BSB:
Thank you for your message. Sorry I cannot reply privately as I do not subscribe to this service. I agree with your comments.
I do believe strongly in the science although I have a number of open questions, the last of which were communicated recently to Iwasadiver who responded by saying that he would re-read these and then attempt to shed some light.
Allow me to give you the courtesy of my thoughts as they relate to the question as to what my angle is.
SCIENCE:
1. PFS: In the overall picture, while a primary endpoint(and that won't change IMHO no matter what the new/modified SAP spells out), PFS will not have much decisional significance especially if this endpoint is not achieved. Very simply, PFS is a surrogate for overall survival so that trials do not have to play out for the much longer overall survival metric. Overall survival is the gold standard. Period. The trial has gone on long enough so that this surrogate's decisional importance is diminished. The failure of the JTM article to discuss PFS blinded data, just the same as OS blinded data was addressed, suggests that the PFS data was at worst confounded and required adjudication. Absent adjudication, one might conclude that at the very least, PFS blinded data may have been too close to call. Although, admittedly, it appears that according to LL, the long living patients in the trial apparently did not experience PFS eventing and that certainly bodes well if most if not all are in Tx. Basically, for immunological therapies, PFS may not be a good correlative of OS and thus OS takes on much greater significance especially for this trial that has run for so long. No real need for the surrogate when you have sufficient OS data as we do in this trial.
IMHO, what may be important is whether, even though PFS eventing may not significantly exceed that of SoC, given enough time for the vaccine to take hold the rate of progression is slowed, and in some cases reduced to zero, thus contributing to longer overall survival and a much better QOL. I hope the revised SAP addresses this question.
Furthermore, what is important, in my view, is the delta between PFS eventing and OS. If this delta for Tx is significantly longer than control then it may corroborate diminishing rate of progression.
Bottom line, PFS may, in the whole context of the trial, pale in significance to OS especially if the results are stellar.
My only issue with the possible lack of achievement of the PFS endpoint is whether the market understands what I have delineated hereinabove assuming that I am reasonably correct rather than trumpeting an absolute failure of achievement. Hence it is important how this metric and its results are portrayed in the announcement of top line. Unfortunately, I do not have great confidence in management to communicate this effectively given past performance or lack thereof. Further, the hiring of David Inness does not change my view. Pure and simple, he has no IR or media communications experience and was a broker, and not even one with a VP title, in a backwater satellite Oppy office. He has rather continued the obfuscation and has acted as a convenient and expensive proxy for LG. IMHO, while I do not blame Innes, he was an un-necessary and even poor hire on the part of NWBO management. No improvement in the IR function that I can discern.
2. OS: The secondary endpoint is OS. Of course the crossover and the fact that about 90% of the trial population was afforded the vaccine at some point in the trial(early vs late), may serve to confound results. There may not be sufficient separation between the Tx and control(cross-over plus non-crossover) arms despite the length of the trial. However, IMHO, crossover patients did not have a second surgery to obtain a second sample(perhaps only 3 patients did) after progression. The cancer is heterogenous as well as highly mutative and thus, I would not think that the crossover patients would fare significantly better than non-crossover patients. Thus, I would think that there would be sufficient separation. I am not sure how significant a comparison of Tx with non-crossover alone would be given N=33 which may be too small a sample. Furthermore, it appears that upon progression, the cancer mutates wildly into a highly aggressive cancer(about 85% mutation to mesenchymal (MES)). So, without benefit of a new lysate and a rapidly progressing cancer, I would think there would be significant separation in the curves especially as you go out in time.
However, even if there is not significant separation, is this necessarily a bad thing? Might it not support the notion that even though early vaccination is preferable, there is some benefit to late vaccination anyway? Imagine how much better the results might be if a second lysate were made after progression? It could be indicated that the vaccine is indeed so powerful that even in rGBM and no second surgery, the vaccine still works to some extent. Thus the pronouncement of Dr. Ashkans, the PI in the UK, that the vaccine works to a greater or lesser degree and should be given to all patients.
