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And there are protocols and procedures in place for many years that have been overtaken by new information and data overturning the older and out dated paradigms. Older and many years protocols may be right until they aren't.
Jeeze, give it up.
She may be traveling so fast that the universe is over and she never had a chance to cash in. Poetic justice, relatively speaking.
You can time travel into the future but not in the past----at least in this universe.
Yes, this is a bad one with a direct hit on Shizuoka Machi with sustained winds at about 60 m/s and 400~600 ml rainfall. My factory is fairly near an estuary and could have flooding. Moved valuables to second floor. This one is much bigger than no. 15 last month. Did a lot of cleaning and batten down the hatches. May go to my condo in Tokyo to ride out the storm as power restored quicker there than in Shizuoka. Luckily not much of anything in the refrigerator but frozen tea packets are toast if power outage. Nice country but too many natural disasters. This taifu could be a killer. Kanagawa-ken(Hakone) will be hit hard. As they say....sho ga nai.
If I don't post anymore, you will know why.
Best,
U
There is no evidence that tachyons exist. Yes, if you were able to go back in time, you would not return to this world(Stephen Hawking's cosmological barrier) but to any number of parallel ones where what can possibly happen, does indeed happen. In such worlds, not only does NWBO never announce TLD but NWBO never existed. Perhaps many investors here wish they inhabited such a world.
Many worlds courtesy of Hugh Everett.
Insofar as NWBO dates are concerned do you mean massless or meaningless? Even if you argue that NWBO dates have a little heft, they can weigh very heavily upon investors' shoulders since mass/energy exponentially approaches infinity the closer you approach "c". Jest my invested two cents which I hope approach infinity as the NWBO rocket blasts off. :)
Might also be true of "basic investing" at least insofar as NWBO is concerned.:((
Yes, another way to look at it.
Yes, no matter how fast we go, if the goal post is moving at "c", the goal post recedes from us at the speed of "c".
Some speculation---and I stress speculation---on the SAP.
In my experience as a regulatory attorney(involving the FCC, not the FDA), it appears that regulatory agencies have their own agendas and in reviewing and rendering decisions desire broad leeway without committing or seeming to commit to those whom they regulate. Perhaps nothing new here and even obvious to all.
Accordingly, it is my speculation that the RAs are not going to "bless" or otherwise give any assent or even guidance wrt the SAP submitted to them by NWBO. I believe that the RAs, after a rather cursory review, will essentially and simply tell NWBO...."Let's see what you got and what the data shows." I don't believe they will go much beyond that.
Accordingly, I don't believe that RA "blessings" or "comments" on the SAP submitted will be a significant pacing item. I am reasonably certain that with their many contacts with the RAs, NWBO knows the regulatory game pretty well by now. They pretty much "know" that the foregoing reaction is most likely. They may still not have submitted the SAP to the RAs by now and are using silence and even innuendo that it is the RAs who are "dragging" their feet, not NWBO, giving NWBO an excuse and even more time to delay TLD in the name of dragging the trial out further.
Just a thought and a concern that TLD may not be announced in 2019. Are they pointing to ASCO 2020? What happens to the warrants? Do they expire "just like that"? Kind of scary and not such a bizarre thought after all. The games frustrated minds can play!! JMHS(peculation).
Yes, too bad he won't be the permanent head of the FDA. JMHO.
This interview is just plain outstanding and exhibits the excitement by the "common man" on a therapy which is relatively unknown by the the public at large. Gaining some public awareness and momentum. Every bit helps!
Could not disagree more with those who call it an embarrassment. JMHO
Increase the shelf
You did not miss a beat. Very nice research.
I may be off base here but it appears that from their research, LL and RP were focused upon immunogenic/non-immunogenic cancers and found that although MES was very aggressive, with a relatively short median OS, it responded quite well to the vaccine. Aggressive MES fits within the profile of M- which is characterised with an overall historical 12.7 mOS SOC as per the JTM. MES/M- may have an even shorter mOS. M+ cancers tend to be relatively less aggressive, like pro-neural, where we saw as per the JTM article that M+ overall had an SOC mOS of 21.7 months. MES/M+ may be less aggressive than its counterpart in M- due to the fact that methylation interferes with the cellular repair mechanism in addition to being immunogenic. Apparently, in the particular case of MES, DC VAX L was particularly effective regardless of methylation status. MES, in a very real sense, appears to give DC VAX L a good head start: higher level of residual T-cells to start with and a less immunosuppressive micro-tumour environment giving more infiltration time to the killer T cells, macrophages, etc.
This is particularly encouraging because MES is a relatively large sub-group and quite aggressive especially in the M-group. Even though MES mOS in the M+ group may be relatively longer, it may still be less than the overall M+ mOS SOC of 21.7 months.
