Replies to post #142407 on NorthWest Biotherapeutics Inc (NWBO)

[TiltMyBrain]

Thanks Flip. Let me buy you a drink!

[john1045]

Great post Flip and agree with your assumptions

Message in reply to:

So, there is more than meets the eye here.

First of all, what is fuzzy in that video. You guessed it? The amount of volume enhancement from DCVax is only 13%. Stop and think about that. In a non-new lesion, that is not an increase of 25%. Literally, go back to the video and ask yourself if you thought it was higher the first time you watched it.

Second, UCSF's Dr. Prados stated in a video filmed at Seattle Science Center, that he did not see pseudo-progression response to DCVax injections, instead he saw no imaging response to injections. So, while I agree that this film contradicts that with a little/some anecdotal evidence (Kudos to AVII), this is not necessarily a common event after injection with DCVax, although it is known as a common effect after chemoradiation and peptide therapies such as Rindopepimut.

Third, as RK stated again and again, there are *more imaging techniques to confirm or rule out progression than MRI. Remember, the subtitle of that video is "Pitfall in the MRI diagnosis of tumor burden.
(*This is the argument that AVII and RK had nonstop for a number of months.)

Fourth, for those pseudo-progressives to chemoradiation that remained in the trial, this video seems to indicate they would have likely had their MRI enhancements shrink (not increase) as a result of DCVax-L therapy.

Fifth, the likelihood of response of placebos to DCVax-L therapy upon crossover (progression) is mitigated by the fact typically only 25% to 30% of progressed patients are eligible for and/or seek out a second resection beyond biopsy.

Sixth, Dendreams, AVII's and (Highwayman's -- apparently now) views that the first screening partial halt was for a first interim analysis recommendation of futility, even if taken as true, would be the time when the results would look the worst, BECAUSE, AS YOU CAN SEE FROM THE EXAMPLES GIVEN, ANY DCVAX ENHANCEMENT RESPONSE SHOWN WAS EARLY ON AND THEN RESOLVED. WHICH MAY VERY WELL MEAN, EVEN IF THERE WAS SIGNIFICANT ENHANCEMENT, IT WOULD HAVE ONLY MOSTLY SKEWED EARLY TRIAL (Interim) RESULTS, AND LATER BENEFITS WOULD NOT HAVE SUCH DRAMATIC MRI ENHANCEMENTS.

Seventh, the attempt to remove pseudos to chemoradiation was extensive in the phase three trial early on, and therefore the majority left would not likely be as reactive. In other words less early psPD, likely means less methylated MGMT and this likely means less highly reactive (psPD) tumors left in the trial caused by DC therapy. IMHO.

Eighth, according to at least two investigators on the team that spoke about the partial screening halt (public video interviews), they said it was done to review the data. One of the investigators, Charles Cobbs, went further and stated it was to see if they were looking at the next blockbuster or not.

Ninth, the screening partial halt was lifted. AVII and some others argue this was strictly due to an agreement not to enroll any more patients, but if the partial halt was for futility, this would not make sense at all. If the partial halt was for futility, the likelihood is that the lifting of it would be for lack of futility, imho. This would also make sense, because if there were a number of patients misdiagnosed as progressing, that would have happened, apparently, literally two months after the first injection. This would, if it occurred with much regularity, occur on the front end IAs, but have a reverse impact, imho, on the final IA.

Tenth, by August 31, 2017, Dr. Bosch presented a slide:

Quote:
Statistical analysis on available [blinded] DCVax-L Phase 3 Trial Data showing the potential for significant efficacy with progression free survival (PFS). -- Boshie


It is very hard to imagine Dr. Bosch would do that just over two months ago, at the end of the trial, knowing full well Boshie was trying to determine if there was a likelihood of separation, unless Dr. Bosch was also hopeful for this result.

One thing this video certainly demonstrates is why there is an external independent review team at the end of the trial.

Finally, it is important to note that at this critical time Cognate continues to issue job listings that would seem to correlate well with the timing for preparation for commercial manufacturing. The types of high level positions that have been advertised this year and recently highly increased over the last 45 days and continue to literally hours ago suggest they have worked through the issues.

Whatever the results, and I personally they will be positive on both endpoints, I strongly believe we are going to get more than one set of PFS observations from separate groups. This has been done for other types of cancer trials recently, and I'd think it will occur here as well. In the end, I personally believe the number of contested misdiagnosis will be quite small.

[Doc logic]

flipper44,

Great post and I believe we are seeing multiple possibilities still able to provide the rational for success which is a very good indicator. Best wishes.

[jammyjames]

"The amount of volume enhancement from DCVax is only 13%"

Am I looking at the wrong thing? I´m seeing a volume change from 2cc to 13cc ...a 550% increase

[MI Dendream]

You misunderstand my position. I do not believe the DMC found the study to be futile, just the opposite. I believe they recommended the trial be halted for efficacy and the company refused.

