FeMike:
I think that you are wrong. The fact of the matter is that LP and LG are not making decisions in a vacuum. They are doing so on important strategic issues on a collaborative consensus basis with all the advisors they have.
LP is being counseled by extremely experienced and top advisors who can afford to be objective about the direction the company is taking.
For example, I can guarantee you that their outside counsel including Gibson Dunn for legal and regulatory matters are extremely experienced and have extensive networks. LP is not ignoring their advice on regulatory, legal and business matters, you can be sure. Firms of that caliber are very conservative and careful and their reputation is of the utmost importance. They don’t need NWBO’s business and if there is even a hint of impropriety they will investigate and withdraw if they have to. There is no question that she is collaborating with her SAB, independent consultants, Principal investigators and other experts where she is paying not insignificant sums for their input and advice. She would be foolish to make decisions in a vacuum. Further, LP and LG are not inexperienced themselves. So it is the ENTIRE TEAM that is contributing to the decisions made and not just LP and LG. Further, they are in possession of a lot more information than ordinary shareholders and denizens of MBs like iHub.
I am certain that their outside counsel has recommended that NWBO engage in silence rather than to give essentially meaningless updates on timelines and progress where at least some of it is completely out of their control. What is meaningful is TLD and much more importantly RA approvals. Short of that(pun intended) other information revelations will not move or sustain the needle much if at all. Until they are ready to reveal important information, it is better to be silent.
Naysayers FUD that management is hiding something, that if the trial were a remarkable success, the data would speak for itself and it is not necessary to tie TLD to a journal publication. And if the data were so remarkable, a top tier journal would have accepted an article by now or at least it would have been written and submitted for peer review and this announced by now in conjunction with TLD.
The fact of the matter is that it is not quite that simple. And NWBO is playing to three separate audiences: RAs, the medical community and Wall Street wrt MC. It would not be a surprise at all if NWBO missed the original primary PFS and secondary OS endpoints. In that respect, the naysayers could well claim that the trial failed. Within that context, LG has insisted in conversations with me and others I know that the “trial has not failed”. Even DI has indicated in certain conversations with MBers that if the trial had failed they would have had to reveal this and certainly by now.
What I believe is not adequately remembered or understood is that this is an adaptive trial. Further, the trial concerns an orphan disease. What the former means is that the trial can be modified within the context of advancing knowledge and techniques not known or reasonably foreseen at the time of original trial design provided that the trial remains blinded. This resulted in the modified SAP with the reordered and added end points. The orphan disease designation allows for and encourages the trial sponsor to engage and have easy access to the FDA for guidance. There can be little doubt that the resulting SAP was developed in accordance with FDA guidance. In fact, the guidelines developed by the FDA were drafted in connection with at least some input from these discussions and back and forth with the FDA. Support for these guidelines from members of the FDA were mentioned in recent Lancet publications. IMO, it is reasonably certain that the FDA at least implicitly if not tacitly agreed with the modified SAP and resulting endpoints especially considering the adoption of these endpoints by European RA counterparts. I think it is reasonable to conclude that the 4 involved RAs are in agreement with these endpoints regardless of whether the US clinical trials org was updated or not. Hence it is a true statement that even though the original endpoints may not have been achieved that this trial has not necessarily failed given the modified SAP. Admittedly, this does not mean that the trial absolutely succeeded but may be in a “grey area”. Accordingly, NWBO has not directly confirmed that the trial has been a success but rather nuanced that it has not failed at least wrt to the modified end points even though it may have failed to achieve the original endpoints.
I am reasonably certain that NWBO has succeeded in meeting the current OS endpoint as compared to synthetic external controls by a significant margin. In addition, NWBO has highly likely achieved the 6th endpoint(secondary) with respect to immune agent infiltration. At a minimum, NWBO has almost certainly achieved to meet two endpoints. In addition, NWBO will also be able to demonstrate a long and robust tail. All especially wrt the new definition of GBM. With the achievement of the foregoing, it is a reasonable certainty that at least the MHRA will relatively expeditiously extend marketing approval. This will get the ball rolling with the other RAs. I believe a precursor to MHRA marketing approval will be its preceding GMP approval for Sawston. The MHRA would not waste its time giving GMP approval for a “failed trial product.” Accordingly, marketing approval by the MHRA is very likely to follow suit. I think it likely that the MHRA(as well as the other RAs) has been given a peak at the results. The foregoing as a minimum and worst case scenario is almost certainly sufficient enough for approvals from all 4 RAs including the FDA which will not risk being an odd man out especially given its guidelines and FDA staff endorsements in recent articles. There is just too much pressure upon the FDA given almost certain approval by the MHRA, the Biden administration’s stance on cancer and familiarity especially wrt glioblastoma and the need for an alternative therapy that is reasonably efficacious and SAFE for patients afflicted by this disease. Further, the results of this trial will compare extremely favorably with Optune as we have seen with the blinded results comparisons and the divergence seen as one goes out beyond two years which is where Optune actual data stops.