So it appears that DC VAX L is a very good fit for a relatively large molecular sub-group and methylation status, alone, is not necessarily determinative of the level of efficacy. Immunogenic status appears to play an important part, as was suggested by LL and RP. This, alone, appears to bode very well for DC VAX L. And.....I am quite sure that the SAP will address this issue. It is that important and I think that they have accumulated sufficient data to make an SS finding. JMHO.
I may be kicking the can a couple of months or so, not two years. Relatively soon, we will know if it is a home-run or not. JMHO.
Abeta:
WRT to C3~ uMGMT assuming that is significantly composed of MES, Prins and LL found that MES is more immunogenic than other groups. They did not break down MES into M+/M- groupings. Accordingly, there appears to be a higher level of T-cells in overall MES which are multiplied through the action of the vaccine as well as a less suppressive micro-tumour environment allowing more time for the T-cells to infiltrate the tumour. In less immunogenic groups, it is theorised that a combination of CIs and DC VAX L will "make" the cancer more immunogenic where the CI staves off immune system shutdown in order to allow more time for T-cell infiltration. That is...the micro-tumour environment becomes less immunosuppressive through application of the CI.
WRT MES/M+, I theorise that this group may be susceptible to even longer longevity if not complete remission. In addition to being immunogenic, methylation affects cellular repair mechanisms--damaged cancer cells are not repaired--and so there are at least two "pathways" that extend OS leveraged by the application of adjuvant DC VAX L.
Thus, it would appear that DC VAX L works significantly well in at least three major groupings: M+, M+/MES and M-/MES. In addition, it may have efficacy in the case of EGFr amplification(classical) and whether or not G-cimp status. Dr. Ashkans has been enthusiastic in his support of DC VAX L and as a clinician, he has seen many GBM cases of all stripes. Hence, when he states that the vaccine should be available to all, because it does work, to a greater or lesser degree for these cancers, and that patients are living longer, this is a huge endorsement. I am sure that Dr. Duffy, with his extremely relevant background, is convinced of DC VAX L's efficacy and broad rather than narrow application. Big P is watching and no doubt there are other believers in big P just like Dr. Duffy.
Thanks for your research.
JMHO.
Why do you say that? When they unblind in months, probably this year, we will know if it is a home run or not. Won't take 2-4 years.
Yes, but how long after 2000 did it take them to get there?
Perhaps my recollection is inaccurate but I seem to remember LP saying that they would be looking at molecular sub-groups as part of their "many chances to win". LL is very interested in molecular groups from her research and I am quite certain that she has made suggestions along these lines for the SAP. I also seem to recall that LL/RP concluded, again from their prior studies, that the vaccine, whatever they used, had little to no effect on pro-neural. No mention was made to G-Cimp +/- or other specific signatures. The conclusion was generic.
You may indeed be correct, but the molecular landscape is still confusing--at least to me. That is why I have addressed these issues in hopes of some clarification. Your point of view is certainly not a negative. JMHO.
Thank you Abeta. I am familiar with the data in the graphics you provided. These variances obviously contribute to the confusion. I guess the only way we will know, at least wrt to DC VAX L, is when the trial is unblinded and we get the full analysis. Hopefully these issues will be addressed by the analysis.
Hi Doc:
Thank you very much for your response.
I cannot comment upon your analysis wrt the hold but your speculation seems reasonable to me.
The issue that concerns me is the abstract's categorisation of M+ and M- broken down into associated molecular groups. The abstract is rather recent(February 26, 2018 publication date) and it focuses upon molecular groups. The graphic is pretty clear IMO wrt to M+. It does not indicate that M+ is predominantly pro-neural but rather suggests that M+ is ALL pro-neural in contra-distinction to M- which is PREDOMINANTLY made up of MES, classical and neural. This in itself causes some confusion because if M- is PREDOMINANTLY composed of these groups(not 100%) where does the remainder go? M+? If so, molecular groups other than pro-neural should be insignificant according to the graphic. Is the graphic wrong or is it misleading in some way? As an aside, neural is considered insignificant and is largely ignored in other studies as an important molecular grouping.
The question is: what molecular groups precisely compose M+/M- and what are their proportions? For example, is pro-neural 80% of M+ with classical and MES 20%? This is not addressed in the literature I have reviewed. It is possible that I missed something.
WRT to M-, I have to believe that a significant proportion is composed of MES. Much of the literature that I have reviewed suggests that between 25% to 45%+ of all ndGBM is MES(not broken down into methylated/un-methylated). MES is characterised as the most aggressive of the molecular groupings and this would follow the signature of MES/M- because there is no methylation and accordingly effecting of the cellular repair mechanism as would be the case for MES methylated which would inhibit it thus slowing down MES's aggressiveness in line with historical SOC OS medians for M+. No contradiction here. In fact, the combination of the immunogenic and methylated pathways would bode extremely well for MES/M+ as DC VAX L would be particularly effective and likely result in remarkable longevity, pursuing two pathways. However, I would suggest that MES/M+ is relatively a small molecular sub-grouping.
