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The final 32 patients who were added to the trial after the halt but only given the option of treatment were consented prior to this and both they, their treating physicians, and likely the company were blind to this fact until the data moved to publication. Even then it is only inference that they, the last patients entered, are the reason for the imbalance in assignment, and until the code is broken it is not fact. I added this to the discussion almost immediately after publication release. I believe they are viewed by regulators as having been randomly assigned to be the lucky few who received a quarter with heads on both sides of the flip.
Thus, they are part of the trial and the IIT treatment analysis of efficacy. Fact... not up for debate in my mind.
I believe they will be used as an internal trial comparator when evaluating cross-over impact and other sensitivity analysis of efficacy. Whether these patients need to cross the presumed 36 mo finish line is up for debate. I believe as stated earlier, the trial will be reported in August and a complete submission to NICE will occur then. Therefore, I believe that we can expect a ‘business update’ which includes laying out the timeline for expected top-line results in the coming weeks. I believe they held off doing so at ASCO both to create additional buzz and to line up a clear financial strategy to get across the finish line.
We are weeks, not years, away from the big reveal.
And it is shaping up to be spectacular!
It is fair to say they are no longer blinded as of the publication date...data lock starts.
Doc,
One more thing to add to counting “hash marks”, all the focus has been on the front end when the back end is far more interestante.
If you count those between 30 and 36 months, you see the number likely to be close to 100% alive now. Adding all the tickmarks. You also realize then that there are a group of patients after 36 months that we’re not represented in the hashmarks on the graph because it ends at 36.
Flip,
In result to a older exchange regarding NICE submission wher you believe unblinded dat begins in August and I suggested earlier is quite possible, I add my previous post.
It is m understanding the between Bundes institute, EMEA, NICE and United States regulators, more than one has the ability to unblind without company knowledge.
ROOT,
It is m understanding the between Bundes institute, EMEA, NICE and United States regulators, more than one has the ability to unblind without company knowledge.
PEACE
PGSD that is an interesting add. The implications here are two-fold and meaningful.
I believe the monthly death-rate actually continues to drop substantially as Dr. Bosch’s Prediction data would suggest. For me, this goes down to 1.25 per but lats say for simplicity 1,75 per giving you (15 x -1,75 = 27 folks) then giving you something like
100 - 27 + 9 (of the 12 LTFU) = 82 alive and kickin’.
You could also be in that cure population already, however which would leave you more like
100 - 8 + 10 = 102
Now wouldn’t that be something....
Doc et al.
In terms of those LFTU patients, I have not been able to read up on much of the coversations. So, I apologize if you have discussed this already. It is my understanding that the reason you maintain the “hash mark” so to speak is that the patient is likely not dead but can’t be “carried forward” without validation.
It has been sometime since I have experience here, but if you don’t see a death report after scanning all state databases and Canadian, German and British national databases, it is highly likely they are alive... but you have to hire detectives to track them down. In my case, we needed them to complete a study return, but for an OS endpoint that may not be true. The agencies take time and are pricey so who knows if they had the cash and knowledge. One might infer that this rather unique way of representing those alive with a hashmark suggests that they are doing so and will return many of those patients to the chart in at least one future space > 15 mo out.
Hope this helps.
Flip, your thoughts please. I just realized something that may be of interest.
When you think about the cohort that is alive >36 mo as of the paper, it is reasonably small because there were only about 20 people enrolled 88 mo before (which is the median of the cohort). Thus, it was rather critical that they get this predictability out now.
Once the cohort that has since passed >36 mo in the last 15 or so months have now passed, this predictability that Dr. Marx presented will shrink, not because it gets worse but because this group will dominate the median calculation and drive the number down. It will presumably be a much large group.
To me this is a Brilliant move by LP!!!! I have regained my confidence in her strategery. Check for now, but soon to be mate.
The beautiful thing about all cause mortality, at least in the USA, Canada, UK and Germany is that publically available records capture individualized death statistics and are evaluated to search for patients lost to follow up in a trial.
