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If you look back and find the company PR's announcing the expansion of the trial to reduce PFS threshold to 4 months from 6 months, the same PR's state that they have added subgroups.
Every time you add a subgroup you add a chance at a win that did not exist before, and increase the odds of winning by a statistical fluke. For that reason, you eat up some limited amount of such fudging. I have forgotten the vocabulary, but remember the principles. They make sense.
Flipper and Pyrrho and AVII (in particular) and many others are more knowledgeble of these statistical issues. Maybe they will chime in.
I don't know if this is the same issue, or completely seperate, but straight math wise, statistical significance for a 40% subgroup would be much harder to achieve than for the overall trial; simply because there are fewer patients in the subgroup. I don't know if the FDA holds to that issue strictly or not.
However, for this trial, if the approx 40% mesenchymal subgroup demonstrated efficacy anywhere near the levels suggested by the mature Phase 1 data (assuming it was representative data which many, including AVII, have argued it was not) then in spite of being a smaller patient population, statistical significance would easily be achieved in the phase III.
It would seem likely that subgroups were added that corresponded to high efficacy in the maturing data from the open label phase 1. The data that Linda Liau presented about 6 months ago, now famous / infamous.
If so, then mesenchymal would likely be one of the subgroups added. Another might be methylated. Another might be methylated mesenchymal... etc.. I am sure others could do a better job of guessing.
There is a cost for adding each subgroup, however.
Yeah, he's being sarcastic afford. And he has been pretty funny. You all have been pretty funny.
Odds are you will also have your laugh at the end of the week, but you have to take into account the magnitude of the financial and medical gain if it goes the other way. Odds are you will have your laugh, barely. I think it is near even odds that by the end of the week you will once again be standing in the corner, hiding your faces. Like after Celldex collapsed.
I think the longs should decide where the party will be. Just hang on a while and we will tell you three where to go.
"In short, trying to get approved on either a subset or a secondary with the primary ITT failing is unlikely.
They need to hit PFS in the full population, probably need OS trending very well, and still need a generous review."
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I don't think so. There has been a lot more focus on subgroups lately. Further, NWBO defined subgroups before any type of efficacy look. It might makes sense for them to insist on SS within a subgroup, or projection thereof with a confirmatory, and that would be very hard to achieve unless efficacy was outstanding, but a flat rule that there would need to be SS for the broader population would seem off to me.
Biden would kick their asses if they stuck on some technicality that did not have a solid statistical basis. Matthew McConaughey and friends would help Biden.
I believe they added subgroup approval options at the same time that they expanded the trial. This presumably being before any unblinding of the data.
If they added specific subgroups before any unblinding, including to the DMC or the PEI or anybody who might leak back hints, then I don't think it has the same statistical degradation that it would otherwise have.
Just adding subgroups does effect the statistical significance, but nothing like the effect of adding subgroups after some kind of feedback.
Very funny. I do have a tendancy to get dramatic before apparent catalysts, and so far my stats have not been great. It irritates even some longs.
But of course this time is different. It makes too much sense that they have wrapped up the investigation and are preparing to air their clean and dirty laundry. First the dirty, as was likely reported by them to the NASDAQ. Now the clean... or less embarrasing.
All in time for... hopefully a read by the Germans that is positive. But it might not be. My guess is that they did show substantial efficacy for a subroup, but then had to show they could identify that subgroup before surgery. My guess is that the Germans, or whoever, are chewing on that last input of data regarding identifying the subroup.
I like going way out on limbs guessing all the details... You should like that too because that is ammunition for you later on.
Duke-Polio: It is only an open label, single leg, phase 1, and it does not complete for 8 to 20 months, depending on what you call complete.
Stated otherwise... this is not news, but for some reason it is getting a lot of attention on the eve of expected news about NWBO and it's GBM trial.
Not responding to your question... that is for others.
https://clinicaltrials.gov/ct2/show/NCT01491893?term=polio+gbm&rank=1
Condition Intervention Phase
GBM
Glioblastoma
Glioma
Malignant Glioma
Biological: PVSRIPO
Phase 1
Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Dose-finding and Safety Study of an Oncolytic Polio/Rhinovirus Recombinant Against Recurrent WHO Grade IV Malignant Glioma
Estimated Enrollment: 65
Study Start Date: January 2012
Estimated Study Completion Date: January 2018
Estimated Primary Completion Date: January 2017 (Final data collection date for primary outcome measure)
"NorthWest Biopharmaceuticals is at booth 10147"
Actually 3 Booths totaling 9,100 Sq ft. Maybe one is not technically a booth, not sure.
