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I'm afraid that you are incorrect on the first two points, which is the reason 3-6 month studies are necessary (at the very least), since the placebo effect gradually dissipates.
NeuroInvestment
<<Neurologists have a set of standard tests to assess cognitive function in mild AD: identify objects displayed as superimposed outlines; carry out simple arithmetic in your head; name as many different kinds of fruit as possible; etc.>>
1) The MMSE is the bluntest instrument imaginable, the ADAS-cog is not much better.
2) There is a placebo effect with Alzheimer's patients, which is one of the reasons that you can't do a quick cognitive test and hope to establish divergence and hence effect. Mice tend not to show placebo effects.
3) If one could show quick acute POC, do you think small companies would be running 3-6 month studies?
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NI's database of Alzheimer's programs-in-development totals 159 programs. The NI database of ADHD programs in development totals 21 programs. That is relevant to appraising strategic priorities.
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To get disease modification POC, as was suggested, minimum of $200-300 million--I'm guessing, because it's never been accomplished.
To get tentative POC of cognitive effect on ADAS-cog sufficient to ensure partnership, you have to go out at least six months tx duration, though it's more likely you have to go out 12-18 months. Unless you get lucky in a Russian study like Medivation did, you are still talking at least $20-50 million. In general, Alzheimer's is too expensive, with too much competition for patients, for a small company to do Phase II trials in. It has nothing to do with whether "Cortex believes they could be part of that process"--it's whether they have the money to play. The PET scan trial was intended to show whether CX717 has a biological effect, which would not in itself establish that it had any functional effect on cognition. In terms of leveraging a few million into a significant deal, ADHD is a more efficient vehicle than is AD.
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Iggs, it's not surprising that you could project 'battle of egos' on to that. But this has to do with facts--the fact that to demonstrate an impact upon progression, one would need to follow several thousand patients for several years to document the impact of a medication. At the cost of...at least $200-300 million? No one has ever carried out such a trial, so no one knows how long it would take. It's just such an absurdity to suggest that Cortex should have done that instead of its 24pt ADHD trial.....
Back to polishing brass and rearranging deck chairs.
NeuroInvestment
I was thinking about discussing the size of trial, duration of trial, and the cost of trial that would be required to carry this out. Or the literally scores of other mechanisms competing for the same goal. But that would bring far more reality into this discussion than you'd like. So I'm going to skip all that stuff. Think what you want.
NeuroInvestment
OT:CORT (Corcept): It got a lift because there was more data released suggesting Corlux improves metabolic indices in patients getting Risperdal. Unfortunately, Corlux isn't a candidate for ongoing use. There is Corcept's GR-II selective preclinical drug being tested by Lilly to see if it helps with olanzapine induced weight/metabolic problems, but with olanzapine going generic--I suppose Lilly could try to make a combo drug, just like we've talked about regarding an Ampakine/opiate combo, but that's not an easy road.
Corcept ran three Phase III trials that failed because--they finally concluded--the dosing was wrong. Now they hope the fourth works, another factor perhaps pushing the SP up a bit. I think their window of opportunity passed them by.
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Whether iggs is a 'basher' or not is of close to nil intrinsic interest to me. But it would be incorrect to presume "there's too little left to bash." Just as Cortex is negotiating with more than one partnering possibility, they are just as surely also talking to more than one possible source of financing. Any such entity which is seriously looking at doing so has a very clear interest in making sure that the price at which they buy in is as low as possible, since such pricing generally is calculated at something like 'the average of the closing price for the five days preceding etc. etc...' And with demand restrained by anxiety about the vanishing cash, it's pretty easy to dribble out shares to push the price down.
NeuroInvestment
Well, given that there has been some discussion that Cortex should have gone after Alzheimer's, this provides a cautionary note that there is no magic there.
Allon and Prana will both probably partner eventually, Allon was able to raise money to see them through. Prana's social skills are among the poorest I have ever encountered in a company. Titan is toast. Cortex's program is, in my view, the most attractive, but that's not news.
The drop-dead date for Cortex is sometime late April, I believe. I can't imagine Varney/Stoll will ride the jalopy closer to the cliff edge than the next couple of weeks: Either one of the companies doing DD accelerates the term sheet process or Cortex will raise money.
