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I don't see anything disturbing about calling out subgroups. It de-risks the trial if you somehow compensate for the alpha spend and increase the total patient numbers to allow SS at an obtainable median efficacy for each of those subgroups. And they did increase the patient numbers. I think they might have compensated for the alpha spend by not doing any efficacy looks until the trial reaches the primary endpoint.
The cost of that de-risking is that the trial becomes a little more expensive and the total $ gained for that trial might be a little less, but maybe not as much less as you think. When you narrow approval to subgroups you increase efficacy for the approved patient pool. Since reimbursement is based on efficacy, at least to some extent, the reduced future patient numbers are offset by increased cost per patient. Approval by subgroup is also the more ethical way to go about this. I am certain of that.
If you made the commitment to build a super expensive manufacturing infrastructure for a drug in trials, expecting an enormous market on or soon after approval, you might just chose to de-risk that investment at the relatively small costs described above.
To clarify another point: An unusual % increase in OS for a true progressor would not have to be a very large absolute increase. So while the end OS for that treatment subgroup may not be very large, it might be worth adding to the pseudo's after all. Again, that would make life a lot easier for the Reefrads of the world.
This is probably old hat... but just in case you guys didn't go here before.
I appreciate both of your comments Flipper.
Correction: "She must have good reason to suspect that such is true... with more than just the placebo efficacy effect on OS as the culprit."
I meant the possible unexpectedly high efficacy of the late administration of DCVax-L after crossover (not the placebo efficacy).
"Feuerstein-Rutain Rule" The phrase makes me want to puke. I consider a reference to that offensive vehicle for manipulation to be a bad sign.
I am not all-in yet because I am not rolling in cash this year; so I don't post much. But hearing reference to that rule gets me out of my shell.
There is definitely foreshadowing of Ph 3 failure. There are the early statements by LL regarding both legs doing better being bad for the trial, and there is the recruitment hold, allegedly by the Germans. Those things are good cause for the SP to have dropped from $12 down to $2 maybe... but here we are at $.35/sh, I believe a gift if you do not bet the farm.
While the cheerleader in me wanted to believe that the Germans would be the last to let a trial detail interfere with a trial, what are the odds that something like that happened? The Germans are sticklers to rules and detail as well as being rational types. Would they hold up recruitment over a GMP detail if efficacy stats looked good? Of course they might. But more likely there was no look at efficacy. In the era where the screening hold occurred there was a worldwide hunt for any repetition of a problem seen at some other (not NWBO/Cognate) facility where mold grew on a patient sample or some such. So they found mold at a Cognate facility? Maybe, but more likely they came up with a specific strict inspection guide-line of mfg GMP details within the wiggle room of interpretation of existing rules, that would have prevented the case with the mold, and then scrutinized every facility from that perspective. Perhaps they found the vulnerability at a Cognate facility and reacted with the screening hold.
So... they did this in spite of the results of their look at efficacy for consideration of hospital exemption reimbursement????? Maybe there was no look for efficacy. The company says there wasn't. But if so, then why not?
Maybe at this point there is not a forced look for futility? Maybe the futility concern is more about the sponsor wasting time and money than about patients being provided a useless new drug. Or... maybe the FDA can step in if they see futility, but maybe they can't initiate the look at efficacy. So if the sponsor does not call for a look, maybe the FDA does not have the opportunity to intervene.
The company made statements along the lines of not wanting to waste alpha spend. I don't remember the exact statements, but clearly they got paranoid about their SS margins (if only within multiple ways to win fall-back subgroups) when they expanded the trial. So leaning as low as they can in their soap-box derby car, by avoiding the alpha spend of an efficacy look would fit what I know and what they said.
Restated:
Prima Facie, the Germans took an interim look at the data in consideration of futility and or early reimbursement evaluation and found futility, and in response put a hold on recruitment. But what are the other possibilities?
1) Aforementioned GMP detail that may or may not effect trial outcome in spite of a positive read on the data.
2) Aforementioned GMP detail that may or may not effect trial outcome (and no read on efficacy has yet occurred, as the company has stated.)
Why then the defensive posturing by LL, even in her most recent presentation? Same reason every company postures defensively as trials come to full data. The trial is blinded, so they do not know what the outcome will be, period. Sponsors have to take a defensive posture. UCLA, and LL herself have to do similar posturing. Take a look at some recently approved drug that was not open label and see what kind of statements were made by those companies before the final read on efficacy and or FDA decision. I doubt you will find a company that did not posture in a scary way to investors. (though I admit I have not done that DD.)