WRT to MES/M-, I would suggest that it makes up a significant proportion of the total M- group. I would also suggest that Drs. Liau and Prins' prior findings wrt to MES covered ALL of MES not just MES/M+. They did not break down MES into M+/M- in their studies. In fact, they concluded that particular efficacy wrt MES employing the vaccine was due to MES' immunogenic signature with significantly lesser micro-tumour environment immunosuppression(Treg down regulation) allowing more time for multiplied T-cell infiltration. There was no mention of methylation effect. In fact, according to the cited abstract, MES signature does not appear to involve mgmt methylation. Characteristics include NF-1 transcriptional errors and p 53 mutations. There is no mention of methylation.
As I have stated previously, M- OS 36 survival percentage is low at 14.3%. This may be due to the finding that about 50% of all ndGBM involves EGFr over-expression characteristic of Classical. You will recall that CLDX focussed upon this molecular sub-group(with HLA1/HLA2 immune system signatures). Assuming that Classical and MES are evenly split, the much less relative effect of the vaccine on this group could well mask remarkable survival of the equally large MES group.
The upshot of all of this suggests that the vaccine is quite effective for at least 50% of all ndGBM--M+ which might compose significant pro-neural(if the abstract is correct and not misleading)and a smattering of other molecular groups that exhibit mgmt methylation plus MES/M-. I don't see any significant overlap between M+ and MES but rather see these groups as distinctive and additive. There may be some lesser effect upon other molecular groups such as classical/EGFr which may not even be SS. Anyway, Dr. Ashkan's view is particularly noteworthy that as a clinician, he believes the vaccine should be made available to ALL patients as the vaccine works, to a greater or lesser extent, across the ndGBM landscape. It should also be noted that ndGBM tumours are not 100% one molecular group or another. There is great heterogeneity and accordingly, availability and use of the vaccine should be a function of patient/physician decision rather than imposed by regulatory fiat. Thus, if reg approvals are forthcoming, I believe they will be broad rather than limited and at least in line with Novocure.
BTW, I have long addressed the foregoing issues with other oncologists as well as with Dr. Boynton(who has never responded despite repeated follow-up; ditto with Innes and Dr. Rago) without clear response. Most did not address the foregoing and gave rather general responses. I must admit that all that I have talked/corresponded with are positive about DC VAX L potential and are anxiously awaiting results. The hire of Dr. Duffy is absolutely huge IMO. This confirms that big P is watching. This confirms the potential of DC VAX L. Dr. Duffy is extremely well versed in this space due to his academic credentials-he even has an MBA--and experience. He is willing to bet his career and reputation on NWBO. This is just a huge endorsement and a signal of great things to come.
Seems pretty obvious to me and I have been pretty much a skeptic in the past. JMHO. GLTA!
Hi Doc:
Thanks for the response. I wonder whether you had a chance to review my earlier post addressed to you regarding certain anomalies raised by the February 26, 2018 abstract I cited and which is referenced in the iHub message board intro.
By way of quick summary, the abstract provides a simple graphic that breaks down the M+/M- major groups into associated molecular sub-groups where M+ appears to be predominantly if not 100% pro-neural and M- predominantly made up of mesenchymal(MES), classical and neural. You will recall that results were very remarkable for M+ blended as per the JTM and updated at SNO. M+ is not as aggressive as M- appears to be(with MES included in this categorisation) and appears to have characteristics associated with pro-neural which, in fact, the abstract categories as being composed of pro-neural. This is in contradistinction to earlier UCLA studies that found DV VAX to have little no effect on pro-neural. Further, these earlier studies found that the vaccine was particularly effective on the most aggressive sub-molecular group, MES. The reason was that MES is more immunogenic(like, for example, melanoma)meaning a greater residual level of T cells which DC VAX boosts and a relatively lesser immunosuppressive micro-tumour environment allowing the T cells more time to infiltrate before immunosuppressive brakes are applied. I don't know the extent to which MES MGMT methylation is as a proportion of overall MES but I suspect that it is rather small especially when considering that the abstract considers M+ being at least predominantly composed of pro-neural. In any event, MES mgmt methylated would have two pathways: immunogenic as well as cell repair interference which could imply at least sustained remission if not an overall cure. The abstract also went on to say that ndGBM is 50% characterised by EGFr over-expression/mutation and is also a molecular group included in M- as classical. The blended results for this M- group as shown in the JTM were remarkable with a delta of 7 months between SOC median and blended(from surgery). At OS36, M-survival, though, was only 14.3% (as per updated SNO). This truncated survival for M-, as a whole, could mask superior remarkable longevity of MES due to the fact that the vaccine may have relatively lesser effect on classical, thus a more abbreviated survival percentage at OS 36 as well as blended median survival which is a large percentage of overall ndGBM just like MES(reported to be anywhere between 25%~45% of all ndGBM).
