$NWBO DEDUCED RECKONING: Northwest Bio reports Phase 3 results.


1/ "Only 5% of glio patients survive for five years. So how stunning is it for DCVAX-L to see life expectancy at 60 months rise from 5.7% to 13%, an increase of 228%. Some patients have seen total remission glio and are cancer free more than a decade after treatment.
2/ For example, Brad Silver participated in the Phase 1 trial 17 years ago and is cancer free now."

3/ Here is the TOP Line Data, as presented to the New York Academy of Sciences:

4/ DCVax-L Phase 3 Trial Results
6/ Adjuvants and combinations will likely combine well with #DCVaxL turning on the immune response:

9/ From the top line data presentation, the potential for combination therapies:
10/ A notorious jounalist who advances the short case has repeatedly literally and pathologically used what I would call weak case distortion to argue contrary to facts and reality, one such argument is whether the current combination therapy trial is actually #DCVaxL.
12/ Further this journalist and hedge fund commenter who shorts this stock, are quite far off track on the details and facts, but that does not seem to be a problem for them. They accuse all shareholders who comment and defend their investment of being "paid promoters".
13/ I hold $NWBO stock. I do not communicate with the company, nor do I or have I ever received any compensation from anyone to promote ANY stock.
14/ I invested here because my focus is cell therapies that modulate immune response and because I have relatives who have died of cancer, including a brain tumor, and because after my research, this treatment appeared to be severely undervalued because of rampant shorting.
15/ In that context, and with regard to that journalist, who seems to have more at stake than just "the truth", but his reputation and saving face, please read the below article thoroughly:
16/ Northwest Biotherapeutics stock woes highlight the harm of short sales washingtonpost.com/business/north…
17/ See also, other comments:
31/ #RollingReview often comes with accelerated pathways, what are the advantages of a rolling review?

33/ FDA has the Real-Time Oncology Review or #RTOR program fda.gov/about-fda/onco…
35/ Interesting info from a commercial source, but informative alacrita.com/whitepapers/fd…
36/ One interesting discussion on this page discusses various studies on accelerated pathways, which often offer approval based upon a "surrogate measure", an intermediate or expedited measure meant to substitute for a direct or primary measure of patient benefit.
37/ Accelerated trials are often approved based upon a "surrogate measure" of a hoped for direct benefit to the patient.
38/ The surrogate measure is intended to be a quicker measure that is believed to statistically be linked to an improvement in the direct benefit, though that linkage is not always real.
39/ For instance, maybe instead of extending survival, the end point could be measured much faster by measuring recurrence than going out to measure the patient's long-term survival, which can take years, maybe out to 5 years for the last patients to show the full impact or…
40/ …lack thereof. So the accelerated trials frequently measure an endpoint that is a surrogate measure of that hoped for direct benefit to the patient.
41/ They might use recurrence (known as "PFS") as a measure instead of survival, because they might know fairly quickly if a cancer has recurred, maybe they could know for each patient only in a matter of months.
42/ Often the companies are obligated to prove that survival really is a benefit in a study subsequent to accelerated approval, but then they are not ultimately able to prove that benefit, though the drug may have become a mainstay by that time and a regulator might be very…
43/ …hesitant to cancel its approval. Many companies fail to provide such evidence or complete such studies that would prove a direct benefit such as an improvement in OS.
44/ Also, only a low percentage of the accelerated approval trials prove direct benefits like an increase in OS or ongoing survival.

#DCVaxL's primary endpoint was switched from a #SurrogateEndpoint, #PFS to one that is considered the gold standard, #OS or ongoing survival.
45/ This was done because this was a very early immunotherapy trial, and they did not anticipate that the intended immune reaction might look initially like recurrence on a scan of a patient's brain.
46/ However, the notion that the increased data proving a direct benefit, survival (OS), would be less preferable to the FDA or any regulator than proof of a surrogate meant to only statistically possibly show OS, like PFS, seems ludicrous.
47/ But this is Adam Feuerstein's main argument for why #DCVaxL will be deemed failed. You can see how silly that argument sounds, once you know what he is actually talking about.
48/ Sometimes companies unblind and knowing they cannot show a direct benefit, will look for something they can CLAIM statistically is a surrogate for a patient benefit, but which they know is not. This is clearly not that situation.
49/ Here are other articles on that subject of surrogate endpoints, for understanding:

