and held preliminary meetings with the various regulators. I think this could be the first submission with the UK included, and the process may take a little ironing out. Anyway, it appears that Northwest Bio has the necessary funds to carry this forward. Here’s another link to add to your excellent post:

Project Orbis: Implications for Access and Pricing in the UK
February 17, 2021
Marc Matar, Graham Tatham, Rachel Rowbottom, Sam Calderwood, Katerina Stavri

Post-Brexit, the UK’s MHRA is looking to join Project Orbis, a global program to speed up patient access to innovative cancer treatments. This article looks at the implications of Project Orbis for commercialization in the UK and the key considerations for industry in considering the project as a pathway.

With the UK leaving the European Medicines Agency (EMA) regulatory process in late 2020 as part of Brexit, the UK Government and the Medicines and Healthcare products Regulatory Agency (MHRA) rolled out new approaches for the commercialization of pharmaceuticals. One central tenet was to establish the UK as an attractive market with the potential for fast marketing authorization pathways, and a keynote program was the UK joining Project Orbis.

Project Orbis is a global, collaborative, program launched by the FDA Oncology Center of Excellence (OCE) in 2019, which aims to speed up patient access to innovative cancer treatments through a framework of concurrent regulatory submission and review. Today, there are six Project Orbis Partners (POPs): Australia (TGA), Canada (Health Canada), Singapore (HSA), Switzerland (Swissmedic), Brazil (ANVISA) and most recently the United Kingdom (MHRA). While FDA serves as the coordinator for application selection and review, each country remains fully independent on their final regulatory decision.

Project Orbis Process
Selection of applications for Project Orbis is coordinated by FDA, although the participating regulatory agencies can also identify candidate products. When selected, the FDA approaches the manufacturer and, once confirmed, a product or indication is shared with all POPs to confirm interest in participation. Notably, manufacturers can be selective in the markets they include in their Project Orbis submissions, even down to engaging only one other POP market in addition to the FDA. This permits manufacturers to assess the accelerated approval opportunity-risk trade-offs per market, and only include markets where there is a positive case for their commercialization strategy.

There are three types or Project Orbis submissions which depend on the timeline of submission to the FDA and the POPs:

Type A – Regular
Applications submitted concurrently or near-concurrently (within 30 days) to FDA and the POPs; Type A submissions allow for maximal collaboration during the review phase and the possibility of concurrent marketing authorization with the FDA

Type B – Modified
Applications submitted with a greater than 30-day delay or a regulatory action greater than 3 months of the FDA action. These allow the possibility of concurrent review with FDA but no concurrent marketing authorization

Type C – Written report only
In cases where FDA has already taken regulatory action, it allows the FDA to share their completed review documents with the POP but there is no concurrent review or marketing authorization with FDA.

The First Year of Project Orbis
In an analysis from de Claro et al.,1 we find that in the first year of Project Orbis, to June 2020, 60 marketing applications were submitted across the 6 participating markets (FDA + 5 POP), across 16 unique products. 21 of these applications were to the FDA with a median of 2 additional POPs involved; the most included POPs were Australia (N=14) and Canada (N=12), notably both cost-effectiveness driven HTA markets like the UK. No application included all markets, and Brazil only received one application under Project Orbis.

From these applications, 38 marketing authorizations were granted; the FDA approved 18 of 21 applications (86%), Australia’s TGA approved 7 of 14 (50%), Health Canada approved 8 of 12 (67%) Swissmedic approved 1 of 7 (14%), Singapore’s HSA approved 4 of 5 (80%) and Brazil’s ANVISA had not approved the single marketing application it received at time of analysis.

Impact on time to marketing authorization
Since leaving the EMA Centralized Authorization Procedure, the MHRA,2 has published guidance on eight new routes by which a manufacturer can apply for a license to market a medicine in the UK, including 6 national routes and 2 international routes. Most products are expected to be assessed through the national routes, with a procedure timelines ranging from 67 to 150 days, depending on the type of application, level of innovation and whether the product is already marketed in another country.
?
Project Orbis is one of the two available international routes, aiming to speed up regulatory approval timelines for innovative oncology products. From a patient access point of view, Project Orbis has received significant positive press however an open question remains on whether access timelines are truly expedited in all markets.

From the analysis of de Claro et al., the median time-to-approval of all products in the first year of Project Orbis was 4.2 months for FDA submissions (range 0.9–6.9, N = 18) and 4.4 months for the POPs (range 1.7–6.8, N = 20). For new active substances, the timeline was slightly longer taking a median of 5.1 months for the FDA (range: 3.9-6.9, N=6) and 5.9 months for the POPs (range 3.9-6.8, N = 7).

These timelines are significantly shorter that the average EMA marketing authorization timelines which last around 1 year, suggesting MHRA marketing authorization under Project Orbis hold potential to deliver faster access than if the UK had remained part of the EMA.

