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I doubt that Samyang evaluates the merit of their investment on the basis of day-to-day share price changes at the end-of-the-year.
NeuroInvestment
<<Samyang has been burnt again. I wonder what their feelings are about Cortex at this time.>>
The financing was announced October 26. That was six weeks ago. Can you remind me what event was scheduled to transpire during those six weeks, that did not, and thus left Samyang "burnt?"
NeuroInvestment
OT: (TRGT)
They are using three BID (twice daily) dose groups:
1) 0.5, 2, 4mg
2) 0.1, 1, 4mg
Remember these patients will already have been treated with a SSRI or SNRI for eight weeks when they are taken (based on underresponse) into the actual trial, and randomized to one of the three drug groups or placebo, in addition to the SSRI/SNRI. They saw a response in the Phase IIb 8 week period, and not in the Phase III. Since there's already been drug-on-board, I don't think anyone really knows whether there is a time lag to be expected with the adjunct being added. As you can see, they are experimenting with a minimum-effective dose, ( 0.1mg BID) as well as going to the other extreme, the full 4mg BID for the full eight weeks.
Generally, if you don't see a benefit within eight weeks, you're not going to see one--so this should be long enough.
NeuroInvestment
<<Wish I had a more profound purpose, instead of simply being a troublemaker for the sake of trouble.>>
Succinct and on-target. Bravo.
NeuroInvestment
(OT: TRGT)TC-5619 is selective for the nicotinic alpha 7 receptor, AZD3480 is selective for alpha4beta2. The former looks a lot more promising than the latter.
NeuroInvestment
Gfp: As today's press release shows, ADHD is still on Targacept's list of indications, they are going into Phase II. In an indirect way, this is potentially good news for Cortex, because the message is: A nonstimulant option for ADHD is still worth the investment.
NeuroInvestment
The nicotinic antagonist approach, both for mecamylamine and its enantiomer, TC-5214, has been built on the concept of combo therapy. The precedent is Abilify, Abilify was tested as an adjunct to SSRIs in Treatment Resistant Depression, for which it now sells close to a billion dollars worth per year.
This design is different than most TRD trials--but it's a clean way to test an adjunct, for Treatment-Resistant Depression. Here they vet the population for TRD via failure in the trial itself, rather than going on some potentially unreliable history of antidepressant failures. It makes sense given that their first goal is to obtain approval as an adjunct--and leaves open the possibility that some additive/synergistic effect could boost an inadequate response to the monotherapy into something meaningful. It's what worked in Phase IIb, except there, all patients were first tried on Celexa--in this trial, there were a number of SSRI and SNRI drugs allowed. That could introduce some 'static', though Abilify's Phase III testing also included a number of antidepressants, and the FDA would require a range of concurrent drugs. A separate Phase II trial is underway testing TC-5214 as a monotherapy.
NeuroInvestment
OT:TRGT
They need to hit on two of the three remaining Phase III efficacy trials to file the NDA. It's not unusual to miss on a pivotal trial for an antidepressant: One scientist who ran the pivotal programs for two of the most successful antidepressants told me that his rule of thumb was that you have to run five pivotal trials to get two successes in depression. Which--as I have mentioned to TRGT--would mean they are one short.
They have not said how the trial failed--nor should they, since that could confound their enrollment in the remaining trials--but it makes a difference: If the trial failed because of a high placebo effect, that's common in psychiatry. If it failed because there was no observed benefit, that would be a different, and more worrisome, outcome. But it would also beg the question of problems in the trial enrollment--since this one ran so much more quickly than the other adaptive-dose trial. I have heard of depression trials where only 20%(!) of patients turned out to actually take the antidepressant drug being tested, and depression trials are particularly vulnerable to 'ATM patients', who enroll for the money, not because they have depression. It's hard to achieve an effect in someone who wasn't depressed to start with.
So I still am hopeful that the TC-5214 program will be successful, but my presumption that the magnitude of effect in Phase IIb was so strong that it would certainly emerge in Phase III--has been battered. A number of companies banking on Phase IIb POC studies are now being questioned by their investors as to whether POC can be assumed from PhIIb.