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One of the issues in play here involves the question of just how tough is it to obtain partnerships these days? As context for what seems to be so drawn out a process for Cortex and CX717. So I looked back at 2008, extracting all small company CNS indication POC trials for unpartnered programs that were completed last year.(mostly during2Q/3Q, with a few in 1Q r or 4Q). I may have missed a couple, this was a quick look, but this should cover most of them.
There were thirteen (I am counting the two Cortex RD trials as one). Only 7 of the 13 POC trials were successful or even semi-successful ( a couple hit secondary or posthoc endpoints, enough to keep the program alive). Addex, Alexza, Acadia, Antipodean, Epix, Trophos all failed.
Of the seven which succeeded, four were from companies that would like to partner now (NeurAxon, Neurogen do not, EnVivo hasn't been sure, though I suspect they will). Those four are Allon, Cortex, Prana, Titan. Their current status:
Allon Therapeutics/AL:108/ Alzheimer’s: Not yet partnered
Cortex/CX717/respiratory depression: Not yet partnered
Prana/PBT-2/Alzheimer’s: Not yet partnered
Titan Pharma/probuphine/addiction: Not yet partnered (postscript on Titan—the USPTO turned down their US patent, so all they can try to partner is Europe.)
Bottom line: None of the small CNS companies who had positive POC data and wanted to get a partner have been able to do so. This says a lot about the partnering environment at present.
If anyone can think of other CNS programs that fit these criteria, please remind me what they are.
FWIW.
NeuroInvestment
Two thoughts:
I think your characterization of the AMPA/NMDA receptor relationship is similar to mine--they are both postsynaptic receptors, there is no intracellular 'crosstalk' between them that I know of. Gfp's point however is that binding to the AMPA receptor has a subsequent effect upon the 'behavior', the function, of the NMDA receptor. 'Downstream' thus refers to causal sequence.
I also agree with Atheroprevent on the FDA's view of intervening in 'learning disorders.' Unless there is some unusual LD variant which is specifically related to synaptic efficiency issues, while others are not (doubtful), applicability would probably be seen as relevant to the heterogeneous, large-scale cornucopia of learning disorders. Which are anything but rare, not orphans. We do not yet understand the etiological/structural variations between LD subtypes. The FDA would see approval for one type as tantamount to opening the door for use in children/adolescents across the board. Which as is the case for MCI, scares the hell out of them.
NeuroInvestment
Similarly, that would continue your tradition of incorrect assumptions.
NeuroInvestment
Your powers of observation remain as accurate as ever. I posted three hours ago.
NeuroInvestment
Using musical intonation along with verbalization to rehab speech is an old idea, used in stroke rehab--well they were doing it when I did my postdoc in 1990. The premise is that it recruits the intact right hemisphere (activated in singing) to compensate for the damaged left hemisphere. But in stroke, one is trying to stimulate 'rewiring'to the intact side, whereas in Alzheimer's, the whole system (bilaterally) is gradually eroding.
Not to be overly cynical, but one could play Swedish Xmas carols for my mother during her late-stage AD and she'd seem to respond. But it didn't accomplish anything for her functionality.
The fact that 'stringing five words together' is still an accomplishment after so many billions of dollars have been spent on Alzheimer's research...it's kind of pathetic.
NeuroInvestment
Thanks. Much appreciated--what an elegant piece of work. Indicating an APP degenerative pathway parallel to, but distinct from, AB toxicity. And since both BDNF and NT-3 were used to replicate 'trophic support', it again points to the possibility that BDNF upregulation could be neuroprotective in AD--the question is whether Ampakines can do so in sufficient 'volume' (of neurotrophin upregulation) while remaining safe.
In response to Gfp's query about tau in AD: The Tauist approach to AD has had something of a renaissance; The clinical data last summer from both TauRx and Allon Therapeutics, both of which address tau, buttressed the utilization of tau as a target. There is probably some crosstalk between the tau and amyloid pathways, and if anything, the tau approach may have better clinical data thus far in its support--though neither one has definitively established itself.
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Mea culpa. Actually I've had trouble logging on to the full pdf, and Nature acknowledges only that they've received my complaint. Looking at the abstract, it wasn't clear whether the "fragment" of APP (post BACE cleavage) had aggregated or not--but in thinking about it, probably not. So based on only partial access to the info, it looks like they are positing an extracellular locus for the 'event,' as opposed to intracellular effects from soluble AB. They are keeping BACE as the key cleavage event, which is disputed by some.
