Register for free to join our community of investors and share your ideas. You will also get access to streaming quotes, interactive charts, trades, portfolio, live options flow and more tools.
Register for free to join our community of investors and share your ideas. You will also get access to streaming quotes, interactive charts, trades, portfolio, live options flow and more tools.
Been there done that. Trust me, you DON'T want a R/S. Especially prior to top line. The shorts are in control. They are pushing for a R/S. They will short this to a buck on a 10:1 R/S. The,y love the altitude this will give. Been through a couple of such splits and it wasn't pretty.
If Dave knows anything, he will put your advise where it belongs, in the round file. Please do me a favor Joey. No more advice. Thank you kindly. JMHO.
OK Sukus, here is some enthusiasm and encouragement.
TOP LINE:
PFS delta is 9 months
Tx vs crossovers and non vs non-crossovers deltas: 12 and 18 months respectively
OS36 Tx survival is 37%; OS60 Tx is 28%
Especially good results in M+ and MES which cover about 60% of all ndGBM
P=0.0000000000000000001 and HR is 0.13
Trial has unprecedented success in all areas.
After these results revealed, pandemonium breaks out and share price spikes to $125. Bidding war among major BPs and Merck wins with a bid of $523.43 per share. LP refuses bid and wants to wait for FDA approval.
FDA broad approval in three months. Share price spikes to $1,003 per share. Bidding war resumes and big P consortium offers buyout at $3,356.73 per share. LP accepts. Complete date is February, 2020.
AF reveals he was long all along and accumulated 10 million shares.
How's that for enthusiasm? LOL.
Marzan:
Thanks for the civil post. I believe you have stated a number of misconceptions.
First, I have never said that mPFS and mOS are primary and secondary endpoints. If you read my posts carefully you will note that I rather refer to them as PFS and OS respectively.
Insofar as PFS is concerned, it has been used as a surrogate for OS because a strong correlation was demonstrated between PFS and OS. In order to shorten the length and expense of a trial, PFS was used as a surrogate to OS. PFS or progression free survival means that the disease does not progress, i.e., the tumour does not enlarge. The tumour need not shrink, all it needs to do is stop growing larger. The confoundment with PFS in the current trial has to do with enlargement of the tumour. The question is whether it has grown because the disease has not been arrested or is due to the ameliorative effects of the vaccine causing enlargement due to inflammation. This has been hard to detect/confirm in earlier patient scan studies but has improved over the years. The facts that NWBO has been silent on the PFS blended data and the need for adjudication suggest but do not necessarily confirm that the achievement of the PFS endpoint, a 4 month delta vis-a-vis control, is in jeopardy. That said, regardless of whether PFS is now considered a less appropriate endpoint for immunological therapies, the fact is that PFS is never-the-less a PRIMARY endpoint.
IF top line revelation shows that this endpoint has not been achieved, the market will note this failure and assume that approval may be in jeopardy. At the very least, the risk associated with approval has been enhanced as a result of this failure. Thus, this likely market perception may rather give undue weight to this failure and gloss over or even ignore countervailing positive data as extra-curricular and of questionable consequence. This is especially true of shorts and hedge fund manipulators who will run their propaganda machines 24/7 and exploit the various shortcomings (pun intended) of the announced results. This will put a lid on the upward momentum of share price and possibly deflate the price because of unrealised but rather dashed expectations. We have seen a precursor of this when the very favourable JTM article was published and had relatively negligible effect upon the stock price. If the manipulators could do it then, they will certainly re-double their efforts with top line unveiling especially if an important endpoint in the trial protocol has not been achieved. That is why LP is pulling out all the stops and doing all she can to eliminate or at least mitigate a less than successful result in these endpoints. Accordingly, LP is in no rush to data-lock, has been vague about time-lines and is otherwise playing for time to cover all the bases as best she can.
I must emphasise that even IF these aforementioned endpoints are not met it does not necessarily mean that NWBO won't obtain regulatory approvals with other very positive data. But failure to achieve trial protocol endpoints may have a deleterious consequence insofar as share price is concerned.
The announcement of top line is a seminal event and significant chance to raise the share price as one of the directors alluded to at the ASM. Missing endpoints could deal a devastating blow to sustainable share price appreciation which will be necessary in financing NWBO's future needs, lest it falls prey again to toxicity and the ensuing side effect of continued dilution. JMHO.
Marzan, may I proffer a bit of advice? I respect well argued views that may conflict with my own. I am admittedly not the sharpest scalpel in the operating theatre and I can learn from opposing views. Hopefully I can then become a better investor. Yes men, always agreeing with my position, are a bane to my existence. JMHO.
Still friends Marzan?
