Replies to post #321984 on NorthWest Biotherapeutics Inc (NWBO)

[Extremist223]

This team sees hurdles right through the walls. :)))) farsight!! lol

[Bill B]

Thanks for that breakdown. Very educational.

[Doc logic]

sentiment_stocks,

Nice job laying out the rational for utilizing external controls in this case. Best wishes.

[CaptainObvious]

This is great, senti. I'm so glad you are on this board.

[Lykiri]

sentiment,

Thank you! Very educational as usual!

[flipper44]

Senti, was the new statistical method now used confirmed by management to you? Is it step down, step up or some other statistical methodology? Thanks.

[iwasadiver]

You are something Senti; this is really, really, good. I think you may be right on the alpha here also. But the way you show how the guidance fits the trial perfectly in such a clear way is really helpful to all. And if it wasn’t written with DCVax specifically in mind then it’s the largest coincidence in history. The fact that NWBO appears to have had an ongoing and quite continual dialogue with the FDA seems to me to have paid off not just for this trial, but for all kinds of future trials. Great work, and thanks

[br8k0ut]

This is brilliant. Thank you for sharing this analysis!

[Harry1969]

This is awesome, thank you. I’d love to see the Twitter naysayers try to rebuke any of this. Though I’m guessing they wouldn’t try.

[GBMwife]

WOW, you are amazing! Thank you!

[GoodGuyBill]

Spectacularly brilliant. Thanks for sharing your due diligence in all things NWBO.

[Chiugray]

Senti, I learned so much from your post. Of course you won me over at “examining… FDA Biological Products Guideline.” :-)

It’s great to gain insight into why the revised SAP is a superior plan and why having our sequence of a single primary endpoint and 5 secondary endpoints is strategic. This points to the genius of LP & team. I never knew how alpha was allocated in a clinical trial until 2 rereads of your post plus a splash of cold water.

And the climax, the FDA language/excerpts, explaining why the FDA may accept historical data in place of a control arm. More importantly why it is a perfect fit for our GBM trial (ie has a highly predictable death rate given current SOC).

No wonder the stock price has increased so much recently. The SAP is the waterloo moment for DCVAX's ultimate success IMHO.

[Doc logic]

sentiment_stocks,

This analysis and the endpoint order does look like the full alpha spend is being passed down from one endpoint to the next. When I first saw the endpoints posted I assumed that this was the case immediately and it seemed so obvious that I didn’t even comment on it as I was assuming market response was factoring this in. When you posted this it still did not occur to me how poorly understood this might be but upon further review and look at the market reaction I understand that folks just don’t get it yet, even some of the analysts out there.

Look at the 1st secondary objective again and you will realize that NWBO believes that SOC patients that were in captured chemo/rad pseudoprogressors that crossed over are doing well and that enough true progressors that crossed over are receiving salvage treatment benefit from L and or combo that it warrants comparison to other historical SOC/placebo. That is a big statement that goes right in line with research I found long ago about salvage therapy repotentiation created by use of DC therapy as well as the relationship of mesenchymal phenotype, created at progression by up to 85% of all tumors, being more susceptible to DC therapy. Putting this endpoint at the number 2 spot suggests a very high degree of confidence that these relationships exist to the point of statistical certainty. Best wishes.

[meirluc]

Awesome stepwise alpha spend analysis and with the new FDA guidelines, practically assures this trial's success with all 4 regulators aboard.

[H2R]

What a well written, logical and thought through post Senti!!

And if I may you do sound super smart :)) Thank you so much for your many, many contributions throughout the years, and thank you for this one. I think you are on to something. You put together lots of info and your own inference might just be right on.

I raise my grapefruit juice glass to your health :)

Best of luck to Patients, NWBO, and Longs!

[reg2015]

sentiment stocks, amen and thank you. Hope it saved as a sticky. Blessings always and again and again, thank you. It is your opinion, I grant you that, but I also think it is logical and represents the new thinking of the FDA and its guidelines. Peace Reg 2015

[MasterKit]

Senti-
First time caller, long time listener. For alpha, the easiest way to describe it is if one were to repeat the experiment 20 times, 19 of those times they would come to the same conclusion for an alpha of .05. I don't think you need to subtract any alpha for the various endpoints because there were no interim analyses performed. So I agree with your conclusion.