But maybe LL was more defensive than usual. If so, why... ? She seems to concede that the outstanding efficacy numbers stated for Phase 2 will probably not be reached in the phase 3. She must have good reason to suspect that such is true... with more than just the placebo efficacy effect on OS as the culprit. Maybe she feels that is a potential embarrassment and or exposure for liability. But what long investor would be shocked by a phase 3 showing less efficacy than a phase 2? None. Literally none. At least nobody that has been around the block at least once.
And LL did continue to claim that she and many others in the position to know as much as possible, believe that DCVax-L will prove out to be effective at least in some subgroups. She didn't say it would get approval... and the debate about subgroups is over my head, but the fact that with all the final posturing she feels comfortable continuing to claim efficacy in at least some subgroup(s) makes the fair price for this stock a lot higher than $.35 in my opinion, and the odds of some kind of approval much higher than AF and company would have you believe.
Why subgroups over my head? I don't know which subgroups were called in advance and whether a subgroup that was not called in advance can get approval after some alpha spend and or SS threshold hit penalty for not calling it in advance... or whether it is simply ineligible. I believe they called the methylation variable in advance, and I believe that gives them a pretty descent fallback for approval. Not sure about mesenchymal. The efficacy of that subgroup may have become apparent too late for them to have listed it as a subgroup. Not sure. I know they added subgroups pretty late in the game, and I believe that was legit... just don't remember mesenchymal being talked about. (In fact, adding subgroups late in the game, though prior to a read on efficacy, as they did, may have used up a lot of alpha spend and thus motivated them to do no further spending that would have resulted from any optional early looks at efficacy.)
Then there are the early progressors... (a separate trial...? I admit I don't remember.) If the combined real and pseudo's show efficacy as a group... then that would be very convenient, as they would be so easy to identify. My understanding is that the pseudo's are believed to benefit a great deal from DCVax-L, but I would think the opposite for true early progressors. If so, a distinction must be made and numbers are smaller than the combined group. And that distinction is problematic, though the methods have improved in recent years. But... do the true early progressors show unusual benefit for some strange reason????? I have read about this dozens of times and do not remember, I must admit. But I hope to spark a review of that issue.
Please excuse my lengthy post without full DD... but these days I do not post very often. So this is several months worth of babbling.
"they are attempting to educate us, their colleagues and regulators that immunotherapy is different, and a strong tail of 25% or more with near cure results is sometimes better than say a couple months improvement in mPFS or mOS."
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You are talking about the no-effect that a 25% cure rate could have on median efficacy... while being a huge step forward...
But weren't some the checkpoint modulator clinical results of that shape, and yet did gain approval? Maybe for malignant melanoma.
Questions: LL says methylation is a standard test now. About time. But is she talking about tests on tumor tissue or tests on any patient tissue to determine "methylation". I believe that test can be done on any patient tissue, but it would be nice to be more sure. I have been asking this question for well over a year.
Mesenchymal, or not; I am pretty sure requires testing of tumor tissue. That is problematic, because who does that testing? Maybe the frozen tumor gets stored in sort of an escrow status with no specified owner until the results of a tumor biopsy come in. Then the tumor goes to whoever has the best proven therapy for that tumor.
Seems to me that DCVax-L is likely to prove to be effective on Methylated GBM, or Mesenchymal GBM, and if not SS for either of those then certainly for the combination of the two, which is still a descent sized subgroup. However, while I believe methylation was called up front as a subgroup, I am not so sure about Mesenchymal. If not... then what? How good of results do you need before not calling a subgroup can be excused? Is it flat statistics and alpha spend, or are there hard and fast rules on that, that only a USVP could force to be re-thought?
LL seems to think that some subgroup will show efficacy... but does she think that the subgroup will get approval? Not the same question.
A Normal PR!
Very first Phase 3 results are pending.
I won't try to defend the full history of the company, but DCVax-L for GBM is the first product that they chose to carry through phase 3, and they are apparently on the verge of completion. This is a very different situation than in the past, and should not be compared to the past.
You (all) were right. Combo was DCVax-L not Direct. I really thought it would be Direct.
For me... hard to judge what this foreshadows for the GBM P3 trial except for one clue; the cost of DCVax-L is apparently not prohibitive. There is no plan to exit L due to cost as some have suggested.
Thank you RK.
Direct: Cytokine production correlated with survival as I recall in a recent PR. My question is whether there is evidence that the level of cytokine production was due at least in part to the DC's, rather than the adjuncts alone.
Hoping you find a way past that pain for the very limited and special time you have left. Most end up wishing they had found a way.
My deep resentments are with other family members. Things seen that I will probably have to take to the grave. If nothing else, the experiences shed light on the Illiad or was it the Odyssey.