It's still a work in progress, and getting a lot of play considering that there is anything but consensus on the cleavage/molecule aggregation/locus combination that leads to AD.
But point taken--I was incorrect in referring to the plaque aspect.
NeuroInvestment
There is a hint from the Tessier-Lavigne group that Ampakines might be helpful. They refer to the 'death receptor 6' as being inactive, becoming activated as 'trophic support' diminishes. This might be addressed by increasing neurotrophin levels that provide this trophic support--and high impact Ampakines are intended to do so.
Question is--when during the developmental process does endogenous trophic support drop enough to allow the DR6 receptor to be expressed/activated? And once present and active, would it matter if you subsequently upped the neurotrophin levels, or has the genie been let out of the bottle? If the latter, one would have to provide trophic support, via Ampakines or something else, on a prophylactic basis--for years, most likely. Which would up the ante on both safety and pharmacoeconomics.
Bottom line--this article, which is getting an amazing level of coverage, that's the magic in the Genentech name--raises as many questions as it answers. But it certainly leaves open the possibility that an Ampakine might eventually participate in AD therapy.
NeuroInvestment
BTW--an afterthought. For those who think Cortex should have emphasized Alzheimer's instead, this is a cautionary tale. We understand RD and SA infinitely better than we understand AD. The role of beta-amyloid, or of its varieties, remains debated. Those who claim there is a consensus usually represent one of the Alzheimer 'ideologies', they have a causal axe to grind. Cortex's approach is not integrally linked to a specific theory of what causes AD, what causes cell death within AD, it is not as ideologically-bound: neurotrophic activity might be helpful to cognitive function regardless of the root cause of the disorder. But even so, So the risk of pursuing something that is a dead end, or pursuing something that ends up eclipsed by an alternative, is much higher in Alzheimer's than it is in anything that Cortex has chosen to pursue.
NeuroInvestment
It's an interesting story, and Tessier-Lavigne has a solid reputation. But it appears to rely on the concept that extra-ceullular amyloid plaque, which is insoluble, aggregated beta-amyloid sitting outside the cell, is the causal killing agent in AD. There's a lot of reason to question that, many AD experts think of amyloid plaque as a physiological afterthought, not a causal key (it is the nonaggregated, soluble AB that has received more attention of late). The fact that you can kill cells by dumping beta-amyloid on them and linking to these receptors does not mean that this is what happens in Alzheimer's. Bob Langreth is a smart reporter, and Tessier-Lavigne has forgotten more neuroscience than I'll ever know--but this is far from an established premise.
NeuroInvestment
Whoops. I spoke prematurely. You now score lower than Roland Burris. You are in Blagojevich territory. Fortunately, I have as little invested in you as you have in Cortex.
If you think I'm now going to continue with this little ping-pong match, that would be incorrect. You aren't worth the time. But occasionally, when your version of reality becomes just a bit too sleazy, I will call you on it again. Like picking up a stray piece of trash on the sidewalk and tossing it into a container, it's kind of a civic duty: Distasteful, but necessary.
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I was trying to assess where your level of sincerity ranks on the sincere-o-meter, and it finally became clear: It's just under the score Karl Rove gets when he bemoans the lack of bipartisanship in Washington DC, just above the score for Roland Burris when he says he has 'nothing to hide.'
This isn't a 'stone,' it's an observation.
NeuroInvestment
Just to clarify: my comment about the challenge of running Phase III for RD was not to indicate it can't be done--it can--but to note that it was not the kind of fast/cheap process that a small company could pull off. Certainly not within Cortex's reach.
The 'safer better opiate' concept is extremely valid, particularly with the FDA requiring opiate marketers to produce new safety plans. But it won't utilize CX717, because this is a chronic use indication. It also will not be cheap or easy--but it could conceivably produce a monopoly in the opiate market, since the FDA itself has said that it might require less safe competitors to be pulled from the market if a demonstrably better alternative is produced. But not all companies would have an interest in both acute RD (hospital market) and chronic use opioid development.
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I tend to agree with you. This presentation was a non-event on a holiday, where few people had expectations either way.
