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Thank you. You are one of the few posters who I greatly respect and am appreciative of your response. Good luck to you and to us all---patients and investors.
Respectfully,
U
We really do not know what LL meant. I believe you are incorrect when you claim that she referred to early enrollees versus late enrollees. Rather she was referring to early vaccinations versus later vaccinations as a result to crossovers upon eventing and comparing the two. In fact, it may be that there is no significant separation which is good for patients but not so good for the trial.
When she said that patients are living longer than expected, what does this mean? Does it also refer to the non-crossovers? Perhaps as an overall group, patients are living longer than expected but this could also include the non-crossovers which are about 14% or about 46 patients. She would not know about these patients. And what is she comparing this expectation to? The usual 15-17 months mOS? She probably did not mean long tail or 36 months at the time she made the statement. WRT to M+, the comparator was 21.7 months mOS and blended was 34.7 months. Looks good with the comparator chosen for the article. But......there are studies that have SOC at 29 months or even 34 months. Are these outliers? We have unconfirmed ideas what comparators will be chosen and those selected will be extremely important to success or failure of the trial.
So, you can now see that long tail/36 months is extremely important and the reason why LP and the SAB are dragging the trial out:
1. Most probably, due to pseudo-progression, I believe that even with adjudication, the primary end-point of the trial will be missed. Does this threaten success if other sign posts are positive? In my opinion, no. Firstly, OS is the gold standard and PFS is used as a surrogate. By now, NWBO has enough data for OS and long tail. What is more important is the "distance" between progression eventing and OS. Secondly, even though there may be earlier PFS eventing than expected, it may be that as the vaccine effects begin to take hold even after progression eventing, the rate of progression is slowed and in some cases, perhaps to zero. So, failure in the PFS primary end-point is not a killer to trial success. But it certainly is a concern, especially if other markers are not significantly positive.
2. WRT to OS, it appears that this is more promising especially when you look at bended numbers both for M-(19.8 months) and M+(34.7 months). So, paraphrasing the words of Dr. Ashkans, the vaccine appears to help across all groups to a greater or lesser degree. Much more so wrt to M+ than M-. However, success is largely dependent upon the comparator used. If it is a combination of crossovers plus non-crossovers as control, there may be confoundment and extended survival. We just don't know. Further, there are studies that show control to exceed the commonly referred to the overall 15-17 months more commonly quoted. The success in M+ which appears to be made up of predominantly pro-neural seems to contradict Dr. Prins'/LL's earlier findings that pro-neural seems little or not affected at all by the vaccine and chemo/rad due to its being less immunogenic than say mesenchymal which is found in M- and was found to be a better responder to the vaccine in earlier studies. So, in summary, there are question marks wrt to OS as the secondary end-point.
3. Thus, one can easily understand the focus on 36 months and long tail out to 60 months and beyond. LP stressed, in so many words, that this is the new gold standard for immunological therapies like DC VAX L and that this is the criterion that investors should be focused upon. If 1 and 2 above are not successful, mixed or ambiguous, 36 months/long tail need to be home runs. These probably need to be in any event. There is no second chance. Once they unblind, they either hit it out of the park or it is over. Forget D. They want it to be undeniable(note LG remark on April 27, 2018) on at least the 36/longtail not only for reg approvals but for QALY/ insurance purposes as well---and not to mention relatively quick reg approvals. A lot is at stake here. It is digital. There is no in between. Thus, the odds may be that the trial drags out beyond November and into next year. Neither good for investors(more dilution, uncertainty and pps devastation) nor patients(obvious if it works). November is a critical month. Can LP/LG hide an accounting at the ASM assuming they don't delay it indeterminately? JMHO.
Meirluc:
Nice try but very difficult to provide a rigorous mathematical reverse engineering to demonstrate 23.1 months from the info given in the publication. As I raised in a previous post, there are quite a few issues that are left hanging.
While the blended results for M+ and M- are rather good, it really depends where you place the control stakes for the deltas. Further, LL's statement that all patients seemingly live longer appears rather disingenuous. Does this pertain to the non-crossovers as well? She could not know that. I do believe that crossovers may be living longer but without resection and a new lysate, to what extent if any is unknown. I think if LL said "On the whole" patients are living longer than otherwise expected" is a preferable statement as compared to.."All patients......."
Given that the ITT trial population was divided into methylated(M+) and non-methylated(M-)--except for the first 38 patients enrolled at the outset of the trial--and that blended mOS for M- was 19.8 months and 34.7 months for M+, how arithmetically was the overall 23.1 months mOS calculated? I calculate an overall mOS between 26-27 months. Perhaps someone more mathematically inclined can do the arithmetic exercise. TIA.
Can you reverse engineer how the 23.1 month mOS was calculated?