Thank you for your contributions to the board in recent months. I am in the background but I do check in on occasion. You are certainly doing your part in holding the fort. You seem to have found your groove style wise.
Someone please give a link to a normal SEC filing!!!!!!!!!!!!!
I don't see a single 8K nor 10K nor 10Q nor..... . I have never seen a company not have a single normal SEC filing.
From the company that recently handed the entire retail float over to the institutional investors using an illegal death spiral, they now give you....
nothing. Not a single meaningful SEC filing and a 10 fold range in the possible percentage they will earn in sales iff their lead drug is approved.
This is definitely the place to put your life savings.
"Double Digit" percentage of sales to AEZS. WTFart does that mean? Somewhere between 10% and 99% of gross sales goes to AEZS. Why not say the percentage? Is it 10% !!!!!?????
For the record: I say I lost many of my shares by gambling. What I mean by gambling is leveraging on good news. Knee-jerk (at best) grapefruit juice comparisons, etc, repeatedly took the SP down upon good news for a couple of years. That still goes on but it doesn't appear to be as effective at this point.
In the era in which AF and others had bite, I had no income, I so did this "gambling" in an attempt to maintain share count and still pay bills.
For the record.
Thank you for clarifying the equities transfer issue.
I had been talking about transfer from a regular trading account to a Roth. I was wrong. Glad to hear you can do it from another IRA, though that was not my particular situation. Hope it is Xena's situation.
"TDA told me I could not transfer shares into my Roth." Your right. A year ago I made two stock transfers... but looking back at my records, those were distributions, ie out of the Roth not in.
I just called my broker, TDA, to check. He verified that you can only move equities out of the Roth, not in. You are right.
Many months ago I thought LP was quoted as saying that she did not want early results for the DCVax trial. That she wanted fully matured data.
If I remember that correctly; I want to point out that the advantage of full maturation may not just be increasing the odds of approval, it might increase the measured efficacy that would be used to determine reimbursement.
That is... I would think that when they measure efficacy for consideration of reimbursement they use the bottom of the shot-gun spread of possible underlying true efficacy. If so, narrowing that shot-gun spread by increasing the amount of data increases reimbursement.
So that a rolling review started early makes good sense, but an actual snapshot of efficacy for AA might be disadvantageous.
Roth IRA's:
Most here know more about financials than I do, but there may be a few who are unaware of what a Roth IRA provides you. In the US, Roth IRA's are retirement accounts where you don't have to pay taxes on gains within the Roth. Your contributions to the Roth, however, are not tax deductible as they would be in other types of IRA's. That is, you do not list them as a deduction during the year that you contribute, or ever; it is just your money going into the Roth.
You can trade your shares within the Roth, just like any other equities account, though I don't believe margin is or should be available within the Roth.
(I believe that) One cannot cash-out of a Roth prior to age 55, and you have to have the Roth for 5 years before cashing out. Both of these restrictions, however, are in reference to gains. You can cash out the $ amount that you put in, at any time, without penalty.
NWBO is certainly a gamble, but with the upside as high as it is... Apparently there is an equivalent to a Roth in Canada.
The annual max Roth contribution depends on your income. It is a little confusing. But it can be as high as $6,500 or $6,500 worth of equities. You can transfer shares into a Roth. If someone were to transfer (their income dependent) full amount today, they could transfer the full amount again on Jan 1, 2017.
I am not recommending anyone do this. I am just educating as to the option.
Business and jokes aside; let me not forget how enormously important progress in this realm would be to current and future cancer patients.
Ship In a Bottle:
Etienne brought up Roth IRA's about 2 years ago, back when I had XXK shares of NWBO. This made me wish I had bought them in a Roth, but it would have taken 12+ years of allowed Roth contributions to do that anyway.
Since then, I lost all my shares. I had to eat some of them, others I lost while gambling to try to keep them.
Thank you LP and Les for shrinking the SP enough to allow me to recently recoop all of my shares + a tad more, with 2/3 + now in a Roth. Kind of like a ship in a bottle.
LP and Les: It is now time to re-size the ship, either by hanging the Phase V contributors and exonerating LP, or by reporting efficacy, or an impressive partnership. And if none of those are available, perhaps you could study Captain Nemo's methods. And again, thank you.
That this presentation just restated those results is pretty reasonable. It did so to people not following AVXL. People not like us.
I am not great at critiquing clinical or mouse data, but the original PR sounded pretty good to me. A pre-clinical is not a great measure, but it is a measure, and these results sounded fantastic.
And the results came from a Swedish Stewardess. Everyone knows that Australian men from the outback and Swedish Stewardesses can be trusted.
