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Uh no, topline WILL NOT be negative. Normally, a topline announcement is simply a brief statement whether the trial met its primary or secondary endpoints with statistical significance or not, then further data and analysis is presented in a peer-reviewed journal or conference a month or more later. That Northwest Bio intends to spend a few weeks with the full data and their SAB before even making any such announcement, indicates that they intend to be fully in control of the narrative. At a minimum, there will certainly be positive data (pre-selected MGMT Methylation Status) from the trial, which will be emphasized. Even if an endpoint did not reach statistical significance, the headline could still read something like” Northwest Biotherapeutics Announces Positive Survival Data From Phase III Trial of DCVax-L.”
And ae, just to be clear, I think that is the worst-case scenario. I actually think the survival data will be unprecedented and will be a major advance in cancer treatment, with milestone survival triple or quadruple historical comparisons.
Thanks a lot Extremist!
I’m certain there will be great interest in Northwest Bio’s DCVax Platform. Not sure if this has been posted, has anyone read the full article?
Dendritic cells dictate responses to PD-L1 blockade cancer immunotherapy
Science Translational Medicine 11 Mar 2020
Checkpoint musical chairs
Anti–PD-1 or PD-L1 antibodies can reinvigorate antitumor immunity in a subset of patients with cancer. To better understand the mechanisms behind successful therapy, Mayoux et al. characterized various ligands on the surface of dendritic cells (DCs). PD-L1 on DCs can bind B7.1 on the same cell, potentially preventing PD-1 ligation on T cells or B7.1 ligation of its partner CD28. They saw that PD-L1 was expressed in excess of B7.1, likely preventing T cell stimulation through these two pathways. Patients with a high DC signature before treatment were more likely to respond to PD-L1 blockade. These results reveal that in cis interactions on DCs have immunological and likely clinical consequences for checkpoint blockade therapy.
Abstract
PD-L1/PD-1 blocking antibodies have demonstrated therapeutic efficacy across a range of human cancers. Extending this benefit to a greater number of patients, however, will require a better understanding of how these therapies instigate anticancer immunity. Although the PD-L1/PD-1 axis is typically associated with T cell function, we demonstrate here that dendritic cells (DCs) are an important target of PD-L1 blocking antibody. PD-L1 binds two receptors, PD-1 and B7.1 (CD80). PD-L1 is expressed much more abundantly than B7.1 on peripheral and tumor-associated DCs in patients with cancer. Blocking PD-L1 on DCs relieves B7.1 sequestration in cis by PD-L1, which allows the B7.1/CD28 interaction to enhance T cell priming. In line with this, in patients with renal cell carcinoma or non–small cell lung cancer treated with atezolizumab (PD-L1 blockade), a DC gene signature is strongly associated with improved overall survival. These data suggest that PD-L1 blockade reinvigorates DC function to generate potent anticancer T cell immunity.
https://stm.sciencemag.org/content/12/534/eaav7431
Full text requires $
https://stm.sciencemag.org/content/12/534/eaav7431.full
BSB, I’m not here to provide false hope or self sooth, and I know what I own. I agree that in hindsight, some mistakes were made and things could have been done differently, but things don’t always work the way that you think they will or want them to, or in the timeframe that you want them to. I’m aware of your opinion about management and I’m not here to change it, but I will say this; everyone has qualities that are not always apparent. Tenacity is one that shouldn’t be overlooked.
Senti, I have thought that L & D were different products and would each have their own label with their own extensions. I posted that because it gave some credence to Doc’s thoughts, and it’s certainly possible with the updated FDA guidelines.
And by the way, I’m sure that both manufacturing processes are at least partially automated. They will have to be for commercialization, and it’s one of the “pioneering” steps that Linda was referring to. Have you seen the products Advent and Cognate have been working with? According to Lykiiri’s research, Advent has bee working with this:
MicroDEN® Perfusion Platform, Corning Life Sciences
The Corning® MicroDEN® System reduces the cost, time, and variability associated with the manual generation of dendritic cells in well plates and T-flasks.
* Reproducible
* Automated, closed system, optimized for dendritic cells
* Proprietary perfusion culture designed to accommodate adherent and non-adherent culture
* Up to 25 million DCs per run
* Reduces the 11-step manual process to 5 steps
* Translates from well plates and T-flask protocols easily
* Leverages benefits of polystyrene culture surface
Corning MicroDen is a streamlined, perfusion based system programmed to perfuse cell culture media over the dendritic cells during expansion. Through automation, MicroDEN eliminates several steps required to generate dendritic cells (DCs) in the current 'gold standard' manual process. The technician loads the isolated Peripheral Blood Mononuclear Cells (PBMCs) into the system with preferred cell culture medium and incubates. The system supports generation, wash, and harvest of dendritic cells.
The closed system kit reduces the risk of contamination. The cell culture flasks are tissue-culture treated polystyrene for cell adherence and optical clarity.
https://us.vwr.com/store/product/27675745/corning-microden-perfusion-platform-corning-life-sciences
And we know that Cognate has been collaborating with Flodesign Sonics and Terumo BCT., and these are their latest products:
FLODESIGN SONICS® ANNOUNCES THE OFFICIAL COMMERCIAL LAUNCH OF THE FIRST PRODUCT WITHIN THE EKKO™ LINE
This disruptive platform has the ability to process cells in a gentle and efficient way compared to traditional mechanical methods such as centrifugation or spinning membranes. The first product within the ekko platform has been specifically developed for concentrate and washing applications throughout the process. It is applicable to a range of processes, including single cell suspensions such as T-cells, and cell aggregates that are typically found in pluripotent stem cell cultures.