Booth Space Dimensions
#10147 4500 sq Ft 90’ x 50’
#10155 4000 sq Ft 80’ x 50’
#Reg85 600 sq Ft 30’ x 20’
Genentech is the largest presence at 10,000 sq ft. I think NW might be #2.
AbbVie has 4900 sq ft and a market cap of $98B
Maybe leasing all that space will be very embarrasing this year... or not. My bet is not. The Doktor is in, all-in. Not because of the booths, but because I think an efficacy look is in progress, and at this price, I want to be here for the result of that look. Further, I think the apparent pending catalyst next week to sell the warrants is real, if not super dramatic. NWBO has something good to say next week. Maybe not the efficacy measure that I would hope for, yet, nor even an abstract foreshadowing such, but if not, something substantial. Maybe something about the investigation... or maybe that as a starter and something more with the abstract release.
"Hey this is exciting!!!"
I hope the polio cancer treatment is for real, but what have you constantly said about single patient results?
Further, surgery was in 2011 with recurrence in 2012. That could be anywhere from 1 day later to 2 years later... an enormous range / very vague.
Could what they saw as recurrence have been massive inflammation of residual tumor, ie pseudoprogression? What variety of tumor was it? Was it methylated?
"I don't see any swimming pools around here to save you."
See "Grappling Hook" and "Mahogany Door". I'm not sure he needs a swimming pool.
"DCs, if properly activated, can manipulate their environment to get antigens to present themselves that would otherwise remain hidden."
This is the part that is news to me. I didn't know that was one of the behaviors that could be modulated.
Seems likely that some mutations disable the basic protein presentation function altogether. If so the cancer would be extremely hard or impossible to detect; unless the cells have redundant mechanisms for protein presentation based on different genes so that any given mutation can't disable the function altogether; and (sounds like you are saying) some of those redundant modes are only set in motion by the right cytokine environment, while the more standard mode is always at work unless mutated out of existence.
"I am also convinced the little redhead did not go to the ball without her suitor waiting and ready. We'd still be OTC. "
But didn't AVXL report a month or two ago that the Donopezil adjunct group was (surprisingly) no longer showing greater efficacy than the Anavex 2-73 monotherapy group? Or am I remembering that wrong... or did I misunderstand?
Or is the guy in the Tuxedo maybe someone other than Eisai Co. or Pfizer?
Yes. I swear I had not gotten to this post yet when I (last night) posted the same cut and paste from your earlier post, with the same pre-amble. Yes, you condensed the article enough to make it much easier to see all-at-once. Thanks!
Your post #59745 summarizes and clarifies the Prins article. I follow you now.
flipper44 Member Level Tuesday, 04/26/16 12:11:58 PM
Re: Doc logic post# 59742
Post #
59745
of 59783 Go
Doc logic,
That may be the case, but my point in the thread we are discussing is this.
IMHO.
1. TIL count does not correlate with survival when standard of care is used. -- UCLA
2. TIL count does correlate with survival when DCVax-L is used.
3. ALC does not correlate with survival when SOC is used.
4. ALC does correlate with additional survival when immunotherapy (CI) is used, but we are waiting to see if this is an additional biomarker for DCVax-L.
The point is that with TIL, Dr. Prins states that, as a simple explanation, DCVax-L helps reactivate an immune response in tumors that are immunogenic but previously suppressed an immune response.
With regard to absolute lymphocyte count (peripheral blood lymphocyte count), patients in the DCVax-L trial have an absolute lymphocyte count ≥1,000/mm3. This means they do not start DCVax-L treatment in patients with lymphopenia. In other words, patients are more likely to still be able to mount an immune response, which may, we shall see be exploited by DCVax-L to fight the cancer.
You are taking it a step further and assuming I'm saying the ALC means there is an active response against the tumor -- prevaccination. I'm not saying that is necessarily the case. I'm just saying the inclusion criteria used patients that are more likely to have immune systems against the cancer activated and/or reactivated by DCVax-L and/or made more robust.
(This is not a black and white issue, because even where there is lymphopenia, the chemoradiation may have simultaneously temporarily compromised regulatory immune cells and thus allowed DCVax-L time to get a foothold -- sometimes. That is an area where there is controversy in the literature, and I believe the phase III trial might provide more data on that issue.)
Now add the recent UCLA paper, it's not just TIL count, but also, "significant overlap in sequence between T cell receptors in the tumor and in the peripheral blood was correlated with extended survival." This additional correlation was found when DCVax-L was used. Interestingly, even some patients that did not have overlap prior to DCVax-L treatment, developed it afterwards.
"She was a relatively new Board member"
If that is true then I see your position. I see why that would push things over to the question of Ondra's responsibilities. And that I think is a far more difficult question. One that you and others have the background to debate but I do not.