And it is not the meat it's... the notion. Everyone knows that. The notion here is that Anavex 273 could really help some people. MJF included. The question is whether the results will be looked at for the near term grants... I think they will, but I do not know anything more than anyone else here... and if George says too late for this round... well George is always positive... so... maybe not this round.
I have some major reservations about AVXL, but much is alleviated knowing that Parkinsons has at least one major subclass that is an orphan candidate. A very large subclass that is just barely small enough to be orphan. Alzheimer's also has such subclasses.
I have not been looking at AVXL recently until these preclinical results. I think they are exciting. I am excited for MJF and MJFF and all the Parkinsons patients around the world.
Technical Analysis, NWBO:
SP steady as a rock today on extremely low volume suggests a rising Little Teacup Iron Cross. This is considered very bullish in an Olympic Year unless extremely low volume does not hold on the subsequent day in which case this indicator becomes unreliable.
AF says that NWBO waited until the very last day to finance. How would he know that? I don't think anyone beyond a few core people in the company would know what the total payments due are and all possible places to try to pull money from are. Is that something you could pull out of SEC filings? I don't think so.
So why would he say that? Just to confirm that he is more of a manipulator than a reporter? Why?
Regarding conspiracy theories and the autologous immunotherapies. I recently accused AF of taking part in an effort to shut-down NWBO as a renegade effort to develop an autologous immunotherapy: specifically that the Big Pharma's had come to an agreement / deal of some sort with the insurance companies long ago that they would not pursue autologous immunotherapies due to their estimations of high mfg expense, and that he was likely involved in some way:
That is my suspicion only. Most realize that, but want to be clear about that. I have never seen the beast, I just see the water swirl and the rest seems very likely.
At the same time I recently conceded that the FDA pushing NWBO to go with crossover to get more patients to enroll in their Ph 2/3 was not a plot to undermine the trial: I want to back-off from that concession to a certain extent. It is a known that big pharma has the ability to influence patient enrollment / selection of a given therapy for trial via the large influence it has on physicians and clinicians. Those are the people advising the patients. Some patients and friends and family attempt to learn about every possible treatment, but even then, many feel the need to cross check with their physician. There is competition in these trials and it is possible that NWBO's inability to enroll sufficient patients with the original DCVax-L trial design was to some degree the result of focused efforts by Big Pharma. Not presenting any evidence in that direction, but it is certainly a possibility.
One reason I changed my view on this was recently reading about another Autologous Immunotherapy + Blockade Inhibitor currently having difficulty enrolling patients. Based on what I know about that therapy and trial, this should not be the case. It doesn't make sense. So I wonder if the missing piece to that puzzle is Big Pharma influence. And that makes me wonder if that was part of NWBO's problems enrolling many years ago. If so, could BP have influenced the FDA to influence NWBO into using crossover as the solution... ? I think it is a possibility. It really doesn't make much sense for the FDA to have suggested that solution given that PFS as primary endpoint had risks. Risks that the FDA was fully aware of. Again, this is similar to saying; we think your high wire act is too risky, but you have chosen to go ahead with it, and you are not selling enough tickets, so we strongly suggest that you remove the net so that you can attract a bigger audience.
Adam Feuerstein: "Oh, and your mesenchymal subgroup conjecture is pure fantasy because it's a retrospectively defined subgroup of patients."
I understand why defining a subgroup after the fact is not generally allowed. But if there is new flexibility at the FDA to ensure good drugs do not get rejected out of excessively rigid rules, then this might be an area worth debating.
Defining a subgroup after the fact could allow approval of a subgroup purely out of random variance for that subgroup. But the amount of variance is not infinite. So, while I admit I do not fully understand these issues, it seems to me that an alpha hit makes mores sense than simply denying any possibility of consideration for approval.
Maybe an alpha hit is not the right term. I don't mean using up some freebie margin that does not effect the required efficacy for approval, but rather, a raising of the bar to account for / offset a reasonable level of statistical advantage from defining a subgroup late in the game.
In the end, if it is blatantly obvious to a human that the methylated mesenchymals (15% to 22% of all patients) will nearly all gain a complete response if DCVax-L is administered, yet consideration of approval is not allowed based on the rules, then the rules should be looked at closely.
Here, for you Adam Feuerstein to point only at a rule, with no statement about claimed efficacy for that very large subgroup, larger than the actual subgroup that Celldex trialed for and failed, shows your hand. A hand that has always been about trying to snuff out NWBO because your buddies in Big Pharma all agreed among themselves, in negotiations with the Insurance companies, that they would not pursue autologous cancer vaccines due to the estimated manufacturing expense, making Northwest Biotherapeutics a renegade that must be eliminated.
