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I might be missing your point, or repeating what you are getting at, but:
1) If the data from the rapids is compelling, as it reportedly is
2) If the data from the rapids is so compelling that the fact that their info arm has no control group doesn't matter...
3) If then the only hole in that rapid progressor data is the possibility that a bunch of pseudoes got in there...
4) But if the combined rapids + pseudos is so compelling that the fact that the rapids did not have a control arm doesn't matter...
Then maybe the group they might be looking for approval on is simply the early progressors, without regard to whether they are rapid or pseudo.
If so, that would simplify things a great deal.
Not saying this is likely, just putting it out there for debate by the people that would see the holes, such as you Sentiment, and others.
"she understands what's going on"
Vmlg27's wife get's it, what's your problem Afford?
Mostly wondering what they call "mesenchymal" if there is no resting state mesenchymal. Anything that is generating mesenchymal runners? If so, there would be multiple types of mesenchymal and you would expect efficacy to vary. DCVax-L might work on the runners, but what of the stationary tumor? It has to work there too.
.. unless as I was getting at, the resting tumor is actually in a losing battle already if not for the mesenchymal runners.
I did sort of understand what Doc was saying, but you have clarified it further. The underlying genetic code does not fully specify which antigens will be presented because it does not fully determine which proteins will be built. That gets modulated as per cell type / as the shape changer changes form. Thus the various implications that you two brought up.
Interesting... to me anyway, and probably to you (if not to a lot of frustrated investors not interested in this stuff)... the transition to mesenchymal can be spurred by stress... as you have said with the locust analogy, etc, and as it says in the papers you have quoted, including hypoxia. Removing the tumor is certainly stress... so if they wanted to generate more mesenchymal characteristic antigen, maybe they could put the tumor in luke warm saline for a little while instead of freezing it right away, allowing some transition to mesenchymal... or not. I wonder how long it takes... ie how long the tumor cells would have to be kept alive but hurting, for such transition to occur?
They do get to sterilize the tumor lysate later, I would suppose, as far as pathogen reproduction side effect goes. Freeze thaw may not be enough to kill pathogens... but if they really do a lysate procedure involving an alkaline agent then that would probably kill everything.
"args phase 3 is for rcc, no connection with GBM."
Oh yes. I knew that but in all the recent discussions about competition (in the longer haul for multiple indications) momentarily lost that. Thanks. So, not an explanation for the delay or a clue at timing. Plenty of other explanations provided recently / today by you and others.
Adds the info that Proneural can become Mesenchymal and that in general there might be transitions between types. But still not super clear just what constitutes a mesenchymal tumor. If mesenchymal denotes the migratory form then there is no such thing as a purely mesenchymal tumor... only tumors with some mesenchymal cells, whether those cells hang around or immediately migrate?????
If one assumes they migrate soon after transition then a mesenchymal tumor would be any tumor that is generating mesenchymal-radiation of sorts. Sort of like evaporation.
This mesenchymal-radiation would be a survival advantage (for the tumor) so that a weaker tumor might survive with this going on, that would not survive without this going on. So that if DCVax-L were to kill the migrating mesenchymals-radiaton, as you speculate, it could tip the balance for the rest of the tumor cells toward death. Maybe.
Restated... a tumor that would normally not quite survive immune system attack might survive because it is constantly moving, via this mesenchymal radiation, perhaps away from local cytokine dominance by the good immune system. Thus killing off the migrating mesenchymals could be enough to allow the immune system to kill off the tumor.
"If you are not genuine"
Afford is genuine 100%, I assure you of that CherryTree, as are you.
"But the SEC forms I read paint a slightly different picture.
Feb 29. They raised $9,210,000 by:
5.9M shares stock
2.9M Series A warrants (ex. $2.25)
5.9M Series B warrants (ex. $3 and expired in 60 days). These had the kicker that if exercised the purchaser would get Series C warrants also
Well, 60 days came and of course the Series B options at $3 were not excised. So NWBO changed the terms. Result
May 15. They raised an additional $4,235,000 by:
4.4M shares common stock via the series B repriced from $3 down below $1
Repricing the existing 2.2M Series A down to $1
Repricing the new 2.2M Series C down to $1
Adding Series D to purchase 2.2M at $1.
Not even close to the Feb 29 terms. "
What do you come up with as the fully diluted share count at this point if all outstanding warrants get exercised, and what would be their $ gained from the exercise of those warrants?