NeuroInvestment
OT (BLRX):
It's the immovable object of the sector's lack of enthusiasm for BL-1020 versus the irresistible force of their desperation for late-stage projects. I think that the former will win out, at least in terms of high-profile partners at good terms. They can probably get a backend-loaded deal (with most of the money predicated on Phase III success and NDA approval), but that dilutes the gains from partnering now. Phase IIb data from far-off lands lost much of their credibility with Dimebon, and AZ/Targacept's recent Phase III failure, after glowing Phase IIb data (largely from India), has further soured companies on taking Phase IIb as establishing 'proof' of anything.
NeuroInvestment
(OT) There are a number of entities (I doubt that they would constitute biotech 'companies' as we think of them) in Russia, China, and (apparently) South Korea that have been charging large sums for cell implants that have not passed regulatory muster. Even in the US, there are a couple of neurosurgeons who have charged large fees to implant fetal cells in Parkinson's patients, sometimes with disastrous results (I presume they have done so under a Physician IND, and with lots of signed waivers).
I am not aware of any connection between Samyang and of the above. SK Biopharmaceuticals is the only Korean pharma company that I follow, and they have nothing to do with this kind of activity.
NeuroInvestment
(OT) The question of what you have to do to maximize survival and expansion of implanted cells has yet to be resolved. The companies with cell therapies now in the clinic for CNS disorders--Geron, ReNeuron, NeuralStem, StemCells--do not, so far as I recall, provide any adjunctive administration of neurotrophic factors (if someone knows otherwise, I'd be interested). If they did, it would be unclear whether it was the cell or the neurotrophin that makes a therapeutic impact, the kind of thing that worries the FDA. SanBio is using cells simply to deliver neurotrophic factors, rather than replacing cells per se. So there is a school of thought that you have to implant both neurons and glial cells, the latter providing trophic factors.
NeuroInvestment
No direct effect, and the only likely indirect effect would be to boost the cynicism about novel mechanisms already present, which is not helpful to Cortex and many companies like it. It will also diminish faith in Phase IIb findings, and particularly those obtained in unusual populations/geographies.
NeuroInvestment
OK, maybe this angle will clarify it better than my first two posts did: Pharmas partner by geography all the time. If you have rights in the US, you have it for whatever indications you choose to pursue. CX-516 was sliced up by indication, with Servier having worldwide control over neurodegeneration. A company partnering with Cortex in North America could only develop CX-516 for indications other than Alzheimer's, Parkinson's, Huntington's, and could have been faced with another company trying to sell the same drug in the same territory, but possibly for a different price. That is not what this current scenario would produce.
NeuroInvestment
OK, I see your point. But the territories don't overlap. As I recall it (which could be off...), the 'two indication' question was--Could CX-1739 be licensed to one company for RD, and a different one for ADHD--in North America...
Would acceptance of the geographical split be affected if the indications differed? Offhand, I can't think of an example where that's occurred, and I suppose one could argue that a US partner might worry about elderly Korean patients receiving the same drug for AD or PD. But the principle of splitting off Asia is so embedded that I don't think this would be a significant issue. I look forward to the day that a US partnering prospect is so interested in an Ampakine that they'd give any thought to the question.
NeuroInvestment
First--you're jumping ahead here. A memo of understanding does not translate into clinical trials in the near future.
In the past, there has been discussion about a partner being nervous about having someone else taint their compound, though I believe it was in reference to two different companies developing a compound for two different indications. A company developing an Ampakine for ADHD would not want a problem in someone else's apnea trial, for example, messing up their ADHD chances. In this circumstance, where an Asian company might run a trial eventually in the same indication(s) as the NA/EU partner, that is not particularly a concern; it is how business is often conducted, with this kind of geographic split. You generally need a local partner for Asian drug development.
For example, and going back to Lexapro, Lundbeck licensed it to Mochida for clinical development/marketing in Japan. They ran the risk that, if something bad happened in a Japanese trial, that could have interfered with their marketing of a blockbuster drug where it was already approved. Small companies will sometimes sell Japanese rights early to generate money for US development costs, as EnVivo Pharma did with EVP-6124, their nicotinic drug for sz/AD.
Thus--I don't see a problem here, it's how companies often divide up rights.