The ekko platform is a closed and automated system that processes continuously. Whether preparing an apheresis product for its downstream steps or harvesting cells from a bioreactor, flexible control and design allow for a wide range of process input and final concentrations, yields and process time. Applications also include buffer exchange and formulation, volume reduction down to 5ml, and single cell depletion for aggregate cell cultures.
https://www.fdsonics.com/index.php/news-events/news/flodesign-sonicsr-announces-official-commercial-launch-first-product-within-ekkotm-line-phacilitate-world-leaders-summit
ARM Presentation by Nina Bauer on Ekko
https://www.fdsonics.com/index.php/news-events/media/flodesign-sonics-presents-alliance-regenerative-medicine-meeting-med
Terumo BCT Launches First-of-its-Kind Device to Accelerate Cell Therapy Manufacturing
FINIA® Fill and Finish System: A New Automation Solution for the Production and Delivery of Cell and Gene Therapy
October 2, 2019
LAKEWOOD, Colo. USA - October 2, 2019 - Terumo BCT's latest cell therapy technology, the Finia Fill and Finish System, is a first-of-its-kind device developed to help bring reproducibility and control to cell therapy manufacturing to get therapies to more patients who need them.
Finia is a fully automated, modular, functionally closed system that creates the final formulation of cell and gene therapies and divides them into user-defined doses for patients. The technology automates a process that is currently manual and labor-intensive with the added risk of error.
"Terumo BCT technologies have been automating the collection and processing of blood and cells for decades," said Antoinette Gawin, President and Chief Executive Officer, Terumo BCT. "Now, we're translating this knowledge to support technology breakthroughs in cell and gene therapies. Finia helps cell therapy developers and researchers simplify processes while increasing accuracy, consistency, reliability and reproducibility -- key to securing regulatory approval."
The Power of Automation
"The production and delivery of cell-based therapies is a complex and logistically challenging process," said Delara Motlagh, Vice President, Cell Therapy Technologies, Terumo BCT. "Developers and manufacturers appreciate support in determining when to automate, which processes to automate and how to integrate automation into their existing process."
Finia combines, mixes and divides the final product into predetermined volumes, all under controlled, refrigerated temperature. It automatically removes air before it seals the final product bags, simplifying the downstream process. Finia also works with Terumo BCT's Cell Processing Application software in the customers' network to facilitate compliance to current good manufacturing practices (cGMP), including electronic recordkeeping, control of process workflow, user credentialing and permission, and guidance of operators through the process with an intuitive user interface module (UIM).
"With Finia, we are expanding our portfolio of automation technologies aimed at this growing industry," said Motlagh. "We are bringing multiphase solutions for cell and gene therapies helping to scale manufacturing and drive toward commercialization to reach larger patient numbers."
https://www.terumo.com/pressrelease/detail/20191002/473/index.html
thanks for sharing the video sharpie. It’s a great intro, or for most of us, a reminder why we’re invested here.
10bagger, yes this board does have some amazing posters. Credit for this one should go to RKmatters who transcribed Linda’s entire presentation, and who used to post here with some outstanding information. I merely re-posted it to show any doubters that Doc logic’s speculation was actually quite reasonable.
I’m not a trader, (but I do swing trade occasionally) so I’m probably not the one to ask about technicals, but when volume dries up, it could indicate that both buyers and sellers are waiting for a news event. In this case, it’s likely due to anticipation of a 10-Q or data-lock announcement.
The most important part of the quote from Linda Powers at the Oppenheimer Healthcare Conference got cut off in my response to Doc. Anyway, it’s the second paragraph.
"Now this is the platform technology that I have explained. It is embodied into two key product lines, two major products. The first one that you see up there, DCVax-L, is for all types of operable tumors, and the second one is for all types of inoperable tumors. Both of the products use the same two key ingredients: that's the immune cell, the dendritic cells themselves, and the biomarkers of the tumor that we want the immune system to hit. The difference between the two products is just in how we get the biomarker ingredient. With the product for the operable tumors, when the tumor’s surgically removed in the operating room, they just drop the tissue in a kit and send the kit to us. It literally takes a couple minutes in the operating room. And then we process it and we get the biomarkers from that tumor tissue. Well for the inoperable tumors, we don't have the tumor tissue to get the biomarker, so instead we activate the dendritic cells in a little bit different way. We directly inject them into the tumor, in the body, and the dendritic cells pick up the biomarkers on-site, in the tumor, and from there on out they operate the same, to mobilize the immune system.
And that again brings up one of the key values and competitive strengths of our technology. Our technology, both products, the one for the operable tumors and the one for the inoperable tumors can apply to any patient. We are not limited by tumor characteristics and we're not limited by patient characteristics. So we can treat with the same product, made the same way, all of these diverse cancers. That also means that from a regulatory pathway standpoint, after we get the first approval, in the first cancer, each additional cancer is just a label extension. You're not starting all over again with the whole clinical trial pathway. "
thanks hope4. This part caught my attention:
“The modifications we have made to our final SAP will help create a more robust dataset by increasing the overall amount of information derived from the Phase 3 trial . . . . and believe the steps we have disclosed today will produce an improved data package to support future regulatory filings.”
Hmmmm, a new SAP to support future regulatory filings. Sounds like a pretty good idea.
okay thanks Doc. Best wishes.
interesting video alpha. Have you seen Branko Krstevski’s model? He updated his with the SNO 2018 data, and I think his estimates will be pretty close.
I updated my $NWBO survival model using their latest Phase 3 trial data release.
— Branko Krstevski (@KrstevskiBranko) November 27, 2018
My modelling shows this #GBM tx may produce very high survival rates.
OS% -> 1Yr, 2Yr, 3Yr, 4Yr, & 5Yr
91, 51, 32, 25, & 23https://t.co/4M354Zn82H -> very risky investment pic.twitter.com/pqwwPbNKVw
nice post Doc and I agree with much of what you wrote.