Marzan:
You seem like an intelligent person. I believe that you stated you have a PhD in Chem. Eng. Your responding post is not what I expected from someone like you. Intelligent discourse is what I am looking for. I believe my thought about failure in the endpoints and the consequent effect upon share price is a valid concern. I would be grateful if you could dispel such concerns. For example, stalwart longs like Flipper, Doc, Iwasdiver, etc., all believe that the endpoints will be achieved and with a good margin. That is a reasonable position. OTOH, I am not so sure. NWBO's silence on PFS data and a call for adjudication seem to suggest that this endpoint may be in some jeopardy.
please be civil and respond accordingly. Thank you Marzan.
I don't know that they have or have not been achieved. I have admitted that. My explanation in connection with the share price involves the supposition IF. IF the primary and/or secondary endpoints are not met, then, most likely, the market will react negatively because its perception may likely be that the trial failed despite other positive data which will be treated extracurricularly, mostly as an afterthought and as a "spin' defensive argument. I believe, but do not know for sure, that the endpoints may be in jeopardy and that is why PFS blended data has not been addressed and why adjudication is/will be performed.
What I think about milestone survival rates, etc. is irrelevant to the point I am making above. JMHO.
Sukus:
Why do you ask this question in connection with the post to which you are responding?
The point I am making is that market perception will most likely be negative if the primary and/or secondary end points are not achieved. The market, which as you well know by now, wrt NWBO stock, is manipulated with odds on probability. The market has a very short attention span. It usually glosses over the fine print and tedious explanations. Once you are forced into defensive explanations the market discounts it and moves along. This is all yada, yada, yada to the market. The headline may be "NWBO fails to meet primary and secondary endpoints in what has been a ten year long trial. However, and incidentally, overall survival for those patients initially treated with the vaccine was 30% at 36 months.....Will this be enough to offset failure in the primary and secondary endpoints and gain FDA approval? Stay tuned". That message will be hammered relentlessly into investors' minds creating significant FUD and a tepid, if any, effect upon the share price at top line announcement. Certainly not a ringing endorsement insofar as attracting enthusiastic buying in volume and significantly increasing share price.
Unfortunately, top line goes by without a significant and sustainable boost in share price and NWBO stock is stuck in the doldrums until a decision by the FDA(and/or other RAs) is forthcoming. No doubt, NWBO will require funding to keep going in the interim and after the sale of its remaining Sawston real estate, it's back to toxic funding injections and the horrible side effects of dilution. Unless of course, the endpoints are met and this nightmare scenario is thereby averted. Hopefully, adjudication will save the day for PFS. Hopefully(for the trial but unfortunately not for patients), crossover/late vaccine treatment will have little effect and there will be sufficient separation. It does not look that way but I hope I am wrong. JMHO.
If the stock does not rise upon top line revelation, due to the failure of the endpoints, I cannot imagine that the stock price will go anywhere near a dollar. The market, in all probability, will regard this failure as a failure of the trial despite other positive results. The risk of approval is greater through this failure and having to depend upon other factors for approval creates significant FUD.
In any event, after top line revelation, the process of approval will commence. The period for evaluation and approval by the FDA(and other RAs) will likely be lengthened due to the need to evaluate and weigh all of the data including the failed endpoints. I am guessing that approvals will probably issue in 2021 in that case. During this interregnum, NWBO will need to keep the lights on and no doubt will need to go to the capital well a number of times after it undoubtedly sells the remainder of its Sawston property. There will undoubtedly be significant dilution due to the depressed stock price certainly and significantly below a dollar per share. Many erstwhile longs will be disappointed with the stock price after top line revelation adding to the pressure on the share price. This depressed stock price will persist until approval.
Will the stock appreciate significantly as a result? In all probability, fully diluted shares(including warrant conversions) will be well over 2 billion shares unless an R/S takes place, where IMHO, the shorts will take advantage of the higher altitude and vigorously short the stock. There will be issues wrt to commercialisation and the ability of current management to meet this challenge. The naysayers' propaganda machine will be in full swing spewing all sorts of FUD and proclaiming that "proof is in the pudding" and show me the money from commercial operations. To date, it is obvious that NWBO has been battered by market forces and very successfully at that. Just because NWBO receives approval for its product does not mean that its business will be a success. Current management has no credibility with Wall Street. A mixed top line showing certainly won't enhance its credibility. If current management will lead efforts in commercialisation, would their lack of regard by the market be changed just due to approval? I think not. Management will need to prove itself in the commercial world before any appreciable price rise is seen and sustained.
The above scenario can, of course, be avoided if the primary/secondary end points are met. The share price and quickness of RA approvals will crucially hinge upon meeting these endpoints. Ultimate approval may not so depend assuming very positive other data. However, share price appreciation and sustainability is crucial. That is why LP is not rushing to announce top line. She is buying time to try and salvage the jeopardy of failure in these endpoints. Again, I am not categorically saying that they have failed. However, I think that it appears they have failed and that bodes ominously for the share price upon top line revelation. How they handle that scenario is of utmost importance. That is why I think Dave Innes is a key hire. JMHO.
