Replies to post #439329 on NorthWest Biotherapeutics Inc (NWBO)

[MI Dendream]

Reefrad, Before I give you any leeway here in my mind, answer me this.

Just how did the company become aware that treated patients were having pseudoprogression? I do have a suggestion here but it leads you down a long trail of inquiry AND this requires FDA agreed to an ECA before seeing a validated data set for the ECA… super, super, super duper risky move which would have been voluntary if you want to say it was because of the adaptive design that allowed this. Remember, this has not been done before, it assumes FDA would agree to an ECA after a very short review of data without validation (you lost me here), and even if external data suggested the issue was a problem the study was already powered to detect a difference on OS. The standard process if you believe after an interim futility analysis that your study is not futile but may not be able to detect a difference as currently designed is to expand the enrollment, not reduce it…

Without an interim efficacy peek, you are asking me to believe FDA would agree to a radical new trial design that has not been validated, based on conjecture from open label patients that you MAY have an issue, and acceptable techniques to address this were avoided for this new pathway which again has not been validated yet. Sorry, not plausible.

Why would this company driven, highly risky change to design and protocol (…IRBs again) not be a material event that must be disclosed to investors that would as a result be waiting 7 years or more to learn of this change after TLD is released?

Unfortunately, I do not think you can do better than this, but this was a great shot on goal…just not good enough to get past Eddy Belfour on a bad day.

[flipper44]

It’s true people are speculating. Since we are,

1. A slide UCLA publicly provided in a ground round presentation by LL, appeared to infer all placebos had likely had recurrence events by December 2016 (most of us didn’t see the video until 2017)
2. This was based off shipping records for aliquots of DCVax-l. The shipping monitoring was discussed in the 2018 JTM paper which covered data from March 2017.
3. They rounded some numbers in that paper, which made it impossible for outsiders to determine if more recurrence events occurred.
4. A couple years later, Dr. Liau confirmed to the best of her knowledge, no further had occurred in number of crossovers. The number she gave was consistent with her presentation in December 2016. She told Lykiri he’d have to ask the company if he wanted additional information.
5. My due diligence toward the end of 2016 concluded it was likely, had this been only a standard of care trial, that 98% to 100% of patients would have normally had a recurrence by around November 2016.
6. In April of 2019, I believe, Dr. Liau stated most very long lived patients in the trial had not had recurrence events.
7. She also stated, based on her therapy outside of the trial, that many patients responding to DCVax-l had at least some mesenchymal features. Normally, under SOC, mesenchymal are more aggressive tumors with worse prognosis.
8. In 2011, Dr. Prins and Dr. Liau noticed that mesenchymal and classical tumor signatures appeared to respond to DCVax-l, while proneural was less decipherable in that regard. After that, Dr. Liau was reluctant to treat proneural with DCVax-l.
9. By November 19, 2021, WHO memorialized the new definition of GBM, which now excludes proneural tumors.
10. Back in April 2019, Dr. Liau also stated at the UW grand round (on the video we later saw) that it is important to get DCVax-l early.
11. Back in June 2015, the NIH funded Shashi Murthy with a four year grant to develop an automated closed system production method for Dendritic Cells.
12. Dr. Liau recently acknowledged (2022) cell immunotherapies have been challenging in the past to manufacture. A year prior, she stated we’ve got to find a way to get this treatment to patients.
13. One month after Flaskworks patented the dendritic cell generator, NWBO acquired them.
14. One month after that, NWBO achieved data lock in the Phase iii trial.
15. In approximately 2021, Dr. Pazdur stated any new/prospective/incoming standard of care must be able to reasonably ramp production.
16. In December 2014, Linda Powers stated the only way to meet potential massive demand, which they had been thinking about “a lot,” was to develop an automated closed system production method.
17. In or around late July 2015 (just a month or so after Shashi Murthy began his four year grant) the trial’s screening process was halted.
18. By March of 2018, it was clear to realists that over 28% of blended patients were alive at three years from time zero.
19. In 2022, Dr. Pazdur was adamant that the FDA would, in many cases, take action to protect placebos in trials that demonstrated obvious efficacy, even if that meant having to change the trial’s endpoint to an external control arm.
20. In 2021, the Lancet stated hybrid trials that could not simply stick with or go to solely placebo controlled comparisons, could be made more statistically powerful by modifying the control design to also incorporate external controls.
21. This month, Mike Scott confirmed Sawston is ready to manufacture more DCVax-l
22. This month, Flaskworks patented a more state of the art cell manufacturing system that recently added a antigen/lysate pulsed cassette feature to the patent design.


Question, how in the hell do you “buy” over a half decade of time to develop Dendritic Cell commercial manufacturing method before you take a trial to data lock?

My guess is our consternation is another person’s solution. Hopefully, in the very near future, patients will get a commercially viable product to help them with one of most otherwise feared and intractable cancers known to humans.