I have questioned why the direct trials have not started, especially since they had funding after the Swaston real estate sale, the direct contract was negotiated with Cognate, and clinical trials were approved (or nearly approved) with the FDA. I'm not buying the excuse that resources were too tight, so what you say makes some sense. I know that Northwest Bio’s management was “very happy” with the revised SAP, and it likely spells out expedited pathways. Linda Powers has said on a couple of occasions that she thinks L & D are essentially the same (partially matured dendritic cells). Here’s a quote by her at the Oppenheimer Healthcare Conference many years ago (courtesy of RK Matters):
“Now this is the platform technology that I have explained. It is embodied into two key product lines, two major products. The first one that you see up there, DCVax-L, is for all types of operable tumors, and the second one is for all types of inoperable tumors. Both of the products use the same two key ingredients: that's the immune cell, the dendritic cells themselves, and the biomarkers of the tumor that we want the immune system to hit. The difference between the two products is just in how we get the biomarker ingredient. With the product for the operable tumors, when the tumor’s surgically removed in the operating room, they just drop the tissue in a kit and send the kit to us. It literally takes a couple minutes in the operating room. And then we process it and we get the biomarkers from that tumor tissue. Well for the inoperable tumors, we don't have the tumor tissue to get the biomarker, so instead we activate the dendritic cells in a little bit different way. We directly inject them into the tumor, in the body, and the dendritic cells pick up the biomarkers on-site, in the tumor, and from there on out they operate the same, to mobilize the immune system.”
I also agree that with exceptional data, an expedited pathway, or rolling submission will be likely. I know they have been in close contact with the FDA throughout the year, and I think this may be one of the reasons Linda said that it will take a few weeks to review the data with their Scientific Advisory Board, as they may be sharing key data with other entities, including the FDA, prior to public notification.
7. Pre-BLA/NDA meetings:
* The purpose of the meeting is to discuss the planned content of the application with the appropriate CBER review division. Applicants are strongly encouraged to request this meeting. ?
* The pre-BLA/NDA meeting should be requested sufficiently in advance of the planned submission of the application to allow for meaningful response to CBER feedback and should generally occur not less than two (2) months prior to the planned submission of the application. Thus, the meeting request should be submitted at least four (4) months prior to application submission. ?
https://www.fda.gov/media/84040/download
I’m also sure that with good data, there will be great interest in the DCVax Platform by multiple BP’s, including Merck. BTW - Is this what you are referring to WRT Merck’s manufacturing? MERCK’S CUTTING EDGE FACILITIES TAKE MANUFACTURING TO NEW HEIGHTS https://www.merck.com/about/featured-stories/flex-center.html
I agree with Know-Fear about the “optimized” work in Germany, and sometimes have trouble with your (innuendo) writing style. I have thought “optimized” referred to the manufacturing process using automated tangential flow filtration system that was implemented at the same time. I know it was considered “state of the art” back then, but it’s really not any more. Is this what you are referring to?
(page 27) Manufacture of the immunotherapeutic DCVax®-L for brain tumor patients
The manufacturing process for the immunotherapeutic DCVax®-L has been optimized and implemented as part of a clinical trial conducted by American biotech company Northwest Biotherapeutics, Inc. The therapeutic approach is based on autologous dendritic cells and aims to improve the treatment of glioblastoma, a particularly aggressive type of brain tumor.
https://www.izi.fraunhofer.de/content/dam/izi/en/documents/Publications/AnnualReport_IZI_2017_short.pdf
Most companies simply give a timeline to topline and then announce topline, but normally don’t announce the steps along the way, like finalizing the statistical analysis plan, query resolution, and data lock. Since Northwest Bio has included it on the timeline, I think they will announce it. I suppose if they don’t announce it though, they will have a little wiggle room.
Data freeze is a very critical step, and they absolutely have to get it right. If the database has to be unlocked after it has been locked, due to missing data or an error, then data integrity will be questioned. Usually there will be a “soft lock” and a dry run performed to ensure that any missing data or errors are noted and corrected before the all important data lock step. This is one of the many reasons data lock can be delayed.
I don’t think it’s as harmful as you say not to announce it, but I think being on the OTC, and trading for pennies, it would be more beneficial to announce it, than not.
Agreed BSB, and I communicated this to Dave the last time I talked to him (last fall when I foolishly thought we were close to data lock). He said that he understands the importance, for a number of reasons, and would like to communicate this achievement. He also said that he didn’t think Linda was opposed to it. In hindsight, I think he knew they were farther away from it than I knew at the time, and probably hadn’t even had the “data-lock conversation” but at least the seed was planted. I'm guessing they are a little delayed, but will eventually announce it.
I’m surprised the 10-Q isn’t out yet. Does anyone know if any other D-1 warrants received the same extension terms as Linda Powers? I’m guessing that Cognate’s 52M did, but it would be nice to know.
Speaking of Merck, some interesting (edited) comments on Merck’s Q1 conference call from Tuesday as it could relate to Northwest Bio, and the impact of COVID-19 on BioPharma sales and clinical development. They basically said that they are seeing declines in physician office visits, and elective and non-critical surgeries, but they are continuing to enroll and launch new clinical trials. And although they will temporarily discontinue their stock repurchase program, they still continue to search for “value-enhancing” companies with which to partner and acquire, which remains a top priority.
https://news.alphastreet.com/merck-co-nyse-mrk-q1-2020-earnings-call-transcript/
Ken Frazier - Chairman and CEO
In many markets around the world, including the U.S., while our offices and laboratories remain open, our colleagues are primarily working from home. And for patients currently enrolled in our clinical trials, we're making every effort to ensure that patients in affected areas are able to continue their treatment and receive appropriate care and monitoring. Conditions are fluid and evolving. But as conditions allow, we are enrolling patients in ongoing studies, and we're starting new studies. . .
Importantly, our financial strength and strong balance sheet allow us to continue with our capital allocation priorities, including investing in R&D and in our growth drivers, investing in manufacturing capacity expansion, paying our dividends, and continuing our search for value enhancing business development, which remains a top priority. . .
And in the United States physician office visits across various areas of medicine are currently running down in the neighborhoods of 70% versus pre-COVID-19 levels. . . Non-urgent elective procedures have also been postponed or cancelled in most major markets in order to slow the spread of disease and enable hospital prioritization of COVID-19 patients. . .