NeuroInvestment
Asian markets are a world unto themselves. For example, Lundbeck's Lexapro, which is about to go off-patent next year in the US, was just approved for the first time in Japan earlier this year. These countries require trials with their own populations, and larger companies often outlicense those rights and headaches. Cortex and Samyang appear to have agreed that Samyang will (my guess, I haven't seen the MOU, obviously) have some priority in negotiations for these compounds, and would have a shot at widening their Asian territory. But there is no money changing hands on this, and no binding commitment on either side, so far as I can tell.
Anyways--this expression of interest vis-a-vis these Asian territories should not have any negative effect on any future negotiations for North America/Europe. The full range of clinical studies will be required in Asia, and there is a huge gap between this MOU and the start of any such testing. I don't think Samyang's expression of interest is going to have any impact on large companies--but it is a reminder to Servier that they do not necessarily have a monopoly on the Ampakine franchise. Which is a good thing.
Re: Neurolixis
Mark Varney and Newman-Tancredi are longtime friends, and Varney is providing very limited assistance to N-T in setting up this company. It has nothing to do with Ampakines, there is no transfer of IP or management, and hardly any time. It's not material to Cortex.
NeuroInvestment
First of all, I do not know what the Neurolexis/Varney connection is about. I am working on getting some clarification. But I am quite sure that it is not some nefarious conspiracy to transfer IP. Besides the fact that I believe Varney is ethical, there is a very pragmatic reason: If a small company were to violate its fiduciary obligations to shareholders in that way, the company acquiring those assets would be vulnerable to the inevitable ensuing legal action. In other words, the IP/assets would be tainted, and that company would be unable to raise money for the several years it would take for that legal challenge to be heard, and to be resolved. No one is going to invest millions of dollars if ownership of the IP, or gains therefrom, could be stripped away by a court decision.
So that's what it isn't.
NeuroInvestment
MJFF has tiers of grants, ranging from those which fund target validation; to preclinical testing in various animal models; to preclinical testing intended to prepare drug for human testing (e.g. Prana's metal binding drug); to human testing (e.g. Ceregene's in vivo gene therapy trial, being funded in Phase II). At each step, the grants are fewer in number, but larger in size, because each step is more expensive.
IF the current Ampakine trial were to produce positive results, Cortex could then apply for the next step, and MJFF would decide which of those applicants looks most promising, and deserving of funding.
Bottom line: There's nothing guaranteed, but if an oral Ampakine were to look like it slows the course of the disease (which the Lilly compound did back in 2002) it would be competitive.
NeuroInvestment
As I said, this doesn't set a high benchmark for valuation. It depends on whether Cortex can generate any interest elsewhere in CSA/low impacts or high impacts for neurodegeneration, building from this option exercise. Living in SoCal, where there is a lot of media coverage of the Michael Jackson trial, and the discussion regarding propofol risks, one would think some interest might percolate around the more general RD application, but then again, I've thought that before.
Bottom line: It depends on whether Servier continues to be the only interested party as the funds dwindle.
NeuroInvestment
I am not aware of any interest on Servier's part in respiratory depression or ADHD. They do have a cardiology component, so CSA associated with CHF is potentially of interest. If they were to develop Ampakines for AD/PD/HD, it is likely that there would be some internal discussion as to--What else could we use these for--all companies try to leverage products into wider applications. But that probably would not be part of nearterm licensing/acquisition calculations.
NeuroInvestment
The most important message that this sends is that the high-impact Ampakine is viable. Seizure risk had been seen as endemic to the breed, but Servier has concluded that CX1632 can be sufficiently safe to be taken into Phase II. At the very least, Servier will now have to consider whether they might want to license Cortex compounds as backups or next-generation Ampakines, or acquire Cortex in order to control the entire Ampakine franchise for neurodegeneration. For anyone saying--isn't it awful that Cortex only receives $3 million (plus some unspecified milestones/royalties)?--had the option not been exercised, the message to the industry would have been that the class is worthless. Will this in itself awaken wider interest? I'm skeptical, but Phase II data would, and Servier might want to lock up everything before such wider interest eventuates. The only negative aspect to this news is--it sets a low bar for valuation.