The beautiful thing about KM curves is that you can censor those patients by just removing them from both the numerator and denominator at the point information goes dark and if you cannot make for certain a call on their live status.
Longfellow,
I believe that whatever the trigger and plan it was agreed to with FDA last February thus lifting the halt on the trial and the restrictions on certain trial communications that were in place. It always starts in February with the Spring refresh leading to data view in May.
I believe in 2015 this February process initiation led to a data review that ultimately put the halt on new screening put in place, in 2017 this led to the path to ASCO announcements and paper drafting and in 2018 it leads to final analysis, reporting certain updates tomorrow and an eventual top line data release and NICE submission in August.
I expect an update on number of survivors tomorrow and I hope that the timeline to top line data announcement is clarified. MB should be able to state “we expect to report top line data in early Q3 2018.” A statement like that should be an achievable if not beatable finish line and would hopefully unleash the buy side pressure that this company desperately needs.
You are probably right about the CRO and the blond. It still means the company was likely required to take several additional and unusual steps.
AF - is that fracking guy still hanging around somewhere? I have kind of missed being able to validate credulity against a clear alternative
Ponder me this:If the SOC survival at 3 years is about 10% and thus the treatment effect for DCVaX is about 40% survival, how blessed are 10-12 of the 34 final people on trial, and what a shame it is that greedy people have prevented MCC and other solid tumor patients a similar opportunity to enroll?
Ponder me this: since the last 32-34 patients were required to go on therapy after the new screening halt, what did FDA know at the time that the company “didn’t” and what else did they require of the company in addition to dropping the placebo in these subjects?
I know for one that a company in this situation would be instructed that they cannot divulge this fact to anyone including the investigators until instructed otherwise. I know also that these consented patients remain randomized and double blind because no one involved in the car and evaluation of these trial,participants knew that these people would be the first lucky recipients of the new “addition to standard of care that is feasible and safe” at the time that they were consented.
“The addition of DCVaX”. SO SAY WE ALL....SO SAY WE ALL
If you direct a leading neurooncology treatment center that is ready to offer DCVAX after rapid approval, then you want your peers and patients to know it. You want to be associated with your role in bringing forward a new standard of care for patients previously given a death sentence who now have hope of being that 1 in 3 treated who survive 4 years instead of 1.5 years. You want to participate in future combo trials that may push this survival rate even higher and want to signal to the sponsor that you are onboard. How do you do this?
You sign your name to a publication of data.
AVII,
This has been my investment theory since Aug 2015 which has led me and friends
/family willing to listen to my 30 minute stump to sextuple our holdings. See post 142426 re: what I believe transpired back then. All of the bread crumbs have substantiated this theory since, but yesterday’s enrollment data confirmed this in my mind.
If you have an alternate theory as to why only previously consented patients could finish out enrollment and then they were only offered treatment per regulator mandate, then I am all ears. I don’t believe another story that fits everything we know exists.
PFS is in the bank, and the enrichment of the treatment arm with 15% more patients adds to the size and power of the treatment arm, thus increasing likelihood of OS separation statistically, making for a very fat tail.
Smokey,
See posts 142407. The only answer to the last 32 on therapy is that FDA knows it works and mandated so as of 8/21/15.
Final randomization seems to indicate that the last 30ish patients enrolled after the halt were put on treatment only rather than randomized to placebo. This confirms in my mind that the halt was due to an efficacy signal and regulators required randomization to placebo to be stopped. The trial continued but it was no longer ethical to randomize patients to the inferior arm.
Great news! Big days ahead
Flip,
Based on prior signal points, not the least of which was the data and event announcements at ASCO last year, I believe you are being conservative regarding the timing of spring refresh to data lock. Fewer patients living means shorter refresh period thus equating to clear status by ASCO. I think, as we swapped earlier, that late August will be the timing for a top line PR and unblinded clinical data package submission to NICE. Although this is all splitting hairs, it is fun to speculate because we are clearly close.