TIA
Yes, indeed, and I calculate conservatively that overall Tx mOS is at least 28 months. If SOC is 20 months, then the delta, overall, should be in the 8 month range. While a primary endpoint, mPFS would not matter as much since it is used as a surrogate. Even if eventing were occurring earlier than expected, the delta between that and OS would be important. Additionally, earlier eventing could be followed by a decreasing rate and perhaps decline to zero as the long term effect of the vaccine took hold. Of course, success or failure is highly dependent upon the placement of control/SOC placeholder. JMHO, but I think 20 months is rather aggressive.
While I am reasonably optimistic that DCVAX L will ultimately be approved, the JTM publication does raise some questions. Perhaps some of our enlightened MB posters can shed some light.
1. The ITT of 331 patients was allocated to two main groups: Methylated(M+) and Un-methylated(M-). The M+ group was stated to be 39.6% of this total where N=131. However, 38 of the earliest patients were not classified in either group. But the remainder was apparently allocated to M- where N'=200. This would imply that all of the 38 unclassified patients were included in the M-group. In fact, the number of M- is 162 patients. Thus the total of the classified M+/M- group is 293 patients. Accordingly, M+ constitutes 44.7% of the classified group.
2. Additionally, the blended mOS of the M- group was 19.8 months. The blended mOS of the M+ group was 34.7 months and yet the overall blended mOS was stated to be 23.1 months. I do not claim to be an accomplished statistical mathematician, but I come up with a blended mOS of between 25-26 months. Tx would come out as approximately 28 months. The success of the mOS end point obviously depends upon where the control stake is placed but assuming 20 months, the delta would be 8 months. Perhaps someone more mathematically inclined can point us in the right direction but I think the mOS of 23.1 months is a bit low to say the least.
3. According to the graphic on iHub MB, M+ is predominantly composed of pro-neural. In prior studies, Robert Prins found that DCVAX had little to no effect upon this molecular sub-group. This was because pro-neural is less immunogenic as opposed to mesenchymal which was much more susceptible because it is more immunogenic. According to the extant literature, mesenchymal is the largest sub-group and accounts for between 30%-50% of stage IV glios. Classical is also found in M- and accounts for approximately 20%-30% of stage IV glios. Both of these sub-groups respond to DCVAX, mesenchymal more than classical, due to their immunogenicity. Mesenchymal is especially aggressive which appears to be borne out by the SOC mOS of 12.7 months for the M- group. The blended results, however, seem to paint a somewhat contradictory picture where M+ appearing to be predominantly composed of pro-neural according to the MB graphic is much more dramatic in its blended results. I have asked Dr. Boynton for his opinion on all this through several emails but to date he has not responded. Perhaps it is much more complicated, but IMHO this was an unexpected result.
4. It has been averred that it seems as though succeeding enrollment tranches after the first 38 have witnessed continuing improvements and particularly with respect to the final 31 patients all of whom were placed in the Tx group. This is confirmed by the JTM. There is speculation as to why this was done, however, there are no hard facts. There may have been tweaks to the process, however, the authors of the article did not find significant differences between succeeding enrollment generations. Les has been adamant that no changes have been made in conversations with me and he called MB speculation wrt this "nonsense". This appears to be contradictory but perhaps minor tweaks could have been made resulting in improvements without requiring equivalency testing. Accordingly, Les was walking a fine line with his adamant denial. I just don't know.
I have other concerns and comments but I have rambled enough on this tome.
Thank you Senti for the confirmation. So essentially, out of the 300 patients about 200 were Tx and 100 were control in round numbers. The control remained the same and 31 were added to Tx. This was 11 more than the approximately 220 Tx out of the 331 and 11 less than the 110 control.
As I said, this appears to be rather encouraging. I would surmise this was at least part of the back and forth with the FDA and the final allocation to Tx done either in agreement with or by mandate of the FDA and is suggestive of ethical considerations because the vaccine...........
Senti, what you aver is possible but not confirmed fact as far as I know. Of course, I could be mistaken. It has happened before.
Firstly, a 2:1 ratio for Tx/control on the original 348 would yield 232 Tx and 116 control, not 110. So under your assumption of first filling all Tx(232), they would be short 17 patients in control, not 11, based upon 99 patients allocated to control. A 2:1 ratio of Tx to control on 331 would be 220Tx/110 control(+1 to either arm).
Anyway, overall, they were short 48 upon an enrollment of 300 patients. They enrolled 31 more patients and were short 17 of the 348 total. Instead of enrolling all 31 in Tx, they could have chosen to proportionately enrol the remaining 31 patients among the Tx and control arms. The reason why they would have chosen to enrol only in the Tx arm is obviously important. And it would have been done only with agreement with the FDA; or enrolment in the Tx arm may have been mandated by the FDA for possible ethical reasons. This is all supposition and not fact. In keeping with the trial protocol, they could have allocated 220 to Tx and 110 to control(+1 to either arm). The crossover arm was created in order to facilitate enrolment.