It is worth noting however, that whilst some national routes are depended on other regulatory body processes (e.g., EC Decision Reliance Procedure) the standalone MHRA process is the National procedure, which is expected to take 150 days for marketing authorization. Comparing this to the Project Orbis timelines of 5 to 6 months, MHRA timelines are projected to lead to faster UK access than engaging in Project Orbis.

Regardless of the type of Project Orbis submission, to be eligible for Project Orbis in the UK, the drug under consideration must also qualify for the national Innovative Licensing and Access Procedure (ILAP). While the manufacturer does not necessarily have to have engaged with the ILAP prior to requesting inclusion in Project Orbis with the UK as a POP, the MHRA will arrange an “Innovation Passport” meeting to confirm eligibility. Reversing this rationale, manufacturers who do not want to engage the UK in Project Orbis are likely to remain eligible for, and gain the advantages of, other innovative access routes into the UK.

While considering the advantages and risks of Project Orbis, the second “Access Consortium” international route must also be considered, defined as work-sharing procedures between national regulators. Notably this consortium includes all Project Orbis markets, excluding the US and Brazil, and not restricted to oncology indications. While there may be synergies through this approach, offering a more attractive commercial opportunity than to the UK market alone outside the EU, the benefits of this route will likely be dictated by manufacturer engagement and submission.

Implications for UK market access and pricing
In the UK, NICE acts as primary gatekeeper to the public coverage of the majority of the population, with reimbursement recommendations derived from clinical and cost-effectiveness assessments. Aligning the UK marketing authorization process with the US through Project Orbis potentially expedites marketing authorizations and as a result expedites HTA assessments. With a significant proportion of oncology drugs going through the FDA accelerated approval route in parallel to Project Orbis, and in some cases approval granted in advance of trial data publication or before key efficacy endpoints (such as overall survival) reach maturity, it can be inferred that these expedited NICE HTA assessments could be conducted with a limited and early data package. Consequently, this will result in less robust evidence submissions, greater uncertainties surrounding the product’s efficacy and therefore greater difficulty in demonstrating cost-effectiveness.

Oncology therapies launching in the UK with limited evidence packages (e.g., immature outcomes) are able to utilize the UK’s Cancer Drugs Fund for funding through time-limited Managed Access Agreements whilst awaiting future clinical trial read-out. However, there are current uncertainties on the future composition of the CDF, potential changes to the entry requirements and risk of proportional rebates on budget overspend. Furthermore, additional discounts are expected on entering the CDF resulting in lower net prices for the interim funding period and potentially a signal of the net price potential during reappraisals. In the current policy, the net price agreed through the Managed Access Agreement is disconnected from any future achieved price through routine commissioning (although a true separation is unlikely in practice).

One response for manufacturers is to pursue marketing authorization through Project Orbis and then delay HTA evidence submission until further supportive data becomes available, a trend that can be observed in other comparable markets. This enables manufacturers to take advantage of a single Marketing Authorization submission across several markets, and expedited licensing, but pursue reimbursement at a commercially viable subsequent timepoint. For example, the five latest TGA submissions through Australian participation in Project Orbis, indicate a delay between marketing authorization and HTA submission to PBAC. New chemical entity priority review submissions of Qinlock (ripretinib) and Tukysa (tucatinib), which received marketing authorization through Projsct Orbis in July and August 2020 respectively, have yet to go through a PBAC assessment. Both are expected to be evaluated in March 2021, more than 6 months after marketing authorization. Similar delays in submission between marketing authorization and HTA evidence submission can be observed in the other cost-effectiveness-based market, Canada, and across multiple products, including Qinlock (ripretinib), Tukysa (tucatinib) and Calquence (acalabrutinib).

Conclusions and key considerations
The entry of the UK into Project Orbis presents an opportunity to leverage a coordinated submission approach across multiple markets and to gain patient access earlier with marketing authorization feasible with less mature data. However this must always be considered alongside reimbursement expectations; consequent delays to NICE submissions or data collection agreements through the Cancer Drugs Fund may be required to ensure data is available to support cost-effectiveness.

We outline three considerations for pharmaceutical manufacturers to evaluate whether the UK should be one of the markets engaged through Project Orbis, if invited to make a submission.

1. Consider Project Orbis and ILAP early in clinical development
Alignment across Medical, Regulatory and Market Access functions will be required to evaluate the feasibility of meeting UK ILAP requirements depending on clinical trial data cuts. Early cross-functional understanding of the requirements of the UK ILAP Target Development Profile and Global-to-Local support in its development with the MHRA is essential to reflect expectations for clinical outcomes and increase chance of success.

2. If UK early marketing authorization through Project Orbis is feasible, consider the potential NICE evaluation outcomes
The implication of NICE Single Technology Assessment based on the clinical evidence submitted for Project Orbis must be anticipated. Modelling cost-effectiveness based on the early data cut will be required, and areas of uncertainty identified. The likelihood of a recommendation at an acceptable cost-effective net price must be taken into consideration as part of the decision to pursue Project Orbis regulatory approval for the UK. Therefore close dialog between Global/Regional and UK affiliate Market Access and HEOR teams is required, with consideration for the net price floor and international list price referencing implications.