In addition to the data and publications, just image the convoy of news to follow a positive PR of topline results...detailed outcome data, sub group analysis at congresses, financial stability with favorable stock sale, approvals, launches, combo trial initiations, DCVaX Direct study initiations, new DCVAX-L indication trials, first 1000 patients treated, etc, etc.
NEWS, NEWS, NEWS!
This is gearing up to be a long, exciting trip.
The ‘all are living longer” quote to me could split either way. Yes, it could me that those who event and thus go on to a highly effective therapy will live longer and thus narrow the treatment effect. Or, it could me that both KM curves get shifted to the right in a similar fashion as time goes on, leaving the delta for the PFS consistent with OS. Or, it could even mean that the algorithmic decline for DCVAX improves more with early intervention than late and the mOS gap gets larger than for PFS. It does not tell you anything about the fate of delta OS.
The ‘“all are living longer” statement is consistent with all 3 possibilities.
What it does tell you in all of the three (sorry ex), however, is that DCVAX improves survival. That is because the combined blinded OS data has been running at at least a 50-75 percent improvement upon history at every stage. By now the mile marker benefit is likely to be greater than a doubling of historic norms which are highly consistent in the literature.
The “not good for a study” comment refers to how long it would likely take to reach data markers that create a high likelihood of success. I just hope to all hell that the Spring “refresh” gives them enough certainty.
Doc,
From this trial, in rGBM it will be roughly 2:1 Treated:Untreated, however, selection was not random. Today’s FDA may accept this as proof of efficacy, but it has potential bias.
Don’t they also have a randomized subgroup within the trial? These two data sets together may be considered enough confirmation to prove efficacy. In such case, that could lower the bar with IIT requirements for mOS efficacy difference.
Interesting to see what happens. It better come soon.
Martin
To me the blinded data is for internal trial monitoring and for medical/public interest generation, but not something a regulator gives a hoot about. That does not mean that it does not have great value, just not to NICE, FDA, or any other regulator for this trial. However, iwhen DCVAX becomes standard of care for GBM, then the grouped data set become the yardstick by which other companies monitor their outcomes by in a future blinded set.
What gets me really juiced up is when I will see that they have similar data in metastatic colon cancer, and other rescectable tumors. That’s when shorty has been crushed and Longs will rule momentum for a massive escalation in value. We will look back at the promise of 4zee, 8zees as the good old scrappy days, when millions looked like big numbers.
Flip,
I mean no offense, but do not think a sophisticated and challenging regulatory review such as NICE would begin this stage of review with blinded data. The first submission may include batch validations, process quality and other manufacturing data such as stability measures, but I think unblinded results would need to follow quickly behind as there is no point evaluating something that does not work. The NICE as far as I understand adds a unique review of pharmacoecomic data. This type of information would likely be provided in the later stages of a multi-step submission. Preliminary clinical results have already been reviewed thus affording the August opportunity which LP would be absolutely crazy to pass on.
I think we get a clear picture of timing very soon followed shortly after by topline results to include both PFS and mOS outcmes. They were hoping to get an early pop from unblinded 2017 publication to raise the roof multiple times in succession but they didnt have the clout or luck to pull it off as it now appears. The may or may not provide deeper cuts initially, but likely this rolls out over time to maintain a drum beat of positive noise (or at least that’s how it is typically done by experienced marketer-research partners).
I will say that Imhave been sleeping easier and dreaming big again. Things are looking really upbeat right now to my watchful eye.
Here is to your Dendreams coming true in the near future for all longs. I smell the ‘Rope-a-Dope’ coming this round!
I am not a statistician but have worked closely with several in my career. I believe the answer to your question depends on the number of evaluable patients remain at or after the 36 months. If a large proportion of the assumed 80ish alive patients comes from the say 75th percentile enrollment cohort who were enrolled now over 3 years ago, then the statistical powering improves.