NeuroInvestment
Cell/gene therapies are on the ascendant these days, with several companies in clinical trials for Parkinson's, ALS, Spinal Cord Injury. Having said that, I am surprised too--if I was really curious, and I'm not quite that interested, I'd look up how many shares Adams owned of Sepracor when it was taken out at a high premium by Dainippon, and how many shares he owned of Inspire when Merck bought them out at a premium. He has a track record of dressing companies up for sale, and probably made a lot of money in each deal: he could probably provide capital as well, since Neurologix only has a quarter's worth left.
Anticipating the 'why doesn't Cortex bring in someone like that?'question--there may be several components (does he have connections to the Neurologix board??) but at the very least, during the current news cycle, Ampakines are seen as old news, gene therapies have regained cachet they'd lost for some time.
If Cortex is still around in a couple of years, it is possible the cycle could turn the other way. But at the moment, in the CNS world, they seem to be perceived as an old story. In the cardio/CSA world? I don't know how they are perceived, but it wouldnt be as old news.
NeuroInvestment
You might consider reading the date on the release before getting snarky.
NeuroInvestment
No.
None.
Other than APOE4, which simply assists in identifying the type of dementia present in a dementing patient, nothing has really been validated for clinical use in the field.
They can use amyloid-plaque detecting neuroimaging (i.e. Lilly/Avid) to track plaque load, but there is no correlation yet established between plaque load and dementia course--and the meaning of changes of tau or amyloid in the CSF is also not yet defined (not that anyone would really want to routinely do lumbar punctures on these patients).
At the moment, these tests are for companies trying to show that their drugs address a certain target (e.g. amyloid plaque). Then they will have to show that hitting those targets is correlated with functional benefit.
The functional validity of neuropsych testing changes is also debatable, though at least they show quantifiable shifts in specific cognitive abilities.
NeuroInvestment
If one were buying or selling shares in the companies involved, that might present a perceived (even if not real) risk. If the position already existed and remains static, there is no problem, since no trading occurred.
NeuroInvestment
I receive nothing unless a transaction is completed--and I have no fore-knowledge of deals: If I make an introduction, I play no further role. Sometimes companies will tell me they aren't going ahead, but silence doesn't necessarily mean anything either. Until the Biovail deal was announced, I did not know that my work from the previous summer had come to anything.
NeuroInvestment
I can think of one nonrandom factor--I do not know it to be true, but it makes as much sense as anything.
My guess is that Cortex has spoken with many dozens of companies in their search for a partner/acquirer/financier. If the opening premise is of interest, the other company can agree to sign a confidentiality agreement (CDA), which allows them access to nonpublic information. I have no idea what proportion of conversations go to that second phase--30%? (for others, the matchup does not work with their strategic marching orders in terms of indication, stage of development, or some other factor). I'm just guessing. Now, of the 30% working under CDA, no one involved with those conversations can legally purchase Cortex stock, because of the nonpublic information. Let's assume for the moment that they adhere to that. The other 70% would have no legal barrier, though their own company might prohibit stock ownership that could present a conflict of interest issue.
As I noted in a previous post, of the companies I contacted, almost all ( at least one had not, they were very under the radar) indicated that they'd already had contact with Cortex. My written presentations of partnering concepts rely upon public information, so in theory, with the same caveats, someone receiving that information might choose to buy Cortex stock once the corporate decision has been made to not take the discussion further. In other words--a company could decide that they aren't interested, but an individual who has looked at the materials could decide that it sounds like a good opportunity for a small investment.
This is pure conjecture--but there is a small audience of informed individuals out there who have recently looked at Cortex in context, and could have come to the conclusion that they're worth more than 10 cents a share.
NeuroInvestment
Actually, I retract my 'zero tolerance' statement. If I have to respond to every uninformed or mean-spirited comment you make, I won't have time for anything else. So have at it, you're not worth the time.
NeuroInvestment
What latest developments? The RD/Ampakine patent solidifies their IP position, but I have not been thinking that it was IP that was getting in the way of a partnership--it didn't stop Biovail, for example.