3. Evaluate alternative funding routes available in the UK
A focus on cancer funding in the UK has delivered earlier access for patients in the UK through mechanisms such as the Cancer Drugs Fund. While this may be undergoing changes, into the £500 million Innovative Medicines Fund, this has been reported to include a ring-fenced budget for oncology. However, uncertainty on the future entry requirements, opening to wider therapeutic areas and net price position signaling may make the CDF a less attractive option for manufacturers in the future, thereby risking the benefits of an earlier marketing authorization.

Marc Matar is a Partner, Graham Tatham is a Partner, Rachel Rowbottom is a Director, Sam Calderwood is a Senior Consultant, and Katerina Stavri is a Consultant in Simon-Kucher & Partners Life Sciences division based in the company’s London office.

https://www.pharmexec.com/view/project-orbis-implications-for-access-and-pricing-in-the-uk

fmuller, please give the original poster (sentiment_stocks in this case) credit when you repost their work, or at least post in reply to the original message. That was extremely poor etiquette.

sentiment_stocks original post:
https://investorshub.advfn.com/boards/read_msg.aspx?message_id=161709089

What Biden's Presidency Will Mean for Cancer
Published March 2021

https://cancerdiscovery.aacrjournals.org/content/11/3/527

c'mon ex, give it a rest.

Merck isn’t alone, they follow Bristol Myers, AstraZeneca, and others:

Accelerated Approval: US FDA Review Of Expedited Program Could Bring More Withdrawals
Sue Sutter | February 23, 2021

Executive Summary
Oncology Center of Excellence’s ‘industry-wide evaluation’ of accelerated approvals leads to removal of indications for two PD-1/L-1 inhibitors, AstraZeneca’s Imfinzi and Bristol-Myers Squibb’s Opdivo, both of which had failed confirmatory trials.

The recent withdrawal of accelerated approval indications for two cancer immunotherapies is part of a broader US Food and Drug Evaluation review of the expedited pathway and could portend more oncology drug and indication removals for failure to confirm clinical benefit.

On 22 February,AstraZeneca PLCannounced the withdrawal of its PD-L1 inhibitor Imfinzi (durvalumab) for use in previously treated adults with locally advanced or metastatic bladder cancer. The withdrawal announcement came almost a year after the company announced the failure of a required confirmatory study, the Phase III DANUBE trial in first-line metastatic bladder cancer, on an overall survival endpoint.

The regulatory action follows the 29 December removal of an indication for third-line metastatic small cell lung cancer (SCLC) from the label ofBristol Myers Squibb Company’s PD-1 inhibitor Opdivo (nivolumab) because confirmatory studies completed in 2018 did not meet their overall survival primary endpoints. (Also see "Keeping Track: Submissions Galore Start The New Year; US FDA Clears New Indications For Enhertu, Xalkori" - Pink Sheet, 18 Jan, 2021.)

In both cases, the sponsors said the withdrawal decision was made “in consultation” with the FDA and in accordance with agency guidelines for evaluating accelerated approval indications that do not meet their postmarketing requirements and “as part of a broader industry-wide evaluation.”

Neither the companies nor the FDA would say why the withdrawals took so long following the failed confirmatory studies. The agency took less than six weeks to review BMS’ labeling supplement for the Opdivo indication’s removal, and a mere two weeks to review AstraZeneca’s labeling supplement for Imfinzi.

“Both withdrawal decisions were made in consultation with the FDA and as part of a broader industry-wide evaluation by the FDA Oncology Center of Excellence,” the agency told thePink Sheet, adding that further details regarding this evaluation would be announced at a later date.

While the details of the agency’s “broader industry-wide evaluation” are unclear, there are a number of similarities between the two recent withdrawals that could highlight areas of agency focus.
Both Opdivo and Imfinzi are part of the PD-1/L-1 class of therapeutics that has revolutionized treatment of many cancer types. Drugs in the class carry a long list of indications, some of which remain under accelerated approval. Since the accelerated approval of the Imfinzi and Opdivo indications at issue, the treatment landscape has changed, with other therapies in the class gaining either full or accelerated approval for the same uses.

For Imfinzi and Opdivo, the indications in question received accelerated approval on the basis of overall response and durability of response data, while the confirmatory trials used an overall survival endpoint. In addition, both immunotherapies are labeled for other indications and will remain on the market, so the question of complete product withdrawal was never an issue.

The now-withdrawn indications for Imfinzi and Opdivo “were sort of the classical working of accelerated approval, where the early indication was approved based on an intermediate endpoint” but the confirmatory trials did not pan out, Friends of Cancer Research president and CEO Jeff Allen told thePink Sheet. “This is accelerated approval working as it was designed.”