Many sources are reporting current declines in elective procedures of over 70% with urgent procedure volumes also being affected, though to a much lesser degree. . . And even oncologists are delaying appointments and procedures as they prioritize patients based on severity and the immediate needs of different tumor types, resulting in extended dosing schedules for existing patients, as well as delays in the start of therapy for newly diagnosed patients.
Rob Davis - EVP, Global Services, and CFO
. . . In addition, as Ken noted, business development remains a priority, and we will continue to look for the best external sources of science to augment our pipeline. We will assess the environment on an ongoing basis and consider reactivating the repurchase program as warranted.
Roger Perlmutter - EVP and President, Merck Research Laboratories
So let me begin with our operational status. As an early point, our global clinical operations team recognized the importance of the SARS-CoV-2 infections that were reported in Wuhan, China, and made advanced preparations to manage what became the COVID-19 pandemic. These preparations included prepositioning clinical supplies, strengthening our clinical supplies network, putting in place processes to enable virtual monitoring and over time developing processes for home deliveries, investigational agents, including in some cases, developing alternative infusion sites. Operating virtually the clinical operations team, including data management and our quality organization has been able to maintain our overall clinical trial schedule. We have in some cases reduced enrollment in certain jurisdictions. But we have not halted enrollment and are continuing to launch new clinical trials across most jurisdictions.
As examples, our team processed 36 database logs in the month of March, and enrolled more than 700 new patients across our Europe, Middle East, Africa sites. These numbers provide substantial reassurance that our clinical programs are moving forward. Indeed, although I cannot predict what the course of the pandemic will be in the future, for now, our 2020 MRL objectives are not in jeopardy. This progress is owed entirely to the extraordinary work of teams across our organizations spanning five continents, and a very broad set of government regulatory agencies with whom we interact.
Q & A
Terence Flynn with Goldman Sachs
So can you just give us any more detail, the main driver there, is that you see an increasing number of M&A or BD opportunities now in this environment?
Rob Davis
. . . And then on your question about share repurchase program, just to be clear, and I had it in the prepared remarks, but it's worth reinforcing. We really decided to temporarily stop the share repurchase program predominantly out of an abundance of caution. Our financial position continues to be strong. And as we said, it really was to make sure that we can continue to do all of the investments we want to do in R&D and CapEx to support our future growth, and in business development, as you asked. So it's really across all those areas that we want to make sure we can prioritize investment. And we will continue to look at it and very well could reinstate the share repurchase as we see the situation evolve in the marketplace.
ex, it was in the 10-K :
ITEM 9A. CONTROLS AND PROCEDURES
Evaluation of Disclosure Controls and Procedures
We, the management of Northwest Biotherapeutics, Inc. (the “Company”), are responsible for establishing and maintaining adequate internal control over financial reporting of the Company.
We maintain disclosure controls and procedures (as defined in Rules 13a-15(e) and 15d-15(e) under the Exchange Act) that are designed to ensure that information required to be disclosed in the reports that we file or submit under the Exchange Act is recorded, processed, summarized and reported within the time period specified in the SEC's rules and forms, and that such information is accumulated and communicated to our management, including to our Chief Executive Officer and Chief Financial Officer, as appropriate, to allow timely decisions regarding required disclosure.
As required by Rule 13a-15 under the Exchange Act, our management, including our Chief Executive Officer and Chief Financial Officer, evaluated the effectiveness of the design and operation of our disclosure controls and procedures as of December 31, 2019. In making this assessment, the Company’s management used the criteria established in Internal Control — Integrated Framework (2013) issued by the Committee of Sponsoring Organizations of the Treadway Commission (“COSO”).
Our management concluded that as of December 31, 2019, our disclosure controls and procedures were effective, and previous noted deficiencies have been remediated, as described below.
Management's Report on Internal Control Over Financial Reporting
The management of the Company is responsible for establishing and maintaining adequate internal control over financial reporting. The Company's internal control over financial reporting is a process designed to provide reasonable assurance regarding the reliability of financial reporting and the preparation of financial statements for external purposes in accordance with generally accepted accounting principles. Because of its inherent limitations, internal control over financial reporting may not prevent or detect misstatements. In addition, projections of any evaluation of effectiveness to future periods are subject to the risk that controls may become inadequate because of changes in conditions, or that the degree of compliance with the policies or procedures may deteriorate.
A material weakness is a deficiency, or a combination of deficiencies, in internal control over financial reporting, such that there is a reasonable possibility that a material misstatement of the Company's annual or interim financial statements will not be prevented or detected on a timely basis.
Management of the Company, including our CEO and CFO, assessed the effectiveness of the Company's internal control over financial reporting as of December 31, 2019. Based on this assessment, we determined that we have effectively designed and implemented, consistently performed and tested the functioning of these controls.
Based on the efforts identified above, we have concluded that the previously identified material weaknesses in the Company’s internal control over financial reporting have been remediated through the following efforts:
1. To
maintain effective controls over the operating effectiveness of information technology ("IT") systems that are relevant to the preparation of our financial statements, we designated a Chief Information Officer, formalized and consistently implemented appropriate IT policies, and strengthened the oversight of the Company’s third-party service providers with regards to maintaining documentation related to the areas of: managing user access, IT change management, IT infrastructure (cybersecurity, network security) and IT operations (physical security, contingency planning, disaster recovery, backups). The Chief Information Officer oversees and approves all of the activities performed by our third party service providers.
2. We improved our level of documentation to support reviews and retention of such documentation to support management’s review activities. This documentation is used as evidence of such review procedures being performed by management over the processing, recording and reviewing of transactions related to certain contracts, accounting memos and certain monthly closing procedures. We have also invested additional resources to continue to improve our financial control environment through the hiring of an additional executive dedicated to these efforts as the Chief Financial and Accounting Officer (CFO/CAO).
3. The Company has formalized and implemented a complete set of financial operational policies and related procedures which govern our system of internal controls over financial reporting. These policies were reviewed and tested to be effective as of December 31, 2019.