In any event, is it a fact that 232 patients are enrolled in the Tx arm(and 99 in control)? If, in fact, the remaining 31 were all allocated to Tx, this is possibly suggestive of efficacy one would think.
Best regards,
U
Senti, just curious but why do you think these last 31 patients were all placed in the treatment arm?
TIA
Sorry, Senti but that seems a stretch. I am 99% certain that her husband must have been aware of her affiliation with NWBO and the basic mechanism of DC VAX requiring tumour tissue. Likely she was conscious and knew of the diagnosis before going into surgery. I am quite certain she would have asked.
However, why not save tumour tissue? What does she have to lose by doing that? It preserves her options on what therapies she can pursue after surgery. Not saving tumour tissue does not make a lot of sense. Unless.......she did not think it works. But very strange indeed. You would think they would want to study it after taking it out. Maybe the whole thing was just botched. Who knows. Perplexing to say the least.
Marzan:
I hope you are right, but unfortunately, I do not believe any partnership or BO is on the horizon. Everybody is waiting on results. They need to be stellar, otherwise the pps will not rise appreciably and dilutions would become extremely painful. NWBO would quickly lose support and the shorts could easily and inexorably drive the pps down.
This is why the trial has not been unblinded and may not be until sometime next year. The data will be carefully analysed, sliced and diced all to best advantage and all this will take time. I would not be surprised if we finally get top line on or about ASCO 2019 or even later. The pps will be devastated if they wait that long but the plan and hope is that the long tail is stellar and confirmed and the end points SS with enough separation. Such results could recover, if not all, at least some significant amount of the devastated share price. Unblinding too early with mixed and overall middling results spells the end of NWBO. Faced with that fear, LP and the SAB are continuing the trial in hopes that by doing so stellar results ultimately will pan out. Otherwise--the end. They have essentially just one chance and they will go with the lesser of two evils--prolonging the trial. JMHO. Stay tuned.
LP is working on funding--non-dilutive. Large NWBO investors have warned her no more dilutive fundings until the pps appreciate considerably. She is working on selling Sawston. She has several bidders but not closed yet. JMHO.
LP is NOT working on a BO or partnership. Much too early for a BO and big P will not pay anywhere near her asking price now or even if DC VAX L is approved. I believe the best BO offer would be at about $1/share, otherwise she goes it alone. Commercialisation will be the big issue and it will be years before the pps reaches even $2-$3/share assuming she goes it alone.
The above assumes good but not really great unassailable results. The reason the trial is taking so long is to get the best unambiguous results she can and that is focused on the long tail. She needs unrestricted approval, not a limited approval for some sub group. Without stellar results, the stock will remain sub-dollar and direct will have no value until stellar clinical trial results. As a number of posters have come to realise, this is a multi-multi year investment. The journey will continue to be long and bumpy. Again, JMHO and hope that I am wrong.
Doc:
You have averred this about D quite a few times. Why are you so excited about D? I don't recall anyone else quite so optimistic.
I do not believe that LP would ever sign a term sheet now or that BP would make any offer. It is too soon. LP has two views: buy now with no reg assurances at a high price or wait and buy when reg approvals are received at a much higher price---your move. BP is not going to pay what LP wants now for blended results. Never happen. They will wait after results. If results are mixed, probably no BO or one at a low valuation for maybe 1-2 billion tops. That's why LP is stretching the trial in hopes of blockbuster results. These are in the long tail and its composition. There has to be confirmation that, as Dr. Ashkans says, the vaccine helps across the board but to varying degrees for broad reg approval. If that happens, then BP will talk. But there is still risk and the burdens of commercialisation. Thus, I believe if there is a BO in those circumstances, it will be in the 5 billion range, relatively soon after results/approval. However, I think LP is stubborn and believes NWBO deserves a much larger valuation. Hence, no BO anytime soon. Even with approvals, I doubt the share price will be over $3 w/o a BO and that won't happen right away. JMHO.
Doc:
Nonsense. It is clear that competitors are way behind. And many don't believe this is the right path. And it is naive to think that serious competitors haven't looked at or are otherwise unaware of the research and path taken by NWBO. What NWBO is attempting to do is extremely complex, difficult and time consuming not to mention expensive. BP, with all its resources in hand, has chosen not to pursue this same avenue. It is just too difficult and better to buy it rather than emulate, if successful. It just does not fit the business model.