Lots of good info. No, I don't remember anything about radiation inducing cell transitions, but I believe you.
Still a little unclear as to what they call a mesenchymal tumor. Are all epithelial tumors called mesenchymal, or do some epithelial tumors not tend to make this mesenchymal transition for migration? Does an epithelial tumor have to have some minor population of mesenchymal state cells for the tumor to be called "mesenchymal", or is the latent potential to do so enough?
Ie could an epithelial GBM tumor be called "Classical, or Neural, or Pro-Neural? I suspect not Neural or Pro-Neural, but could it be called Classical with the observation that it is not generating any mesenchymal cells?
"And I do believe for a hold this long, some step in approval must be being discussed."
If there is/was an efficacy read for DCVax-L, and a request for consideration of some kind of approval, then I think the regulators would want to look at the efficacy of all other GBM therapies possible before they decide. Especially with subgroup issues becoming a focus for some therapies.
There was the Celldex Ph 3 trial some time ago to look at, then two Phase 2 unblindings for presentation at ASCO (one may have been open label, but still data compilation and presentation) and as you guys are pointing out, very recently the look at ARGS phase 3 50% interim data. Since the ARGS data is very recent... I think some reason to believe that there is a chance that this was the last of the data to be considered before making a decision on this alleged approval for DCVax-L.
"At least 6 months."
6 months from the notification tripping point, which has not been reached yet. At that point most companies usually apply for an extension, and are given another 6 months. So probably a year from a point in time that has not yet been reached but will be reached one week from today.
They have a few days to notify the public of the notification, so they will likely delay that till (next week's) Friday, after market.
"I do believe there are corporate governance problems and structural issues with how this company is managed. I would bet dollars to donuts that's why many institutions have kept away."
Not a radical thing to say, but it is substantive because it distinguishes the reason from advance knowledge or guesses at eventual demonstration of efficacy.
About 2 years ago a true whale (I believe) wandered onto the message board briefly and after a few back and forths, left with a final comment matching what you are saying. He claimed that the unusual business relationship between Cognate and NWBO was why he and other whales were staying away. I think implied was the unusual control that LP has. (Not to say that some of the current posters do not appear to be whales)
My opinion on that is relatively unimportant, however, over the years I did grow to appreciate the tremendous advantage to NWBO that the Cognate relationship could provide. The tremendous advantage in having complete control over critical mfg issues with complex budgets and timelines as well as technical challenges. Leaves all kinds of room for abuse, and the relationship may have been abused, but there was a huge advantage. It makes total sense... just a question of whether or not it was abused, or to what degree, in my opinion.
"Potentially more neoantigens"
I point out again to Doc, however, that only the T-Cells, and (maybe) antibodies know the difference between a self-antigen and a neo-antigen. This quoted line and a similar line in the post you are replying to makes it sound like the cell is preferentially modulating the presentation of specifically neo-antigens, when in fact, the cell does not know the difference between self and neo antigens. If it did, the immune system's job would be much easier.
Thanks: Re Mesenchymal<->Epithelial transitions. Sounds like there is definitely a relatively stationary version of epithelial and a migratory version of mesenchymal, but is their a stationary version of mesenchymal?
I ask because you would think that a GBM tumor grouping of "mesenchymal" would describe a relatively motionless mass of cells, rather than a mass of epithelial cells that had previously metastasized via temporary transition to the highly mobile mesenchymal state.
"During migration [after/during epithelial to mesenchymal transition], cells overcome this problem either by creating a dense array of short-branched filaments as found in lamellipodia, or by bundling filaments as found in filopodia."
------------------------------------------------------
If this "dense array of short-branched filaments" has exposure to the outside world, then I would agree that this is consistent with some possible transient increase in vulnerability to immune system attack, like a turtle's legs when it walks, as you said. Just the increased surface area due to the "dense array of short-branched filaments" might increase vulnerability, but maybe something more dramatic, as you suggest. Maybe a reduction in immune blockade function on that large, specialized, transient surface area; combining our guesses as to why DCVax-L may be more effective on mesenchymals.
You are saying that the mesenchymals do more of this fast movement than the other three subgroups?
May 2, 2015 PR: "Well over 300 patients have been enrolled."
Aug 21, 2015 PR: "Total anticipated enrollment is 348."
