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You have still missed my point, but never mind, it may not be important. I have no idea whether the delay is due to pursuing a narrow vein of gold, desperately tunneling in hope of finding an airway, and/or (and this could apply to either of those two) trying to negotiate a deal. If the SA trial was a bust, I don't particularly see what the point would be of holding the results while devising 'an exit strategy', since they are not out of money. If there was something there of unclear value (my guess) the delay could be in the service of clarifying that value, conceivably (less likely) in terms of providing a potential partner with a requested period of silence wherein to conduct DD.
NeuroInvestment
<<SoCal is chock-ablock with competent biomedical statisticians>>
You're missing the point--the choice of rational comparisons is based on the sleep apnea construct. I'm not sure any place is chock-a-block with SA experts.
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The less variability permitted, the slower the enrollment....can you imagine? However, you raise an interesting possibility--the 'subset' could be those who came into the study with less variability, for example.That would be easy to establish statistically, and probably was an early factor they checked.
But one other thought in response to something Enemem wrote--if one runs a statistical analysis of every possible factor checked against all others, that introduces spurious results simply by virtue of multiple comparisons. Which is why the Bonferroni correction is used in situations where multiple comparisons are being done--to reduce the risk of false positive conclusions, to squeeze out some of the statistical noise.
No matter how you do it, the process of choosing which posthoc comparisons to make is also rendered suspect by its posthoc nature, one is looking at the data and choosing additional analyses in a nonblinded way. But there can be a rational approach to choosing additional comparisons based on the context of sleep apnea, rather than--'these numbers look promising'. Choosing on a rational basis is less likely to produce spurious results. If they take data to potential partners and say we ran 3000 t-tests (or whatever), the partner is going to say that they were bound to have something show up. But if they say we ran analyses of ten additional comparisons based on the recommendations of outside sleep apnea experts, based on what they consider important in SA outcomes--those results would--I think--be seen as less biased, more substantive.
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I don't think so, but sleep studies are not my area. I'd be curious what DavidAl would say about the possible range of data one can get from a full night of sleep monitoring.
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<<If the results are indeed of the subset success variety, that would be as every bit as material as clearcut results showing success or failure, because subset success is equivalent to failure for the near term purposes of Cortex. >>
I do not agree. How big is that subset of SA? How much effect is achieved, and do experts think that it is enough to translate into broader health benefits? To what degree is this offset by any negative effects? For example, if they concluded that it was useful (I'm making up this number) in 50% of the SA population, a subgroup that can be pre-identified--and made a clinically significant difference, with acceptable side effects (which may be a matter of opinion), that would not be a failure. On the other hand, if it helps only 5%, and the responders cannot be pre-identified, that would for all intents and purposes be a failure.
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Big Pharma can bury almost anything it wants--short of pivotal trials--on the grounds that with their scale, a single data event is not 'material.' I have been pretty consistent in saying that anything from this SA trial would be potentially material, and should/would be disclosed immediately. That has not happened, obviously--so what can we make of that?
My belief--and that's all it is--is that had there been clearcut success or failure, it would have been disclosed. Had the topline results shown anything at p=.10 ("trend") or better, it would have been disclosed. Had there been no evidence of anything, it would not have taken this long to sift through the data and conclude--there's nothing. So my working hypothesis is that there was something, some signal, but sorting out what it is, and what it means, may be time-consuming. For example, say there was a trend towards lower apnea scores for patients receiving CX1739, but it was only significant at p=.20...meaning a twenty percent chance it was a fluke. That is not generally reported as a positive finding, yet it means there is an 80% chance it reflects a genuine divergence (whether it is clinically meaningful is another question entirely). That is when serious data mining starts: Is there a subgroup of responders? If so, what differentiates those responders from nonresponders? That is a question that could require input from sleep apnea specialists who can look at apnea patterns/symptoms in a more detailed way. Does apnea response correspond to impaired sleep(a concern raised before), which would require specialist input as to whether the benefit exceeds the sleep 'cost?' And so forth.
There have been two successful SA drug studies in the past that I can recall offhand, BTG's and Galleon Pharma's, but the latter was never reported in any detail (private company) and BTG's was a long-duration study, so it may not be instructive vis-a-vis this trial.
It is possible that the delay could involve some type of due diligence process on the part of a potential partner bringing in their own SA expert consultant.
Nondisclosure becomes a SEC issue if someone benefits from it via selective disclosure, cheating and profiting by it. We have not seen any particular uptick in price or volume, so no one can claim to have been victimized here, at least thus far.
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Don't be peeved. I was simply paying homage to your conceptual logic: If I didn't know about it, it didn't happen then--and if it didn't happen then, it must not be happening now.
NeuroInvestment
<<they have never ventured, to my knowledge, to sell the company.>>
Well, then it must not have happened, because they certainly would have run it by you first.