Hi Doc:
You are confusing approval with share price appreciation. I thought I made it clear: I am, for the record, reasonably certain of ultimate approval, in all 4 jurisdictions applied for, even IF the primary/secondary endpoints of the trial are not achieved.
I do believe that IF one or both endpoints are not achieved upon top line revelation, despite other positive data, the market perception will be that the trial failed(at least technically). Although the "spin"(as averred by the naysayers) pointing to other positive data, importance of long tail in immunological approaches as being the "new" gold standard, etc. will undoubtedly be defensive mode counter-explanations, the market, bolstered by the incessant chorus of the shorts, will otherwise perceive the uncertainty engendered by the failure in achievement of the endpoints as, at best, mixed results thus blunting any explosive rise in the share price. The weightier news, at least insofar as the stock market is concerned, would be the failure of the endpoints. The other positive, and perceived extra curricular, data will be relegated to a second seat in the all important world of perception. The results will not be undeniable and the FUD thereby engendered will register uncertainty, at least where market perception is concerned, and thus weigh upon the share price. The market dislikes uncertainty and NWBO has a long history of that. The risks associated with RA approvals will be heightened.
The better scenario is one where you, Flipper and others are correct about achieving the PFS endpoint as well as OS. Then, there is little to deny by the market. The results will then have met the endpoints and achieved a new gold standard. The share price should then rise significantly and sustainably.
To me, it APPEARS that the PFS(and OS) endpoints are in jeopardy. LP has let the trial continue on and has been rather vague on when data-lock, top-line, etc. will take place. In addition, other than the mention of adjudication, there has otherwise been silence on the primary endpoint. A reasonable assumption may be that these endpoints are in jeopardy according to LP's experts and by letting the trial run longer and being vague in stating timelines, NWBO is doing all it can to salvage these endpoints in the meantime.
In summary, IMHO regulatory approvals will ensue despite failure to achieve one or even both primary/secondary endpoints if the other data is otherwise positive. However, such a circumstance will bode negativity in terms of market perception and the share price upon top line revelation. Hopefully, in this scenario, Mr. Innes will be up to the challenge since the market is his bag. JMHO.
NWBO E-VALUATION:
I believe that based upon the JTM and SNO updates that DC VAX L will ultimately be approved by the FDA(and other RAs). How quickly it will be approved obviously depends upon the data.
What concerns me is whether the primary and secondary end-points have been met, not so much in terms of approval but in terms of share price appreciation. Of course, the FDA(and other RAs as well) will look at the totality of data in making regulatory determinations including the primary and secondary end-point achievements. If milestone and long tail data are very positive, I believe that even though there may be failure on these end-points, approval will ensue. Comparative analysis with Optune where DC VAX L is at least competitive, has demonstrable long tail data(works on the back end), as well as safety and QOL factors will afford patients another alternative in this deadly disease where progress has been relatively minimal to date.
While the trial is still blind, it does seem that there is concern that achievement of the PFS end point is in jeopardy if not otherwise a failure. The only significant mention of PFS has been that adjudication will be applied. However, there has otherwise been silence and no discussion of blended PFS data as in the case of survival. Essentially, there would normally be discussion of the primary endpoint on a blended basis and little need for adjudication if the blended results pointed toward success. Thus, adjudication appears(does not confirm) that NWBO is throwing a Hail Mary pass in hopes of salvaging this primary endpoint.
Further, there is concern that there will not be significant separation between the control/cross-over arm and the treatment arm wrt the OS endpoint.
Of course, these possible failures can be defensively explained and counterbalanced by other strong data(home-runs) wrt a thick and long-tail, etc.
However, failure on both or even either one of the endpoints places NWBO in a defensive position. Once you need to explain the results in defense mode, this places a lid upon and even deflates the share price upon revelation of results after unblinding and analysis. The shorts and naysayers would trumpet failure of endpoints and thus failure of the trial(albeit technical).
Imagine a headline in the WSJ heralding that NWBO failed its primary endpoint but then in the body of the article, "spin" on the long tail home run, as a defensive excuse, is offered. At best, as interpreted by the market, this would be at best a mixed result and any pop in the share price, if there were one, could not be sustained. The hoped for significant increase in the share price upon unblinding announcement would be dashed and any price appreciation would need to await RA approvals which would likely not issue quickly, at least in the US, due to the "mixed" results and increased time for regulatory approvals because the results were not undeniable on their face. Obviously, a depressed share price, continuing after top line on to ultimate approval, would significantly adversely affect financing and engender more of the same toxic and limited alternatives. Significant dilution would undoubtedly ensue.