I believe that a BO could happen tomorrow if LP were to agree to a couple of billion. Pocket change to BP. The reason a BO at this price won't happen is that LP would reject. Anyway, BP would NEVER offer 2-3 billion. Why? Because if LP accepted at this "low" price, they would smell a dump and something rotten in Denmark. So a buyout won't happen anytime soon. This could change if DCVAX L results are unequivocally stellar and then BP could see the potential of DC VAX D. But to pursue this now from relative scratch and to surmount all the research, reverse engineering, resource requirements, legal, regulatory, etc. moats---nope, not likely. Best to buy as cheap as possible and that is what has been pretty obviously orchestrated.
Further, if you can come up with the DD all from public info, you don't think BP, etc. cannot do the same or better in a fraction of the time with all of its resources? Do you work in the field? Are you an "insider"? What makes your DD so special and unique?
Practically speaking, NWBO has built a big moat. That has been the strategy all along. To most of those of us invested, we have very good reason to believe in the success of the science and manufacturing. Others less interested without skin in the game, take an opposite view. The market at large needs education to realise value which is not easily duplicated. Saying you know something which others likely don't which could impact competitors and buyouts, etc. in an important and far reaching way smacks very much of Alice in Wonderland and fairie land. Easy for nefarious forces antithetical to NWBO interests and valuations to attack and debase. Again, if you have something, let's see what you have. You don't need to spell out a blue print, which in any event I don't believe you can do. Otherwise, it is best to remain silent unless you don't care about your credibility. Best wishes to you, too.
Agreed. I, for one, would be deliriously happy if we can get a BO for $3/share. I think that this is reasonable and achievable. But $8-$15? I am afraid not in our lifetime. JMHO.
Really? A big buyer waiting? Is this your opinion or an "inside" fact that you know? Please stop with the "hints" Doc, there are too many on this board. JMHO.
Doc:
You are one of the posters that I read without fail. Your insights are pretty spot on and worth my time.
Having said that, you have stated several times that your DD convinces you(and most probably others if they did a similar DD from publicly available sources) that DC VAX D is the real value. However, for some reason, at least not apparent to me, you are not sharing this convincing DD unless there is a threat that the company may be sold for relative peanuts and that, accordingly, this DD that you possess would be made publicly available to thwart any under-"realisation".
Sounds very clandestine and mysterious. Not clearly revealing what this is(and not hints which are difficult to evaluate, just like a lot of "hints" from NWBO, Journal, etc.,) relegates your statements to the same BS pile as those made by pumpers and bashers. It besmirches your credibility and right now you have a lot at least for me. Unless you are willing to come out with it, please don't go on about this "secret" DD. Either say what it is, and if it is convincing what is the harm of revelation as it will keep everyone honest, or just keep quiet. JMHO and 2 cents.
The drug is for rGBM, monoclonal and EGFR receptor. NWBO is for nGBM.
While I don't say you are wrong, I believe that if there were a buyout tomorrow, NWBO could do so for $3 billion or roughly $3/share. However, LP would rather go it alone than sell at that price. BP knows it. Go big or go home. LP is not here for "pennies on the dollar" as it were. JMHO.
Al4door:
I don't think that LP threw longs under the bus as you call it. The decimation of the share price was caused by lack of reported results. This was all FUDDED by investors going the other way and perhaps illegally. Right now, we have no smoking gun proof. LP and company decided that silence was the best policy. I don't think saying anything short of great results would have saved the pps. The length of the trial and the uncertainty it has bred has been a major cause of the decimation. Obviously, vultures took advantage of all this and drove the pps lower. But LP has put her money where her belief is. Sure she has monetised Cognate and maybe, to some extent, it was on longs' backs, but LP is not stupid and is not going to waste good money after bad if she does not believe that the odds are in favour of success. She has a lot more info and experts versus the general investor and has skin in the game. These small biotechs are risky. Attacks are common with investors going the other way. And there are good arguments for it. I am betting in favour of success. IMHO, I think that argument is better. LP's willingness to put money in regardless of how she may have raised it has got to be a positive. Yes, she has a better deal than most retail, but she stepped up to the plate, so I don't really blame her for getting a better deal. If she succeeds, so do longs. We may not get the $100, $50 or even $20 we had hoped for but at my base investment, and I averaged down considerably, I would be happy with $3 which is reasonable if DC VAX L is even somewhat successful. I don't like where the pps are and I am as frustrated as the next investor. The pub is certainly very encouraging and so is the support from a number of physicians/scientists. I think that the pps are severely undervalued. Shorts and bashers don't. Differences of opinions are what make a horse race. I believe that DC VAX L will receive approval and it will be broad as it appears to work across all groups to a greater or lesser extent. Each tumour(s) is different and personalised. That is what DC VAX L is all about. JMHO.
Completely agree.
Very interesting thought!!!!
From my experience, the SEC has loose dentures and wakes up late in the afternoon.
