NorthWest Biotherapeutics Inc (NWBO)

[Umibe5690]

ATL:

I read and very much appreciate your posts. You appear to be very knowledgeable and articulate your views quite well. Perhaps you can help me understand the science a bit better. I have had these questions for a long time, have posted them a number of times and have attempted to address them with NWBO including Dr. Boynton to little avail. I will also express my own predictions on the trial results.

The major classifications are methylated (M+) and non-methylated(M-). The sub molecular groups are MES, classical, pro- neural and neural. Relatively recently, the neural sub classification has been deleted as it is rather de minimus and not worth a separate classification.

In the above regard, there is an abstract dated February, 2018 which you will find in the iHub message board intro if you scroll down a ways where these sub molecular groups are correlated to the M+ and M- major classifications. For example, you will find that pro- neural is classified as M+ and that there are NO other sub molecular groups included. On the other hand, in the M- classifications, MES and classical are listed. As I also understand it, classical accounts for perhaps 50% of nGBM, pro-neural for about 15% and MES for about 35%.

Earlier studies conducted by LL and RP at UCLA circa 2016 suggested especial efficacy wrt MES, however, pro- neural not at all. The efficacy wrt MES was especially welcome because it is extremely aggressive and is highly immunogenic meaning that the tumor sub micro environment is less immunosuppressive and that there is a higher incidence of residual TILs. The aggressiveness of this sub molecular group with a sharply attenuated survival would be expected in the M- grouping since that group has typically demonstrated a shortened mOS. The JTM showed an historical mOS of 12.7 months from surgery, not randomization, for the M- group wrt SOC. JTM blinded results showed 19.8 months mOS or a delta of about 7 months from date of surgery. However, the M+ group, composed of pro-neural, as per this particular abstract classification, showed an historical SOC mOS of about 21.7 months from surgery and a blinded mOS of 34.7 months updated to 35.1 months as per SNO, 2018 or a delta of 13.4 months.

The confusion arises due to the classification for pro- neural in the M+ group as the only sub molecular group in that classification. Indeed, pro-neural is properly included in M+ because it is characterized by longer survival and is more typically found in younger patients. However, this appears to be rather contradictory to the earlier findings of Liau and Prins where DC VAX had at least de minimus effect upon pro- neural and that it accounts for perhaps as much as 15% of the overall nGBM population. Indeed, it is true that no tumor is 100% pro- neural or anything else but even though heterogeneous (MES appears to be very heterogenous) it may be predominantly pro-neural with a slow rate of mutation. Further, pro-neural which is characterized by IDH- mutant(MES is characterized by IDH-wild) can be favorably intervened by DC VAX dependent upon whether it is GMP/non-GMP but in a very small set of cases. However pro- neural is a relatively small sub set at 15%.

Assuming that this abstract classification is not entirely accurate or that I may have not fully understood it, I would suspect that M+ might include MES as well as classical. The M+ MES would be less aggressive than its counterpart in M-. We do have a known case of long survivorship in the classical sub molecular group characterized by over expression of EPGRviii in Brad Silver going on over 15 years and I believe if memory serves that his classical was M+.

If so, then the relatively shorter mOS of the M- group could be understood by a more efficacious effect on MES leading to a longer mOS and significantly off set by shorter mOS of classical and de minimus effect upon pro-neural resulting in a delta of the above mentioned 7 months.

Incidentally, the SOCs quoted in the JTM article accord very well with more recent abstracts that quote SOC historicals of between 12 and 16 months for M- and 22 to 25 months for M+. It should be noted that for OS 36 month milestone the M- survival was 14.3% blinded updated at SNO 2018.

One other thing I should mention is that I cannot quite figure out the mOS of 23.1 months mathematically when considering a blinded mOS of nearly 20 months for M- and an mOS of 35 months for M+. I would think that the fully blended mOS would be higher at about 25~26 months.

After all this background rumination, bottom line, I believe the following for the primary end point:

If we assume 16 months SOC for M- from historical adjustments and comparators for randomization, and Tx of about 21 to 22 months we have a delta of between 5 to 6 months. If we similarly assume about 26 months SOC for M+ And a Tx of about 37/38 months, we have a delta of between 11 and 12 months.

Further, if we assume that only 50 out of the top 100 survived about 60 months, and about 46 were in the Tx group,then about 20% survived 60 months and perhaps growing more. In this regard, LL has said that about 25% survive with DC VAX L therapy. Although I do not know exactly what she meant, I believe her meaning to be that with DCVAX, about 25% survive 60 months. Or she could have meant that the vaccine is efficacious for only 25% of the ITT. However, this would fly in the face of her statement that it appears all patients are living longer and Dr. Ashkan’s objective that the vaccine is made available to all because it is efficacious albeit in varying degrees for all patients. Although I do believe that the tail will be robust, I do think that a majority will be composed of M+ and MES non- methylated with a lesser classical classification. Hence I believe that the vaccine will be largely effective among major groups with perhaps little to no efficacy wrt pro- neural and thus much more than 25% of the ITT.

WRT rGBM, I believe the end point will be met. Although this was not a proper rGBM trial and insignificantly little resections undertaken to account for mutations, rGBM is characterized by about 85% mutational shift to MES where DCVAX is especially efficacious.

Finally wrt PFS, I strongly believe that even IF the end points are not achieved, there will be a showing that as time unfolds, the Tx group will evidence a SLOWING of the rate of progression as the immunological effects take time to manifest. This, indeed, would salvage any PFS underachievement. I did discuss this with LG some time ago, and he admitted it was a good point and that all will be considered. He did not say whether this particular metric would be definitely addressed so it is my opinion.

All in all, I envision significant results along the lines described herein even though I have some confusion, perhaps of my own making. I hope these ruminations help stimulate thinking and render some positives to expectant longs. GLTA.