In such a case, where one or both endpoints are not met(but can be defended by "spin" as the shorts would aver), I cannot imagine any significant and sustained price appreciation. Certainly not anywhere near to the dollar level. This would be highly disappointing, even to stalwart longs, placing even more pressure upon the share price. Significant and sustained price appreciation may not be seen until FDA(and other RA)approvals earliest in late 2020 and more probably sometime in 2021, almost two years from now. During this interim, significant dilution would occur further blunting any significant share appreciation. And......even with RA approvals, there may not be any appreciable share appreciation then, in addition to massive dilution, due to commercialisation and other issues raised in the incessant drumbeat of negativity of the naysayers.
I believe that NWBO management is extremely aware of the possibility of the foregoing scenario. How top line revelation is presented in such a case is crucial. I believe that this may be an important reason for Mr. Innes's hire. Specifically, rather than hiring someone with PR/media marketing and communication experience, NWBO management decided to employ someone with stock market experience in order to help formulate and execute a strategy to anticipate market reaction to cover this possibility where the odds against it are not insignificant. Mr. Innes has the necessary market experience in order to gauge and anticipate how the market might react and how to meet this particular challenge. As such, he is a key hire.
At this point, share price appreciation is crucially important without which NWBO will again find itself in a toxic hole. While missing the endpoints may not be fatal for RA approvals, it may be a mortal wound insofar as financing and as an investment go. That is why LP is in no hurry to rush to top line announcement right now. She is in treacherous waters and she knows it. She needs to get her ducks in order. She gets only one chance. JMHO.
You are quite correct that the trial is still blinded and the achievement of endpoints are unknown. However, there are opinions(and these can only be opinions until the data is unblinded and thus no conclusive evidence) claiming otherwise by my sources who are credible and whose opinions I respect. JR is claiming that his sources say the PFS endpoint has failed. If so, what evidence does he have?
Just because NWBO has not said anything about PFS does not mean that ipso facto they are hiding failure. Obviously there is confoundment due to pseudo-progression. This is/will be adjudicated. Until then, there is only speculation/opinion.
Frankly, even supposing that the PFS endpoint was not met, I do not think that it will have a significant bearing on the approval process. If all patients are living longer, I think looking at the delta between PFS eventing and over all survival is more interesting. Further, consider the possibility that, indeed, PFS eventing is not significantly better than control. In immunological therapies it may take time for the vaccine to work. Over time as the effects take hold, progression rates slow and in some cases cease. Accordingly, PFS eventing, in and of itself, may be a poor prognosticator for overall survival which is the gold standard after all.
I just think saying this or that failed, while still blind, is premature and rather aimed at creating FUD or venting frustration because we still don't know anything, at least for sure. JMHO.
Funny JR but my sources who are also very trustworthy say exactly the opposite. You say that the evidence points to failure for the PFS endpoint. Please educate me on the evidence. I'm listening.
The IR guy was hired at behest of the BOD? Highly doubt it. Nobody gets hired without LP's blessing. The board may recommend but LP decides.
I can confirm that Dave knows exactly what he is doing. I know he has a great position with Oppy and is making a very good living. He is invested in NWBO and has recommended it to many of his clients. He has been in close contact with NWBO management over the years and has given them a lot of advice. NWBO reached out to him. He would not be taking a flyer on NWBO, giving up what he had, unless he were pretty confident. You don't make a leap like this unless you are pretty sure. BTW, to be clear, I can tell you that Dave is no dummy. Far, far from it. And very articulate. He understands shareholders and to his great credit, he ain't a lawyer!
An excellent choice, no if, ands or buts. JMHO.
I very much doubt that explanation. Certainly, even if there were an emergency, and she were incapacitated, someone, most likely her husband, would have been there with her. Obviously, they would have known her association with NWBO and DC VAX. They would have likely known that tumour tissue had to be preserved for a possible DC VAX treatment. It strains credulity that someone who was intimate with DC VAX due to their board position was somehow denied the availability of this treatment. Georgetown is in Washington, DC not far from Bethesda. Hard to believe that neuro-surgeons were not made aware of NWBO/DC VAX and Mrs. Bayh's relationship and the necessity of preserving the tissue. It is possible but I find it improbable.
Equally likely, is the possibility that DC VAX was not selected. It is possible that Mrs. Bayh left the board in part because she was not a believer in DC VAX efficacy and opted elsewhere. Who knows? Seems like Mrs. Bayh is not talking but the odds appear to favour that DC VAX was not chosen. JMHO.
I agree with your post. It is logical. I also agree that GBM is complex and it is highly likely that a lot more has been learned after the UCLA studies.
The chart that I am referring to is the one on the iHub message board with all the NWBO info which you scroll through to get to the messages.
All the best,
Um
HI Abets:
The chart is excellent. For now nothing to add, modify or delete. Your chart summarizes extremely well.
