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Ex -
I think the speculation of mine that it is SAP agreement with FDA blocking the process is equally consistent.
Ex - I may be totally off, but I am of the opinion now (since the ASM) that TLD may be released the traditional way (via PR) and a paper will come later. If that is the case, AK would not see anything until they started working on the paper. We are all guessing at this point though.
Anders - I believe what you and Senti said - AK is not on the SAB and that is good news for us (in terms of where we probably are in the process).
Thanks Marz.
Thanks Senti - That is actually good news. Means his comments are coming from someone who would not necessarily know what is actually going on with the data analysis and interpretation. I would take everything he said regarding Covid delays with a grain of salt.
King -- Someone posted an interview with LL not long ago here in which she pretty much explained the source of this comment. Her point was that GBM was such a heterogeneous disease that it was unlikely any single intervention would work fully for all patients. She stated that for an intervention that was actually effective, efficacy in certain subgroups would be expected. For DCVAX, I assume she is thinking that it works particularly well for methylated patients (based on blinded data published previously). These same data suggest that it may also work to some degree (but not as well) in unmethylated patients. That seems to capture her comment in a nutshell.
Anders - I hope you are correct in your interpretation. If AK is not on the SAB, that comment could just be made in ignorance (hie is out of the loop). However, I think I recall that AK is actually on the SAB. The SAB and company leadership would both see the full statistical results as soon as they were available. That would be standard practice and consistent with what the company has said. That review is what would guide how results were interpreted and how TLD would be released. If the SAB and company have not actually seen the results yet for some reason (despite how long it has been since data lock), then AK could have said what he said meaning more generally that "this process has taken a very long time because of COVID delays, so we still have not seen results yet." So, in this scenario the statisticians could be almost ready to give results to leadership and the SAB any day now. Maybe the comment about not actively collecting data for the past year is referring to past barriers rather than current barriers. If the SAB (and AK) are still blinded, they could regardless at any time have seen more up to date BLINDED results to know how many in the trial have survived to date (basically a further update of the last SNO data that LL presented a couple of years ago). That could explain his knowing about 7 year survival.
Anders - No, I believe them when they say it was locked, and I agree that you cannot go back and unlock to fix/add things. I always assumed that when they locked and said analysis would follow that this referred to a hard lock. I guess it could have been a "soft lock" that did permit adding data (IHD?) but I really doubt this given what they said. What gets me is that no matter how complicated a dataset is, 7 months to analyze it and see what it showed is absurdly long. Anyone who has ever done an analysis of a trial dataset would known this. Over the summer, I did two separate complex analyses for different papers based on a large dataset we had, wrote publications, and had them published, all in less than 6 months. Prior to the ASM, I had assumed the publication was the holdup. But, at the ASM, they used language to me that sounded like they weren't even to the point of writing a publication. If anyone can reinterpret what was said at the ASM so that it could be consistent with them having a publication ready or under review, I would love to hear it. I am just confused at this point.
In terms of explaining why TLD is taking so long, missing data that they have been unable to get (due to COVID or whatever) makes way more sense than analyses or interpretation taking 7 months. It just doesn't take that long. How you reconcile that with their prior clear announcement of data lock, I have no idea. My read on the ASM language was that it did not sound like they were in the publication phase yet, but who knows. I am confident things will be ok in the end, but I am really curious to find out why it took so long. Hopefully someday we will know.
Thanks Ex. I misread that.
The other issue is that DCVAX data will be compared to actual prior trial results with similar "cherry picked" selection criteria, and we know from LL's recent talk what those pooled numbers look like. DCVAX trial data clearly exceed these historical controls that will be used for comparison. Excluding people who are not GBM or who have insufficient tumor lysate will not change the OS results - these are random factors that would not alter OS.
Ok - So the question is, does the DCVAX blinded data indicate that patients significantly exceeded these numbers?:
Patients who potentially could have been included in a trial before the start of concurrent RT/TMZ had a median survival of
16.4 months, and the 2- and 5-year survival rates were
33.3% and 8.6%, respectively.