[FloatServe]

A+ .... as usual

Let’s look forward to a little R&R on the beach in the near future. Drinks on you, VB lessons on me :)

[joeycav11]

Thanks Sentiment. Imo this information can be used to justify investment by big pharma and biotech hedge funds.
Your words will be rewritten and submitted as a reason to invest in Nwbo.
This kind of due dilligence is priceless. Opens the eyes of big money. Thanks!

[Know-Fear]

Very cool......very very cool.

[eagle8]

Fantastic post sentiment!
What a great piece of work!

Thanks and best to you.

[anders2211]

thank you sent,

Its great to wake up and read this post. Brilliant!

[Mionaer1]

Wow. Great DD...

[erg61]

Thanks Senti!
You took the words right out of my mouth. Saves me a lot of typing-lol

[erik007tc]

aMaZinG!!!! Incredible DD. Ty!!!! Just wow!

[evanstony]

a great deal more than sentiment... beautiful job

[biosectinvestor]

Thank you Senti! Fantastic and detailed opus. I had gone through the guidance directly and had satisfied my own concerns but you did such a systematic and complete effort here. Thank you!

[Hbpainter]

Excellent work Senti.

[Flexroy]

Okay I read that whole post while riding the stationary bike in my basement it took 45 minutes and it was amazing great post! Well worth the read

[Kkhors]

Incredible analysis.

[Pharmboy46]

Honestly Senti, an analysis like yours has the power to make people understand the opportunities we have and to move the pps up even more than Mrs Lappin! You rock!

[Sub Atomic master]

Thx Senti, that was greatness rt there, your work and care for us has always been Phenominal. Didni spell that rt:):):):):).

[sukus]

Great detailed analysis Senti. Thank you.

[kfa670]

Awesome snowy Saturday reading

A masterpiece

[learningcurve2020]

And, just look at all the glowing replies to Senti’s somewhat impressive post. Not a one out of step!


The P value, whether it .02 or .05, will likely be nonsensical
at this point. No accounting for initial inclusion / exclusion criteria. If it’s found surviving patients went on to other treatments or the Expanded Access “arm” who failed initial inclusion criteria are figured in the tld, for better or for worse, the SC / FDA may just be making a Go-no-go decision based on a multitude of external factors.

[hyperopia]

Outstanding post senti, thanks.

[abeta]

Hi Senti

Your post takes my breath away. It's brilliant -

and I don't know of any other trial - in all of cancer -
that is following the route that NWBO has decided to take for
THE REASONS YOU LAY OUT IN YOUR POST.

There are alot of NERDS that haven't found DCVAX - YET -
so I hope there is someplace you can sticky this for a couple
of years so that they can find it quickly.

Who did what? - did MRK or BMY or the other BP use this in their
immuno submissions - or did NWBO "invent this" because the rules
said they could "invent this"

The only word I got is - brilliant - so I hope it is sufficient.

regards

[Astavakra]

Senti- Home run! Thanks!!

[reachjo]

Thanks senti. Brilliant!

[Truthfan]

Applause….applause! You continue to be the Prima Ballerina on the NWBO stage.

[meirluc]

Senti, I have a question pertaining to your excellent analysis. It involves the estimate that for the early Treatment arm, the current DCVax-L trial protocol assumed a mOS of at least 28.3 months from surgery.

That presents difficulties if we still assume that the blended trial mOS of 23.1 months which was likely obtained from the first 165-166 patients, is still valid.

If the mOS of the Treatment arm were indeed 5.2 months longer than the mOS of the entire trial (28.3-23.1=5.2) then the mOS of the SOC arm would only be equal to about 10.9 months after surgery (28.3-23.1=5.2
months; 5.2 months X 2.34=12.2 months; 23.1 months-12.2 months = 10.9 months;).

EXPLANATION: I multiplied 5.2 months (the difference between the assumed 28.3 months minimal mOS of the Treatment and the 23.1 months blended mOS) by 2.34 (the numerical ratio of 2.34 Treatment patients to 1.0 SOC patient) and obtained 12.6 months which were subtracted from the 23.1 months overall mOS, to yield the hypothetical mOS of 10.9 months of the SOC arm.

However, an mOS of 10.9 months for the SOC arm is IMHO very unrealistic. I am therefore assuming that the final mOS for the entire (blended) trial is higher than the original 23.1 months and is most likely much closer to let's say 25 months. That would be consistent with about a 17 months mOS for the SOC arm, a more realistic outcome IMHO.

