Expert Financial Analysis and Reporting

Executive Summary

I have tried to make this report as short and readable as possible so that in many cases I provide links to a previous article I have written or other pertinent data, rather than recreating the information in this report. So, you will find lots of links. The intent is to give the reader my conclusions in short form in this executive summary, but also to provide access to in-depth information for those seeking more detail.

Adam Feuerstein and his employer, Stat News, continue to falsely allege that the phase 3 trial of DCVax-L failed. This is a jaw dropping accusation given that:

• The 70 plus investigators who participated in the trial co-authored a paper describing the phase 3 trial and its results and concluding that the trial had successfully reached its primary endpoint of median overall survival (mOS) in newly diagnosed glioblastoma (ndGBM) and the secondary endpoint of mOS in recurrent glioblastoma (rGBM).
• The prestigious New York Academy of Science featured a presentation at its conference on May 10, 2022 in which the presenter unequivocally stated that the trial successfully reached its primary and secondary endpoints. This was the first time that unblinded topline data from the trial was made public.
• On November 17, 2022 JAMA Oncology, a Journal of the American Medical Association publication, printed a peer reviewed article clearly stating that the trial successfully reached its endpoints. This was, of course, based on the paper co-authored by the 70 plus investigators’
• On November 23, 2022 the lead investigator in the trial, Linda Liau, was invited to make a presentation at a plenary session of the prestigious Society of Neuro-Oncology in which she stated that the trial was successful. SNO is the foremost medical conference for neuro surgeons and others involved in the treatment of glioblastoma. The decision to prominently feature Dr. Liau’s presentation speaks volumes about how many physicians will view these results.

These are very powerful endorsements for the view that DCVax-L holds the promise of extending survival and represents a significant medical advance in the treatment of GBM, a disease in which half of patients die within roughly 16 months of diagnosis and only 5% survive for five years. The phase 3 data shows that DCVax-L added to current standard of care impressively increases survival in ndGBM. Also shown in this trial was that DCVax-L added to SOC is the first therapy ever shown to increase survival in rGBM. Having said that, I must emphasize that while these endorsements give me very strong confidence that DCVax-L will be approved by regulatory agencies, they are not a lock solid guarantee.

I believe that F-stein’s argument that the trial failed are clearly false. Let me take on and debunk his primary arguments one at a time

• He makes the serious allegation that Northwest looked at the data from the phase 3 trial in an interim look in 2014 and saw that the trial had failed. This is just wrong. The interim look was conducted by an independent group, the Data Monitoring Committee, and the Company remained blinded until the data lock in October of 2020. Only the DMC and FDA saw the data.
• Having falsely concluded that NWBO conclusively knew that the trial had failed, he alleges that the Company changed the endpoint from progression free survival to median overall survival. He is correct that the endpoint was changed, but for very understandable and legitimate reasons. This is explained in an eloquent manner on pages 8 and 9 of the Statistical Analysis Plan (SAP) that is an integral part of the phase 3 trial. Please refer to this link to the SAP for that comprehensive explanation.
• It is completely legitimate for a Company to change the endpoints of a trial if the study remains blinded to the Company which is clearly the case and if the statistical analysis plan is submitted to regulatory agencies prior to data lock and unblinding which is also the case. Again this is explained on pages 8 and 9 of the SAP that I just referred to.
• F-Stein repeatedly and falsely claims that progression free survival (PFS) was the primary endpoint of the trial. A quick glance at ClinTrials.gov shows that PFS was not even a secondary endpoint. See this link. The primary endpoint is clearly stated as mOS in ndGBM and the secondary endpoint is mOS in rGBM. Both endpoints were achieved with strong strong significance. Nevertheless, he repeats and repeats that PFS was the primary endpoint.
• I would also point out that PFS which is based on tumor expansion is a surrogate endpoint. Overall survival is the gold standard measure for oncology trials. OS as a data point can’t be manipulated or cherry picked as death is an absolute event. Somehow, F-stein has persuaded himself that determining whether a tumor expands is a better measure of outcome for the trial than how long the patient survives. He makes the curious argument that even though patients are achieving medically meaningful, longer survival with DCVax-L that we should ignore this and focus on tumor expansion which is only an indirect marker of survival to determine if the trial was successful.
• The company was forced by the nature of the trial to use external controls. This is the one aspect of the trial which draws the most scrutiny and on which F-stein focused. The most common practice in clinical trials is to compare a group given the drug to a control group not given the drug. Again see the previously cited pages 8 and 9 of the SAP for details on why Northwest chose to use historical controls.
• F-stein alleges that the FDA will not accept external controls, but there is strong precedent that the agency will do so. The medically exciting CAR-T drugs Kymriah, Yescarta, Tecartis, Breyanzi, Abcema and Carvytki were all recently approved on the basis of phase 2 trials in which there was no control group and in which their results were referenced to external controls. It is also important to note that they were also approved on the basis of objective response rates (i.e. tumor shrinkage which was not accompanied by any data on duration of effect) rather than the much cleaner, more informative endpoint of survival. I would argue that the FDA would very likely approve DCVax-L as it did the CAR-T drugs without the use of external controls. However, the use of external controls makes for an even stronger argument for approval.
• Indeed, there was a time when the FDA was not receptive to external controls in clinical trials, but this has changed. The example of the CAR-T drugs is illustrative. Also, there was an article entitled “External control arms in oncology: current use and future directions” that was published in Annals of Oncology January, 2022 by Dr. Richard Pazdur and 12 colleagues from the FDA. See this liThis article lays out situations in which the use of external controls might be appropriate and the steps companies should take if they wish to use external controls. NWBO believes that its SAP which was developed two years prior to this article closely fits the criteria laid out.
• Richard Pazdur, M.D., one of the authors of the Annals paper, is the director of the FDA's Oncology Center of Excellence (OCE), which leverages the combined skills of the FDA's regulatory scientists and reviewers with expertise in drugs, biologics and devices to expedite the development of novel cancer products. In his role as director of the OCE, Pazdur is responsible for leading the effort to develop and execute an integrated regulatory approach to enhance the cross-center coordination of oncology product clinical review. He will likely be a key person at the FDA in determining whether DCVax-L is approved.