But I think most of the energy left in this debate comes from people not knowing or remembering that you believe Katherine Wolfe was new to the Israeli company's board.
Re: Screening Halt and Recent Increased Subgroup Knowledge:
Back before the screening halt, at the point where NWBO modified the trial for the lower PFS threshold of 4 months vs 6 months, I believe they also added subgroups or more subgroups.
Maybe they have learned more about subgroups since then. There is the Dr. Prins report... maybe that was the question you were addressing.
I had been thinking that the info in this new Prins et al report might be input to the regulators if they are making decisions based on an efficacy look; for this reason:
While NWBO may have specified subgroups such as mesenchymal, even if SS efficacy is demonstrated there still might be an issue of whether NWBO can identify that subgroup prior to starting treatment. Prior to treatment is pretty important if different therapies are vying for different subgroups.
Maybe NWBO can't easily identify mesenchymal before surgery. Or maybe not in a way that makes time and economic sense. But maybe it is close enough to identify that TIL count is high or ALC is high or both or something. Maybe that mostly detects mesenchymal... but not exactly, but close enough for hand gernades and DCVax-L. Maybe in fact... as I think you may have said... identifies Mesenchymal and a small number of non-mesenchymal where DCVax-L is also effective.
But you can't just make up subroups after the fact AVII would tell us, correctly. But maybe when the subgroup is so closely related, ie mostly detects Mesenchymal... you can. And so maybe that has extended this dramatic wait. Ie time for the agencies to consider these questions and these test results.
DOC: If a tumor manages to hide a number of mutated / non-self antigens I understand that the DCVax-L lysing + DC exposure would sniff those out. What I don't understand is how the resulting T-Cells would then find their targets?
Is the reasoning that the T-Cells don't need antigen match at the surface of the tumor cell in order to do damage. Ie that they penetrate better than DC's ?
It seems the T-Cells do infiltrate the tumor... but that is interstitial, is it not? So if the antigens are not presented... the T-Cells don't actually penetrate the Tumor cells looking for antigen do they? Could they do that and then get back out without damaging the cell? I wouldn't guess so, but it sounds like you likely know, and do not have to guess.
Your saying that Prin's (et al) study did not report increased survival with high tumor lymphocyte penetration nor with high lymphocyte blood concentration?
Sorry to hear that. I misunderstood the report. Was there anything good?
I think what you say here to DOC makes sense, and adds some perspective. But what I think most have been surprised about is that you are arguing that Katherine Wolf may not have known about the years long, ongoing lawsuit between NWBO and the Israeli Company she is on the board of, or that she would not consider that to be a conflict of interest. There is a tiny chance that one of those is true, but from a distance, it is such a slim chance that it does not seem reasonable to take seriously. Thus you do not appear to be your usual intelligent and rational self on this one.
I did work for a company that had lots of people listed as board members that knew little about the company. They were apparently there for optics/decoration for getting acquired. Is that what you are visualizing? Or maybe the Israeli company is so large that this ongoing lawsuit is just noise in the background?
"Whole-Tumor-Lysate Pulsed Dendritic Cells for Breast Cancer." I have long wondered why NWBO does not go there. Maybe it is because there are existing, hormonal therapies for many breast cancer types that have low side effects or maybe it is because it is sacred ground due to the large market, and NWBO has leaned toward letting their plans be dark and impenetrable as night, at least on this major league, BP dominated, indication.
Hey, Steppenwolf is here too! Truely an NWBO reunion.
$Three million times how many executives? Peanuts. To the extent that it indicates foul play I understand the concern. To the extent that it indicates that the motivation for the trials may be to line the execs pockets and keep Cognate fed... I understand your concern.
But if the trial is real and chances for efficacy are real then at least in terms of magnitude, $ wise and otherwise, that is peanuts.
Looks like all the old-timers are crawling out of the wood-work for the impending... party or funeral or both.
Added very late to my last post: The delay in alleged pending regulator decisions about L could be due to pending study results, no longer pending, regarding the ability to predict L efficacy prior to treatment based on examination of blood or tumor biopsy samples.
I think NWBO may have requested a final decision wait until the results of that study could be uploaded to regulators for consideration. How long would it take regulators to consider those results? I don't know. Those results are very recent. One or two weeks ago?
My guess is that major news is pending and you will be burned only if the news is bad. It is possible however, that the news was expected by NWBO sooner so that they would be forced to dilute due to the delay, as appeared to have happened recently. But even if so... I would think it would be a relatively small dilution unless they have reason to believe that the news is no longer imminent.