NeuroInvestment
Bladerunner is absolutely correct. Cortex doesn't yet have a hi-impact in the clinic, and only North American (plus sundry) rights for the Servier compound--which has yet to complete a Phase I trial. They might get $5 million upfront for a high-impact deal that is strictly preclinical.
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1) A full preclinical package on each molecule is somewhere between 500K-1 million.
2) Someone pays any clinical setting to do human testing. Those academic/research settings that have that capability contract with CROs to do so--they are a profit center for the host institution. Clinical settings are not sitting around waiting to do charity work.
So the answer to your question is that Cortex does not have the money to develop multiple molecules preclinically or clinically at present. Nothing is free. Small grants--like the MJ Fox grant they received--defray portions of such costs.But there is no source short of a major partnership that would fund this kind of comprehensive program.
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Do you have any idea how many compounds look good in animal models and enter Phase I, with exactly the same boilerplate commentary? I'm not making a negative appraisal of the program, I'm happy that a Cortex-shared high-impact made it into PhI. But if you think the 'Market' cares about compounds starting Phase I......
At a meeting last week, someone from Pfizer said 10% of drugs that enter Phase I end up with a filed NDA. That seems high to me, but that gives you some perspective on what hurdle has been passed--it's an early one.
So far as valuation is concerned: Whatever Cortex's share price is at the end of this year will be--IMHO--much more dependent on the outcome of the SA trial, the status of the IND for CX-1739 and ADHD trial timing, and/or partnering, than it will pertain to this Servier project.
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How you draw that conclusion from my comments is a complete mystery to me.
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I think it's a non-event vis-a-vis the current stock valuation. It could be a very significant event down the road, but nearterm value will be determined by SA/IND news--or some other wild card. I don't think 'the Market' could care less about Servier at present.
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I believe you are confusing this with the Yahoo board, where mindless pumping and bashing tend to reside.
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Cortex took back the neurodegeneration rights, but Servier retained ability to develop some co-owned compounds for (generally) outside North America. Servier would fund trials related to their territories.
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As the double expresso finally exerts an effect: The other possibility is that, if the compound shows well in a EU Phase I, Cortex could then assess whether they think it is better than whatever Les Street et al has devised here, and it would have the advantage of having shown it in humans. If so, they could then file an IND in the US with the Servier Phase I data, and could initiate a Phase IIa in Alzheimer's. That decision-point could be in 12-18 months.
But I'm a lot more focused on the next--days? weeks?--than I am in possibilities for 2012.
NeuroInvestment
Cortex has no obligations, and this does not interfere with their ability to pursue Alzheimer's. They are probably entitled to some type of milestones and royalties if this compound progresses, but I suspect that the milestones are backloaded, connected to events like Phase III, NDA, etc. But they've never been disclosed, so we'll just have to see if anything ever eventuates. Servier has taken so long to just go into Phase I that I wouldn't be expecting anything in the near future. It's vaguely positive that Servier decided an Ampakine is worth developing in Alzheimer's, but otherwise, this is a non-event.
Addendum: Actually, I think my bleary-eyed cynicism initially overlooked an important positive element. No one has yet succeeded in developing a high-impact up to this point, and if CX1632 turns out to walk that tightrope successfully, that would be significant. With Cortex having North American rights--it's not that they will run US Phase III trials, but if Servier has success in EU testing, that could elicit a NA partnership for Cortex. But that would be a factor in three years or so.
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Whatever you say. You are the expert.
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I know them well. Spotty but interesting Phase IIa data. The program deserves a shot at Phase IIb, and this Australian government grant gives them a start at it--it's not enough to finish Phase IIb. If they were an American company, they would have gone bankrupt two years ago. Their management can't be bothered to return phone calls or communicate unless under duress.
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With sz and depression available again, their ability to do a low-impact partnering deal--perhaps one that uses an option model ('you get xx million more if we like the PhII data') is far higher than it once was.
BTW--Valeant is dumping the Respiratory Depression program. They have now deleted five of the six programs Biovail had inlicensed.
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Actually, this is not the first time I've said it. I don't know any other CEO's who answer inquiries in this way, and while I believe Varney's motivation for doing so is simply to be helpful, it sometimes ends up seeming to be more trouble than it was worth. But I suppose that's for him to decide.
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I have no info as to why the delay, and as I have previously posted, I am inclined to see these results as material and warranting dissemination. So---is there any situation where this delay could be justified? I sent this in reply to an email inquiry, and figured it might be of interest:
My candidate for most-likely explanation is that the simple topline analysis--drug vs placebo overall-- it didnt show much, but that there is some variability: Perhaps some patients, but not all, who received drug showed changes.