Frustrated with inefficiencies in the accelerated approval process, Center for Drug Evaluation and Research leaders have expressed interesting in taking a hard look at the expedited pathway. Of particular concern is the need to complete confirmatory trials in a timely fashion, and the ability to swiftly and easily remove a drug or indication if clinical benefit is not confirmed postapproval. (Also see "Accelerated Approval Under Review By US FDA: Completing Confirmatory Trials A Focus" - Pink Sheet, 4 Nov, 2020.)

Oncology Center of Excellence director Richard Pazdur has called for a re-examination of the accelerated approval program’s strengths and weakness, and consideration for potential changes, in conjunction with potential 21st Century Cures 2.0 legislation. (Also see "Cures II Wish List: Reconsidering Accelerated Approval?" - Pink Sheet, 17 Jun, 2020.)

Project Accelerate
* "OCE launched Project Accelerate in February 2020 to track the oncology approvals using the accelerated approval pathway. The team created a tracking database with the accelerated approval application information and corresponding postmarketing requirement(s) to verify clinical benefit. The team also met with international regulatory authorities to discuss experience with equivalent programs such as conditional marketing authorisation program (European Union), notice of compliance with conditions (Canada), and provisional approval (Australia).”

FDA Oncology Center of Excellence 2020 Annual Report

In February 2020, OCE launched Project Accelerate, which is described as a framework for reviewing the US regulatory experience with accelerated approvals. (Also see "US FDA ‘Project Post COVIDity’ Will Track Infection Impact On Cancer Patients Using Real-World Data" - Pink Sheet, 15 Feb, 2021.) The initiative also involves analyzing comparable programs in other parts of the globe, and determining areas for improvement by reviewing similarities and differences in the global experience.(See box.)

Pazdur’s desire for a “fresh look” at the accelerated approval program led an FOCR multi-stakeholder working group to suggest changes. The recommendations included reframing the focus of accelerated approval on a drug’s risk/benefit profile rather than the effect on a surrogate endpoint, and having sponsors submit for continued approval instead of putting the burden on the FDA to get the drug or indication pulled. (Also see "Accelerated Approvals Could Be Improved By Focusing On Benefit/Risk, Making Withdrawal Easier" - Pink Sheet, 9 Feb, 2021.)

Pazdur previously has said that a change in the available therapies for an indication could inform a re-examination of whether an accelerated approval drug’s benefit/risk profile is still appropriate. Only drugs that hold regular approval for a given indication are considered “available therapy.”

Drugs Linger On Market
The quandary created by confirmatory trials that take years to complete and yet fail to confirm clinical benefit is of particular concern.

Withdrawals under the accelerated approval program have been few and far between. Prior to the recent Opdivo and Imfinzi indication withdrawals, 10 drugs or indications had been withdrawn for failure to complete a postmarketing trial or to confirm clinical benefit, according to aPink Sheetanalysis, with withdrawals sometimes occurring more than a decade following accelerated approval. (Also see "Accelerated Approval Withdrawals Through The Years" - Pink Sheet, 25 Apr, 2019.)

Genentech, Inc.’s Avastin (bevacizumab) is the only withdrawal that has gone through the public hearing process under the accelerated approval regulations. However,AMAG Pharmaceuticals Inc.is challenging CDER’s proposal to withdraw accelerated approval of the preterm birth prevention drug Makena (hydroxyprogesterone caproate) and has requested a public hearing. (Also see "Keep Makena Under Accelerated Approval Pending More Studies, AMAG Tells US FDA" - Pink Sheet, 19 Jan, 2021.)

Makena has been on the market since 2011; its confirmatory trial, which took nine years to conduct, failed to meet its coprimary endpoints. In proposing to withdraw the drug, CDER cited the failed confirmatory trial as well as the “integrity” of the accelerated approval process. (Also see "Accelerated Approval: US FDA Request For Makena’s Withdrawal Goes Beyond Failed Confirmatory Trial" - Pink Sheet, 5 Oct, 2020.)

Opdivo Holds New Record For Time To Removal
Opdivo and Imfinzi typify the challenges inherent in quickly removing accelerated approval indications from the label when confirmatory trials fail to verify clinical benefit.

At the time ofEli Lilly and Company’s withdrawal of Lartruvo (olaratumab) in April 2019, the sarcoma drug represented the shortest interval (2.5 years) between an accelerated approval and removal. (Also see "A Successful Failure? Lartruvo’s Speedy Withdrawal Sets New Bar For Accelerated Approval Drugs" - Pink Sheet, 25 Apr, 2019.)

Opdivo’s SCLC indication has now beaten the Lartruvo record for shortest time on market, clocking in at two years and four months. Nevertheless, the SCLC claim did not come off the label for more than two years after BMS announced top-line results from two failed confirmatory trials.

Opdivo was first approved in the US in 2014; in August 2018 it received accelerated approval in third-line SCLC, making it the first-ever immuno-oncology agent in this cancer type and the first SCLC therapy approved in approximately 20 years. Subsequently, Imfinzi and Genentech’s PD-L1 inhibitor Tecentriq (atezolizumab) received full approval for first-line SCLC, whileMerck & Co., Inc.’s PD-1 inhibitor Keytruda (pembrolizumab) holds accelerated approval for third-line SCLC.