You haven't been hearing those kind of numbers continually for years. The hold might delay things, so that they may not be as close as it appears above, but a year ago you didn't have much enrollment info.
At this point they have so many trial sites that enrolling the well-less-than-48 further patients would not take long. Iff they don't expand the trial. I guess that would be your concern. Yes, I agree that could happen. But the situation is not stagnant. They have slowly increased the number of sites allowing much faster enrollment if needed.
We are nearing the likely end of a very long wait for Phase 3 trial readout. A failure is already anticipated by the current SP while a surprise has about 30X upside potential in the near to mid term, possibly more. That seems pretty simple to me.
"You may well have had a reasonable estimate at the time."
You were being nice here. When I look back over PR's
-------------------------------------------------------------
Aug 21, 2015:
"Well over 300 patients have been recruited. Total anticipated enrollment is 348"
and a more recent PR
May 2, 2016:
"..., well over 300 patients have been enrolled."
------------------------------------------------------------
I would have to agree with your original critique that 348 having been screened at the time of the screening hold seems unlikely. Possible, but unlikely.
Sorry for all those with good memories that have been through all this scores of times now. I need to refresh often.
"Problem is, the pipeline of screened patients has evaporated. They can not enrol somebody who is 9 months past surgery."
Why do you assume that screened patients did not continue to get enrolled after the screening hold?
"As a separate issue, it is course also non-sense to think the FDA will accept a datacut decision based on unblinded results."
True. That is definitely not allowed. Such would allow you to take advantage of variance / noise. You are right.
As for the number screened being enough for full enrollment... I will have to look back over the facts. I am going from my iffy recollection of how it looked to me at the time. I will get back to you.
My guess is that if HE reimbursement suggests a PFS improvement of 6 mo + some margin for error for not being fully mature yet, then their DMC would recommend an efficacy data read at 248 PFS events, as you say. But if the HE reimbursement suggests a marginal, ie 6 months exact efficacy, or less, then they would recommend just continuing the trial to the end, first re-opening screening, if necessary, to get to the full patient population for the revised trial. As I explain below, I don't think they would need to screen any further patients to reach full enrollment for the revised trial plan, but I am sure others here know better than I about that.
This assumes that either NWBO or their DMC can infer efficacy from the HE allowance for reimbursement.
Alternatively, if the PFS advantage suggested by the HE reimbursement projects much greater than 6 months, then the DMC could recommend some sort of AA with confirmatory be applied for. I don't know those trial details well, ie early approval vs AA, but I think they would only have to carry the confirmatory out to 248 progression events in that case.
Of course the trial is messy with PFS being a difficult read for GBM and with OS being spoiled to an unknown degree by crossover. Further, I don't know if the HE reimbursement level is based on PFS or OS. If OS, then all of the above would be different and more complications ensue. Over my head with this level of detail, just agree that the level of enrollment and screened patients was conspicuous when the hold occurred with the number enrolled being roughly the number needed to demonstrate SS for 6 months PFS advantage (old bar), and I believe the number screened being about the number needed to demonstrate SS for 4 months PFS advantage (new bar), if all those screened were eventually enrolled.
"It is very possible that NWBO has about 312 or more patients currently enrolled. Than if NWBO reached 248 events some time this year. Wouldn't NWBO just need the PFS and OS to be greater than the amount given before the resize in trial happened?"
That was my guess from the beginning as to why the screening stopped where it did. That would require sponsor involvement, however... but maybe indirect involvement. Maybe NWBO and the PEI negotiated when the look would occur to evaluate HE reimbursement, and NWBO pushed for the point where 312 were enrolled, matching the required enrollment to reach SS for 6 months PFS advantage, the old bar, as you said.
In that scenario it would be PEI calling the hold on screening, but really NWBO selecting in advance when that hold would occur.
Of course the point in the trial where this data look for HE reimbursement consideration occurs would have to be acceptable to the PEI, but maybe it was. Just a two-fer for NWBO. I like two-fers. I am sure LP likes two-fers. Whether she likes or will like the results of the alleged look... is a different question.
"NWBO will be on sale for two for a dollar soon"
The known facts may warrant a low share price, but they do not warrant the current extremely low share price, let alone a further drop as you suggest. Even Woodford recently stated that he thought the share price was out of wack with reality.
The question is whether the conspicuously low valuation is due to advance knowledge of bad news or manipulation by shorts or foes of NWBO.