As you will note, the issue is about MOA and pathways in which DCVAX works. Although glioblastoma stage IV is a generic nomenclature, the subclasses of MES, pro neural, classical and neural therein are different cancers. Why is DC VAX seemingly so effective in M+ but overall not so in M-. Is it due in great measure to the immunogenosity of the cancer? In the case of MES, it would seem so as found by LL and Prins. But not generally in pro neural although there is at least one sub class of pro neural where it is relatively effective. I recall that there was a comparison made with CLDX on classical(HLA-1 and 2, EGFRviii) where DC Vax was just as effective if not more than the single agent approach due to heterogeneity.
Doc Logic from his own research indicates that DC VAX is effective in a very small MES methylated group. From the chart that I have referenced in our discussions, this seems valid because the methylated group as a whole did significantly better--on a blended basis--than the non methylated group of which MES is a part. However, while I have no reason to doubt Doc Logic's research, I have explained why I believe that LL/RP were referring to the larger MES group due to the different pathway available as a result of the immunogeneity of MES as a whole. It may well be that it is even more effective in the methylated group because in addition to immunogeneity you have an inhibition of the cellular repair mechanism. The reason that M-, as a whole did not perform better may have been due to the counterbalancing classical and neural groups that may respond significantly less than unmethylated MES and which, accordingly, brought down the performance of the M- group as a whole. I believe that LL/RP were excited because the vaccine worked very well on a significantly large MES subgroup rather than just upon a relatively de minimis subgroup. Again, I am no expert. Trying to understand this better and throwing out thought experiments that others more knowledgeable can consider and correct. My own understanding improves and I can then feel either more or less comfortable with my investment depending upon the various viewpoints--or then again, not at all. Hope I have not confused you but JMHO.
Best,
Um
I don't mean to be argumentative, however, I am rather confused by your response.
Firstly, according to the JTM article, it appears that the methylated group is doing far better in terms of delta and percentage survival as compared to unmethylated. And according to the graphic display, M+ is composed of proneural. If there is methylated MES, it is not mention and probably insignificant.
In prior studies and statements, LL was highly encouraged by results re MES. This is a very large molecular sub group and could consist of nearly 50% of ndGBM according to some studies. In other words, this group appears to be rather prevalent and therefore one would expect to find a significant percentage in middle of the road as you call it.
In discussing the effect of the vaccine on MES, there was no mention of methylated status. Rather, LL pointed out that this significant subgroup was much more immunogenic than say proneural. LL mentioned that in the case of MES, there is a higher level of killer T cells to begin with and further, there is a more reduced immunosuppressive tumor micro environment. The combination of a higher level of T cells synergistically combined with a lesser immunosuppressive environment allowed for more time for multiplied T cells to infiltrate the tumor. What was also exciting was that with this significant sub group, CI may not be required and DC VAX as a sole adjuvant to SOC(reducing tumour burden)would be sufficient. I frankly don't see the excitement if the vaccine is highly effective in a very small methylated subset of MES. The excitement, rather, was because the vaccine appeared to do so well in a broad subgroup that was highly aggressive and deadly. It also appears that M+ MOA works through a different pathway involving the inhibition of repair mechanisms on cancer cells this constraining proliferation.
At least, that is how I understand it and accordingly this could well be the basis of my confusion. If my understanding is otherwise correct, this would be extremely good news in that the vaccine works well in at least over 50% of ndGBM both in M+(Proneural) and M-(where MES is a major component along with
Classical). JMHO.
Thanks for your follow up. Interesting information. It would be more instructive re MOA if we had molecular data to analyze. Would be very disappointing if all we really had were methylation status.
Anyway, it is what it is and I do anticipate significant positive results at least insofar as milestones and long tail. I am not so confident about the primary/secondary endpoints but we shall see.
GLTU.
JR:
I have clearly stated my belief that Primary and Secondary have probably not unequivocally achieved "undeniable" results and may have even fallen short...and that NWBO probably feels this way but does not know for sure.
I do not, for one moment believe that NWBO, botched the trial. The endpoints were chosen long ago and they appear not to be appropriate endpoints for this type of trial. If the trial demonstrates strong results for milestone OS and long tail, I do not believe that failure in the primary/secondary endpoints doom approval especially in light of the now very favorable reg environment.
I think that the FDA will look at all the data. Failure in the primary/secondary endpoints will take on greater weight if the milestone/ long tail results are not so strong. Further, I have not averred that the FDA has made any assurances. Quite the opposite. However, the FDA is enlightened insofar as immuno-therapeutic approaches are concerned and understand the importance of long tail in these types of trials. Thus NWBO is re-writing the SAP with the tacit agreement of the FDA. However, the FDA has not stated that it will sign off on any re-written SAP. Essentially, the FDA with its more flexible orientation is saying....OK you can submit a re-written SAP and then we will see what you got...