NeuroInvestment
Yes, but that's only true if there are no other events foreseeable in that hypothetical 6-9 months that you mention. In Cortex's case, there are two such events that could preclude the necessity of a PIPE: SA data in May, ADHD data in December (the latter would fall beyond 6 months, obviously).
The anticipation of those events, paid for by upfront money, mean that a PIPE would not necessarily be expected, and thus would not be priced into the valuation in the same way.
NeuroInvestment
<<We would anticipate upfront payments here helping us move forward in 2009.>>
Given his caution about public statement, that's more than I expected him to say about deals-not-yet-signed. It is a step or two above what I expect as boilerplate--"We are hopeful that..."
It is a strong indication that they expect one or more to produce upfront money. But until one or more are signed, they can't be sure they'll get the $12-15 million they want, so financing stays on the table.
So far as due diligence is concerned: In pharma, that's the 'kicking the tires' part, which can involve not only going through all lab, preclinical, clinical data, but sometimes taking a compound into one's own lab to crosscheck results. A confidentiality agreement has to be in place, but companies like Cortex are always alert to the possibility that a company might conduct due diligence in order to get information for competitive reasons, not to complete a deal. Some initial term sheet discussions as to what might constitute a framework go into the decision of whether to let another company into your inner workings. But the real exchange of detailed term sheets usually follows the information gathering of DD. Most likely, they have more than one company, and companies may be at different stages: For example, one company might have started looking at term sheets, while another could have come in late and be running rats around a maze while marinating them in CX1739. Varney isn't going to say how many companies and what stage they're in, so 'due diligence' covers the process pretty generally.
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Right--and when they had to commit to the time slot, a couple months ago, they would not have known whether they'd have news or not. They might as well use the time.
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No, actually I was responding to Iggs' snarky reply that <<the strategy has changed with the wind for years>>. As if this was all based on whim, rather than dictated by fiscal reality. I didn't have any issue with your being curious....
So far as a HI deal is concerned, I believe Aiming is correct when he says that they wouldn't get anything worthwhile. Big Pharmas are focused on programs where they can see commercial potential in the near future, relatively speaking. The HI's havent shown that yet.
At the moment, LI's in SA and ADHD are of more value at the moment, and RD as well, since they have POC, even though it's a smaller market compared to those two.
Vet medicine would have seemed a painless way to get some cash, so the fact that we have heard nothing more makes me believe that Jim Coleman didnt have any luck raising partner interest, and instead moved on to bigger things (RD/SA/ADHD).
Personally, I don't expect to hear anything new at Roth, though I'd be happy to be surprised. If there was something material to report, and that's the only kind of news I care about, ordinarily they'd have to send out a press release beforehand. Now, with the market closed, perhaps that changes things. But Roth is a relatively local event,mainly Southern CA companies (it's all of 45 minutes north of here, and it's never been worth my time to go). it's not something with a high profile where one would aim a major announcement.
And nothing satisfying can be said until it is material and must be said, because until that point, it is confidential and still in process.
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One minute people are complaining that Cortex is spending money on SA rather than hunkering down and focusing on getting a RD partner, then they complain that Cortex isn't advancing all programs simultaneously, including the high impacts.
So let me ask you: Which of the LI programs that they are prioritizing: RD, SA, or ADHD, should they shut down so that they can prioritize the high-impact and/or veterinary programs?
NeuroInvestment
<<For POC to be established, cor first has to get FDA approval, and then get good data.>>
What? The FDA has nothing to do with this. They have European approval to run a trial in SA, it should be enrolling shortly.
Otherwise--I understand your points, it's a valid alternative view--but I don't agree.
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The animal models of SA are not particularly good. But this is not just a random walk, the most interesting element (to me) in that SA release was this: <<Further analyses of these clinical studies also showed that CX717 reduced both the number and duration of apnea events caused by the opioid.>>
So in a human 'model' of SA, induced by opioids, where there is a demonstrated incidence of apnea events, CX717 reduced the number and duration of those events. Because of the fentanyl, obviously no inferences regarding sleep-interference can be drawn, but as I noted before, they do have their Phase I human data on CX1739 that may be relevant in terms of sleep cycle changes--insomnia is a side effect that has to be monitored. If all of their Phase I subjects had been begging for an Ambien in order to sleep, Cortex's enthusiasm would be tempered.