In other words, I don't think they are holding back bad news. I think they really don't know. I think the only scenario where they are holding back bad news is if they somehow found a way to qualify a delay thereof due to an ASCO abstract submission or something, hoping to delay that bad news (about L) so that it will be simultaneous with good news, or relatively good news about Direct.
But more likely, the are waiting on news; and recent study results showing a way to detect success up front from blood or tumor biopsy may be what regulators were waiting for at sponsor request to make that final decision.
"Price per share increase? Okay, and what do you expect will take the price higher?"
(He is asking this to Flipper.)
You really are a new poster then. Flipper has written a book on all the possible reasons we could have a share price increase.
I would point out that even if there were misapproriation of funds, unless there were mass amounts of money involved, the degree of share price drop over the last 9 months is completely out of praportion with the situation. They are at the point where an efficacy read from the German HE would be expected... at least by us longs. There could also be more data on Direct. All those early progressors... how many were actually not progressing but just inflamming? We will soon know. Maybe none, but if many or most... OMG$ Short it into the ground! That is my advice! Hurry!
Who benefits if the company goes under? Future patients? Current patients? Investors? Nobody.
Regarding the ethics of the screening halt if for financial reasons...
Chiugray and Astravaka! And Etienne has been showing up lately. That makes it official. It is a major NWBO event. Something is in the air. May it be something good.
Whether these therapies ultimately prove out or not, it is certain that you and Flipper and John and many other posters have done their parts to try to help Northwest get through the trials to find out. I'm not taking anything away from the honest critics, some of them extremely intelligent and honestly motivated, but my hat is off to you Sentiment for this level of dedication to what remains a possible significant new pathway for cancer therapy.
These contributions do matter. Someone once posted that hundreds of retail investors read these posts. I am sure that it is not just retail investors that read these posts. You guys do make a difference. And if all goes badly, none of you ever gaurunteed a positive outcome, you just understand the weight and value of a positive outcome and assessed honestly that there is a significant chance thereof if the company makes it through the trials.
And LP's sister died of Leukemia when LP was fairly young. And LP's father battled cancer multiple times, not just the final brain cancer.
"The price of LP's gifts were reported at $.00 cost:
950,000 shares from 2010 at 1 for 16 is 59,375 shares;
950,000 shares from 2012 at 1 for 16 is 59,375 shares;
and another gift in 12/2012 of 59,405 shares"
So that's about $1M at the average SP over the last couple of years. I understand that you thought is was $16M and would be somewhat concerned.
What I don't understand is; are you sure these are company shares, or are these LP's shares? If they are LP's shares, then why does it bother you?
It's possible that Katherine Wolf was caught dropping her pencil repeatedly at the big roundtables. That may have clued LP to look further into her background.
"MDSCs, lactate, and a low pH in the tumor microenvironment inhibit the function of natural killer (NK) cells and T lymphocytes, hence allowing for disease progression."
From the next to the last paper that you linked.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3881600/
It doesn't make any sense to me that low pH would be specificly suppressive to the immune system. Tumors grow fast and with less vasularization than normal tissue. For that reason they tend to produce more CO2 than they can efficiently get rid of. That would likely be the single largest factor determining pH in the local environment. A local low pH then would be a clue, among others, that a malignancy is present. Detecting such clues is a key function of the immune system.
For that reason, I find it surprising that a low pH is talked about as immunosuppresive. A low pH is suppressive to all cells, not just immune system components. I think that is overlooked here, and it is something pretty basic to overlook. So... is this article biased? Are all the articles biased?
Probably not, but it makes me wonder a little.
Certainly you have done well to collect all these articles, and I will examine them further.
Re DCVax-L expectations: At this point I would be happy with 6 months PFS for the methylated mesenchymals. 6 months for all mesenchymals would be even better... with the complement to the methylated being a challenge that would hopefully be quickly overcome. If the LL presentation data was as meaningfull as LL conveyed, then I think the latter of these will be found, possibly soon. If not... as many ar arguing, then us longs are in trouble soon, at least for a while.
That is a lot of good research RK. But isn't it kind of standard for a small biotech to unleash shares just prior to expected buying? If they didn't do that, the stock price would drop, or would drop more.
Would it be better to do this through an underwriter / financial firm? Those firms take a cut, and from what little experience I have, they are sometimes not very honest. I started opening an account with one of them so I could get warrants with shares and after closely examining all the agreements, I just couldn't do it. There were lots of little gotchas that apparently most people don't read. Ridiculous provisions. If I was LP, I would avoid such firms if I could.
"Cognate is not NWBO. And NWBO is not Cognate. Investigators are looking into NWBO's conflict of interest 'pubic' practices."