I believe that LL's earlier findings on the vaccine's efficacy on MES included ALL MES and not just methylated which I believe is a relatively small proportion as explained herein above.
If the abstract cited is accurate, this bodes extremely well for DC VAX as it appears to be very efficacious for M+(pro-neural and 40% of trial ITT and 45% of overall categorised group--N=293) and a significant percentage of M- due to MES. This would cover at least 50% of all ndGBM!
In addition, I made reference to PFS and the possibility that DC VAX L has the effect of slowing progression as time unfolds and the vaccine begins to manifest its growing strength thus enabling increased overall survival even though there may not be at least an SS advantage in delta between SOC and Tx. I hope that the revised SAP addresses this possibility.
I also made reference to possible lack of SS wrt Tx and control(including x-over) for OS and that this is not necessarily bad in that it could show efficacy even for "late" vaccinations. Personally, I believe that there will be significant separation as you go out on the curves.
I ask again if you could review this and my previous post and provide your comments especially on the findings made by UCLA and subsequent findings I alluded to herein. Also with respect to what molecular sub-groups are in M-/M+. Are they as stated in the cited abstract or are they(or I) missing something?
Appreciate your response, Doc. BTW, very pleased by the Duffy hire. It is a great inflection point for me!
It would be unethical and a lie for NWBO to say that the trial failed at this time. LOL.
Whatever it is, Dr. Duffy is worth it. I have a lot of confidence that he knows what he is doing and if anything he serves as a confirmation as an "outside" expert betting his career on it. It don't get better than that. JMHO.
Geez LF, ya just can't win.
Who said anything about a secret sauce? Look, the point I was making was that the hiring of Dr. Duffy was great news. Obviously, big P is following along. Iwasadriver's oncology colleagues are following along. Oncologists who I know are following along. Things appear building to a crescendo. Whether this is a coordinated effort or just a personal endeavour, it's huge. That's all. Beyond that, it is mostly speculation
Absolutely spot on!
The hiring of Dr. Duffy is just huge. There is no doubt about it. It shows that BP is watching. If Dr. Duffy, who was a mid-level executive at Merck knows enough to be compelled to join NWBO, others, at all levels in all BPs know about DC VAX and its potential. Dr. Duffy broke ranks. His joining NWBO can be interpreted as a validation of big P interest in DC VAX. Dr. Duffy is not just a scientific/research type with a focus upon pharmacological oncology and experience with immunological approaches but also a business type as evidenced by his MBA/experience.
People like Dr. Duffy don't jump blindly into something wrt which they have not done extensive due diligence. There is no doubt that he talked to a lot of people including key individuals at NWBO. He has the scientific background to understand this stuff backwards and forwards as well as 10,000 ways from Sunday. He is definitely not going to bet his career on a wing and a prayer. That is for sure. Is he a super star? That is not the right question and it is irrelevant. Dr. Duffy is a very experienced and smart guy with the necessary core competencies with big P background. An excellent fit for both Dr. Duffy and NWBO.
Just a clear signal about what we can expect. You don't make these hires unless you are pretty sure about what is gonna happen. LP is way ahead of the game and with her phalanx of consultants, advisors, et al she pretty well knows the outcome. The length of this trial and the data collected is heavy on actuals and extrapolation to 5 years et al is much more predictively accurate as opposed to therapies like Optune. The data will likely be undeniable. Dr. Duffy is going to a company where he has concluded from what he already knew and found out through extensive DD that the odds of success are high. An asymmetric calculated risk as SOS might say. JMHO.
And a dumb-stick to boot :)
God bless you.
Kabu:
I agree. Dr. Duffy is no dummy. He has a stellar background and the right credentials. He could go anywhere. His move to NWBO is not primarily based upon personal belief. He did not go begging for a job at NWBO. They needed to do some "selling". People like Dr. Duffy don't make moves that are highly speculative. Of course, there is risk but it is highly calculated. I am sure that LP pulled back the covers. LP & co. know a hell of a lot more than most with all the data they have, consultants, SAB, PIs, professional statisticians, etc., etc. NWBO had to lay it out for Dr. Duffy rather than say "stay tuned" or "trust us". I am sure that Dr. Duffy asked a lot of questions and LP, Boynton, Bosch, et al gave him what he perceived as satisfactory answers, enough so that he was compelled to join. He has all the right credentials to do DD and ask all the right questions. And he got the answers we, the shareholders, would love to know. In a sense, if Dr. Duffy is convinced enough to join the little "engine that could", this is absolutely a huge vote of confidence for shareholders.