I am going with manipulation. I am going with the notion that this is a blinded clinical trial and nobody yet knows the results. I am going with the view that while business improprieties have apparently occurred, they may not prove to be significant improprieties, and if efficacy is demonstrated, that fact will trump any business issues, both ethically and financially.
"Should be bitter at the CEO that's vaporized and abandoned this co to be delisted - not me for making newb buyers aware"
There is no eminent de-listing. It doesn't work that way. If a significant catalyst comes in the next 6 months there will be no de-listing. But I suspect you know that.
dade: "I thought you might find this article on Seeking Alpha interesting:"
There are no Federal or State Judges on this message board to my knowledge dade.
To be clear; I think that down the road such judges might be very interested in that Phase V article, who the authors were, and who funded it. But this is not the time or place for that dade. All in good time.
dade: "I thought you might find this article on Seeking Alpha interesting:"
There are no Federal or State Judges on this message board to my knowledge dade.
Could be, as you speculate, that the Mesenchymals are more vulnerable in their walking/running state. But I have wondered if they have less Immune Blockade function making them more immunogenic / vulnerable to DCVax-L, with some other survival features that normally offset this weakness, perhaps this horrifying fast travel mode being one of them.
You may remember statements counter to that from the research; ie about Mesenchymal and Immune Blockade function. But since I don't remember any talk about that, I wonder if the other 3 subgroups have strong Immune Blockade/Checkpoint function in their arsenal, while Mesenchymal is successful without it.
"and other technologies such as:
http://hub.jhu.edu/2016/06/09/predicting-speed-of-brain-cancer-spread "
That is a very disturbing video.
This particular trial has known complexities for interpreting the clinical data. This is likely something that LP spoke to Biden about. Payment for these new scientific advisers is probably with shares, but if so, why would that be a bad thing, and if not, I wonder if the Feds are funding it?
I hope you are right that they were testing for which of the four GBM subgroups the tumor fell into. I updated my previous response along those lines.
Methylated or not? Infiltrated with some T-Cells already?
Or maybe he misunderstood. Maybe he is aware that many patients tumors do not get handled properly, so those patients get eliminated, but he assumes that the qualifying handling of the tumor is testing, when in fact it is freezing that is key.
But I hope you are right that they are looking at which of the four GBM subgroups the tumor falls into.
Maybe they were balancing the subgroups at that point, or maybe they had already decided to begin populating only the mesenchymal subgroup at that point. A huge subgroup.
So paid in shares is a bad sign? Golly Eddie, if you say so.
An aside Flipper. Don't want to start a useless tangent, but if the only DC's that aren't matured after pulsing with Lysate are the ones not activated, then it would seem advantageous to leave them alone, ie let them stay immature scouts rather than mature runners.
The macrophages presumably eat the excess, and I would hope have a tougher time eating the faster runners than the scouts. Any DC not activated ideally gets deselected somehow during the mfg process, but if not, might as well get preferentially weeded out in the patient.
But of course this is down into the detail where it might not quite work like that.
"IF NWBO GOES BK EVERYONE LONG HERE WILL JOIN CLASS ACTION SUIT AGAINST COGNATE AND LINDA"
I don't know about that. I would have to think hard about whether anybody at NWBO was really responsible for my loss. Whether I would participate in such an action would depend on the details. If all details remained obscured, then maybe, at least long enough to get those details. But in the end, whether I stayed with the action would depend on those details.
Afford: Maybe you should unwind your last add if given the opportunity, but regarding your higher basis: What are the odds that ultimately the NAS violation will prove to be the only substantial business wrong-doing? What are the odds that L will show efficacy, at least in a subgroup? What are the odds that Direct will prove out with or without the BP BI partners?
And if the business side is not as corrupt as your fears, and the efficacy is demonstrated, then you will wish you had not been so harsh, because after all, this is a major branch of the new cancer immunotherapies under the microscope. This is a big deal.
There is definitely a chance that LP will prove to be so much more concerned with the success of Cognate than that of NWBO that we will get burned, but the fact that there is a substantial chance that this will not prove to be the case outweighs that concern, in my opinion.
There is a chance that your fears will prove unwarranted Afford. You know that. Maybe not a reason to buy, but a reason to be careful not to lessen those odds. I am going to try to remember that going forward.