That did not occur to me Pip. Thanks a bunch. What did occur to me was that since Bank Suisse (or something like that) really did recently get fined some record fine for partial denomination transactions, that this might be such a transaction. Obviously such illegal transactions really do occur.
"Probably the scariest post yet on this investment message board."
Let me translate... "Share price means nothing".
Efficacy trumps all and the SP does not reflect the current situation regarding what is known and not known about trial maturity and efficacy.
Tried to sell some other calls to buy straight NWBO and could not. My ask was 10 cents, and I was out-offered at 7 cents. Note that options trade in 5 cent denominations.
This is the third time this has happened. Different stocks, same $ numbers. A 7 cent ask squeezes in and sells off blocking my 10 cent ask.
TD Ameritrade told me these are probably from straddles or some other coordinated transaction which forces a partial transaction for one component.
I just don't believe it. Why does this only happen when I have an ask of 10 cents?
Bank Swiss recently hit with a record fine for partial denomination transactions. May have been straight stock sales, but I wonder if it was or included calls.
Interesting that the author mentions nothing positive like that in the free part of the publication. He associates NWBO or DCVax-L with a failed drug... but you have to pay to see the relationship... then presents none?
I don't know. I am in the vast majority who chose to not pay. Who chose to read just that first misleading page. Was this deliberate? Probably.
"Fortunately, if you inject intratumorally, you can reduce the dose of checkpoint inhibitors by many fold. Intratumoral injection is less likely to cause a cytokine storm than infusion."
As I said earlier, I would think that any benefit from injecting locally would be greater using an antibody that binds to the tumor side (PD-L1) of the pair rather than the T-Cell side (PD-1). The reasoning being that once blocked, the Tumor side might stay blocked, while any local T-Cells blocked might be replaced with new T-Cells after the antibody / blockade inhibitor has diffused itself through the body, away from the tumor.
For that reason I would think that the PD-L1 variety would be important to try out locally at the tumor. If you could only test one or the other, that is the one I would test. But of course they can test both, separately, and they probably have. Are they clear in the study that John posted which half they blocked in the mouse study? The term PD-1 is probably used loosely at times.
That sounds like a pretty likely explanation to me Flipper. Not only is it cheaper to cover that way, they don't create a spike that would bring eyes to the stock. Preventing that seems to be a big part of AF and other professional bears' job.
I thought arranged trades were illegal. On the other hand, I would think the day to day activity of MMs would be illegal, but to the contrary, the exchanges requireme MMs. Ie, you have to have dedicated MMs or you can't remain on a given exchange.
When AF and the local bears talk about the lack of transparency, etc being an unusual or even unreasonable risk, I don't mind. But AF and often other bears go beyond that to talking with absolute certainty what the trial results will be, and other unknowns.
For AF to talk with certainty about what these trial results will be after repeated bad calls in the recent past, is kind of incredible.
Seconds after the close today would fit what I read and posted, but just not sure who gets to trade in that time period. Clearly someone does. Not me though.
Still, not saying the sky is going to fall. I agree that these buys are meaningful. Just don't agree that the sells are due to official re-balance. Maybe unofficial re-balance, or expectation of a dip by some due to the pending re-balance. Logical to expect... but maybe those 8 million buyers know better.
I agree. Maverick did the right thing and disappeared after he sold until his point of re-entry.
That was the right thing for him to do. He could have hammered the stock in the interim to gain better re-entry price, but instead he sat it out. A fair thing to do. Not as fair as altruistic Flipper or Senti or CherryTree or John... etc... but as an investor, about as nice as you can be without sacrificing your investment.
I think you guys are ahead of yourselves by one day. I read this as rebalance after close today, ie Monday.
https://www.ftserussell.com/research-insights/russell-reconstitution
"June is the month that the preliminary reconstitution portfolio is communicated to the marketplace. Beginning on June 10, preliminary lists are communicated to the marketplace and updates are provided on June 17 and 24. The newly reconstituted indexes take effect after the close on June 24."
"In hindsight, after Brexit, it is fortunate we are in both locations in Europe."
Yes. With all the talk about the extra load that the UK carries for the EMA, nice to reflect that Germany is probably not part of the UK's burden.
As for cooperation between Germany and the UK, Merkel said this morning, "While the negotiations are ongoing, Britain remains a member of the EU. All the rights and commitments that pertain to this membership are to be respected and fulfilled until the actual exit (2 years +). This applies to both sides."
Merck has Avelumab that binds on the PD-L1 (Tumor) side. I don't know much about it.
Merck, however, seems to be in bad financial shape just like Astra Zeneca and Roche.
So what about GSK and BMY?