Fair enough. Stay tuned.
I am not an expert in all this. I do not know your credentials either. However, the UCLA studies apparently did involve molecular sub groups and made some conclusions therefrom. Dr. LL is a principal investigator in the US for this phase III trial and who was also involved in the prior UCLA studies. Drs. LL and RP made some important findings wrt MES, pro neural and classical. LP according to my recollection referenced molecular sub groups as possible multiple chances to win. In speaking with LG, he confirmed that sub group analysis would be part of the study. Even Dr. Boynton indicated that we would know something when the trial was unblinded and data analysis was completed. So you will forgive me if I withhold judgement on your rather dogmatic statement.
Accordingly, I find it difficult to believe that molecular sub group data was not collected for analysis and that nothing deeper than methylation status was collected as a rather limited basis for data collection and analysis.
In any event, we will find out who is right after the trial is unblinded and the full results are revealed.
Stay tuned.
Correction: proneural is a component of M+ not M- as I have mis-typed.
Sorry for any confusion. Typing on iPhone is a challenge with fat fingers.
Doc:
Where in the JTM or other studies is it found that the best responding are methylated MES. I may be missing something and hope I can be corrected, but I do not recall anything along the lines that METHYLATED MES responds best to DCVAX. I believe that LL and RP make reference to MES but do not further delineate it. With respect to other molecular groups, it would appear from the chart showing M+/M- major groups which then link the molecular sub groups, that pro-neural is a major component of M- where the JTM article showed, albeit blinded data, that the M+ group responded especially well. The question is why. This seems to be unexpected according to previous UCLA studies. The question is then why?
Wrt to Methylated MES, you may be right but there seemingly is no data to back it up unless I missed something. Then the chart is wrong in stating that M+ is proneural. However, I suppose an argument can be made that methylated MES is relatively insignificant and therefore M+ is predominantly pro neural and Meth MES de minimus. However, it does not appear that LL/RP were excited about a de minimus slice of MES but rather the entire sub group that was responding well to the vaccine. JMHO.
Why is the SAP being re-written and why is there continuing vagueness of the timeline for data lock("progressing" toward whatever that means)/unblinding? I believe this is essentially the question you are posing and I am attempting, poorly it seems, to respond.
Allow me to dumb it down:
1. The trial is blind;
2. Until unblinded, no one knows for sure whether the primary/secondary, indeed any, endpoint results have been sufficiently achieved in order to warrant reg approval;
3. LP, at the ASM has explicitly declared that they have the "petal to the metal" and have many experts and cannot throw more money to make the whole process go faster;
4. Further, with all these experts, LP has much more info than outside shareholders have and thus have a pretty good idea as to the likelihood of meeting the primary/secondary endpoints;
5. Due to pseudo progression, cross-over and other factors, all these experts have serious concerns that these endpoint results may likely( although they are not sure)fall short and not be SS;
6. Accordingly, LP and her advisors are focusing upon the OS milestones, length and thickness of the long tail as well as its composition(for example, how much M+, M-, cross over arm, non-cross over arm,etc.);
7. Therefore, dragging of feet to finally go to data lock and providing clearer timeline guide lines. They probably feel that a grand slam homerun on the milestones/tail will overcome any failures on the primary/secondary endpoints;
8. Thus, the delay in ending the trial as they want to have enough data to make the results "undeniable" as LG stated on 4/27/18;
9. They want to re-write the SAP in order to shift focus on the OS milestones/ long tail and diminish importance on the primary/secondary endpoints which may not be appropriate for immunological approaches. After all, the original SAP was written before the importance of long tail in immunological approaches was entirely appreciated;
10. They probably had many give and take discussions with the FDA ( and other RAs) and while they have the FDA's understanding and a more flexible attitude, the FDA has probably told NWBO that while long tail is important they will look at the totality of the data within which to consider reg approval.
Thus, bottom line, I think that the foregoing implies that the trial probably did not achieve unambiguous results for primary/secondary endpoints and that NWBO pretty much knows that--but not for sure. Thus, the overwhelming focus and reliance on milestones/long tail. Thus, the continuance of the trial to have enough mature data to make their approval case undeniable and the re-writing of the SAP to shift focus from the primary/secondary endpoints to OS milestones/long tail.
My feeling is that even though the primary/secondary endpoints may not be unambiguous or have fallen short, the long tail results will be homerun enough to warrant approval, especially if results are comparable to those of Optune and have the added benefits of QOL and long tail info and results.
I hope this exposition clears up the confusion engendered in my previous post on this matter.
I do not discount the possibility of your conjecture. I, too, anticipate positive results and subsequent approvals. The data we have points to it. The reg environment points to it. Optune points to it as a minimum bar.
So, yes, I agree to the possibility.