Because these material weaknesses
were successfully remediated and additional material weaknesses were not identified, management, including our principal executive officer and principal financial officer, has concluded that our internal control over financial reporting was effective as of December 31, 2019.
The effectiveness of our internal control over financial reporting has been audited by Marcum LLP, an independent registered public accounting firm, as stated in their attestation report in Item 8 of this Annual Report on Form 10-K, which expresses an unqualified opinion on the effectiveness of our internal control over financial reporting as of December 31, 2019.
Changes in Internal Control Over Financial Reporting
There were no changes, other than those described above, in our internal control over financial reporting during the fiscal quarter ended December 31, 2019 that have materially affected, or are reasonably likely to materially affect, our internal control over financial reporting.
https://sec.report/Document/0001104659-20-034145/#b_007
Hi beartrap, re: Market Holiday Observations
When a holiday falls on a weekend, market closures are dictated by two rules:
* If the holiday falls on a Saturday, the market will close on the preceding Friday.
* If the holiday falls on a Sunday, the market will close on the subsequent Monday.
Therefore, in the US, the stock and bond markets are closed on Friday July 3rd in observance of Independence Day.
Here’s wishing you get a present in time for your birthday.
Thanks BSB. Those price ranges are very similar to my estimates as well, based on historical prices of similar oncology assets at that stage. However, I have tempered my expectations from those estimates to adjust for the current market conditions, OTC exchange, and lack of analyst coverage. Not sure how management plans to mitigate those issues, or even how concerned they are about them though.
Jerry, I’m not so sure that what I wrote was consistent with your post. You seemed to suggest that readers should read two sentences, out of context, again and again, to conclude that the FDA is not likely to approve the DCVax therapy. I suggested that readers should read the entire interview to conclude that Dr. Liau was not actually saying that at all.
And no, I don’t think “the FDA should ignore all its procedures, ignore bad trial design, and approve dcvax regardless.” I’m not sure how you jumped to that conclusion, as I simply clarified what I believed Dr. Liau was saying.
I think the FDA should follow its procedures, and its own guidelines issued over the past couple of years clearly demonstrate that it’s becoming more flexible and taking a more patient-centered approach, so I think they will consider DCVax’s extremely benign safety profile, and evaluate the totality of evidence (including the real world evidence from the compassionate use, information arm, and EAP patients, as well as any biomarker analysis) gathered from this incredibly lengthy and data-rich trial, before reaching a decision.
No Jerry, instead of reading a couple of sentences out of context, I would suggest that it would be better to read the entire interview to understand what Dr. Linda Liau is actually saying about the difficulties in getting a real, paradigm-changing treatment (as opposed to the Optune device) for GBM approved by the FDA.
What I think she is saying is that, because of the heterogeneous nature of GBM, the standard clinical trial methods may be insufficient and outdated, and need to be modernized to capture, and include other evidence of efficacy that is more patient specific, such as real world evidence, and patient reported outcomes. (and I will add surrogate endpoints and qualifying biomarkers)
Q&A with Linda Liau
Posted on March 17, 2020 by Bill Malloy
As Chair of UCLA’s Department of Neurosurgery and the inventor of a personalized brain cancer vaccine, Dr. Linda Liau is widely recognized as one of the world’s most forward-thinking brain surgeons. Having spent more than 25 years on glioblastoma research, Dr. Liau developed the individualized treatment to work with a patient’s unique immune system to detect and attack cancer cells that remain after tumor removal.
Glioblastoma, the most aggressive type of cancerous brain tumor, usually results in death within 15 months of diagnosis. One of the biggest problems with finding a successful treatment? According to Dr. Liau, the fact that the disease is so heterogeneous – that it presents differently from patient to patient – means that the standard clinical trial approach has so far been less than helpful when it comes to identifying a cure.
So, what is the answer? Ever the pioneer, Dr. Liau thinks that comparative analysis may be a good start. Such an approach would allow physicians to treat patients individually, using real-word data to treat the patient according to what is best for them, rather than by strictly adhering to the protocols of a standard clinical trial.
I recently sat down with Dr. Linda Liau to discuss glioblastoma, the current state of clinical trials, and how a different approach is needed to eventually find a cure.
Q: What, in your opinion, is the big-picture problem with glioblastoma?
A: I’ve been working in this area for 25 years now, and one after another, these trials fail. AbbVie had a trial just a few months ago that failed and I think biotech caption was, “Glioblastoma takes another victim.” So, I think we’re going about this the wrong way, because I think everybody’s trying to find a cure but also have a company raise money and get their company launched. But glioblastoma is such a heterogenous disease. I don’t think you could go say, “Oh, I have one drug or one treatment, one molecule target or one drug, and I am going to patent this, license it and then do a startup company. And this is how I’m going to cure GBM.”
More and more, I do think you need to think about appropriation therapies, we need to think about timing of treatments and also the whole process of getting therapies adopted through the whole hurdle of FDA approval.
The entire interview: https://billmalloy.info/qa-with-linda-liau/
Big Pharma Will Turn to Mergers After Crisis, Says RBC
By Bill Alpert April 24, 2020
Drug companies will slow their stock buybacks after the Covid-19 crisis and spend their money instead on buying each other, according to a Friday note from RBC Capital Markets.
Strong cash flows and looming patent expirations will drive Big Pharma to fill its medicine chests through mergers and acquisitions, wrote analyst Randall Stanicky. “We think M&A is set to ‘re-emerge’ as one of the bigger themes post pandemic,” Stanicky said.
The companies most likely to be on the prowl for acquisitions, he believes, are Merck (ticker: MRK), Pfizer (PFE), AbbVie (ABBV) and Johnson & Johnson (JNJ).
Even if the coronavirus crunch takes away some revenue in the next year, the industry will have plenty of cash. Merck and Pfizer alone will generate $100 billion between them in the next five years, after dividends, the analyst said.