As I opined hereinabove, I would not be surprised if NWBO failed to achieve the original primary and secondary endpoints, unadjudicated PFS and OS Tx as compared to control which includes crossover. I think these endpoints were reordered and included under FDA guidance with a recognition that these endpoints should not be ignored and swept under the rug so to speak even though there may be good reasons for possible failure given confoundment of pseudo progression which was not well understood and crossover which if not required by the FDA was at least tacitly agreed by them in recognition of the difficulty in attracting trial candidates as well as ethical considerations. In addition, confirmed PFS(cPFS) may not be statistically sufficient in that even though there may be some or even significant pseudo progression found, it is not possible to accurately ascertain how much longer, if at all, these pseudo progressors may have gone until an actual disease progression finally occurred.
In addition, while not a certainty, I believe that there is better than a 50% chance that the cross over arm as compared to external rGBM SOC could be statistically significant. This would be an extremely remarkable achievement and perhaps even more significant than achieving the primary OS end point for nGBM. This was not a trial geared for rGBM. There were an insignificant number of second resections where mutated antigens were not covered and provided a pathway for more virulent recurrence. However, a significant proportion of these recurrent tumors morph into the very aggressive mesenchymal type which is the sweet spot for DCVAX L. This would be a significant breakthrough for rGBM therapy significantly increasing efficacy in recurrence with safety. If the three foregoing end points were achieved, this would be a grand slam home run which even market naysayers would be hard pressed to refute. This would certainly call for expedited RA approvals. The original OS secondary endpoint would probably not demonstrate a statistically significant separation meaning that even delayed administration of the vaccine is efficacious and particularly in connection with aggressive recurrence. Accordingly, curve separation would be evident in this first secondary end point achievement.
Non achievement of the original PFS endpoint may certainly be evident due to confoundment of pseudo progression. Thus, PFS in this case may not be a good correlative or surrogate for the gold standard OS. It may be that there was no significant improvement in PFS over control but that does not necessarily mean that the vaccine is not effective with respect to PFS. It may be that although there is little to no difference between control and treatment eventing, never the less, DCVAX L slows the progression rate such that OS is prolonged and this might be demonstrated by the improved interval between PFS eventing and succeeding OS eventing. I specifically addressed this possibility with LG and he said that this plus other factors would be considered depending upon the results. So this possibility appears to be on the investigative table.
Hence, with very careful and detailed explanations backed by the data, what might be perceived by the market at first as overall lackluster results with non-achievement of original endpoints including adjudicated PFS, would be eventually reconsidered by the market as significant and remarkable results especially if the rGBM endpoint is met. Certainly the regulatory and medical communities would be quick to perceive a successful trial even if the worst case scenario mentioned above should occur. Market recognition would inevitably follow.
Accordingly, a peer reviewed top tier journal is required in order to provide explanations for what might be perceived at first blush as a mixed bag result, especially by the marketplace. After all, it will be very important for NWBO to gain market recognition for needed financing, without more toxic dilution, through a significant rise in the MC/SP. Therefore, it is absolutely essential that NWBO/PIs provide a carefully explained and supported publication through a high impact journal. That is a key part of their strategy and may be a reason for the length of time thus far taken for journal acceptance and publication. They need to get it right the first time. Such explanations, as suggested above as examples, will have important validation if published in a top tier journal. But they need to be carefully explained and wordsmithed and this takes time and input/reviewed by a number of interested parties.
My point in explaining all of the above is that this is overall a complex process not given to simple explanations that the data speaks for itself. Unfortunately in such a case, the numbers/ graphs are not the whole story. LP and LG are not making decisions in a vacuum considering all these complex parts and how they come together. It is a whole team including NWBO management and their entire hierarchy of consultants and advisors possessing information that we as retail shareholders are not privy to in making collaborative decisions. Even the FDA has provided guidance and input through the orphan status protocol. If one claims that LP does not know what she is doing, then I submit that it is not just her but her whole team. This is highly unlikely.
In the past, I was highly critical of management but I was certainly premature if not entirely wrong in my judgement. These are very smart and experienced teams including LP and LG. Read their backgrounds. Don’t know what they are doing? Not by a long shot in my book.
I strongly believe that the results will be understood by all constituencies as remarkable including the RAs, medical community and patients and ultimately, Wall Street. “Incompetent management” will have a lot to do with this success. JMHO.