Dr. Duffy may be joining for collaborative trial projects involving both L and D, however, in order to be convinced to join, he had to be pretty well convinced on the DC VAX L prospects. Great hire and the beginning of good things to come. Maybe, just maybe, I am wrong about my negativity towards NWBO management. Not ashamed to eat crow with the salve of success for both patients and long suffering investors.
I, for one, could not be more pleased. Great move!
If the abstract to which I referred is accurate, pro-neural only is associated with M+. Accordingly, M+ MES would be a minuscule percentage of M+. There may be some classical/Neural thrown in as well but relatively de minimis. The abstract associates classical, neural and MES as predominantly comprising M-. Hence, if MES is not about 5% M+, it would still be a very small %. JMHO.
What happened to September?
Doc Logic:
You have put your finger on an extremely note-worthy point wrt M- and mesenchymal(MES). According to the February 26, 2018 abstract entitled "Development of Targeted Agents in Immunological Therapies:
A Personal Approach" referred to as per the chart associating molecular sub-groups with M+ and M- in the iHUB message board intro(just scroll down and you will come to it), M- is predominantly composed of Classical, Neural(de minimis) and MES( my recollection is that only about 5% of MES is M+) and M+ is associated with the much slower progressing pro-neural molecular sub-group which primarily affects younger patients. The JTM and SNO updates showed remarkable blended results for both M+ and M-.
Prior studies conducted at UCLA by Drs. Liau and Prins showed that the DC vaccine worked particularly well for MES--because it was more immunogenic, however, it had little to no effect upon pro-neural. This appears contrary to the JTM blended findings with respect to M+ if the abstract's classification of pro-neural being associated with M+ is accurate. In the DC VAX L trial, the M+ population was approximately 44% of the categorised overall patient population(N=293). Pro neural is characterised by IDH 1 mutation as well as PDGFr mutations. On the other hand, MES in the M- group is very aggressive with a very abbreviated survival after SOC is applied. MES is characterised by NF 1 transcriptions and p 53 mutations. MES has been estimated to comprise anywhere between 25%~48% of all ndGBM(and appears to mutate into MES upon recurrence) which is a significantly large molecular population. That combined with M+(apparently at least predominantly pro-neural according to the quoted abstract chart) covers at least 50% of the ndGBM population where DC VAX L appears to be particularly efficacious. In addition, Classical/M- is characterised by EGFr amplification/mutations which comprise perhaps 50% of all ndGBM as stated in this abstract. Apparently, even in this significant molecular sub-group, DC VAX L appears to be at least somewhat efficacious.
The update at SNO indicated that OS36 survival improved to 14.3% for the M- group. However, MES may have significantly superior survival outcomes masked by the lesser efficacy of classical resulting in an overall blended 14.3% OS 36 survival percentage. The long tail at OS 60 may be composed predominantly of M+ however, MES may show remarkable survival percentages at the OS 36 and 48 milestones with a drop-off thereafter due to its highly aggressive signature. Overall, considering the foregoing, the vaccine appears to be working to a greater or lesser extent over all groups(neural is insignificant) and Dr. Ashkan's statement, as a clinician who experiences these types of patients on a daily basis(as does Dr. Liau), that the vaccine should be available to all patients has great import. Accordingly, if reg approvals issue assuming positive results as the blended results appear to point to, such approvals will likely be broad and leave the decision as to whether to invoke DC VAX L as an adjuvant therapy between physician and patient rather than by regulatory fiat. This may also include--perhaps off-label--using DC VAX L as a mono therapy in M-cases such as MES as you have wisely pointed out due to relative ineffectiveness of current SOC.
The abstract has also mentioned, matter of factly, that PFS may not be an appropriate surrogate for OS in immunological trials and that pseudo-progression has been a confounding issue. As I have suggested previously, it may be that even where there may be earlier than heretofore expected eventing that as the DC VAX L therapy gains strength over time, the progression itself is slowed thus contributing to longer OS and better QOL.
Doc, I would appreciate your comments on the foregoing especially with respect to the seeming contradiction between UCLA earlier results and those suggested in JTM/SNO. All in all, it looks very promising. Thanks for your prescient insights. JMHO.
I am talking about blanket regulatory approval as opposed to some type of limited approval. Obviously, the vaccine may not work on everyone at least to the same extent. GBM is a very personal disease and it varies from patient to patient. There is no such thing as a 100% MES or pro-neural, etc. GBM tumour(s). It is very heterogenous as well as mutative. Accordingly, Dr. Ashkans, the lead PI for the UK(and Europe, I believe), stated quite clearly that the vaccine should be made available to all ndGBM patients as the vaccine may work to a greater or lesser extent across the entire ndGBM spectrum.