Big drugmakers spent a third of their capital on share buybacks in the last decade, but Covid-crisis government bailouts and drug development have made stock buybacks look unseemly for now . That will leave more cash for drug companies to use in filling gaps left when products that are currently selling big lose market exclusivity.
AbbVie has the nearest need: Its arthritis treatment Humira, a huge seller, will face competition from biosimilar rivals in 2023. Stanicky said that Pfizer and Merck could lose exclusivity on important products in 2026 and 2028, respectively.
At one of Wall Street’s last conferences before the lockdowns, in March, Merck financial chief Robert Davis mentioned his company’s “urgency” in augmenting its product pipeline. Johnson & Johnson discussed its interest in acquisitions when it reported strong earnings last week .
The RBC analyst says investors will learn more about Big Pharma’s acquisition aims as companies report their March-quarter results. Pfizer’s and Merck’s are each due on Tuesday, and AbbVie’s arrive on May 1.
https://www.barrons.com/articles/big-pharma-drugs-buybacks-mergers-coronavirus-crisis-51587740736
Thanks for the advice longfellow, but I was obviously posting that article in relation to NWBO and their potential new drug launch next year in this pandemic environment, which won’t be going away for a while. We know that COVID-19 is pausing new clinical trial enrollment, which doesn’t really affect Northwest Bio right now, but it may have an affect on pipeline development in the near future, and potential new partnering trials.
One of the questions I would have asked at the ASM is: what impact is the coronavirus having on reaching data lock and topline (if it wasn’t already announced), and what impact do you anticipate it will have on the approval process, potential launch, and partnering trials?
I guess we learned that it’s slowing the process somewhat, but there are work arounds. Since the actual filing of the BLA and MAA , etc., are electronic, and the meetings with regulators are virtual, that part won’t be affected, but pre-approval inspections, and regulatory timelines could be backed up for months.
COVID-19 is bad news for new drug launches. Which will suffer most?
by Angus Liu | Apr 3, 2020
https://www.fiercepharma.com/marketing/biopharma-s-drug-launch-trajectory-bent-by-covid-19-but-some-maybe-more-resilient
The COVID-19 pandemic and the ensuing societal countermeasures are upending operations in many sectors—and biopharma isn't immune.
The current lockdown is not only hurting clinical trial enrollment but also delaying regulatory timelines for drugs nearing a decision. And with tried-and-true, in-person marketing techniques no longer allowed, new launches may also feel the pain—or hold off altogether.
Consider Bristol Myers Squibb and its big new approval for multiple sclerosis drug Zeposia. It's a long-awaited med, but BMS is postponing the launch under the circumstances. Also in the MS arena, a regulatory decision for Novartis’ repurposed ofatumumab might also come late, ODDO BHF analysts noted recently.
Rollouts from small-cap biotechs with little to no marketing experience are likely most vulnerable, however. So are new meds challenging existing drugs—like Zeposia—chronic disease therapies and those that need heavy up-front awareness promotions, industry watchers figure. On the flipside, drugs for life-threatening diseases with few other options would be more protected.
Roche's spinal muscular atrophy drug risdiplam might be thwarted, at least for now. It currently bears an FDA decision date for May. But the ODDO team said, “we would not be surprised if approval was postponed.”
Plus, the FDA will likely feel less urgency to review the drug if its resources are under pressure, given there are already Novartis' gene therapy Zolgensma and Biogen's tried-and-true oral Spinraza on the market.
Potential inspection, approval and launch delays will place Gilead Sciences and Galapagos’ JAK inhibitor filgotinib farther behind AbbVie’s Rinvoq in rheumatoid arthritis, RBC Capital analyst Brian Abrahams noted in a recent report.
As for Biogen, the Big Biotech is grappling with the coronavirus from within as several members of senior management have been infected. Therefore, regulatory filing or review of its key value driver—controversial Alzheimer’s contender aducanumab—is likely going to take more time than expected.
Intercept’s closely watched NASH candidate obeticholid—sold for another indication as Ocaliva—already got the delay message as an FDA advisory committee meeting discussing its approvability has already been rescheduled for months later.
For drugs that just landed on the market, generally, those treating serious diseases with fewer or no competitors will be less affected amid the pandemic. A recent survey by Spherix Global Insights showed that one-quarter of neurologists are less likely to prescribe a migraine therapy that has been on the market for less than a year due to the ongoing COVID-19 crisis. Fellow migraine drugs, Allergan's Ubrelvy and Eli Lilly's Reyvow, were just approved near the end of 2019. But when asked specifically by brand, more neurologists voiced a reluctance to start patients on Biohaven's Nurtec ODT compared to Ubrelvy.
Biohaven, which is in the early days of selling Nurtec ODT, is already shifting its marketing tactics in response to social distancing requirements, resorting to webinars, telemedicine, DTC and social media to boost its presence among doctors and patients.
In contrast, Vertex’s cystic fibrosis franchise—including its newly launched triple combo Trikafta—should be resilient, Abrahams figures, especially as the importance of therapeutic intervention to reduce respiratory symptoms grows in the face of coronavirus.
Sarepta’s Duchenne muscular dystrophy portfolio, including recently approved Vyondys 53, could also be affected, “especially if the inherent higher infection risk from their underlying disease causes some to reduce physician visits,” Abrahams said. But the lack of alternatives and potential approval or launch delays for Nippon Shinyaku’s rival med viltolarsen could benefit Sarepta.
Some drugs are entering disease fields where physicians and patients need to be educated. One example, as RBC's Abrahams noted in a recent report, is Neurocrine Biosciences’ Ingrezza.
The drug is “highly sensitive to sales details and educational efforts” at physicians’ offices, plus it treats the non-life-threatening condition of tardive dyskinesia, which is marked by involuntary movements such as eye blinking. For that, Abrahams’ team now projects Ingrezza sales growth to slow down, with 2020 haul now estimated at $915 million, versus its previous forecast of $1.1 billion.