Opdivo’s accelerated approval in third-line SCLC was granted on the basis of overall response and duration of response data from an open-label trial of 109 patients. As a condition of approval, BMS was required to conduct and submit the results “of at least one multicenter, randomized clinical trial establishing the superiority of nivolumab over available therapy as determined by an improvement in overall survival” in patients with Stage IV SCLC, according to the approval letter.

In October 2018, BMS reported that in the CHECKMATE-331 study, Opdivo failed to improve overall survival relative to standard of care in relapsed SCLC. One month later, the sponsor announced the combination of Opdivo and Yervoy (ipilimumab), an anti-CTLA4 antibody, missed the primary endpoint of overall survival in second-line SCLC in CHECKMATE-451. The latter trial announcement prompted analyst predictions that the SCLC claim was in jeopardy. (Also see "BMS SCLC Chances Dive After Opdivo, Yervoy Combo Flunks Checkmate-451" - Scrip, 27 Nov, 2018.) Yet, the claim remained on label until December 2020.

In announcing the withdrawal, BMS said that since the time of Opdivo’s accelerated approval, the treatment landscape has continued to evolve, leading to the availability of more options for SCLC patients across multiple lines of therapy.”

“Although we are disappointed by the withdrawal, we appreciate that the FDA shared our commitment to bringing an innovative new therapy to patients with high unmet need when the science pointed in that direction,” said Abderrahim Oukessou, VP-thoracic cancers development lead. “Similarly, we respect the FDA’s efforts to evaluate accelerated approvals across the industry to ensure the integrity of this important program.”

Imfinzi Loses Its Original Indication
In the case of Imfinzi, the labeling change means loss of the indication that first enabled the drug to reach the US market in May 2017. (Also see "US FDA Continues Shift From Companion To Complementary PD-L1 Diagnostics With AstraZeneca Imfinzi Approval" - Pink Sheet, 1 May, 2017.) The initial bladder cancer indication was viewed as a relatively small market opportunity that would pave the way for subsequent use in lung cancer, and the drug has since received regular approval for non-small cell lung cancer and SCLC.

When Imfinzi came to market, Opdivo and Tecentriq held accelerated approval in second-line bladder cancer; those indications have not yet converted to full approval.Pfizer Inc.’s PD-L1 inhibitor Bavencio (avelumab) and Keytruda hold regular approval in second-line urothelial cancer.

Imfinzi’s bladder cancer indication, which was on label for more than three-and-a-half years, was granted on the basis of objective response rate and durability of response data in an open-label trial of 182 patients.

In March 2020, AstraZeneca announced that in the Phase III DANUBE trial, neither Imfinzi monotherapy nor Imfinzi plus the anti-CTLA4 antibody tremelimumab met the overall survival endpoints relative to standard of care chemotherapy in unresectable, Stage IV bladder cancer. AstraZeneca is continuing to test Imfinzi in various treatment combinations in several ongoing Phase III trials in bladder cancer.

The company’s withdrawal announcement reflected a tone and language strikingly similar to that of the BMS announcement on Opdivo less than two months earlier.

“The science of immunotherapy has moved swiftly over the past few years, bringing new options to patients at an unprecedented pace,” said Dave Fredrickson, executive VP-oncology business unit. “While the withdrawal in previously treated metastatic bladder cancer is disappointing, we respect the principles FDA set out when the accelerated approval pathway was founded and remain committed to bringing new and innovative options to patients.”

https://pink.pharmaintelligence.informa.com/PS143834/Accelerated-Approval-US-FDA-Review-Of-Expedited-Program-Could-Bring-More-Withdrawals

hey Maverick, this “concern” is often regurgitated by the naysayers. As exwannabe has said countless times, Northwest Bio is not alone, and there have been numerous companies running clinical trials with dendritic cells, many of which have failed. However, there are a number of different ways to produce and activate dendritic cells, and what Dr. Liau is saying is that the specific process that Northwest Bio has optimized and perfected, (i.e. the exact media mix, length of time to mature them, etc.) is considered an “art” and that process is what is patented. In the last part, I think she believes that a company can attempt to patent a specific target like the expression of CD19 on B cell non-Hodgkin lymphoma which has been identified as a target for CAR T-Cell therapies, but this would certainly not work for Glioblastoma which has a high degree of mutation. This is exactly why DCVax, which is personalized to each individual patient's own tumor and uses ALL of that patient’s antigens (potential mutation pathways) to prevent the cancer from evading it, is the most effective treatment for Glioblastoma to date. Additionally, what she doesn’t say in that interview, (which I think was a year ago???) is that the trial itself and orphan status, will insure that Northwest Bio will own the market for Glioblastoma for nearly a decade, even if any real competition comes along.

expired? I believe technically they still have a manufacturing agreement with Cognate. Northwest Bio was in breach, but Cognate didn’t terminate the agreement, instead they reached a settlement. But yes they will have to negotiate a new agreement for the commercial production of DCVax-L, which curiously hasn’t been announced. It does make me wonder how long the negotiations between Cognate and Charles River has been on-going, and when Northwest Bio shared the results with Cognate. While Northwest Bio has certainly had the time to switch manufacturers and run equivalency studies, they’ve made zero indication that they would, or have.