For example, Optune was given blanket approval. There was no showing that TTF works to the same extent across the ndGBM spectrum. If DC VAX L works across a broad spectrum such as M+ and MES which together may comprise over 60% of all ndGBM, I believe that the FDA will grant blanket approval just as it did for Optune.
You are correct that the vaccine may not work in a number of individual cases. However, whether to use the vaccine or not as an adjuvant therapy, should be a decision left to the patient and his physician rather than to regulatory fiat, especially if the results show wide application with varying degrees of efficacy. JMHO.
Iwasadiver:
Thanks very much for your response. After reading acting FDA Director Ned Sharpless' comments, which I found to be highly encouraging, I believe that DC VAX L evaluation will be relatively straight forward and based primarily upon milestones/long tail. I disagree with Dr. Wick's implication that PFS endpoint may be of primary decisional significance due to the confoundment resulting from the cross-over. Dr. Sharpless believes that overall survival is the gold standard. Longevity will be of primary decisional significance IMHO.
In previous posts, I have alluded to the findings published in the JTM especially with respect to M+ and M- and the confusion created by the chart in the iHub MB introduction assigning sub-group categories such as pro-neural to M+ and MES to M-. Methylated MGMT promotor is a rather large sub group which appears to have demonstrated significant survival as compared to control historicals upon a blended basis. M+ appears to be a less aggressive variant than MES which appears to be highly aggressive and with a much diminished SOC survival compared to M+. Due to these differences, I believe that MES and M+ are separate and non-overlapping categories and represent at least two large sub-groupings where DC VAX L would appear to be rather effective especially based upon the Liau/Prins findings wrt MES. M+ comprises almost 45% of the M+/M- total group in the DC VAX L trial population. MES has been estimated to constitute anywhere between 25%~40% of all ndGBM. Dr. Wick has mentioned the fact that therapies, including DC VAX, have shown promise in certain sub-groupings although he has stated that the results published in the JTM wrt to DC VAX L are not helpful in assessing efficacy. On the whole, I did not find Dr. Wick's comments to be negative or unreasonable but rather, bottom-line, a call for unblinding in order to assess efficacy.
An important milestone is, of course, the long tail at OS60 and its composition. It appears that upon a blended assessment of OS for 5 years, there is approximately a derived survival of 20%. Upon unblinding, it is possible that overall Tx could be in a range of 20%~25%. I would guess that the overwhelming majority of the long tail would be composed of M+ survivors and much less MES survivors.
There may be a steep drop-off of MES survivors at say the OS36/48 milestones but never the less notable survival of this group short of OS 60.
Given all this, I feel rather confident that the results will be highly positive on long tail/milestones, PFS will have lesser decisional significance(assuming the the primary end point was not achieved) and noting Dr. Sharpless' remarks wrt glioblastoma, DC VAX L will more likely than not be approved, especially when considering comparisons with Optune and the superior amount of data collected in the DC VAX L trial and milestones beyond 24 months.
I think it is a question of when rather than if approval issues and if the top line is positive as we longs believe, approvals will come sooner rather than later given current regulatory environment leanings. Further, I believe that even though DC VAX L may prove to be more efficacious for certain groupings, the FDA will provide a blanket approval in line with Dr. Ashkan's clinical assessment that the vaccine should be made available to all patients as it works to a greater or lesser extent across all groups. The decision as to whether to use DC VAX L as an adjuvant to current SOC should be a decision reached between patient and physician rather than circumscribed by regulatory fiat. JMHO.
No, I don't believe for a minute that this is a scam. I engaged in hyperbole to make a cynical point because the poster to whom I was responding made a rather specious claim. It is quite obvious that NWBO would want buy in on its SAP from the RAs and would prefer to make a presentation including the feedback it obtained. Hence I used the appellation "cynical."
As I said, I believe in the science, the SAB, the PIs and the authors of the JTM article. I believe LL and RP to be honest and sincere as I do Dr. Ashkans. Not so much in NWBO management. for the reasons stated in my post wrt BSB.
Tilt:
The odds are that the earliest top line will be announced is sometime in 1H2020. They need something to talk about at ASCO 2020 in order to finally justify all those expensive big booths.
Indeed disappointing but it is what it is. Until then, longs are in for a world of hurt. JMHO.
They are presenting, giving a peek to, submitting, etc. to the RAs for their buy in. They want feed back otherwise there is no meaning to "present" or whatever to the RAs. Except if you go with a cynical view. They can blame delays in data-lock/top-line because the feed back loop is on-going and more back and forth is continuing because more questions are engendered.
So yes, it is up to NWBO to do what they want, but they would rather do so with buy-in from the RAs---unless of course, this is all fake news and LP/LG need more time to feed their scam. JMHO.
BSB:
Thank you for your message. Sorry I cannot reply privately as I do not subscribe to this service. I agree with your comments.