[froggmister]

Senti thank you for this and your many contributions over the years to this board.

Minor note on the Dendreon comment. The company lost the 2007 battle not because of alpha spend but because they were seeking approval on 2 small trials (just over 200 patients) when they had a larger 500 patient trial ongoing. Since 4 members of that infamous ADCom panel voted no on efficacy (13-4 vote in favor, which led to death threats and all kinds of other drama -- look it up if you want to read a good story), it made some sense to not cut the knees out from the ongoing trial and wait for the results.

A couple years later alpha spend did play a big role when the company used alpha for an interim look, which was unsuccessful and nearly cost the final look its success. Of course that final approval success was torpedoed by poor execution in manufacturing and marketing and the company imploded, but importantly I believe for DCVAX-L, Provenge's efficacy has continued to accumulate data demonstrating that despite failure to curb progression, overall survival is extended.

After losing my father to prostate cancer at 55 in 1996 I became a true card-carrying Dendreonite, and by selling half of my stake up near $50 a share (should have sold all, live and learn) in 2010 I bought my first small stake in NWBO and haven't sold a share, and adding bigly in the sub .20 cent range. The DNDN boards back then rivaled this one, and included AVII.

I wonder, since you mentioned AVII recently, what your thoughts are on his model and skepticism, which if I remember correctly were based on the cherry-picked enrollment criteria and apples to oranges comparisons to historical trial data, which with the changed endpoints in the EU becomes even more relevant. I have followed AVII on several drugs and have learned to blow off his opinions at my own peril. TIA

[spartex]

Excellent breakdown Lady Senti. A different question for your thougths/views, and those you have gather from discussions with NWBO communications folks and here on this message board.

I was just rereading the Dr. Kevin Duffy PR when NWBO hired him last Sept 2019. Is there any clearer or confirmed information on his role at NWBO before he then suddenly departed in 2020? I realize that NWBO would want to keep any relationship discussions with Merck private, but it would be of value and provide more confidence if NWBO had shared a little more color on his role that shows positive news, versus the "bear hypothesis" that he didn't like what he saw while at NWBO. Thanks to you and any others that may have relatively substantiated information!

https://nwbio.com/nw-bio-expands-senior-management-team-with-dr-kevin-duffy-as-vice-president-medical-affairs-external-collaborations/

[beartrap12]

Senti, please sticky your post. It does a tremendous job of explaining how we will likely get to approval if data is as great as most of us believe!
Thank you! I know that was a lot of work.

[survivor1x]

I might add that the information arm might be helpful when comparing to external controls.

[aperture007]

Sent, Thanks for all the hard work that you put into this post. Really an outstanding job?

[Evaluate]

You wrote: Quote:
The first secondary objective is to compare overall survival (OS) between patients randomized to placebo who received DCVax-L treatment following disease recurrence and control patients from comparable, contemporaneous clinical trials, in patients with recurrent GBM.

This endpoint is really similar to the earlier secondary endpoint from the original trial, EXCEPT, that the control arm will be historical arms, and not the control arm for this trial

IMO, this new secondary endpoint/objective is completely different from the earlier secondary endpoint from the original trial, which did not at all look to compare patients who had a tumor recurrence.
Instead, the old secondary endpoint looked to compare OS between patients who started in the treatment cohort versus patients who started in the placebo cohort.
In this new secondary endpoint, all the patients who started out in the treatment cohort of the DCVax-L trial are not taken into account at all ... instead the ONLY patients from the DCVax-L trial being compared are those who start in the placebo cohort, and then have a tumor recurrence. Thus: recurrent GBM.
And most of these patients would have crossed over upon recurrence and then received the “real” DCVax-L vaccine.
And ... from LL comment that all patients (who received DCVax-L ... early or late), we can assume that this group of recurrent GBM patients did relatively well.
This above group is then compared to Control patients from comparable contemporaneous clinical trials whom also had a GBM tumor recur. And we can assume from the poor prognosis from such patients in the past, with no effective treatment choices, that this control group would not live as long as the above group of recurrent GBM patients in the DCVax-L trial.

[abc1212]

Senti, that post was nothing short of amazing.

It's obvious it must have taken alot of hard work so THANK YOU, THANK YOU, THANK YOU.

[antihama]

If "A picture is worth 1000 words" what picture will these words generate?