FDA Acceptance of Surrogate End Points for Cancer Drug Approval: 1992-2019

50/ Surrogate End Points in Health Policy: State of the Art and the Way Forward

51/ "Abstract
The efficacy of medicines, medical devices, and other health technologies should be proved in trials that assess final patient-relevant outcomes such as survival or morbidity.
Market access and coverage decisions are, however, often based on surrogate end points, biomarkers, or intermediate end points, which aim to substitute and predict patient-relevant outcomes that are unavailable because of methodological, financial, or practical constraints..."
53/ To state it another way, often trials that might look like they can't prove a direct benefit, like survival (OS), will pick a "surrogate measure" of direct patient benefit to get approved.
54/ In the case of the #DCVaxL trial, because of various complicating factors, it was allowed to run for many years and the primary endpoint is actually a direct benefit measure, or OS, ongoing survival. They did not water it down to find some "surrogate" for OS.
55/ But rhetoricians like Adam Feuerstein will use people's unfamiliarity and view that this is some kind of gotcha game, to lead people down to false conclusions. At least that is how I judge his approach.
56/ Speculatively, I can imagine that some such sector writers could need a continuous supply of confidential sources and short traders are rich sources of rumor and possibly explosive information.
57/ One could get into relationships with the dark side, where publishing the information one was told was not about truth, but keeping the flow of information, and taking the sources word for the truth might bring benefits too difficult to exist without.
58/ Loosing one's way, one might even convince oneself that the critique is one's own and one would lose face if it turned out to not be true because too much effort was put into telling the world the critique was absolutely true.
59/ No journalist should act blindly to benefit themselves in such a manner. Hopefully that's not the case here.
60/ Whatever the case may be, $NWBO's #DCVaxL trial chose to switch to measuring the longer, harder and direct benefit measure of OS instead of a surrogate of OS, and they updated their statistical analysis plan prior to being unblinded.
61/ I believe it should be unlikely that a best in class regulator would disagree with that approach.

I also note that the FDA chose to reassess approvals for what are the best in class current immunotherapies because they were approved based on surrogate measures.
62/ While many approvals stuck, it shows that surrogate measures are the issue, not primary or direct measures. Or at least that is how I see it.
63/ These drugs were approved on an accelerated basis, using surrogate measures:

FDA Will Reassess 6 Immunotherapy Accelerated Approvals

64/ "Six indications for immune checkpoint inhibitors (ICIs) granted under the FDA’s accelerated approval process that later failed confirmatory clinical trials are being reassessed as the agency continues an industry-wide evaluation of the pathway."

65/ "Under the accelerated approval program, drugs are able to gain indications more quickly than through a regular approval timeline based on a surrogate end point.
66/ Pharmaceutical companies are then required to conduct a trial that confirms a clinical benefit; if the study is successful, the FDA grants regular approval status.2
67/ The FDA’s Oncology Center of Excellence, which reviews and expedites the development of cancer drugs, requested the April hearings."
68/ ... "“The program allows the FDA to approve a drug or biologic product intended to treat a serious or life-threatening condition based on an outcome that can be measured earlier than survival that demonstrates a meaningful advantage over available therapies.
69/ However, when confirmatory trials do not confirm clinical benefit, a reevaluation must be performed to determine if the approval should be withdrawn.”"

Again, #DCVaxL's primary measure is not a surrogate measure of survival. It is survival, abbreviated as OS.
70/ Don't be fooled.
71/ More background on Surrogate Measures...

72/ This is an opinion piece, and as such anyone thinking of investing should recognize that 1) I own $NWBO; 2) this is my opinion, not a recommendation; and 3) each person should do their own due diligence and make their own conclusions in consultation with appropriate advisors.
73/ I'm not a financial advisor, I am an ordinary shareholder sharing my thoughts and own opinions.
74/ See also, glioblastomamultiforme.it/en/autologous-…

"Basically it is the first Phase 3 study of a systemic treatment in 17 years showing a significant extension of mOS in nGBM and the first Phase 3 study of any type of treatment in 27 years showing a significant extension of mOS in rGBM .
75/ One of the first if not the first Phase 3 study to show a significant increase in long-term survival for both nGBM and rGBM.
76/ Furthermore, DCVax-L is suitable for combinations with a wide range of other treatments (checkpoint inhibitors, oncolytic viruses, cytokines, chemo, etc.). When a patient with DCVax-L has one or more recurrences, new batches of DCVax-L can be created.
77/ DCVax-L can be administered in major cancer centers.
The significant proportion of long-term survivors, consistent with an effect on immune memory by T lymphocytes, changed the natural history of GBM from a uniformly fatal disease to a manageable, chronic disease.
78/ Specific subpopulations have showed an unexpected advantage: older patients and patients with metylated MGMT promoters."
81/ Update to US ClinicalTrials website pending, the EU and UK databases were updated by the local regulators a long time ago to reflect the updated end points.

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More from @eastvillagetwt

May 11
DCVax-L Phase 3 Trial Results

Final Top Line Results, Phase 3.

Delivered 5/10/22 to the New York Academy of Sciences by

Dr. Paul Mulholland, MBBS, MSc, PhD, FRCP, University College Hospital, UK


via @YouTube
If you watch this by idea closely, you’ll note that the trial coins not proceed ethically UNLESS it was a crossover style. But all the patients lived longer including the recurrent ones who got access to #DCVaxL late. THAT was their placebo arm originally. There is no way in hell
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They are saying, hey, we do not know for sure, we are not spies on our customers and are not police, but you should look into this and tell us to stop, if it is actually illegal.

Apparently they file and FinCen never does anything. It’s also possible FinCen wants to spy.
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