I do believe strongly in the science although I have a number of open questions, the last of which were communicated recently to Iwasadiver who responded by saying that he would re-read these and then attempt to shed some light.
Allow me to give you the courtesy of my thoughts as they relate to the question as to what my angle is.
SCIENCE:
1. PFS: In the overall picture, while a primary endpoint(and that won't change IMHO no matter what the new/modified SAP spells out), PFS will not have much decisional significance especially if this endpoint is not achieved. Very simply, PFS is a surrogate for overall survival so that trials do not have to play out for the much longer overall survival metric. Overall survival is the gold standard. Period. The trial has gone on long enough so that this surrogate's decisional importance is diminished. The failure of the JTM article to discuss PFS blinded data, just the same as OS blinded data was addressed, suggests that the PFS data was at worst confounded and required adjudication. Absent adjudication, one might conclude that at the very least, PFS blinded data may have been too close to call. Although, admittedly, it appears that according to LL, the long living patients in the trial apparently did not experience PFS eventing and that certainly bodes well if most if not all are in Tx. Basically, for immunological therapies, PFS may not be a good correlative of OS and thus OS takes on much greater significance especially for this trial that has run for so long. No real need for the surrogate when you have sufficient OS data as we do in this trial.
IMHO, what may be important is whether, even though PFS eventing may not significantly exceed that of SoC, given enough time for the vaccine to take hold the rate of progression is slowed, and in some cases reduced to zero, thus contributing to longer overall survival and a much better QOL. I hope the revised SAP addresses this question.
Furthermore, what is important, in my view, is the delta between PFS eventing and OS. If this delta for Tx is significantly longer than control then it may corroborate diminishing rate of progression.
Bottom line, PFS may, in the whole context of the trial, pale in significance to OS especially if the results are stellar.
My only issue with the possible lack of achievement of the PFS endpoint is whether the market understands what I have delineated hereinabove assuming that I am reasonably correct rather than trumpeting an absolute failure of achievement. Hence it is important how this metric and its results are portrayed in the announcement of top line. Unfortunately, I do not have great confidence in management to communicate this effectively given past performance or lack thereof. Further, the hiring of David Inness does not change my view. Pure and simple, he has no IR or media communications experience and was a broker, and not even one with a VP title, in a backwater satellite Oppy office. He has rather continued the obfuscation and has acted as a convenient and expensive proxy for LG. IMHO, while I do not blame Innes, he was an un-necessary and even poor hire on the part of NWBO management. No improvement in the IR function that I can discern.
2. OS: The secondary endpoint is OS. Of course the crossover and the fact that about 90% of the trial population was afforded the vaccine at some point in the trial(early vs late), may serve to confound results. There may not be sufficient separation between the Tx and control(cross-over plus non-crossover) arms despite the length of the trial. However, IMHO, crossover patients did not have a second surgery to obtain a second sample(perhaps only 3 patients did) after progression. The cancer is heterogenous as well as highly mutative and thus, I would not think that the crossover patients would fare significantly better than non-crossover patients. Thus, I would think that there would be sufficient separation. I am not sure how significant a comparison of Tx with non-crossover alone would be given N=33 which may be too small a sample. Furthermore, it appears that upon progression, the cancer mutates wildly into a highly aggressive cancer(about 85% mutation to mesenchymal (MES)). So, without benefit of a new lysate and a rapidly progressing cancer, I would think there would be significant separation in the curves especially as you go out in time.
However, even if there is not significant separation, is this necessarily a bad thing? Might it not support the notion that even though early vaccination is preferable, there is some benefit to late vaccination anyway? Imagine how much better the results might be if a second lysate were made after progression? It could be indicated that the vaccine is indeed so powerful that even in rGBM and no second surgery, the vaccine still works to some extent. Thus the pronouncement of Dr. Ashkans, the PI in the UK, that the vaccine works to a greater or lesser degree and should be given to all patients.
The vaccine appears to work particularly well on the methylated group(M+). I don't really understand what this means. For example, in the intro to the iHub message board there is a chart if you scroll down far enough where the M+ and non-methylated (M-) groups are delineated. This is as of a relatively recent abstract dated April 18, 2018. The M+/M- groups are further broken down into sub-molecular groupings. The M+ sub-molecular group is only pro-neural according to the chart. The M- group contains predominantly un-methylated sub-molecular groups consisting of classical, mesenchymal(MES) and neural.