Thank you Ike,
What I Would like to see done is that this Spring data look provides confidence to start unblinding to quickly go next to top line reporting. This would mean based on the comments from Q&A that we could get the early top line results by Mid July. What in my heart I know will happen is that the ball will get punted to Fall/EOY reporting.
Ugggggh
A simple answer to any concerns around impropriety for the short term is to communicate and be transparent around the anticipated timing of events. At this point, they can easily provide details about hat the6 either have begun data lock, or will due so in XX quarter of 2018. Simple transparency will provide so much confidence in management. Too many uncertainties have scared away long investments.
Flip,
Right, and those with better memory than I can confirm, but I recall that just about the time that IMUC reported PFS benefit in P2, LP redesigned the trial to enroll more patients and improve alpha spend probabilities.
in order to market a drug that comes second to market, you will need a strong efficacy message. This message must include OS and will thrive if it includes long term Milestones. So, a near term prognosticator at that time would have needed to think competitively which I think was done. The tragic flaw of this protagonist is that she underestimated the financials needed to cross the finish line, in part due to unexpected turns, and in part due to NO ONE DYING. The Cognate relationship cast a shadow on decisions afterwards.
I still have faith and believe the best in people. Happy days will soon be here again,
Senti,
I believe the final two pieces of your statement are an unintentional result of the market attack that followed the halt. None the less, since this was the result, I expect this result to be worth it. I will be very disappointed if it is not.
I do not know whether the ASM transcripts posted here are a reasonably accurate capture or not, but I assume that they are. In this case, management hinted that they were intentionally holding out to ensure capture of milestone data documenting long tail survival benefit of treatment which may be of historic importance. If this is true, then DCVAX-L becomes the standard of care by which other drugs are adjuvant at best until proven. If then a PII MCC trial and renal or other trials, plus all of the combo GBM trials will capture an enormous interest from oncologists ... which will make the wait and dilution more than worth it.
GLTAL and GBM patients! I hope this in our week.
I agree that the halt had nothing to do with a safety signal. This much was certain then, and has since been confirmed by ASCO 2017 presentation of overall safety experience.
I disagree with your assertion, however, that the halt indicates a failed futility signal on PFS. In my experience, the regulators (in this case later confirmed to be FDA) do not step in to halt a trial for failure at futility unless the DSM indicates that treatment may be harming patients (I.e., performing worse than placebo). A company has many options to take and advantages to gain in continuing a trial that may ultimately fail. This also aligns BTW with the above assertion that halt had nothing to do with safety, for this would be the justification to override company judgement. I may be wrong here, but I believe it is highly, highly doubtful that PFS failure explains the halt.
My belief which has been stated here before is just the opposite which is that a statistically significant positive PFS signal was seen upon a June-July 2015 futility review and that the company refused to comply with a DSM recommendation to stop the trial prematurely. Now, management must show a positive OS to justify delaying results by over 2 years, diluting my interest 7 fold since then, and delaying development of DIRECT.
kD,
Thanks for posting. This basically summarizes how I feel.
MI Dendream
Highwayman,
It sounds like you and I are running parallel investment lives. My 600k and the 2M shares of those who unfortunately hitched their wagon to my enthusiasm are voting ‘No’ without any news.
MI Dendream
While the confluence off potential timing seems to favor your suggested series of Possible, I am just flat out sick and tired of trying to read between the lines that are mentally drawn between the lines. My ability to read the tea leaves here has been poor at best.
Why can’t this company leadership just communicate and expected timeline like all other companies? A novel thought would be to set an expectations for the timing of top line results and then actually beat this timing. Could you imagine that?
MI Dendream “still alive, but hasn’t kicked much in 2018”
Reported where?
Right, right, right.... I gotcha!
But the question is which comes first, the publication or data reporting. Do we get a top line nod before full data release? At ASCO Late Breaker? Later?
My guess is the article in review is timed by XXX journal to realease just a monthish ahead of ASCO. That means a best we get a top lone hit or miss due to ASCO embargoe rules.
Flip,
I understand. This possible light is equally plausible as the many dark theories, and it is just one of several lights that are collectively more plausible that the darkness spouted reagularly here.