E.5.1 Primary end point(s)
The primary endpoint of this study is overall survival (OS) compared between patients randomized to DCVax-L and control patients from comparable, contemporaneous trials who received standard of care therapy only, in patients with newly diagnosed glioblastoma.
E.5.1.1 Timepoint(s) of evaluation of this end point
October 2020
E.5.2 Secondary end point(s)
The first secondary endpoint is overall survival (OS) compared between patients randomized to placebo who received DCVax-L treatment following disease recurrence, and control patients from comparable, contemporaneous clinical trials, in patients with recurrent GBM.

The second secondary endpoint, confirmed progression-free survival (cPFS), is confirmed disease progression (cPD) compared between subjects randomized to DCVax®-L and those randomized to Placebo within Study 020221.

The third secondary endpoint, PFS, is progression-free survival compared between subjects randomized to DCVax®-L and those randomized to Placebo within Study 020221.

The fourth secondary objective, OS, is overall survival compared between subjects randomized to DCVax®-L and those randomized to Placebo within Study 020221.

The fifth secondary objective is tumor response compared between subjects randomized to DCVax®-L and those randomized to Placebo within Study 020221

What beauty lies here! Every time I read these endpoints, I see the beauty that flows from them! It's scientific art.

The primary and second secondary endpoint should have been the original trial endpoints but we were still learning about the effects of immunotherapy back then. And I know longs love the third (original PFS) and forth secondary endpoint (original OS) because many believe they could still have been SS. For the first secondary endpoint (OS in crossover patients vs recurrent SOC), I do think it's somewhat ambitious since they are not making lysate from resected tumor but it's probably a low bar they have to hurdle (and on the plus side, tumors revert to a more advantageous form for DCVax-L). And the last secondary endpoint is tumor response, and why not, since so many cancer trials are using TR to obtain accelerated approval. That ship has sailed for this trial but could be a hurdle for future trials that they will need to jump over.

Anyhows, thanks for your input and for everybody else on this board for their contributions. And oh yeah, if I could add a pic to iHub I would but not going to attempt it. Right now for me it's a recent pic of Fall foliage at peak on a mountainside overlooking a roaring mountain stream. Hey, that's me; you guys pick your own be it a Rembrandt or whatever. Luckily, I only have ~180 words (in the endpoints description above) to present a picture of.

[DJNatan]

Hi Sent
I'm probably misreading your thoughts but PFS and OS are independent measures. Each has a hypothesis that is considered separately. Each has their own pvalue, or confidence level.

The hypothesis (PFS Exceeds or not) is written to be either is a significant change or there is not a significant change. Each is assigned the classic .05 confidence level.

"The primary objective of this study is to compare progression free survival from time of randomization between patients treated with DCVax-L and control patients."

This was not true apparently - that is to say it was not measurable in a sufficient number of people. So now the fate of the trial hangs on one primary metric, OS.

Interestingly, some researchers believe that extending PFS without bothering about extending OS is a worthy goal, which has caused some kerfuffle.
https://ascopubs.org/doi/10.1200/JCO.2011.38.7571

On the other hand, compatibility may replace confidence testing. Liau is a champ of this position, apparently, as she has voiced her interest in developing more diagnostics - the roadway to compatibility testing.

https://www.nature.com/articles/d41586-019-00857-9

Cheers

[10baggerz]

Thank you for the wonderful post, really needed it today for a number of reasons.

[ontologizer]

"help answer [my] question rather quickly" lol that's funny! TBH the first link is just too difficult to parse. I'm going to follow Charlie Munger's lead and throw that into the too difficult pile. Thank you for taking the time though!! I'm sure it's helpful to other's with a deeper understanding.

A couple things though:

Closed Testing Procedure - you are saying there is established precedence to split the alpha over the different endpoints?? Just confirming, because this doesn't seem to me how alpha works. I would think each endpoint has it's own distribution from which an alpha is calculated. Honestly, I don't know.

I thought I read that they considered going with alpha = .02 but ended up going with .05.


I am familiar with the fact that the endpoints where changed to use external controls from contemporaneous studies, I believe due to the number of crossovers(?) And am I correct in that the number of crossovers was one of the rationales as to why the study is assumed to be successful? The larger number of crossovers, this was an assumption or well-known?

I think those will be my final questions. Too steep a learning curve here. Wish you longs well, and that this treatment does in fact improve upon the current SOC.

[ilovetech]

Senti- great work! Thx!

ILT