Biosect - I was responding to the question of what would be a better design than what we end up with. A straight noncrossover trial with true placebo group would be a better design that would address criticisms leveled at the historical control comparisons. I totally agree that it would be harder to recruit for which would make it way less practical. Regarding whether it is immoral or unethical, randomized clinical trials (no crossover) are done with potentially life saving treatments all the time. The thought process in providing ethical (IRB) approval for studies like this is the following. At the time the DCVAX trial design was approved by the IRB (and the original noncrossover version was IRB approved at one time), they were planning to compare the standard of care (known to work and what everyone would get if not in the trial) with or without the addition of DCVAX. No one was going to have a known effective treatment withheld, because at that time, no one knew if DCVAX actually worked. No one could say at the time the trial started that getting SOC + DCVAX was any better than SOC + Placebo. That is what is used to justify such a design ethically. With what we have learned from the DCVAX trial in terms of extended OS in comparison to historical controls, ethical approval of a noncrossover design of DCVAX now would likely be more challenging because one could argue that the SOC+placebo group would be having a known life saving treatment withheld.
Thanks Senti - exactly what was in my head!
Why patience regarding TLD is justified:
Delays in TLD could be due either to management incompetence or valid reasons (unknown to us). Is LP deciding on her own to delay TLD for months? Of course not. She has said and anyone who has worked with pharma would know that as a non-expert, she is relying on her scientific advisory board (SAB) to make recommendations on how best to proceed. This SAB has a number of world-renowned experts whom we know want to see DCVAX approved for use in their GBM patients. The advice they give LP will be based without any doubt on what these experts believe will lead to maximum likelihood of approval. Are LP's interests also aligned with the SAB (and investors)? Certainly. She has a personal interest in curing GMB (family experience) AND stands to make tens of millions of dollars if DCVAX is approved. Clearly, she also wants to maximize chances of approval, just like SAB members. We as investors want the same thing. So, even though TLD taking this long makes little sense to us on the outside, the insiders are clearly advising a long and careful process as the best means of insuring approval. Despite a bad history of communicating with investors, I think we have every reason to trust the company (and the SAB experts) to arrive at and and disclose TLD in a way that is in the best interests of all of us. The waiting is the hardest part...
Marz - OS is much more important because PFS is only a surrogate for OS. I would not bother studying PFS in any future DCVAX trials (which will make the trials more expensive due to longer duration).
Marz -- IF they had the time, a large number of sites, and lots of money, they could do a straight randomized trial with no crossover to study OS for DCVAX vs placebo. Probably would be challenging to recruit for but with enough time it might be possible. If successful, that trial would address the naysayers concerns.
Is it worth it? I doubt it - I am not a big believer that placebo effects increase OS, so comparisons to historical controls will probably end up being quite similar to results of a full RCT. Not really worth doing this ideal trial but it could be done.
DF -
The only question that’s bothering me is “if you so strongly believe in the results then why not rerun a proper p3 trial with support from top 5 institutes” Actually, this is a specific question from a Neuro oncologist who I tried to debate this with. I do not have a good answer for this.
I think you are correct based on what was said today.
Thanks Ike. The language used makes quite clear that they are nowhere near having a publication ready to submit let alone accepted. They may not even know what the TLD look like yet. I am mystified by what is taking so long to do this analysis, but maybe that will become apparent after the TLD are announced. Maybe TLD will be a traditional TLD announcement after all.
Karl - Agree about taking money from derisked investment to speculate in another one. I did this 6 months ago (stupid idea) but was very lucky. I sold $20,000 of NWBO intending to keep it in cash to lock in some gains. However, I got itchy fingers, and ended up buying AVXL and SENS. Within about a month, both went up 80-100%, and I sold and bought back NWBO. I was just really lucky, but I am not doing that again.
I thought someone previously indicated that the ASM date this year was the last possible date to be in compliance with the rules for having a meeting within one year (+ one month?) of the prior meeting. If so, I assume they chose this late date to give them the greatest possible chance of being able to announce TLD and a pub at the meeting. Even with stretching this out as much as possible, it still might not happen if the journal is still going through their review/acceptance process. Out of their control. Given the most recent update, if there is no TLD PR before the meeting, I expect them to continue to say nothing about TLD timing at the ASM (because they do not know). But, for all we know, TLD could come 2 days after the ASM just coincidentally.