This SA pilot study probably costs around $1 million or so. Having human POC in SA is the difference between throwing it into a RD deal for $3-5 million more, or getting $25-30 million upfront in a separate deal.
I have no qualms about this being a reasonable risk to take.
NeuroInvestment
Someone from Lilly once told me that their own data indicated that Strattera is effective in 20% of cases--it's fortunate that your friend's son is one of them. It goes to show that blanket statements, including mine, are usually incorrect, there are always exceptions due to the many permutations of genetic/structural/biochemical configurations which mediate an individual's response to a medication.
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This is not entirely OT. Phelps has ADHD (he and his mother discussed this on-camera during the Olympics). And while he excels (to say the least) within the highly structured context of training/competing--structure works well for a lot of people with ADHD--in an unstructured context, he may be even less adept than a lot of people his age at thinking through the 'what if' implications of an impulsive act. Like accepting a bong at a private party.
Stimulant drugs for ADHD would be verboten for athletes in Olympic competition, for all the obvious reasons (otherwise 95% of athletes would suddenly have 'discovered' that they have ADHD, and be medicated for same). And Strattera is largely a waste of space. If only someone could devise a nonstimulant drug for ADHD....
In the other hand, I suppose that even an Ampakine would be considered too stimulating for inclusion in world-class athletics, since it has alertness effects.
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That's the difference--it's a way to acquire a biologics platform, including manufacturing, in an environment where several BPs have decided to emphasize biologics, partly because generic competition can be thwarted. It's the same reason Pfizer overpaid for Rinat Neuroscience three years ago ($500 million).
And that's why it says essentially zip about Cortex's appeal as a partnering target--it's an entirely different dynamic.
NeuroInvestment
That's the first sleep deprivation study--I don't recall what year it was, 2004 perhaps? I'd check my notes, but Gfp will probably be quicker about it.
That is an important question: Can you upregulate the Pre-Botzinger complex and hypoglossal nerve root enough to reduce SA, without replacing SA's sleep-impingement with a different type of sleep interference?
No one knows the answer to that question yet, so far as I know.
Though I suspect Cortex has come to the conclusion that you can walk the dosing tightrope successfully.They have completed the Phase I studies with CX1739, so they do know to what degree insomnia was or was not observed, and they have some idea as to the dosing needed for sleep apnea.
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It's an interesting question. My thought is, in this litigitous age: If you have CX1942 being developed for RD, I question whether some "enterprising dr or med researcher' is going to mess around with CX1739 for an off-label use where the stakes are so high. Who wants to get sued for that? Maybe the CX1942 licensor would want Cortex to guarantee they won't license CX1739 to someone else for RD, but I don't think off-label use for RD is an issue--not in hospital or surgical center settings. Hospital attorneys would go berserk....
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<<cor may have no choice but to offer low-impacts as a class, for any and all indications.>>
Even Cortex has never had to do that, and won't. I think you are right that they'd try to steer partners to CX1942, which has both IV and oral formulations, if I recall correctly, as backups for CX717, also with both. 1942 would be the chronic use option.
They will not give up BOTH 1739 and 1942, the question is whether someone might demand IV717 and CX1739, since the latter already has safety data. They can always throw in another preclinical stage low impact as another backup,Les Street has made a bunch of them.
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Geographically, that happens all the time. But a company dealing with a regulatory agency regarding their molecule doesn't want someone else potentially spoiling things by dealing with the same agency on the same molecule, even if for a different indication.
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I think it's crazy too--but I sat in a meeting last November where most major pharmas were represented, and several of them said quite overtly that they would just as soon wait for small companies to become desperate, why pay more now when they could pay less later? Pfizer seemed to disagree, they emphasized their belief that stock price doesnt serve as a good indication of value, and they'd prefer to look at revenue generation potential, and work back from there. But that was the only BP that made that kind of statement.
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It could be a single deal that has that kind of milestone arrangment, or two separate deals. The company that told me of their interest, and the fact that they are negotiating with Cortex, is really not interested in sleep apnea, it is outside of their area. So that is the kind of situation where a RD deal could be done without including SA--the catch is, would they insist on CX-1739?
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I agree--it's too material. But the scheduling of the presentation--as I said before, is not directly related to anticipation of having something new to present. They may or may not have news, but they have a slot already reserved. The announcement of the Roth slot is not a way to 'telegraph' the certainty of news.
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