From the 10-K:



DCVAX®-L MANUFACTURING AND SERVICES AGREEMENT

This Amended and Restated Services Agreement (this “Agreement”), originally dated April 1, 2011 is entered into, effective as of January 17, 2014 (the “Effective Date”), by and between Cognate BioServices, a Delaware corporation (Cognate”), and Northwest Biotherapeutics, a Delaware corporation (“NW Bio”).
 

SECTION 6:    TERM AND TERMINATION
 
6.1    Term
 
This Agreement will remain in force until the later of seven (7) years from the Effective Date (the “Term”) or five (5) years after the first commercial sales of DCVax®-L Products pursuant to a Biologics License Application or marketing authorization (not a compassionate use, hospital exemption or similar authorization), unless terminated earlier pursuant to Section 6.2

6.2    Termination
 
Either party may terminate this Agreement in the event of a material breach by the other party which remains uncured after notice of such breach for a period of thirty (30) days in the case of a monetary breach, or a period of one hundred twenty (120) days in the case of a non-monetary breach that is material to the contract taken as a whole
  

Confidential treatment required; certain information omitted and filed separately with the SEC.
 

 
8.8    Successors and Assigns

 
Except as otherwise expressly provided herein, the provisions hereof will be binding upon, and inure to the benefit of the respective successors, assigns, heirs, executors and administrators of the parties hereto. Neither party hereto may transfer all or any portion of its rights under this Agreement to a third party other than an affiliate without the prior written consent of the other party hereto.
 

Nice post iwasadiver, but I think there are enough long-term survivors that the results won't be a dud. At worst, some lower secondary endpoints could miss. But more importantly, the data should expand the scientific knowledge about how the various subtypes respond to immunotherapies like DCVax and lead to better designed trials for future label expansion.

There is some recent research which adds to the understanding of which subtypes best respond to immunotherapies like DCVax:

Glioblastoma Brain Cancer Mapped in Genetic, Molecular Detail
February 11, 2021


Source: WUSTL
Glioblastoma is among the most aggressive and devastating of cancers. While rare compared with other cancers, it’s the most common type of brain cancer. Even with intensive therapy, relatively few patients survive longer than two years after diagnosis, and fewer than 10% of patients survive beyond five years. Despite extensive studies focused on genomic features of glioblastoma, relatively little progress has been made in improving treatment for patients with this deadly disease.

Now, a new study led by Washington University School of Medicine in St. Louis, Pacific Northwest National Laboratory, Case Western Reserve University and the National Cancer Institute (NCI) of the National Institutes of Health (NIH) has revealed a detailed map of the genes, proteins, infiltrating cells and signaling pathways that play key roles in driving glioblastoma. The study, of 99 tumors from patients, is the largest and most detailed schematic of this deadly brain tumor.

The research, published Feb. 11 in the journal Cancer Cell, is part of the NCI’s Clinical Proteomic Tumor Analysis Consortium (CPTAC).

“To improve therapies for this deadly cancer, understanding the tumor cells themselves is important but not enough,” said senior author Li Ding, PhD, a professor of medicine and of genetics and director of computational biology in the Division of Oncology at Washington University.

“We also must understand the tumor cells’ interactions with the surrounding environment, including immune cells and the connective tissues and blood vessels. In our study, we performed high-resolution and high-depth analyses on 99 glioblastoma tumors. Harnessing new technologies, including proteomics, metabolomics and single cell sequencing, this study is an extremely deep dive into glioblastoma tumor biology, revealing new possibilities for therapy.”

The study identified new activated proteins — particularly PTPN11 and PLCG1 — that serve as signaling hubs driving tumor growth in some patients; revealed gene expression patterns involved in a process called epithelial-to-mesenchymal transition that is common in tumor formation; identified four different categories by which to classify glioblastoma, based on the number and types of immune cells present in the tumors; and determined how an understudied protein modification, acetylation, may explain some functional differences between glioblastoma subtypes.

“Acetylation changes a protein’s shape and often results in opening up DNA-protein complexes to facilitate gene expression. By adding protein acetylation to our study, we were able to complete the loop from proteins to genes and gene expression, shedding light on important regulatory changes in glioblastoma,” said co-senior author Karin Rodland, PhD, chief scientist for biomedical research at Pacific Northwest National Laboratory.

“The most immediate implications for these findings are better design of clinical trials,” said co-author Milan G. Chheda, MD, an assistant professor of medicine who treats patients at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine.