Correction: the trial is BLINDED
The trial is unblinded. No one knows anything for certain until unblinding takes place. So why would they re-write the SAP and continue the trial even now while "progressing" toward data-lock?
As LP has emphasized at the ASM, they have many experts and stats people advising management. They have much more info than shareholders do. So we can only speculate.
I believe the reason for re-writes and delays is that the primary and secondary endpoints likely have not been met. Their experts are advising them that the ball game is played with long tail and milestone OS. That is where they must hit the grand slam such that approval is undeniable. While in their discussions with the FDA the importance of these latter evaluative criteria take greater importance when considering immunological therapies, the FDA will look at the totality of the data with, of course, no guarantees on the weighting of the various factors involved when considering approval.
The foregoing, it seems to me, is the most likely reason. It does not necessarily point to failure if the primary/secondary endpoints are not met but it is critical that OS milestones/long tail and its composition provide undeniable results.
It should also be noted that long tail data is important for NICE/QALY and that DCVAX is at least as good as Optune but with added benefit of QOL and long term survival.
Based on that, odds for approval with a better reg environment, are quite favorable. I would not bet against it.
JMHO.
Sorry Senti but I disagree. I may not be a good lawyer but if there are areas that I cannot discuss, I say so bluntly. If I can address to some extent the reason why without giving hints, then I will do so. As a lawyer, personally, I would never use MB members as a forum for company discussions nor would I express any personal opinions because they would merge with the viewpoint of the company that I was representing.
IMHO, talking to Internet MB members is extremely dangerous and there is much room for perceived misinterpretations. Better would be periodic updates but taking calls/emails from unknown MB denizens is not only dangerous but also very time consuming. LG has better things to do and he is wasting time and money. Certainly a more enlightened way of communicating with shareholders/investing public can be found. LG is the wrong guy for this job. That is why they are hiring a new IR guy so that LG can hopefully be better employed with less(pun intended) public contact. He is just not good at it and IMHO unnecessarily exposes the company to unwanted liability. Hopefully the new IR person is more skilled, creative and experienced. From my own personal experience with Les, I think NWBO can do better and with this new appointment I think they finally realized this. JMHO.
LF:
You may be right. However, if memory serves me correctly, I believe sometime back, LP talked about molecular sub-groupings as part of "many chances to win". Of course, she was aware of the fact that UCLA studies addressed these groupings. It may be that earlier patients were not so classified just like, for example, methylation status for 38 initial patients, but subsequent patient entries noted sub molecular categorizations that could be analyzed. There was much discussion concerning MOA and the classification of sub types into immunogenic and less immunogenic. MES was very immunogenic and thus more likely to respond to SOC and DCVAX. Soft tissue sarcoma was also so classified. OTOH, pro-neural was found to be less immunogenic but not as aggressive as MES and less/not responsive.
So it is possible that these sub grouping classifications were noted later on in the trial. Whether results from such data are SS is of course unknown. Accordingly, I tend to think that there will be sub group molecular analysis. These sub groupings became well known during the course of the trial which due to its length and breadth is a mother load of data. Hard to believe that molecular sub grouping data was not accumulated for analysis given what was known. JMHO.
Abeta:
I have written quite a few posts on this. Bottom-line is that I cannot be sure.
Please allow me to summarize. If you look at the methylation categories and sub molecular groups associated with M+(methylated) and M-(un-methylated) in the chart with all the info on NWBO prior to the MB, you will note that Pro-neural makes up M+ and M- is composed of MES, classical and neural. If this chart is accurate, then it appears that DCVax works effectively on M+ which means pro-neural. However, in prior UCLA studies it was found that the vaccine had little to no effect upon pro-neural. Rather, it was found that the vaccine was very effective on MES which is highly aggressive but very immunogenic and composes between 30~50% of all ndGBM, a rather significant sub molecular group size. However, from the JTM data it appears that the vaccine has some efficacy though blended data on M-despite the fact that it contains MES and that it is a very large sub group. The vaccine also appears to work on classical which is also in M-. Neural is relatively insignificant.
According to previous studies and the statements by LL and RP, it appears that DC VAX is very effective on the relatively large MES group yet this does not appear to be so according to updated SNO data where M- at OS36
survival was at 14.3%. It may be that the MES group worked very well but the overall M- survival percentage was pulled down by the classical sub group which could compose about 25~30% of all ndGBMs(EGFRviii), in which group the vaccine appears to be less effective.
Other than the M+/M-groupings, deeper dives into the molecular groupings have not been addressed in the JTM or SNO updates or in the Rago paper. Hopefully these seeming anomalies will
be answered by unblinding.
Hope this helps.
If you read his disclaimers carefully, then you know that Dr. Rago actually does state that he is invested in NWBO shares. He has skin in the game and has put his money where his mouth is. I think that is very positive. JMHO.