 

F-stein References Physicians who Express Skepticism on the Trial Results; Let’s Put This in Perspective

Before going further, I want to disassemble the cheap trick F-stein employs in his November 21, 2022 note in finding physicians who are skeptical about the DCVax-L phase 3 study. In his article he cites the opinion of Dr. Chen who is chair of the neurosurgery department at the University of Minnesota School of Medicine and was not involved in the DCVax study.

F-stein says he asked Dr. Chen to review the DCVax study published in JAMA Oncology. Dr, Chen also attended the annual meeting of the Society of Neuro-Oncology (SNO), where the data were presented last Sunday. F-stein claimed that Dr. Chen said: The authors should be congratulated for conducting a study of this magnitude,” but the results are uninterpretable because the analysis was not pre-specified when the study was started in 2007. Importantly, Dr, Chen has no clinical experience with DCVax-L Also, he is in error in stating that the analysis shown in the SAP was not pre-specified.

Likewise, F-stein reached out to Dr. Donald O’Rourke, a professor of neurosurgery at the University of Pennsylvania, for his opinion of the DCVax study. F-stein states that he also attended the SNO meeting. F-stein reported that Dr. O’Rourke stated via e-mail, a  list of confounding issues related to patient enrollment and the conduct of the study that makes him skeptical. He also has no clinical experience with DCVax-L.

It is more than interesting to note that Dr. Steven Brem is also a professor of neurosurgery at the University of Pennsylvania and is the third physician listed behind the lead investigators on the phase 3 trial, Dr. Linda Liau and Dr. Keyoumers Ashkans, as a co-author of the phase 3 DCVax-L study. He has extensive clinical experience with DCVax-L. In a presentation at SNO on November 20, 2022 he said that the results published in JAMA were extremely exciting. Dr. Brem, who has seen DCVax-L’s effects in his own patients, considers DCVax-L a major advance.

It is totally to be expected that you can find physicians who are skeptical of this or any study. I re-emphasize that neither of F-stein’s physician references has treated any patients with DCVax-L and neither has had any involvement with DCVax-L clinical programs. In contrast, Drs. Liau,  Ashkans and Brem have many years of experience with DCVax-L.

F-stein wrote an article during or shortly after the NYAS presentation on May 10, 2022 that falsely stated that the phase 3 trial of DCVax-L failed. This drew an indignant and angry response from Dr. Steven Toms, a board certified neurosurgeon at Rhode Island who participated in the trial and has had very positive experiences with patients he has treated with DCVax-L. He absolutely torched F-stein’s attacks on DCVax-L in a series of tweets that challenge tweets from F-stein and hedge fund employees. This interchange between Dr. Toms and F-stein shines a remarkable light on how F-stein gaslights DCVax-L.  Here are the tweets from Dr. Toms.

May 11 1:55 PM

StevenToms11 Replying to MidwestHedgie and adamfeuerstein and 4 others

As a neurosurgical oncologist who has spent his career working against this disease and the father of a cancer survivor it is nauseating to see you and your ilk diminish the life’s work of my colleague (Linda Liau) for a quick Buck. The data’s imperfections do not diminish the results.