“For most clinical trials, we take all comers and give them the same treatment. We are not designing trials in the most precise way because we have not fully understood the molecular differences between each patient’s tumor. This leads us to call a treatment a failure when in fact it may be helping specific people.”

The new study demonstrates that individual tumors are likely to respond differently to targeted therapies. For example, the immune landscape of these tumors varied widely, fitting into four separate categories. Type 1 tumors contain high numbers of immune cells called macrophages and a few T cells. Type 2 tumors have a moderate number of macrophages. Type 3 tumors include high numbers of T cells and a few macrophages. And type 4 tumors are what Ding calls an immune desert, with few or no immune cells of any type. So, an immunotherapy that targets macrophages, for example, might work well in patients with type 1 tumors but not at all in patients with type 4. Still, a clinical trial that lumps all patients together may not show such a drug works at all, when averaged across all patients.

Added co-author Albert H. Kim, MD, PhD, a professor of neurological surgery at Washington University and director of the Brain Tumor Center at Siteman: “Immunotherapy clinical trials in glioblastoma have been negative so far. And the fact that there are four different immune subgroups may be one of the reasons behind that. We can’t treat all glioblastoma tumors as one disease.”

A group led by co-senior author Tao Liu, PhD, of Pacific Northwest National Laboratory, measured all of the proteins in the tumor samples as well as two specific modifications, called phosphorylation and acetylation, that affect biological functions such as cell signaling. Adding these data into the genomic analysis of the tumors revealed a small subset of glioblastomas that did not fit neatly into any of the typical genomic subtypes. These mixed-subtype tumors were associated with a poor clinical outcome, providing the researchers with clues to the factors affecting the aggressiveness of a tumor that were not evident from genetic information alone.

“These patterns provide additional information for researchers to understand how the glioblastoma subtypes they identified may vary in biological function,” Liu said. “This multifaceted analysis provides an unprecedented level of detail, which is starting to connect the missing dots in glioblastoma.”

Added Chheda, “This paper is an example of the advances that can be made when there is deep collaboration between many experts across the country who the National Cancer Institute has the ability to bring together.”

The researchers are conducting further studies to identify the best drugs to investigate in glioblastoma patients, depending on where their diseases fall on the new tumor map.

The study’s co-first authors are Liang-Bo Wang, a doctoral student in Ding’s lab; Alla Karpova, a doctoral student in Ding’s lab; Song Cao, PhD, an instructor in medicine; and Yize Li, a doctoral student in Ding’s lab, all of Washington University School of Medicine; and Marina A. Gritsenko, and Jennifer E. Kyle, PhD, both of Pacific Northwest National Laboratory.
Funding: This work was supported by the National Cancer Institute’s Clinical Proteomic Tumor Analysis Consortium of the NIH, grant numbers U24CA210972, U24CA210955, U24CA210954, U24CA210985, U24CA210993, U24CA210967, U24CA210986, U01CA214125, and U24CA210979; the National Human Genome Research Institute, grant number R01HG009711; and the NIH, grant number R01NS107833. The MS-based Q12 proteomics work was performed at the Environmental Molecular Sciences Laboratory (grid.436923.9), a U.S. Department of Energy National Scientific User Facility at the Pacific Northwest National Laboratory operated under contract DE-AC05-76RL01830.

Original Research: Closed access. “Proteogenomic and metabolomic characterization of human glioblastoma” by Albert H. Kim et al. Cancer Cell

https://neurosciencenews.com/glioblastoma-cancer-gene-map-17740/

senti, I’m not sure what affect a journal article alone will have on the tumor preservation protocol, but agree that when DCVax is approved, the medical centers that participated in the clinical trials will likely be the first to be certified to offer the treatment commercially, and will freeze the tumor tissue according to Northwest Bio’s protocol. Then, as more and more hospitals are certified to offer the treatment, freezing tumors accordingly will become the standard versus the formalin-fixed paraffin-embedded (FFPE) method of preservation which is now the norm. But just to clarify, I believe Northwest Bio recommends initially freezing the tumor to -70F or -80F which isn’t quite cryogenic. Technically, cryogenic is at least -238F to -460F.

This may be news to learning curve, (this poster is on my ignore list) but it is currently being studied:


Dr. Ramakrishna to Study Automated Tumor Preservation System

08-10-2020
Nico Corporation has awarded Dr. Rohan Ramakrishna a one-year, $30,000 grant to study how the automated handling of glioma specimens affects the quality of the tissue to be analyzed. Dr. Ramakrishna, Co-Director of the Rhodes Center for Glioblastoma at NewYork-Presbyterian, Director of the Brain Metastasis Program at Weill Cornell Medicine, and Chief of Neurological Surgery at NewYork-Presbyterian Brooklyn Methodist, will use NICO’s tissue preservation system to dissociate and preserve the tissue in the operating room for analysis.