The JTM article showed that the M+ blinded data was impressive even though from time of surgery with a blended delta of about 13+ months. The JTM article did not address molecular sub groups, however, if the chart is accurate, the M+ group would be composed of at least predominantly pro-neural. However, in previous UCLA studies, Drs. Liau and Prins found that the vaccine worked particularly well for MES but had little to no effect upon the pro-neural molecular sub-group. They found that MES was more immunogenic which I believe from what I have read that there is a higher residual amount of T-cells as compared to other groups and that the tumour micro-environment(hi-jacked T-regs) was less immunosuppressive thus allowing the T-cells more time to infiltrate the tumour and kill it. As I understand it, methylation of the MGMT gene interferes with the cellular repair mechanism and so cancer cells are effectively killed by the application of Temodar and this MOA is leveraged and extended by the application of DC VAX L. This is a separate pathway. When we talk about the M+ group in the JTM article are we talking just about methylated MGMT? Are there other genes that are methylated that give rise to improved effects? I just don't know. Anyway, the remarkable results upon MES as found by Drs. Liau and Prins seem to be due to its immunogenetic nature. There are other cancers that are also highly immunogenic like MES.
However, while the JTM article showed even remarkable efficacy in M-, which according to the chart is partially composed of MES, one would think that the results should be even better given the LL/RP findings. It is, of course, possible that the results for MES were remarkable but not so much for classical and neural thus pushing down the blended delta for M- as a whole. I just don't know.
The point I am attempting to make with the foregoing meandering is that M+ plus immunogenic(MES) may cover a significant spectrum of GBM where DC VAX L may be particularly effective. For example, in the categorised grouping of 293 patients(the initial 38 were not categorised), 44% were M+. In addition, the literature indicates that MES is a significant population ranging anywhere from 30%~48% of all nGBM.
If this is the case, then easily over 60% of all nGBM would be effectively treated by DC VAX L. That is assuming the chart I referred to is accurate. If it is not, it should be removed. The other point that should be made is that no tumour(s) are completely MES or pro-neural or 100% anything. And there is mutation. Hence I doubt that approval if it issues would be limited to a single or restricted grouping. As Dr. Ashkan has averred, the vaccine should be available to all with a decision made between Dr. and patient rather than by regulatory fiat.
Accordingly, I think the overall survival milestones for Tx will likely be remarkable especially for M+. How MES factors into this I don't know. Neither do I know the extent of efficacy in the other molecular groupings. However, I believe from the blended data and SNO updates that the spectrum of applicability is very broad and that a significant percentage of Tx are relatively long lived.
How all this will be presented in conjunction with top line is an important question perhaps not so much for the regulatory and medical communities but for the investment community which will have an important effect on NWBO financings and their toxicity.
So bottom-line, I am reasonably confident in the science.
MANAGEMENT:
Insofar as NWBO management is concerned, I believe their lack of transparency, obfuscation, silence and questionable "self dealing" have all conspired to bring down share prices just as much if not more than the dark forces LG has alleged. We all have questions as to what expensive hangers on like Cofer Black are doing? What value is Innes adding? Etc., etc. we have gone over management deficiencies ad nauseum.
In conclusion, I have many shares because I believe in the science. At one time I believed in management. No more. I hope they are bought out and I am willing to give up what we MIGHT get in the LONG run by going it alone for a bird in hand, so to speak, on an earlier BO. I'd rather enjoy the fruits of some modicum of success now than push it all off to my succeeding generations.
GLTU and I enjoy reading your posts. They make sense. Please keep in touch.
Kind regards,
U
Wrt unblinding, we are not indubitably getting closer if the goal posts are continually being moved. Even now, I think it is a good bet that the SAP has not been completed and presented, given, handed over, submitted or whatever to the RAs. And if/when the 4 RAs give their blessings to the SAP is out of NWBO management's control. Furthermore, I don't think the remaining queries have all been cleared up. I think we are in for a long, long wait. Top line, I predict, will be announced in the 1/H of 2020 and they are pointing toward ASCO 2020 for the details. The ASM will be a repeat of last year's with Ike Esq preparing another questionnaire. LP will also ask for an increase in authorised shares. Warrants will expire worthless in April, 2020 unless holders pony up additional funds to roll over for another year.
Wrt a financing, we are indubitably getting closer each day. I doubt they sell the 17 acres anytime soon, so we are probably in for another, perhaps several, dilutions and debt financings highly favourable to LP, et al. Death by a thousand cuts.
SNO will come and go with still another meagre blinded update and nothing else followed by silence except for the announcement of the ASM and agenda---probably Feb. 2020.
What happens to the share price in the meantime? Indubitably, it drifts down to new lows and even single digits. The longer silence/waiting plays out, the more probable is the foregoing scenario. From such lows, even with highly favourable results, I don't believe the share price will explode a 1000%. It won't reach a dollar. Further, while I think that the results will be somewhat positive, they won't be stellar. Thus, we will be lucky if the share price reaches pre-ASCO 2019 levels. Approval will be a long way off and it is very possible that instead of an approval, the FDA will issue a CRL. If so, the end. Not a very promising outlook. JMHO.