Hi Abeta:
Please see Flipper44 post about April, 2018 study and my response. Hope it helps you.
Regards,
UM
No I did not read that April 2018 study. Thank you for bringing it to my attention. I waded through it and it will take many readings for me to let it all sink in. However, generally, I agree with your take. The M+ cannot be composed of all pro neural given that this sub group constitutes about 13% of all stage IV glios. Hence if you assume that all the pro-neural are initially methylated(and subsequently evolve to mesenchymal which is M-), then the balance would logically be distributed among the other 3 sub-groups. This makes sense because the other sub-groups are predominantly M- but not 100% which implies that some or all of these three sub-groups are, in some portion, M+. And pro-neural, retaining methylation(low G-Cimp), would be susceptible to DC VAX L. So that works and with methylation(less MGMT expression) interfering with the cell repair mechanism would account for the longevity. DC VAX L appears to extend this longevity dramatically. I definitely agree with this and it all seems to hang together.
I also buy the pro-neural transition into MES and unmethylated. This may account for the very high percentage of MES approaching 50% of all stage IV glios. I agree with you that LL/RP may have been premature on the pro-neural because quite likely, pro-neural was not as well characterised at that time and the sample being small may have been skewed. Accordingly, the article you cited reinforces the hypothesis that DC VAX L works across ALL groups some better than others and this means M+, M- and the molecular sub-groups MES, CLASS, PRO and N. And you can see this from the pub as I have pointed out in previous posts. And... you would expect M- to be susceptible to the vaccine simply because of the high incidence of MES. Possibly, the difference in results, i.e., deltas for M+ and M-, is due to the fact that T-cell infiltration and Treg down regulation for M+ may have more time to infiltrate/destroy cancer cells than seems to be the case for M-, even though MES, for example, presents more antigen targets and is more immunogenic. Just a WAG.
But overall, it seems to me that the study you cited only serves to support the view that DC VAX L works and that it works across ALL groups as Dr. Bosch said. Thanks for bringing this to the attention of the board. It is an extremely important study and I think "good news". I respect and admire your research skills and much appreciated.
If the ITT population is roughly distributed as in the chart you put up, then pro-neural would be about 50 patients, however, N=131 or roughly 45%. What makes up the other 80?
Hi Marzan:
I think it is a sale/leaseback of Swanston. Values are way up and they don't need to own it. Non-dilutive funding and enough until results and maybe a combo depending upon how much they get. The piecemeal funding was just enough to get them to closing of sale IMHO. Just a wild-assed guess but seems to make sense so they can be free of funding overhang for a while until results which I think they believe are good and will result in a sustained rise in the pps.
I just don't think that they will get a partnership on their terms just yet. All will change on good results. JMHO.
Hi JR:
You can look at it this way. They get nothing if they are not successful. If they are, so are longs.
Hi Abeta:
The majority are unmethylated(M-). The March, 2017 study calculated M+ to be 39.6% of the ITT or 331 patients. However, 38 early patients in the trial were not classified as to M+ or M-. Hence the KNOWN classified populations of M+ and M- were 131 and 162 patients respectively or a total of 293 patient. Of the KNOWN population, M+ is 44.7% of 293. Having methylation promoter means you are in the M+ group. What it means is that methylation interferes with MGMT over-expression and cellular repair. That results in longer survival. M+ is characterised by pro-neural and that sub-group which is less than 20% of all stage IV glios is known to have longer survival. You can note that in the publication where control in this M+ group is 21.7 months and the blended mOS is 34.7 months.
M- is unmethylated, i.e., without methylation promoter, and thus sub-groups in this classification are more aggressive. MES is predominantly unmethylated. It can constitute up to 50% of all stage IV glios. LL and RP reported from their own clinical findings that the vaccine appeared to be most efficacious in the MES sub-group. The reason, they believe, is because this sub-group is very heterogenous and presents many antigen targets which plays into DC VAX L's strength. Secondly, MES is immunogenic which means that the micro-tumour environment is less immunosuppressive allowing more time for T-cell, etc. infiltration and T-reg down-regulation. The vaccine also appears to be efficacious for CLASS, also in the M- group, although less so as compared to MES. As you may recall, CLDX's peptide vaccine was focused upon CLASS with EGFRviii mutation in a patient population having HLA1/2 immune systems.
From the publication you will note that the vaccine appears to be quite remarkably efficacious in the M-group. Control mOS is 12.7 months and blended is 19.8 months. The delta to BLENDED is 7 months. For TX, it would be over 8 months. Remarkable.