Thus, FDA said "say what?, you really want to wait? We recommend that you don't...wink, wink. Say what? You want to go all the way to OS? Your choice but we cannot let you put anyone else on PBO, that's just not ethical. You can have the patients that already consented and no more. If you want more, you will have to run an EAP and give it away, give it away, give it away now. And BTW, you are now formally under review, so we are going to watch every damn word that you say. Every damn day, every damn night and especially at every damn conference and earnings call. You best not bias your trial, baby! Shut the Frack up about every damn thing, you got that brah?"

Linda "understood"

The rationale for refusing would be that they would have limited data to market. Trials stopped early are caught with the data in hand and although a long term benefit can potentially be inferred, it cannot be implied or marketed. Without hitting 50% PFS in each arm, you have no median, without hitting predefined milestones by proportion of patients nor 50% OS you have no survival to market. In August (really July), IMUC looked to be poised to have both, leaving a potentially superior therapy with its hands tied re: sales & marketing of weak data. The market understands median and 2-, and 3 year survival rates. The market does not give much value to an early stop due to efficacy.

[flipper44]

Edit: Per JJ's observation of video which was fuzzy (poor resolution) to me.

So, there is more than meets the eye here.

First of all, what is fuzzy in that video. The measurement is volume of contrast enhancement (not percentage), which admittedly, in the examples given did increase significantly beyond 25%.

Second, UCSF's Dr. Prados stated in a video filmed at Seattle Science Center, that he did not see pseudo-progression response to DCVax injections, instead he saw no imaging response to injections. So, while I agree that this film contradicts that with a little/some anecdotal evidence (Kudos to AVII), this is not necessarily a common event after injection with DCVax, although it is known as a common effect after chemoradiation and peptide therapies such as Rindopepimut.

Third, as RK stated again and again, there are *more imaging techniques to confirm or rule out progression than MRI. Remember, the subtitle of that video is "Pitfalls in the MRI diagnosis of tumor burden.
(*This is the argument that AVII and RK had nonstop for a number of months.)

Fourth, for those pseudo-progressives to chemoradiation that remained in the trial, this video seems to indicate they would have likely had their MRI enhancements shrink (not increase) as a result of DCVax-L therapy.

Fifth, the likelihood of response of placebos to DCVax-L therapy upon crossover (progression) is mitigated by the fact typically only 25% to 30% of progressed patients are eligible for and/or seek out a second resection beyond biopsy.

Sixth, Dendreams, AVII's and (Highwayman's -- apparently now) views that the first screening partial halt was for a first interim analysis recommendation of futility, even if taken as true, would be the time when the results would look the worst, BECAUSE, AS YOU CAN SEE FROM THE EXAMPLES GIVEN, ANY DCVAX ENHANCEMENT RESPONSE SHOWN WAS EARLY ON AND THEN RESOLVED. WHICH MAY VERY WELL MEAN, EVEN IF THERE WAS SIGNIFICANT ENHANCEMENT, IT WOULD HAVE ONLY MOSTLY SKEWED EARLY TRIAL (Interim) RESULTS, AND LATER BENEFITS WOULD NOT HAVE SUCH DRAMATIC MRI ENHANCEMENTS.

Seventh, the attempt to remove pseudos to chemoradiation was extensive in the phase three trial early on, and therefore the majority left would not likely be as reactive. In other words less early psPD, likely means less methylated MGMT and this likely means less highly reactive (psPD) tumors left in the trial caused by DC therapy. IMHO.

Eighth, according to at least two investigators on the team that spoke about the partial screening halt (public video interviews), they said it was done to review the data. One of the investigators, Charles Cobbs, went further and stated it was to see if they were looking at the next blockbuster or not.

Ninth, the screening partial halt was lifted. AVII and some others argue this was strictly due to an agreement not to enroll any more patients, but if the partial halt was for futility, this would not make sense at all. If the partial halt was for futility, the likelihood is that the lifting of it would be for lack of futility, imho. This would also make sense, because if there were a number of patients misdiagnosed as progressing, that would have happened, apparently, literally two months after the first injection. This would, if it occurred with much regularity, occur on the front end IAs, but have a reverse impact, imho, on the final IA.

Tenth, by August 31, 2017, Dr. Bosch presented a slide:

Quote:
Statistical analysis on available [blinded] DCVax-L Phase 3 Trial Data showing the potential for significant efficacy with progression free survival (PFS). -- Boshie


It is very hard to imagine Dr. Bosch would do that just over two months ago, at the end of the trial, knowing full well Boshie was trying to determine if there was a likelihood of separation, unless Dr. Bosch was also hopeful for this result.

One thing this video certainly demonstrates is why there is an external independent review team at the end of the trial.

Finally, it is important to note that at this critical time Cognate continues to issue job listings that would seem to correlate well with the timing for preparation for commercial manufacturing. The types of high level positions that have been advertised this year and recently highly increased over the last 45 days and continue to literally hours ago suggest they have worked through the issues.

Whatever the results, and I personally believe they will be positive on both endpoints, I strongly believe we are going to get more than one set of PFS observations from separate groups. This has been done for other types of cancer trials recently, and I'd think it will occur here as well. In the end, I personally believe the number of contested misdiagnosis will be quite small.