My views on PFS are quite simplistic. PFS is used as a surrogate for the gold standard, OS. Obviously long tail(and its composition) is the most important part of OS alongside milestone markers. When you have actual data, you do not need to rely upon the surrogate which is employed as a way to shorten the trial. However, in immunological approaches, PFS may not correlate well with OS.
Further, it is within the realm of possibility that although there may be earlier PFS eventing, this is not necessarily a bad thing. Due to the way immunological approaches may work, as the therapy begins to take hold in time, progression rates may be slowed and perhaps reduced to zero thus contributing to increased OS. What would be interesting to see is a comparison of the deltas between PFS and OS eventing. JMHO.
My view is that they won't submit an abstract. They may go to Industry Theatre. They want to keep their options open and most importantly, keep everyone guessing. JMHO.
Not really. I asked Les a specific question wrt to a possible acquisition. His response was that there is...."nothing off the table." For the right price and conditions, it is certainly well within the range of possibilities.
However, this is not a priority. What is a priority is getting DC VAX L across the finish line and to approval. At that time, value will be better appreciated and things will take care of themselves.
Essentially, LP has a value in mind, which may be achieved in a number of ways whether by partnership, going it alone, a B/O, etc. Time value of money is, of course, part of the equation.
So I don't think JJ was signalling anything wrt to acquisition except that as a possibility, due to share price among other factors, we are not there yet. Pretty obvious stuff. JMHO.
I don't know either and cannot explain it. However, the authors of the JTM stated, if I recall correctly, that there were no significant differences, year to year, enrolment tranche to enrolment tranche. Rather strange and yes it would appear the 108 did better. In many prior posts, I raised a number of other anomalies including this one which I won't regurgitate.
Bottom line--I don't know but then I don't know a lot of things. LOL.
With all due respect Doc, your convoluted labyrinthian expositions defy Occam's razor. I don't know how much plainer management can make it: there were no manufacturing changes, period, full stop. All this conspiratal musing and "art" wiggle room to justify a statement that no, wink, wink, there were no manufacturing changes strains credulity. I rather take them at their word. Are you saying Les "misrepresented"?
No money. First things first. Get L approval. Then they will get $$$$. Till then, I don't expect to see combo trials. As LP said---small company and don't have the resources.
I am a big boy. I can take it.
But.............I can confidently tell you there is no move tomorrow. I am pretty well connected and there is no sign of any move tomorrow or for that matter within the next several weeks. Beyond that who knows? But don't expect info as a result of conferences and ASCO. Won't happen.
RK is likely correct. Getting to data lock with all the sites and getting sign off from 4 RAs on the SAPs is a many months process. As I have predicted, and in line with RK's outside time line of November, 2019, I think data lock is in the latter part of 2019/early 2020 with top line to follow thereafter.
The modus operandi for NWBO management is silence. That will continue until data-lock and/or top line announcement later this year. JJ's ameliorative comments that the picture will be clearer in 3-4 months does not mean that management will PR it or otherwise talk about it at conferences, etc. We are in for more of the same until the latter part of 2019. Unfortunately, this will cause the pps to bleed. Fortunately, it will give intrepid longs an opportunity to purchase more shares at unprecedented low share prices. There is always a silver lining or making a sow's ear into a silk purse. With NWBO, you gotta have a sense of humour.
So if I understand you correctly, NW has not traded(sold or bought) because he is prevented from doing so due to inside information.
I think that biosect answered that issue,i.e., that funds have a way around this. I am sure that it is rather common that funds and a fund manager, in doing DD, may come across, and perhaps inadvertently so, inside information. However, they do not want to be hamstrung by this and so have ways and means to get around it.
However, it does appear odd that if unrestricted, NW would not have sold on the way down. It could be within the realm of speculation that the information he did have, however he came to know it, was so compelling that he held on in fear that if he sold, he might miss out on a quick and huge updraft. Who knows? Obviously, we are not privy to the whole story and the principals ain't talking.
Gopgrip, I respectfully say that you are mistaken. What was said was that they did not sign an NDA that prevented them from trading. In addition, they said that upon occasion they come across "inside" information that may prevent trading, or words to that effect. However, they have not clearly stated that in the case of NWBO they are so restricted. I agree with biosect's explanation. I also think he saw value initially and saw nothing "untoward" with NWBO, which are rather conservative statements. He was an "active" shareholder and has at least implicitly admitted that his fund gets more intimately involved with some companies in their portfolios. NWBO was one of them. I do think he was behind an attempted takeover which failed. He then became a "passive" shareholder but held because ultimately from his own DD NWBO may be the little engine that could. Anyway, his investment is now relative peanuts to his fund's overall value. If it ultimately pans out, he wins. He has already lost over 95% of his investment, so holding on, if there is a calculated chance makes sense. No big deal to him right now. If it hits big, with his stake, he snatched victory from defeat. A real genius after all. JMHO