May 11, 2022 8:52 PM

StevenToms11

No immunotherapy (vaccine or ICB) has worked in GBM as the CNS is immunologically privileged.  DCVax has overcome the immunosuppressive environment and is the 2nd clinical trial recently to reach significance in GBM. More to do but a good step forward. (A trial of the TTF medical device Optune developed by Novocure was the first)

May 12, 2022 6:30 AM

Replying to @adamfeuerstein and @MidwestHedgie

So when will MidwestHedgie and adamfeuerstein come look my patients in the eye and tell them they cannot have a therapy with 20+ years of investigation, a $1B clinical trial and backing of the oncology community then I will engage them again.  Otherwise it is just noise.

May 12, 2022 9:58 AM

Replying to adamfeuerstein and MidwestHedgie

Repeating your lies do not make them truths.  In all of your clinical experience Dr. Feuerstein can you point me to all of your long term survivors who got another therapy and lived this long?  Just one that was not IDH1 mutant please. I will wait.

May 18, 2022 8:27 am

Replying to @adamfeuerstein

I see Dr. Feuerstein is back to protect patients from the clinicians who performed the study and actually care for patients with GBM. You have my name and know I am not anonymous so please stop your falsehoods. End points were changed as we began to understand pseudoprogression.

May 18, 2022 8:42 AM

Replying to adamfeuerstein

Success against a plague like GBM is not presto! It is a long slog of discovery and many ideas over decades that fail to move the needle on survival. Oncologists will not ignore a scientifically sound nontoxic therapy that addresses multiple tumor antigens and improves survival

May 19, 2022 7:57 AM

Replying to @adamfeuerstein

I see the pathological lying about the data continues. Before I head to surgery I was wondering if you had the dignity or data to reply to my earlier challenges to your lies. Waiting for a cogent response to why anyone would care about PFS in immune therapy

May 26, 2022 12:53 PM

Replying to  @Hygro10 and  @adamfeuerstein

GBMs do not live more than 5 years other than those treated with DCVax or TTF.  I have patients 5+ year survival treated on both protocols. I have zero long term survivors in 25 years of practice without. Do the math.  The p value is highly significant.

May 27, 2022 2:08 PM

Toms11Steven

@Hygro10 and @adamfeuerstein

Just emailed by Communications office at my university that a Mr. Feuerstein has emailed them to inquire about the veracity of this handle. If you think you can intimidate me or that I will remain silent while you impugn this work you are sadly incorrect.

 

 

 

 

This last tweet from Dr, Toms is beyond alarming. F-stein has been accused of trying to intimidate doctors who speak positively on DCVax-L. This would be consistent with allegations on Twitter that F-stein intimidated Linda Liau and UCLA to prevent her from giving the presentation at NYAS. She was originally scheduled to do so, but unexpectedly cancelled. He is also alleged to have tried unsuccessfully to convince the New York Academy of Sciences to drop the presentation. This caused them to ban F-stein from attending the conference. How Stat News can support this behavior is not understandable to me.

If you stop now, you can generally understand why I believe that F-stein’s arguments are without any merit. Let me now go on to discuss in more detail, the reasons why I believe that the F-stein position is demonstrably false.

Investigators in the Phase 3 Study Believe That DCVax-L Is a Major Advance

F-stein’s allegations put him in the curious position of challenging the credibility and integrity of the two lead investigators in the trial, both of whom believe that DCVax-L meaningfully extends survival in patients they have treated with DCVax-L. They are:

Dr. Linda Liau is the lead investigator in the US. She is Chair of the Department of Neurosurgery at UCLA, Professor, Department of Neurosurgery, UCLA David Geffen School of Medicine and Director, Brain Tumor Program, UCLA David Geffen School of Medicine. She was formerly Editor-in-Chief of the Journal of Neuro-Oncology. Her research efforts are focused on the molecular biology of brain tumors, gene therapy, immunotherapy, and brain cancer vaccines. Dr. Liau is a highly respected neuro-surgeon.

Dr. Keyoumers Ashkan is the chief investigator for the European segment of the phase 3 DCVax-L trial. He is the clinical lead for neuro-oncology at King's College Hospital in the UK. He has an active research interest in brain tumors and movement disorders and heads the Neuroscience Clinical Trial Unit.  Dr. Ashkan is one of the most respected neurosurgeons in the UK and Kings College is the premier teaching hospital in the UK.

Both of these physicians have impeccable credentials and also many years of hands on  hands on experience with DCVax-L not only in the phase 3 trial, but also in patients receiving DCVax-L in compassionate use. In addition, there were 70 physicians who participated in the phase 3 trial have signed as co-authors who support the JAMA Oncology paper.