On the flipside, Orilissa, which Neurocrine discovered and licensed to AbbVie, may enjoy better sales as patients refrain from visiting hospitals for surgical procedures and instead turn to the oral med for their endometriosis. But a proposed label expansion into uterine fibroids could be delayed.
Similarly, uptake of drugs that require intravenous infusion at a healthcare facility is likely to be hampered as administration resources face constraints and compliance is reduced. Sage Therapeutics’ postpartum depression drug Zulresso belongs to this category. The drug’s lengthy 60-hour IV infusion process already represent a major challenge for patient experience under normal circumstances.
Meanwhile, Karyopharm’s Xpovio entered late in the crowded multiple myeloma market in mid-2019 and was pushed in late-line use. Still, Abrahams said he believes the drug’s novel mechanism for a deadly disease makes it “more insulated than most from pandemic-related challenges.” Then again, the company’s efforts to expand the drug into diffuse large B cell lymphoma and earlier MM could be slowed.
mani you don't sound "happy to be wrong" (or even willing to acknowledge it)
A little late, but thank you IkeEsq for your time and effort to post the ASM Transcript. I listened to it live, (and recorded it) but it's good to see it in writing and be able to dissect it. It was disappointing, but not surprising that the other questions weren’t answered, but I was satisfied that at least a timeline to results was finally given. To me, that was the big one, and it shows that management at least understands this. I’m sure there are some here who have spun it as more can-kicking, but to me, this is very positive, and leads me to believe that they planned to announce data lock before the ASM, (thus the "interesting" comment) and to present topline at ASCO as I suspected. It seems the coronavirus slowed their progress by 4-6 weeks, so I anticipate that they will present topline within 4-6 weeks from ASCO at the end of May. (coincidentally around Glioblastoma Awareness Day) Hopefully, the economy and stock market will have stabilized somewhat by then.
Thank you Ike and senti for all your work on the questions for the ASM. I doubt that they will answer all of these, but your efforts are still much appreciated. I’ve had limited internet access while self-quarantining after returning from south of the border, but catching up on posts, and with my family now. The proxy was pretty standard stuff unfortunately, so hopefully some interesting news will be announced this week, or at least a definitive timeline will be revealed.
tryn2, If MRK bought NWBO with MRK shares, the exchange wouldn’t happen overnight. The deal would be announced but the closing of the transaction wouldn’t happen for at least a month or two. In your hypothetical situation, with MRK trading at say $70 on the day of the announcement, that would mean that NWBO shares would be worth 1/4 of MRK or $17.50. NWBO would likely begin trading close to that price (around $17) from the day of the announcement until the close of the transaction a month or more later. You are free to sell them at the current price or simply continue to hold them. On the day of the announced close of the transaction, then MRK shares will be exchanged in your account for NWBO.
For purposes of capital gains, the cost basis on the new MRK shares is the same as the cost basis on the former NWBO shares. Assuming they are held in a taxable account, if you should decide to sell them at that point, the gains from the sale would be taxed at the long-term capital gain rate, since you held the original NWBO shares over 1 year. Basically, the first $450,000 is taxed at 15% and the rest is taxed at 20%.
Agreed GGB. Merck currently has ~$10.5B cash on hand, and last month announced a spinoff of women’s health, some slower-growth legacy brands, and biosimilars products into a new company to be named later. Merck expects to receive $8B to $9B through a special tax-free dividend from the NewCo., and expects that these funds will be allocated to business development, or share repurchases.
MERCK 4Q & 2019 FULL-YEAR EARNINGS SPINOFF OF NEWCO
https://s21.q4cdn.com/488056881/files/doc_financials/2019/q4/4Q19-Earnings-Deck_MRK.pdf
Haha yeah senti I was thinking of you when I wrote that. :) Your chart is old, but familiar. I lean more on fundamental analysis, but I’ve learned to incorporate Elliott Wave and Fibonacci ratios since all the algos are using them, and so much of the modern trading follows the patterns. I follow an EW trader who has been remarkably accurate, and says that we are in the 4th wave decline (which I also believe was delayed possibly due to the tax stimulus) but he believes there will be one more wave higher to at least 4,000 before the big drop.
The lessons that should have been learned from 2008, unfortunately were not. What the Goldman Sachs and other investment banks actually learned is that they can use extreme leverage and take massive risk without significant personal consequences. Few people understand how close we are to another financial meltdown. (I know for a fact the big investment banks are again leveraged to the hilt) Wanna see a truly frightening chart?
https://twitter.com/Schuldensuehner/status/1236709336921104385/photo/1
marzan, sentiment is what controls the market. The Fed can’t prevent crashes and doesn’t have as much power as people think, but it can help to change sentiment. The severity and duration of the coronavirus’ impact to the world-wide economy are unknown right now, and the market doesn’t like uncertainty, so it will likely fall further. I would much rather Northwest Bio release good news in a frothy market, but it is what it is.
I was waiting for capitulation in the market, but couldn't resist dipping a toe in here. Didn't think we'd see sub $2 again. Throwing the baby out with the bathwater. People will still need the products that Antares sells or partners.
Nice work senti, thanks. I noted most of the same new language, but you saved me the time of digging out last year’s 10-K to compare.
Sounds like they are confident of approval if there is a “need to negotiate a new agreement with Cognate in 2020 for production of DCVax-L products for commercial purposes and new programs.” Wonder what the new programs are.
I would agree that the current language indicates that the SAP work has been completed, but quite honestly, I would be surprised and very disappointed if it wasn’t by now.
I have to admit that I would have preferred different language than “The Company is continuing to consult with its Scientific Advisory Board, independent consultants and the Board of Directors to move forward as prudently and expeditiously as possible to data lock, unblinding and top line data.” While it doesn’t really elaborate where they actually are in the process, that language indicates to me that they haven’t yet reached data lock.
And yes, it is noteworthy and odd that “Item 10, Directors, Executive Officers And Corporate Governance” section was left blank and will be incorporated in the Proxy Statement. I doubt the reason for this is “blah” or they would have just copied last years. I will speculate that this will fall under the “interesting” category.