"But here in US, Gleevec is already going generic."
Then that is what the author should have pointed out. Very different from just saying that drugs should all cost 5 cents.
So what legally prevents Columbia from invoking their own "Hatch-Waxman Act", if anything? Are they in legal rights to do so, but the stopper is just the bullying by the US? Is there a good reason for any legal constraint that applies to them but not to the US?
This is what the article should have been about.
The US has hundreds, or maybe thousands of patents on pharmaceuticals that elevate the cost of critical medications for US and other patients over what their mfg costs are or what a generic version would be. Is that a horrible thing? I don't know. It is a fundamental debate. The people saying it is not so horrible would argue that the drugs in question would not exist if not for the patent protections promised. And they would be right.
The issue in Columbia would not be the $12M, it would be a concern about a systemic ignoring of international patent laws. This would be a test case.
Of course the threat used is disgusting, but so is completely ignoring these other relevant issues in the discussion. It is a difficult debate, not an easy one as depicted.
Not critiquing you DoGood. Great post and great topic. Just saying the author has over-simplified the issue to "Health Care is a Human Right" which I find offensive. It isn't a human right unless Doctors, Nurses, Scientists, etc, are subjugated to be slaves to the rest of us, and I do not believe in slavery.
In Gunsmoke, Doc Adams often treated people for free, but he did that out of choice, not because he was legally required to do so.
"Who Runs Washington?"
Extremely disturbing, but incomplete without info on the patent. Did they have an international patent that should apply in Columbia? You can debate whether such patents should be enforceable, but you have to start with the facts about the patent.
But Prima Facia, disgusting. Prima Facia, like so many things I see go on here, there is nobody in charge; nobody to have to answer to.
I am a big fan of the best drug/therapy for each subgroup that can be identified up front. Linda Liau and Dr. Prins both point at the mesenchymals as the standout subgroup for DCVax-L.
Therefore; worst case scenario I would hope would be pursuit of the mesenchymals or methylated mesenchymals. Not saying they should not or will not get approval for everything, just saying that narrowing to the mesenchymals appears to me to be the worst case scenario.
If that were to happen, they may or may not be powered for that if there is a big hit for them not having called that subgroup in advance. They appear to be powered for a 40% subgroup... but not sure if that is at this point, or at full trial enrollment + maturation.
Worst case scenario they are denied whatever is being considered now, and enrollment narrows to screening for mesenchymals or methylated mesenchymals as they move forward to speed the process. Screening may not be the right word if they have to examine the tumor to see if someone is mesenchymal. If they do need further patients, it might not be very many.
If the numbers shown in the early data prove out in Ph 3 then they are probably done for that subgroup even if there is a big hit for not calling it up front. I don't believe that the FDA would just flat out deny great efficacy results for a universally accepted GBM subgroup. This assumes there is a practical means of identifying this subroup before treatment selection without damaging the utility of other potential treatments.
On a more positive note from me: If a consideration of some kind of approval has been part of the hold; consider all the regulatory statements that have been posted regarding competing therapies. They have to look at everything that is reviewable including competing therapies.
There is a lot going on in GBM. There was the Celldex Ph 3 that could have impacted any decision about DCVax-L and forced a look at subroup issues that had not been delineated by NWBO.
But Celldex is not the only one with GBM trials going on, and since the FDA supposedly looks at Ph2 data also for possible early approval, you have to consider the Ph 2 trials that were timed for data release at ASCO. I can think of at least 2 such trials. It is easy to imagine that once things got delayed for Celldex, and more data requested (for whatever reason) that put them close enough to ASCO to wait for those Ph 2 trials to report. If so, they could be looking at that data now as a final consideration.
Maybe the mfg patent issue was also in there as a chunk of the delay, but these competing trials and ASCO may have added to the mix. How long to review that data? I don't know. Certainly easier a ph 2 than a ph 3, but not sure. At least it should already have been compiled by ASCO.
So, plenty of possible good scenarios where transient SP is a small consideration.
Obviously the decision to provide a priority review should be based purely on potential efficacy / benefit. Obviously such should not be for sale or transfer even within the same organization to a different drug or even indication. Ridiculous!
I am not arguing with Sentiment, or ignoring the weight of what she is saying. This values the priority review. If those numbers are real, then a priority review is incredibly useful... so hopefully we have one going on.
But selling one! Ridiculous!