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New York Academy of Sciences (NYAS) Conference Highlights DCVax-L

The NYAS proudly states that for over 200 years, it has brought together extraordinary people working at the frontiers of discovery. It has become an important and widely-respected contributor to the international scientific community. To drive scientific progress, the Academy hosts over 150 conferences  and symposia annually, connecting experts across sectors, disciplines, and national boundaries. Research presented at the Academy is disseminated globally via in-person and virtual events, the prestigious Annals of the New York Academy of Sciences, and a broad array of digital media.

At the May 10^, 2022  meeting of the NYAS, topline data from the completed phase 3 trial of DCVax-L was selected for presentation. Promising, blinded interim data had previously been reported but this was the first time that the final topline data was presented. NYAS editors first reviewed that data and after concluding that this was an important study then asked external experts to peer review the trial. This was a rigorous process intended to establish the accuracy and credibility of the study.

The study was presented by Dr. Mulholland, an investigator in the phase 3 trial. Representing the other 70 plus physicians in the trial, he stated that the trial had successfully met the primary endpoint of median overall survival in newly diagnosed glioblastoma with a highly significant p value of <0.002. It was also successful in reaching the secondary endpoint of median overall survival in recurrent GBM with a p value of <0.001. He believes that DCVax-L is a major advance in the treatment of both ndGBM and rGBM.

 

JAMA Oncology, A Publication  of the American Medical Association Publishes Peer Reviewed Article on Phase 3 Study

In a November 17, 2022 edition of JAMA Oncology, a peer reviewed article was published that concurred with Dr. Liau, Dr. Ashkans and 70 other investigators in the study along with the NYAS that the trial had successfully reached the primary endpoint of mOS in ndGBM and secondary endpoint of mOS in rGBM. This is the most powerful validation of the results that we can hope for. I describe the internal and external experts that looked at all aspects of the clinical data and the statistical analysis used to interpret it. I describe this in detail in my recent article. See this link.

 

Linda Liau Presents Phase 3 Results at the Society of Neuro-Oncology

On November 23, 2022, the lead investigator in the trial, Linda Liau, was invited to make a presentation at a plenary session of the Society of Neuro-Oncology in which she stated that the trial was successful. SNO is the foremost medical conference for neuro surgeons and others involved in the treatment of glioblastoma. Needless to say, this plenary presentation is another powerful endorsement of the hypothesis that DCVax-L is a significant advance in the treatment of glioblastoma.

Now Let’s Look at F-stein.

F-stein has no scientific background but boasts a degree in political science. Let me ask you a question? If F-stein is trying to convince you that DCVax-L has no chance of being effective in GBM, wouldn’t you expect him to have a good understanding of the biological basis for the product, its mechanism of action and how it is manufactured (this is especially the case for a living cell product)? Of course you would. Failing this, everything else he says is meaningless or highly questionable. On June 20, 2022 I wrote an article entitled Adam Feuerstein Investigates Adam Feuerstein’s Understanding of Dendritic Cell Vaccines. See this link.

In searching through the plethora of articles he has written on Northwest Biotherapeutics, I was unable to find anything remotely resembling an in-depth analysis of dendritic cell vaccines or DCVax-L. So to get some insight into F-stein’s thinking (sic), I had to turns to bits and pieces of comments he made on Twitter, Investors Hub, Seeking Alpha and TheStreet.com. Essentially, I have used Adam Feuerstein to investigate Adam Feuerstein. With his help I conclude, and I am confident that you will agree, that Adam Feuerstein is riding a jackass through the streets of biotechnology with no clothes muttering inanities about Northwest and the sophisticated technology underlying DCVax-L.

After reading this linked article, I think you will concur that F-stein is utterly clueless on understanding the technology. So how does he come up with his articles? Who does he depend on? F-stein hasn’t shared his sources with us. However, he has expressed great admiration for certain hedge funds. A September 27, 2014 article was published in the Washington Post entitled Northwest Biotherapeutics stock woes highlight the harm of short sales executed by hedge funds. See this link.  This article suggests a link between F-stein and short selling. I have no way of knowing if the Washington Post article is accurate and I am not alleging collusion, but this article is in the public record and investors can draw their own conclusions.

Turning to Two Superficial Articles Written by Adam Feuerstein and Published by Stat News

F-stein wrote an article on May 10, 2022 that was published in Stat News during or shortly after the NYAS presentation in which he falsely stated that the trial had failed to reach the primary endpoint which he falsely stated was progression free survival instead of median overall survival. I wrote a refutation of that article entitled Debunking Silly, Fictitious Adam Feuerstein Article Falsely Claiming Phase 3 Trial of DCVax-L in Glioblastoma Multiforme Was a Failure. Here is the link.

On November 21, F-stein published a second article. This was essentially a rehash of the May 10 article so I won’t bother to refute it.

 

Tagged as DCVax-L phase 3 trial, Refuting Adam Feuerstein's misrepresentation that DCVax-L phase 3 Trial failed + Categorized as Company Reports, LinkedIn