Well, I do see why they would have to become board members to get that close a look at NWBO.
"Cognates manufacturing of stem cells"
The DC's for DCVax-L and Direct are grown from stem cells extracted from the patient's blood. I don't know whether that is what the text you are pointing to is talking about, or not.
If not... counter to what I have seen posted here, I think it was understood from early on that Cognate would be serving many customers. For a bear, that is evidence that Cognate is just using NWBO to stay afloat, but to a bull, it also makes total sense. NWBO needs to show the ability to mfg on a large scale to gain approval for therapies that are applicable on a large scale. It does not makes sense to attempt to keep such a large facility afloat and growing with only the business they would receive from NWBO during these trials. If approval is gained, there will be a large jump in the needed floorspace and personel to meet production needs. They cannot make that jump fast enough starting from the small levels of production capability needed to support the current trials. So... they fill up their facilities with as many other contracts as they can get, but keep the contracts flexible enough to allow changeover to NWBO products at a pace that would satisfy everyone, if that need arises.
You failed to rub LP's halo. That is why you cannot see these things as clearly as I do. It's magic!
I wonder whether NWBO is continuing efforts to automate DCVax-L manufacturing. They said in the 10K that they finished automating Direct, but did they give up on L?
"Win or Go Home" may be referring to an efficacy look for L, somehow, in spite of all the reasons that could not be going on. The difference between looking now and looking later is the threshold for statistical significance. 6 months vs 4 months PFS. And the difference between those two numbers relates to reimbursement, at least for the German HE program, and probably across the board. They may have decided that the reimbursement expected for 4 months PFS would likely not cover manual mfg costs. Therefore they are saying... lets just look at the data now and hope that we have 6 months for everything or subgroup(s) where we can be profitable without automated mfg now. Maybe a confirmatory for the 4 month looking subgroups would make sense... and they would continue development of automated mfg of L to make those subgroups profitable... while making money off of the 6 month subgroups now using manual manufacturing. That would support the trials now.
If so, the question for L is whether any subgroup meets statistical significance for 6 months PFS now. If one does, they have a means of supporting Direct development, and possibly a means of supporting automated mfg development for L for the subgroups with lesser efficacy, TBD. But if not... if no subgroup is showing 6 months PFS with SI now... then I think they want to move on to focus on Direct.
So if no automated mfg for L yet, then where did the money go? I have to rub LP's halo to make out the message... it says... Real Estate + Extremely Costly Automated Mfg Dev for Direct (Completed) + a very expensive attempt at developing automated mfg for L which they may or may not have abandoned at this point, but either way, is not complete.
"A little print from the company could have righted the ship many a time, but was avoided. Almost like the price action was preferred. Strange huh?"
I worry about that a little bit. The anti-dilution clause, if I understand it, has much more bang for the buck (for LP) at this low valuation.
On the other hand the anti-dilution clause really is necessary, and the chances that this screening hold is for some very real reason is very high. If for a real reason then silence may be necessary. Very uncomfortable situation agreed, but an apparent conspiracy by NWBO... no. Not apparent.
Regarding BI/CM +DCVax combination therapies. I haven't followed every Blockade Inhibitor / Checkpoint Modulator clinical result but there are clinicals where the efficacy was not great, and there were clinicals where the side effects were horrific. Were there clinicals where there were great results (ie 25% CR where chances were next to nil) and without the large percentage of side effects which include death?
I am hoping that mixing these BI/CM drugs with immunotherapies such as the DCVax's allows either safer BI/CM drugs to be used or lower dosages resulting in lower side effects yet through synergy with the immunotherapies, greater efficacy. This reduction in side effects doesn't get brought up often, so hoping to spark such conversations.
Understood; that if a CI takes a 5% 2 years survival and improves it to a 25% CR with demonstrated 25% 5 year OS, then horrible stats on side effects for a large but minority population of patients is tolerable. But if you can match or exceed that efficacy and also drop the rate of serious side effects, then that is far better, of course.
What would be the best possible news in my opinion would be that NWBO has been thinking along these same lines and has purchased a low side effect BI that shows great synergy with DCVax-Direct in early studies, even just animal studies. How could they afford such? Maybe such a BI does not have a high price tag because it did not show great efficacy as a monotherapy.
Highwayman doesn't BS. I am certain of that. You had better hope that something else saves you.
Apparently that same Zacks small-cap subsidiary did post a $16 target a few days ago. So if you buy the $8 you should buy the $16. The question is what do you think of Zacks and what do you think of the subsidiary which isn't referenced anywhere on the Zacks main website. But it is truely a Zacks subsidiary, verified.