If so, this is when it could get more time-consuming. If they think it is something about the drug-responder subgroup (or nonresponder subgroup) that caused the variability in results, they might have to bring in an SA expert and ask--'can you explain why these eight drug patients showed improvement on CX-1739, while the rest did no better than placebo?' In which case they'd be waiting on the expert to come to a conclusion. (I'm just making up these numbers, just to be clear.)
If they can identify some attribute that can be linked to drug effect, that's a more compelling story than 'some patients did better, some did not, we don't know why.' And much better than 'Overall, the difference between drug and placebo groups did not show significance or a trend towards significance.' They may have decided that delaying the release of topline results that aren't definitive one way or the other is not material.
I suppose one could come up with other scenarios that are more positive, or more negative,but this is the one that I would lean towards at the moment.
Again, and ironically--it was Mark Varney's decision to respond to a shareholder inquiry that led to this being a potential problem. They'd be better off if they didnt bother with such replies.
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You need to read more carefully--out loud if necessary--I didnt make any predictions. I simply noted the possibilities. But do as you wish. It's a free Internet.
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Had Cortex released positive news on a Friday afternoon, you would have been pontificating about the incompetency of doing so when the weekend looms. IF it turns out that they release positive news on Monday, that will be wise timing. If they do not release anything, then your ire will have a point.
The month isn't even finished yet. As eager as you are to castigate, perhaps you should consider waiting until Monday, so that you don't end up looking foolish.
NeuroInvestment
Generally, last patient completed is described as such, 'have data' means that they have then assembled the datasets, made sure they are complete, locked them, and then unblind them. Until unblinded, people generally eschew saying 'we have data.' I don't know this for certain--but I expect he was referring to having some analyzed data by month-end.
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I don't agree. It's material. Once they have the data, they have to disclose it. Could they wait from Friday to Monday, with the market closed, in order to maximize exposure of good news? Sure, but not beyond that.
Based on Mark Varney's statement, I'm expecting a press release by the morning of November 1 at the latest.
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I'm not sure what 'formulation' issues would be. CX1739 safety issues? I didnt expect this to be drawn out either, and I doubt that the delay is related to the compound itself. My guess is that it is an ancillary issue around the protocol/'partner' issue I suggested.
My stance is: The SA trial is supposed to be reported by the end of this month. If we get into November by more than a day or two, I'll worry.
If the SA trial reports, and we still havent heard anything of the IND being filed within a week or two later, I'll worry. Of course, they aren't obligated to announce the filing, and most companies do not--they wait for the IND to be activated, or even for the trial itself to start. But in this case, given the delay, I'd hope that they would. If there is some kind of financing/partnering deal that is part of this, they'd have to announce that anyways.
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Blade:
I do not know what the delay is about--but here are some thoughts about how it could be playing out:
Coordinating with a strategic partner--or source of funding ( it could be either, or both; the former would also be the latter) means two things:
1) Cortex might have to negotiate the IND protocol to reflect either the strategic wishes of the former, or the amount of funding available from the latter. They can't file the IND until the protocol is absolutely final.
2) If either of those candidate entities (but especially if it is a source of funding) is predicating terms of the agreement upon a specific valuation for Cortex, that cannot be wrapped up until the SA results are known: Because that should have a material effect on Cortex's value. I had never thought of the IND as dependent on the SA trial, but in this scenario, it could be.
This is all speculation. Something quite different could be occurring-but these are possibilities.
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That's right.
NeuroInvestment
OT: (TRGT)
The driving force behind Targacept's price rise has been their depression data, and the partnering of TC-5214 as a depression adjunct with AstraZeneca. That's also why the price today was not heavily impacted, their fate rests far more on the depression partnership than on the first AZ deal.
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What about the words "could" and "potentially" did these people not understand? If they are indeed 'familiar with the sector', they should be familiar with the near ubiquitousness of such program descriptions throughout the pharma industry, particularly in smaller companies.
<<Animal models need to be proven to correlate findings of effects in animals with clinical effects in humans>>
As poor as CNS animal models are, there are models which are generally accepted, for lack of anything better, as predictors of human efficacy. If one's drugs perform in those animal models, one can then legitimately use terms like "could potentially."
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One would think so. But there may be means by which Valeant might keep him off his sword.
Re: RD rights. I've written before that the only Biovail program I think absolutely safe is the AZ-004 antipsychotic inhaler from Alexza, but if the FDA gives them any problems with approval, even that would be at risk. If Biovail were to drop the RD program, since it was an asset sale, not license, I doubt it would simply revert to Cortex. Biovail, as the owner, not licensee, could do as they choose. It's the difference between renting and buying.
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I believe Bill Wells (now the Chairman) said something about the end of 4Q seeing the finalization of any culling that would be done. The power-sharing itself may be fully worked out, but I don't know who is the main voice on the portfolio editing. Wells ran McDonalds in Canada previously--he embraced CNS as a business strategy, not a heartfelt mission. If the new CEO makes a case for a shift and can sell it to the BOD...I'm not sure who will fall on their sword to protest.