Soj - The good news about their recent refusal to provide a TLD timeline is that it is consistent with the idea that they have already submitted a publication and cannot give an accurate timeline because they do not know how long acceptance will take. If they had not submitted a manuscript yet, I think they might have used language like in 2018 when the JTM pub was in process ("we are working diligently with the many authors to complete the manuscript...").
Jerry - Who knows for sure what's happening behind the scenes, but for this company struggling to survive, I doubt moral reasons are a big driver of their decisions and timing.
Anders - FWIW - 6 weeks to publication was the fastest possible. If these delays are publication related, my guess would be that the company aimed high to a top tier journal, got reviewed but rejected, and have had to submit to a different journal. This could have happened more than once given how long the delay has been.
Your friend may be basing his negative opinion on historical failures of prior attempts to develop similar vaccines (using different strategies). That opinion may not be unjustified, but it is very unlikely he knows the specifics of the blended data publicly presented in peer review form. This is an under the radar intervention that most expect will fail, but the OS numbers observed to date surely indicate something is working. Nothing is ever guaranteed, but the likelhood that the trial results will represent a total failure is very low. There is a signal in the noise, and they are working hard to show it despite challenges with the "old fashioned" trial design they selected over 12 years ago.
Gus - I think success on all historical control comparisons and failure on the original PFS and/or OS endpoints would totally justify the careful, apparently publication-focused approach they are taking. And success on those historical comparisons will not be bad news at all.
Anders - I don't know about a R/S, but if they think TLD is coming out soon, but not soon enough for the mandatory timing of the ASM, I could see them have a second financially-focused meeting a couple of months later so that we all can hear the good news before they request an increase in share count.
Right on Umibe.
IMHO - Publishing TLD first to start all other processes that have been mentioned (FDA submission, possible BO) makes the most sense to me, and that can take a while. I do think we have to be very close though, given the amount of time that has passed since data lock.
Alternatively - Virtual conferences are crappy, not as well attended as actual conferences, and it was a waste of money to pay for an online booth.
Even with no patent protection, they will get 7 years of exclusivity in the US if approved, and 10 years in Europe.
Thanks for the official word BB.
Bright Boy -
ASM at 4:30 PM on the 18th
True. Same things happened to Amarin around TLD, except from 7-8 different law firms. Nothing ever came of it.
My guess is that the announcement of the annual meeting date will trigger upward price movement. Most will assume they will be announcing TLD before that date, so will parallel upward movement back in the late summer when everyone though TLD would be out by September.
Good point -- If it were a British or European journal, maybe that would work
ATL - Good example that suggests it is possible to publish a non-randomized study in a top journal, although this does not look like it was ever intended to be a randomized trial (unlike the DCVAX trial). Does the publication report the primary/secondary outcomes as described in CT.gov? That is probably the big issue for NWBO - do they update their CT.gov listing prior to publication to match their new endpoints? I am not trying to be a contrarian at all - I just think there are a lot of hurdles to publication in a top journal and am trying to be a realist. So far, it does not seem like they have done what is required to make that more likely. I suppose it is not impossible that a CT.gov update is going on behind the scenes - we would not know until it goes live ("released" by CT.gov). It would be terrific if they can get this trial into NEJM or Lancet.
Senti - The intention of CT.gov is both to help recruit patients for trials, and to address the big problem historically with trial endpoints being changed after the fact (i.e., after the data have been seen). The top journals (but not all lower journals) match up the primary and secondary endpoints listed in publications submitted with what was said on CT.gov. If they do not match, they send the article back pointing this out, and may give the authors a chance to correct this (by revising the text). They do this to reduce chances of publishing a failed study that changed their endpoints after they had seen the data to show significance. I think I have heard that it is possible to change CT.gov after the fact but before you submit a publication in order to match what you report in the article, but I cannot confirm this. You can see (as Ex has pointed out) that NWBO changing the endpoints (although while still blinded) is getting near the gray zone of what CT.gov was designed to prevent. That said, I think it is totally justified given the circumstances in NWBO's case, but it does hinder publication in a top journal (unless of course the original outcomes succeed).