Thanks for keeping the faith.
MI Dendream
Kab - Afford,
I have seen some very suspicious dealings in the world of baby Biotech (see Oxford biosciences and Texas Biotech from years back). When it comes to those with money and influence, really anything can happen.
One of my greatest strengths and thus biggest weaknesses is that I believe and see the good in everyone. The above two examples, though are examples of where I got burned to the tune of a modest fortune. Both ended up with successful science that robbed me substantially with shenanigans. On the flip side, I have won more than not by believing in science and good intentions.
Why I struggle with bipolarity here is that I invested a fortune at $5-7 a share when there were somewhere between 90 and 120 million shares outstanding. I expected dilution at that time and assumed that the shelf would eventually be sold fully. What I never imagined or have never seen before in my over 20+ baby Biotech love affairs is a complete disregard for stock shelf limits. I have never seen a management team sell shares that are not available. I am not naive to the power consolidation and alliance building that is going on to ultimately legitimize otherwise seemingly illegitimate actions. I hate to admit that ex is right when he says we will have 1.5 billion shares outstanding some day soon and nearly a billion now with only 400 million are approved to be sold. That is more than a tenfold dilution of the fortune I invested here. SHAME, SHAME, SHAME!
I have been hoodwinked by the science which I still believe will be proven to be a distructive technology. I believe that I will ultimately reap reward for my fortitude. I trust my gut because I have been right over 90% on evaluating the science, although some of those times I still lost due to skullduggery.
When I see what has transpired with 25 millions in share grants, $12 million in backdoor deals, favorite nation clauses, extremely limited public buy-in opportunities olive-branched at tax loss selling time, suspicious Cognate dealings and now Cognate assest sale, and all this possible because of insider silence and innuendo, I get really scared for my children’s financial future...because that is what is at stake here in addition to peoples lives.
My mind tells me that I have been pillaged again. But then, the science... I mean the science that I know in my heart is game changing. It wins, and I truly believe that I will be vindicated.
In the end, however, even if the science is right, and while I may win here I will still lose. When looking at opportunity cost, I have to admit to myself that I still lose because FOLD, ARRY, XNPT, ONCE and a few others were only modest investments for me because of what I dumped into NWBO.
And, if they are really just crooks and this vaccine doesn’t work- then my progeny, one of whom is a lifelong dependent, will be screwed. That just sucks! So I plead....
Dear God, please make LP just a bad CEO and not the alternative. PLEASE, I beg you on bended knee.
MI Dendream
“Once in a while you get shown the light[ in the strangest of places if you look at it right”
Right on flip... I know the truth when I see it!
Here is my view to your q’s:
1) YES
2) NO - no other sources of rev have to b involved to provoke interest, especially if one is an insider already.
3) YES
4) No more Free Lunch, or I should say running a tab
5) Doubt it
6) To signal elation over plan unfolding, or maybe to signal buying to start. bREAD CRUmBS again.
7) possibly
8)Possible
9) Patents May make it difficult
10) VERY
11) also, to derisk your investment portfolio - cash to risk balance
I can’t decide whether I should bow to the brilliant and masterful series of fortunate events (4LP) or be angry about my being fleeced. I kind of got over the fleecing part a couple weeks ago. I mean sure I was fleeced, and man I was angry but in the end I came back to the science and back to my gut. I have since added to my position.
Now got the board, I am asking a couple questions to validate if my recollection is correct and thus form my current opinion.
1) Do we (NWBO) fully own the England manufacturing facility or does some or all of the equipment belong to Cognate?
2) As far as the manufacturing process, where does the net patent ownership lie? Can Cognate use the process of cell maturation and priming with anyone else? Where is the line drawn?
3) What about rest of world manufacturing? Can we outsource or are we attached at the hip to Cognate?
4) What does this say about where LP is putting her long term bet? NWBO, cash, or both
Brilliant minds on this board have these answers,
Help a brother out?
MI Dendream