For the M+ group which is composed of pro-neural, I am in the dark as to why the vaccine appears to be so effective. It may have something to do with G-Cimp status. However, LL and RP found that the vaccine was not efficacious for pro-neural as a whole, so I cannot reconcile the two results. There is something missing and that is why it is an anomaly, at least to me. I think it is safe to say that the long and thick tail will be made up of M+ predominantly with some MES thrown in. I don't think that cross-over will significantly affect the trial, but even if it does, it is not necessarily a bad thing. It could very well mean that the vaccine is efficacious for rGBM and the trial WAS NOT DESIGNED FOR THAT. It may be that upon recurrence, the tumour(s) mutate to MES where the vaccine is more effective. And this might occur in spite of the fact that a de minimis number of patients had resections post recurrence! Obviously, all this can be analysed upon unblinding. Stay tuned.
Hope this helps.
As in my post in response to Abeta, I believe spring refresh is last data collection. No argument there. I do hope you are right, but my gut tells me otherwise, i.e., we won't know anything until early 2019. JMHO.
HI Abeta:
I'm quite confused myself. Don't have any answers and the March, 2017 data analysis did not correlate Mes, PN, Class and Neural. Only looked at big picture M+/M-.
But having said that, the March, 2017 data appears very promising to me. Let's look at it this way:
For M+, N=131 and we know that the blended results portend that DC VAX is effective. If the agreed upon by 69 authors historical control stake of 21.7 months is used, my calculations show that the delta to TX is about 20 months with a blended 34.7 months. Even if you use 29 months, which may be an outlier(as I think 34 months is too from a 2018 small study), then the TX is still about 9+ months. This is impressive when you consider that pro-neural is M+. So the vaccine seems to work well here. I cannot correlate this success vis-a-vis the LL/RP clinical findings that showed to them that the vaccine had little to no effect on this group. The March, 2017 analysis does not go into these weeds. So, it would be interesting to hear from LL/RP what they think.
Now turning to M-, we know that MES is predominantly in that category. We also know that the MES sub-group is relatively quite large and a large recent study indicated that MES could constitute about 50% of the stage IV glio population. Being conservative, let's assume that it is 30% of the ITT. Then, N=100 for this group. LL/RP said that they found the vaccine quite effective in this relatively large grouping. We also know that CLASS is M- and that it constitutes about 20%-30% of all stage IV glios. Again, let's assume conservatively that CLASS is 15% of the ITT or N=50. Neural is a rather small % of stage IV glios, so let's discount this group where N=0. These are very conservative assumptions and the M- N=200 approximately or about 60%. We know that M-is very aggressive and so is MES, so the agreed upon historical control stake of 12.7 months is reasonable. Blended is 19.8 months and TX delta would be around 9 months. Even if you used 14.6 months used by Bosch(I don't know why he referred to this parameter in the case of M-), the delta would still approach 7 months. Still rather impressive.
Essentially what you have is N=280 where the vaccine is effective across M+ and M- and across the major sub-groups. This constitutes about 85% of the ITT population. Effect seems to be widespread and any approval would be likely to be broad rather than limited to a particular sub-group.
Insofar as the control stakes are concerned, I believe that cross over confoundment will be de minimis for the reasons Flipper has articulated. We should have sufficient and SS separation. We also have a non-cross over group of about 14% as another evaluative control stake.
Thus, I believe the March, 2017 data portends success and the 2018 data will more than confirm this. Accordingly, I have to believe that the spring refresh of 2018 is the last data collection. They will wait till November to end the trial and we will hear results in early 2019 or in about 6 months. I am pretty certain that we won't have a funding overhang because, most likely, there will be a sale/lease back of property which is non-dilutive and enough to carry the trial to completion and to a meaningful(and sustained) rise in the pps. The ball game is FDA broad approval. NWBO wants to leave no stone unturned to achieve this goal. Failure is not an option. This is what I believe the game plan is and why LP/LG are so relatively confident. The data will be mature in a matter of a few months, IMHO.
Caveat: all the above is JMHO.
OK, Flip, do you believe that they should have ended the trial and unblinded by now? Or do you think that they will shortly announce data lock and unblind the trial before year-end? I think that they will not be ready to unblind and reveal top line until at least November. Most probably we might hear something in early 2019. They have a lot of data and will be sure to take their time in fully analysing it. I think that will take a lot of time.I don't believe they have most of it done by now.....but I could be wrong. I hope so.
If you believe the data is mature and that there are severely diminishing returns in continuing the trial, why are they delaying? I don't believe that LP is playing games, keeping the pps low so that she can acquire more shares. I don't think she and Les are so nefarious. Even if she were accumulating more shares, with the knowledge and data she has, it would be positive anyway as this shows firm confidence. Then why wouldn't the SAB give the green light and end the trial/datalock?
What is there to gain, if as you say, the trial has reached a point of diminishing returns? And that there may be a risk of poorer results by waiting excessively?