The vaccine appears to work particularly well on the methylated group(M+). I don't really understand what this means. For example, in the intro to the iHub message board there is a chart if you scroll down far enough where the M+ and non-methylated (M-) groups are delineated. This is as of a relatively recent abstract dated April 18, 2018. The M+/M- groups are further broken down into sub-molecular groupings. The M+ sub-molecular group is only pro-neural according to the chart. The M- group contains predominantly un-methylated sub-molecular groups consisting of classical, mesenchymal(MES) and neural.
The JTM article showed that the M+ blinded data was impressive even though from time of surgery with a blended delta of about 13+ months. The JTM article did not address molecular sub groups, however, if the chart is accurate, the M+ group would be composed of at least predominantly pro-neural. However, in previous UCLA studies, Drs. Liau and Prins found that the vaccine worked particularly well for MES but had little to no effect upon the pro-neural molecular sub-group. They found that MES was more immunogenic which I believe from what I have read that there is a higher residual amount of T-cells as compared to other groups and that the tumour micro-environment(hi-jacked T-regs) was less immunosuppressive thus allowing the T-cells more time to infiltrate the tumour and kill it. As I understand it, methylation of the MGMT gene interferes with the cellular repair mechanism and so cancer cells are effectively killed by the application of Temodar and this MOA is leveraged and extended by the application of DC VAX L. This is a separate pathway. When we talk about the M+ group in the JTM article are we talking just about methylated MGMT? Are there other genes that are methylated that give rise to improved effects? I just don't know. Anyway, the remarkable results upon MES as found by Drs. Liau and Prins seem to be due to its immunogenetic nature. There are other cancers that are also highly immunogenic like MES.
However, while the JTM article showed even remarkable efficacy in M-, which according to the chart is partially composed of MES, one would think that the results should be even better given the LL/RP findings. It is, of course, possible that the results for MES were remarkable but not so much for classical and neural thus pushing down the blended delta for M- as a whole. I just don't know.
The point I am attempting to make with the foregoing meandering is that M+ plus immunogenic(MES) may cover a significant spectrum of GBM where DC VAX L may be particularly effective. For example, in the categorised grouping of 293 patients(the initial 38 were not categorised), 44% were M+. In addition, the literature indicates that MES is a significant population ranging anywhere from 30%~48% of all nGBM.
If this is the case, then easily over 60% of all nGBM would be effectively treated by DC VAX L. That is assuming the chart I referred to is accurate. If it is not, it should be removed. The other point that should be made is that no tumour(s) are completely MES or pro-neural or 100% anything. And there is mutation. Hence I doubt that approval if it issues would be limited to a single or restricted grouping. As Dr. Ashkan has averred, the vaccine should be available to all with a decision made between Dr. and patient rather than by regulatory fiat.
Accordingly, I think the overall survival milestones for Tx will likely be remarkable especially for M+. How MES factors into this I don't know. Neither do I know the extent of efficacy in the other molecular groupings. However, I believe from the blended data and SNO updates that the spectrum of applicability is very broad and that a significant percentage of Tx are relatively long lived.
How all this will be presented in conjunction with top line is an important question perhaps not so much for the regulatory and medical communities but for the investment community which will have an important effect on NWBO financings and their toxicity.
So bottom-line, I am reasonably confident in the science.
MANAGEMENT:
Insofar as NWBO management is concerned, I believe their lack of transparency, obfuscation, silence and questionable "self dealing" have all conspired to bring down share prices just as much if not more than the dark forces LG has alleged. We all have questions as to what expensive hangers on like Cofer Black are doing? What value is Innes adding? Etc., etc. we have gone over management deficiencies ad nauseum.
In conclusion, I have many shares because I believe in the science. At one time I believed in management. No more. I hope they are bought out and I am willing to give up what we MIGHT get in the LONG run by going it alone for a bird in hand, so to speak, on an earlier BO. I'd rather enjoy the fruits of some modicum of success now than push it all off to my succeeding generations.
GLTU and I enjoy reading your posts. They make sense. Please keep in touch.
Kind regards,
U