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OT(ACAD) Blade:
I think that is the major uncertainty going forward--whether Valeant's CEO will support the program--and how the power is actually going to be exercised between him and the Chairman, Biovail's past CEO.
Even though it seems reasonable to continue the program since Phase III has been initiated, given that Valeant had deliberately chosen to exit CNS post retigabine/ezogabine, I'm reluctant to assume anything. And my lines of communication have been at least temporarily severed during the merger process.
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FWIW, this is a brief excerpt noting the mGluR5 hypothesis in Fragile X:
<<Mark Bear at MIT is generally credited with identifying the link between mGluR5 signalling and Fragile X: FMRP knockout mice showed improved cognitive function when administered an inhibitor of mGluR5 activity, which apparently reduced the level of background synaptic ‘noise.’ The premise is that optimal neural functioning depends on establishing a balance between the processes of longterm potentiation (LTP) and longterm depression (LTD), both of which mediate the synaptic patterning underlying new learning. Finding that correct balance depends partially on FMRP’s role in limiting such synthesis, and when FMRP is absent due to this genetic flaw, it no longer functions to maintain that homeostatic balance. MGluR5 receptor inhibition is a means of providing the attenuating the attenuating function normally carried out by FMRP.>>
Novartis, Roche, and Seaside Therapeutics are all involved in clinical trials using this mechanism--the fact that two Big Pharmas are doing so is a welcome change from old school insistence on huge markets.
The Ampakine angle is interesting: MGluR5 increases LTD, but this might also have some negative effects on cognition. Ampakines allosterically boost LTP, which could have a complementary effect on the 'signal-to-noise ratio', and could offset the less desirable mGluR5 effects. How one balances the two dynamics--that remains to be established.
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I don't think so. There are two components here:
1) The license for Merck to develop Ampakines for sz/dep (the license originally signed by Organon, acquired by Schering-Plough, then Merck)--which also excluded Cortex from developing or licensing Ampakines for those indications.
2) The specific compounds (Org24448 and Org 26576) which came from the original Cortex/Organon research collaboration--and whatever preclinical and clinical data was acquired in the testing of those compounds.
The announcement only made reference to #1. Which means Merck cannot develop Ampakines based on that license (nothing stops them from doing so based on the expirations of use licenses, though they don't appear to be doing so). With no reference to 'regaining two clinical compounds', I assume Merck kept the compounds. Since they kept the compounds, they have no obligation to share their data pertaining to them.
It would have been nice to have the compounds and data, to see if there is anything there that might draw interest. Why Merck would choose to hold on to the compounds, I have no idea. But it seems relatively unimportant to me: #1 was the priority, and those compounds are less potent and clean than CX-1739.
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Agreed--the IND is critical. But that in itself is unlikely to change the valuation all that much, it constitutes the avoidance of bad news. My point referred to potential valuation-drivers.
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I'm not aware of any specific expiration date on the license Merck had held. The use patent expirations would have meant that everyone else could have developed AMPA modulators---ironically leaving Cortex as the one company that could not. With Merck not developing them, Cortex might have had grounds for challenging the license. There was no upside for Merck to specifically preclude Cortex from developing sz/dep, when anyone else could do so--fortunately, they finally got around to the same conclusion.
In the long run, this (setting aside the alluring but small possibility of knockout SA results) may be even more important to Cortex's prospects than "the other two things", because a broad psychiatry low-impact platform is probably the clearest route to a major license or being acquired.
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They didnt have the option of trying to partner for multiple indications before. Now that they do, I agree--they would not want to partner CX1739 with an ADHD-only company (like Shire). And I don't think they will. Either they partner/option with a company with wider ranging interests, or they find another route to seeing the trial through.
To restart the IND process as a sz project would require developing an entirely new protocol, new trial sites, getting IRB permissions; doing preclinical work to see how CX1739 interacts with antipsychotic meds, etc. It would be a 12 month delay, I would guess. I don't think the FDA's view of the risk-reward would be so different as to make it worthwhile.
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There is more Pharma interest in the use of Ampakines for improving cognition in schizophrenia than any other indication. The major gain from having these rights come back from Merck is that it allows Cortex to negotiate a wide-ranging psychiatry partnership for CX-1739, and/or other low-impact Ampakines. ADHD itself appeals to a relatively smaller swathe of the pharma world, but now Cortex can market a package which covers all psychiatric indications--and both sz and depression are potentially far larger than the market for a nonstimulant ADHD drug.
For those who have been (justifiably) concerned about the Balkanization of Ampakine rights amongst several licenseholders, this should be welcome news. It has been ten years since Cortex has had the opportunity to partner low-impact Ampakines for their potentially most lucrative, and most widely-appealing, uses.
I don't expect "the Market" to respond to this at all.
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