As a result of all the data and analysis thus far by NWBO's experts, and you can be sure they have looked at this in greater depth and detail than anyone, why wouldn't they unblind? If it is so obvious to you, why not to them? They are professionals aren't they? LP cannot risk playing games and delaying all the while the pps are bleeding knowing with some assurance due to the professional resources she has at hand plus all the data we all are not privy to, that the primary and secondary probably failed or was otherwise inconclusive and thus is going for a Hail Mary pass for a long tail touch down. You can bet if that were the case, there would be a lot of livid shareholders and LP/LG subject to fighting lawsuits for the rest of their short lives. They are not spring chickens. Are they hiding what appears to them to be bad or not really good news? Thus the delay? If so what do they gain? Time to think of excuses when they finally come out? I doubt it as it just is not worth it. If it is likely bad news and cannot be salvaged, best to bite the bullet now and unblind. That is what I think they would be counselled.
Did they obtain FDA guidance and acceptance in all of their back and forth with the FDA during the hold that the most important evaluative criteria is the tail despite the trial stated primary and secondary endpoints? If the tail is impressive, then approval is likely? Why did LP emphasise that the most important thing investors should be interested in is the long tail? Is that just her opinion or is that something shared with the FDA after all their discussions which I am sure took place. So why delay? Because there are serious concerns about the end points and that a SS long tail home run is the only thing that can save them? I doubt that too. The 2017 blended data appears to portend otherwise. You have 69 authors. You have Dr. Ashkan's strong endorsement as he sees this clinically everyday and has been involved for 7 years with DC VAX. He is no fool and would never risk his reputation and neither would the other authors(Linda Liau and Robert Prins are authors). The physicians that were not so enthusiastic had other interests(Stupp with the helmet and Platten with CAR-Ts and he was not a PI on this anyway if I recall correctly). So what's going on here? Are they waiting for the vertical sticks(censors) to pass some important stake? I don't know and neither do you. So is the trial mature? Apparently not now according to NWBO's advisers unless they are all playing games. Stay tuned. JMHO.
Hi Abeta:
Mesenchymal is characterised by a deletion of NF-1 and a mutation of the P-53 gene. It is predominantly M-. As Flipper44 pointed out, the mesenchymal population is relatively large and a large study demonstrated that mesenchymal may constitute nearly 50% of all stage IV glioblastomas. Further, Classical is known to respond to DC VAX although perhaps not to the extent of mesenchymal. LL and RP from their clinical experience stated that the vaccine is particularly effective in the mesenchymal strain. They explained their hypothesis by saying that mesenchymal presents many antigen targets and is immunogenic meaning that the tumour micro-environment is less suppressive thus giving T-cells, etc. more time to infiltrate/destroy. Perhaps they may have been premature in their assessment but I highly doubt it. And from the publication, you can see that the blended OS is 19.8 months. Tx would be greater. The pub selected historical 12.7 months as control SOC. Bosch seems to have selected 14.7 months. Either way, the results are impressive. Classical may account for about 20% to 25%(maybe even up to 30%) of all stage IV glios and neural less than 15%. So mesenchymal could well be performing extremely well but the blended OS of 19.8 months would reflect the lesser affected Classical and Neural strains, thus bringing down the blended figure. Non-the-less, it is still quite impressive.
Tha anomaly is M+ with pro-neural. Here it appears, depending upon where you place the control stake(the pub selected historical 21.7 months but it has gone up as high as 34 months--although a small study and thus likely to be an outlier), that the vaccine works even better although Liau and Prins found that the vaccine had little to no effect on pro neural. I think that was a rather general statement and it would depend upon G-Cimp status. However, and still, the vast majority of pro-neural would not be affected by the vaccine. However, the pub shows quite the opposite of LL and RP's clinical findings in that the vaccine works even better on M- which seems to be predominantly populated by pro-neural, which constitutes about 15% of the stage IV glio population. It would be very interesting to pose this anomaly to LL and RP and get their take on it. Bosch has only commented upon the M+/M- categorisations but has not waded into the mesenchymal and pro-neural weeds. However, all of the foregoing analysis seems to point to the hypothesis that the vaccine works across all groupings to a greater or lesser extent. Even Bosch commented that the vaccine appears to work regardless of whether M+ or M-. JMHO.
That would be nice(no pun intended), but it is highly unlikely. They would need to unblind the trial to know that. That would be material and they would need to 8-K it. I doubt very much that they would unblind to NICE while NWBO continued to be blinded. IMHO, they will continue with the trial primarily for the long tail if not for separation and SS. While you may feel the trial is mature, the SAB seems to not agree just yet. They have a lot more experience, resources and data than you or I. So, in my case, I don't know that the trial is mature. I am not involved, don't work in the field and am clearly not a professional. I don't know your background but I admire your research and posts. But for now, I tend to agree with NWBO as frustrating as it is and in spite of the ineptitude of management in conveying some sense of transparency. JMHO.