“The future of glioma treatment lies in translational research,” says Dr. Ramakrishna. “Extracting and preserving high-quality biospecimens in a standard, automated procedure may allow us to improve the precision of our analysis and help us better tailor treatments to an individual based on that patient’s tumor. With this technology, we aim to understand how tissue processing in the pre-analytic phase affects downstream tissue analyses. Given that NICOs tissue preservation system standardizes tissue collection in a manner that benefits tissue viability, we may see improvements in assays that rely on cell viability relative to the current operating room workflow.”

Dr. Ramakrishna is collaborating with Dr. Howard Fine in Neuro-oncology and Dr. Olivier Elemento  of the Englander institute of Precision Medicine. The team will study whether tissue processing in the operating room affects cell culture results, measures of clonality and heterogeneity, and even tissue immune infiltrates.

The investigation builds on a recent multi-institutional NIH UO1 award funding a study of how biospecimen handling affects measure of tumor methylation. Dr Ramakrishna is co-investigator on that study, in which he has partnered with investigators at the University of Washington and Houston Methodist Neuroscience Institute.

https://weillcornellbrainandspine.org/in-the-news/dr-ramakrishna-study-automated-tumor-preservation-system


I believe this is the clinical trial that is now recruiting:

Improving Understanding of Brain Tumors Through Preservation of Biologically Active Brain Tissue

ClinicalTrials.gov Identifier: NCT04545177
Recruitment Status : Recruiting
First Posted : September 10, 2020
Last Update Posted : November 24, 2020

Study Description

Brief Summary:
Recent experiments are giving researchers insight into the changes (mutations) that occur in an individual brain tumor cell compared to a normal cell. Currently, we do not have enough knowledge about how uniform these changes are throughout a single brain tumor and if different regions of a brain tumor have different groupings of changes. By obtaining multiple samples of the tumor from various regions during surgery, it will allow researchers to better understand these changes, with the hope that they will lead to new discoveries in the diagnosis and treatment of brain tumors.

Condition or disease Intervention/treatment Phase
Glioblastoma Device: NICO Myriad and Tissue Preservation System (TPS) Not Applicable

Detailed Description:
This is a single site, interventional cohort study to assess the feasibility of the NICO Myriad and Tissue Preservation System (TPS) to collect and preserve biologically active tissue in 5 prospectively-enrolled participants with Glioblastoma (GBM) undergoing surgical resection.

The primary objective of this study is to assess the viability of tumor tissue obtained by the NICO Myriad and Tissue Preservation System (TPS) via an automated, standardized methodology in participants undergoing surgery

The exploratory objective of this study is to assess the spatial genomic and transcriptomic heterogeneity of GBM tumors in 3 locations via preoperative annotation and stereotactic guidance

Outcome Measures

Primary Outcome Measures :
1. Feasibility, as measured by percentage of the sample deemed viable by flow cytometry [ Time Frame: 1 year ]Flow cytometry will be performed to quantify viable cells in a cell suspension. This will be reported as a percentage of live cells of the population?

Other Outcome Measures:
1. Number of somatic mutations per region [ Time Frame: 1 year ]Comparison of mutational burden in each tumor region, with the number of somatic mutations per region compared to one another?
2. Gene expression in tumor regions [ Time Frame: 1 year ]Comparison of gene expression in each tumor region via RNA-seq, with the readout being heatmaps of gene expression and quantified via differential gene expression?
3. DNA methylation status in tumor regions [ Time Frame: 1 year ]Comparison of DNA methylation status between tumor regions, with the readout being heatmaps and/or volcano plots of methylation differences to determine activated pathways of gene expression.?

https://www.clinicaltrials.gov/ct2/show/NCT04545177

While I think the Flaskworks’ MicroDen system solves Northwest Bio’s problem of closing and automating a key part of the manufacturing process for Advent, I don’t think it is the be-all and end-all magic machine that some here seem to think. For one thing, it's relatively untested and has never been used in commercial production quantities. I’ve only seen it tested in two University labs using commercially available whole blood products, and it may be unknown how it will actually perform using the cells of sick patients. (although some of this testing work may be on-going with Advent now) Secondly, producing DCVax is a multi-step process, (I would say 5 major steps) and the MicroDen system is used in maybe two or three of these. Thirdly, there are a number of other companies (Terumo BCT, Miltenyi Biotec, Lonza, etc.) that have been in business for years and produce closed, automated cell manufacturing systems that have been used extensively by commercial labs on an industrial scale. In fact, some of the pictures of Cognate’s Memphis facility, show they are using some of that equipment. The MicroDen product is functional, but it is a prototype compared to the equipment that Cognate is using.

Here’s the MicroDen system:
https://www.selectscience.net/products/corning-microden/?prodID=217074

Here’s the Clinimacs Prodigy:
https://www.miltenyibiotec.com/US-en/products/clinimacs-prodigy.html

Cognate's Memphis facility slideshow

https://www.bizjournals.com/memphis/news/2021/01/14/cognate-bioservices-212m-expansion-underway.html

Nice DD ATLnsider, thanks. Interesting connection.