One other difference is that new patents were issued last year:
The 2019 10-K stated:
As of December 31, 2018, we have over 190 issued patents and more than 65 pending patent applications worldwide, grouped into 12 patent families. Of these, 181 issued patents and 35 pending patent applications directly relate to our DCVax products.
During 2018, two new patents were issued to us as part of our worldwide patent portfolio. The newly issued patents cover methods and devices for manufacturing dendritic cells related to our DCVax products, as well as encompassing certain dendritic cell compositions for direct injection into patient tumors related to our DCVax-Direct product.
The 2020 10-K:
As of December 31, 2019, we have 199 issued patents and 65 pending patent applications worldwide, grouped into 11 patent families. Of these, 191 issued patents and 52 pending patent applications directly relate to our DCVax products.
During 2019, six new patents were issued to us as part of our worldwide patent portfolio. The newly issued patents cover methods and devices for manufacturing dendritic cells related to our DCVax products, as well as encompassing certain methods and compositions that may be potential future markets related DCVax products.
This idea that Big Pharma will “buy & bury” (like catch & kill) has been around for some time, and may have been true at one time, but would not happen with DCVax today. Five years ago, the first dendritic cell therapy for prostate cancer, Provenge, was mostly manufactured manually and it was too expensive; it was ~$95k per treatment (and required 3), and the cost of sales was around 50%, The personalized medicine model has not been preferred by BP, but that is changing with the willingness of insurance to cover the staggering costs of Kymriah and Yescarta. That Kite, Juno, and other CAR-T bio’s were snapped up and not buried should be enough evidence.
I would estimate the costs to produce DCVax manually for the clinical trial was ~$100k per batch, and Linda knew this cost would not be commercially feasible. But, I believe Linda’s plea for help in lowering the cost of manufacturing has been answered. Based on the companies Cognate has been collaborating with, FloDesign Sonics on the upstream processing (cell selection, purification, etc), and Terumo BCT on the downstream processing (final washing and concentration following expansion, and final preparation for cryopreservation) the manufacturing process for DCVax-L has been mostly automated and should easily be profitable when produced at commercial scale. I would estimate costs around $40k per batch at startup (not including logistics), lowering to ~$30k at full scale. While I think the treatment would likely be offered less expensively by Northwest Bio than say Merck, I still think it will be made be available to everyone just as Linda, Dr. Ashkan, et al. requested.
Old news mani. SEC investigation was settled in October. Try to keep up.
NW Bio Moves Forward With SEC Settlement
Oct 10, 2019, 17:39 ET
https://www.prnewswire.com/news-releases/nw-bio-moves-forward-with-sec-settlement-300936897.html
https://www.sec.gov/litigation/admin/2019/34-87281.pdf
Thanks maverick. I missed many of those.
Yeah, and I think it was a good one. It made me laugh.
I haven’t seen a notice like that vator, but this is the first time Dave Innes issued it. Maybe he was just having fun. About forty thousand people attend Berkshire Hathaway's Annual Shareholder’s Meeting in Omaha, and they have to plan months in advance too.
I’ve attended a number of shareholder meetings of larger companies and always found them very informative. At the very least, I’m sure this one will be too, and I certainly didn’t mean to discourage anyone from attending. I’m very much looking forward to hearing about it.
haha laser, I had forgotten about us admitting to being shareholders of “the company who shall not be named” almost like the AA meetings. Hi, my name is hyper and I’ve been a NWBO shareholder for two and a half years. :) Hopefully one day soon, we can proudly say “yeah I was a NWBO shareholder back before it was cool.”
Yes, it appears that after all this time, the end of the trial is FINALY near, and all of the unanswered questions will soon be known. If they haven’t locked the database and unblinded yet, I think (hope?) they will soon. Linda has said that ASCO is a great venue when the timing works out, and I would think that they would make a concerted effort to present their “stupendous” (to quote Les) data on the grand stage at ASCO (and no, I’m not talking about the industry expert theater).
I’m not sure what to make of the shareholder meeting, but I think maybe too much is being made of it. Of course the company is going to invite as many shareholders to attend as possible. What should they say? Well you can come if you want, but it’s probably going to be another yawnfest? Typically, big news isn’t announced at these meetings, so I don’t have high expectations that anything significant is going to be announced, and I doubt they could go into much detail even if topline is announced before the meeting. I would wait to see the proxy materials before making plans if you’re unsure. I’ll still be out of the country, so it’s very unlikely I’ll be attending, but I do hope to meet you, and some of the other colorful posters on the best board on Ihub, at the celebration party if there is a buyout.
yes beartrap, what about Dr. Duffy? My belief is that the intention is to go it alone in Glioblastoma, but Linda may be open to partnering combinations for other indications, and that is where Mr. Duffy’s expertise would be required, if “external collaborations” is indeed his role. Seems a bit curious that he would be brought in a year before they even apply for approval though doesn’t it?
Northwest Bio already has an approved trial in combination with Merck for colorectal cancer that seems to be abandoned, a trial for brain metastases that was approved in 2018 which hasn’t started recruiting, and a DIPG trial that was in the process of FDA review and clearance last June, which hasn’t been spoken of since. So I’m not real confident that Northwest Bio is capable of, or has a desire to run and chew gum at the same time. They will surely have their hands full with gaining approval and pioneering a commercial launch for a brand-new cell therapy in FOUR countries. This is a major undertaking, and a daunting task for an experienced pharmaceutical company, much less a clinical-stage company with absolutely zero commercial experience. And we are to believe that they will also partner multiple new combination trials on top of that?
This is why deals are often made at this stage of development; the odds are stacked against the small bio making a successful commercial transition. Meanwhile, Big Pharma knowing this, will attempt to wield their considerable leverage and make low-ball offers. Linda knows what the platform is potentially worth, and won’t accept a low-ball offer. This is why I think it should be interesting.