I don't know that they were design flaws. They designed this 10+ years ago. Today they have a lot more information on how an immunotherapy trial should be conducted. This is also an adaptive trial. I think there is a lot of room for flexibility. Especially since the FDA required a cross over and that this might confound results. The more important criteria is the tail and its composition. I think that the FDA will be a lot more flexible in today's environment and since the therapy is safe and there are little alternatives, with any reasonable show of efficacy, this will be approved. The tail is the key and that is why the trial is continuing. JMHO.
And due to all these uncertainties and anomalies, there is no wonder that the SAB advises, at least for now, to continue the trial. There may not be enough separation or SS for OS and PFS adjudication issues, thus the extreme focus on the long tail. That is what they need to slam dunk in order to gain approval if all else fails or is inconclusive.
Accordingly, I don't see the board and Linda unblinding and ending the trial in August. At the very least it may be in November, but I would not be at all surprised if they go into 2019. Further, if they do end the trial and data lock in November, due to the heavy amount of data and the analyses they will undoubtedly do, I do not believe we will hear anything about the results until 2019 anyway.
I don't think that they will be constrained by funding. And....I believe they will be able to do non-dilutive funding. How about a sale/lease-back of Sawston? If they can do that, for example, then they can let the trial run longer to increase their odds of FDA approval. That is the ball game. CRLs, less than blanket approvals, etc. would be disastrous IMHO, so they will hold out until they feel relatively comfortable with the data they see. Remember, they have a lot more data than we have; expert statisticians; clinical trial investigators; SAB. They will be relying upon these resources and will turn a deaf ear to pressuring/threatening shareholders, especially if the financial pressure is put off by such a sale/lease back transaction. I think we go into 2019. Further, I don't believe that they will release any refresh data anytime soon. They may announce a data lock time-frame and announce that they will be analysing all the latest data in depth but no release. I think we are on hold for at least another 6 months if they can get this financing together. The business news that LP was hoping to announce in the next weeks after ASCO may be just that with no further necessity to release any other news except to say "stay tuned."
That's what it is beginning to look like to me. JMHO.
Correction. I meant to opine that mesenchymal plus classical would easily make up more than 50% of the entire glio IV population and would be predominant in the M- population.
You have made some important points that should be emphasised: heterogeneity and the not so small detail that DC VAX L may work better in some classifications rather than others but that it does in deed work across all groupings to some extent. It also makes sense that NWBO may not want to reveal which sub-groups respond better to the vaccine because they want broad label approval.
WRT to broad label approval, even if there is some limited benefit for a specific classification, DC VAX L may nevertheless be broadly approved. This is due to the fact of heterogeneity and the personal disease signatures of the particular patient. In such cases, rather than imposing regulatory fiat, it will be left up to the physician and patient to decide. Thus, broad label approval may be more likely particularly for insurance considerations. In a disease like glio stage IV, with very limited alternatives, I would think that the FDA is prescient enough to want to make this therapy broadly available.
Having said all that, and taking into consideration the "inconsistent" MGMT you mentioned and found, if I recall correctly, in the 2018 study, mesenchymal is predominantly M-. What that means precisely is open to question. Does predominantly mean 90%, 80%, 70%, etc.? We don't know. As you point out, mesenchymal could indeed make up about 50% of the stage IV glio population. Studies have shown a broad range up to 50%. I was being very conservative. LL and RP have declared that in their clinical experience, mesenchymal appears to respond much better to the vaccine. It is likely because this strain is highly immunogenic(predominantly) and presents many antigen targets. On the other hand, they found that pro-neural is largely unaffected by the vaccine. Pro-neural appears to predominantly make up the M+ group. but pro-neural makes up less than 20% of the glio stage IV population so you would think that M+ would be significantly smaller than the M- percentage(which conversely would be higher).
Anyway, the 2017 data collection showed a very robust and impressive delta for M+, dependent of course upon the historical control selected and agreed upon by 69 authors. Surely they were aware of various studies even outliers including the 2015 study stating an M+ control of 29 months. Of course, at the time of writing the pub, they were not aware of the small 2018 study where control was indicated at 34 months.
Given LL and RP comments, it is very surprising that M+ has done as well as it has given the pub's control of 21.7 months, since presumably, M+ is composed, predominantly, by the pro-neural grouping. Pro-neural is not nearly as heterogenous as mesenchymal. Accordingly, the historical control used in the pub may no longer be representative. On the other hand, one would think, with the mesenchymal plus Classical grouping which respond better to the vaccine and would constitute more than 50% of the M- population, that M- would do much better than M+. Interesting anomalies IMHO. Hard to figure all this out. Comments anyone?