If someone in the cardio area comes to see the value of a CSA/CHF program; if Servier decides the Cortex Ampakine roster is better than their's--the value of Cortex will be considerably higher than it is now, not that this would be saying much. If you're asking for a number, I'm not going to suggest one, because it would be viewed as a target for attack by some, a reason for false solace by others--and with the pharma industry in a fugue state, rational criteria for assessing value are out the window. If they don't already have it inhouse, there is huge reluctance to bring in something mechanistically new. Their own jobs are on the line.
NeuroInvestment
The range of possibilities is narrowing:
1) They could get funding for a CSA in CHI trial--but I don't know the cardio area, so I have no way of assessing the likelihood or lack thereof.
2) Servier could exercise the option, but $2 million doesn't accomplish anything in and of itself, other than to give more time to sign #1. One might hope that they find some flaws in that compound, but decide that they still want to work on AMPA modulation in neurodegeneration--leading to a larger-scale deal or acquisition.
3) I have touched base with a number of companies about licensing/M&A ideas, and I don't think that I have yet found one that had not already been contacted by Cortex. They've covered the bases looking for a resolution: and those bleacher seat viewers who prefer theorizing about sociopathy, shame themselves.
4) Most pharma companies are contracting their range of CNS interests, in spite of how crazy that is from a strategic point of view. Those who are gingerly expanding expect either clinical POC or some type of highly defined mechanistic pathway, preferably with biomarkers. Cortex has none of those.
5) I am baffled that no pain company has been willing to take on a RD-resistant opioid development program.
It's hard to believe no one will take that on....but so far, no.
NeuroInvestment
OT--No, not acquainted with him, but that is an amusing analogy.
NeuroInvestment
If people posting on this thread just want a place to cathart and complain, then they should say so, and others can decide whether to stay or leave. Personally, I'm not willing to stand in the puddles left by people who think that being publicly incontinent is chic.
NeuroInvestment
If you can't tell the difference between reasoned criticism of a company and its management, as opposed to juvenile character attacks, it's time that you figured it out.
NeuroInvestment
Zero tolerance means that, just because you cut-and-pasted a couple of barely-relevant press clippings, you have not purchased a license to distort and denigrate without being called on it. It's analogous to what Guiliani/Bratton did in New York City twenty years ago, when they decided to clean up what had become a sewer of a city by no longer tolerating the little things, like smearing graffiti on subway cars. You're nothing more than a kid with a can of spray paint--and it's time that we stopped tolerating your mess.
NeuroInvestment
At the time that they had to choose where to go with their next low-impact, ADHD looked like a more promising partnering context than Fragile X. Fragile X has heated up over the past 12-18 months as a favored indication, even as ADHD has receded--Fragile X was hardly ever mentioned before then, and even now, there are only two major pharmas actively pursuing it, plus Seaside.
Plus: They know ADHD is addressed by low-impact Ampakines, Fragile X would probably be better served by a high-impact....
NeuroInvestment
1) I agree that, on the face of it, the opioid analgesia angle would seem the most promising, and in the past I wrote optimistic scenarios that have turned out to be wrong. It's not for lack of effort on Cortex's part in that area, and I have also talked to a couple of companies about it, and have run into a stone wall each time. Only Biovail bought the concept, but they were a 'thinking-out-of-the-box' operation, the like of which does not currently exist (and Cypress' brutal smackdown when they tried isn't going to encourage imitators).
It's infuriating that, when companies have spent considerable money developing time-release mechanisms for opioids, and then add-on mechanisms to deter abuse of those products, that no one (other than QRx Pharma) has worked on opioid/RD. I'm baffled as to why not--but I think it boils down to--there is added risk and uncertainty when building a combo drug, even when both components are well-known (e.g. MoxDuo). When one of the components is relatively unknown, and there is no oral version suitable for chronic use with even an active IND, they back off.
2)Sparky--Yes, you have advocated the Fragile X route. The problem has been, and remains, the probability that a more trophic Ampakine would have a better chance of altering Fragile X structural deficits. Seaside Therapeutics is well aware of Cortex and vice versa, but they have two platforms going into Phase III or Phase II in Fragile X and autism, and their ability to take on another has been financially limited to sponsoring academic muscarinic research. They don't have the money to give Cortex what they need for a clinical stage program. Afraxis is focused on PAK1, Roche and Novartis on mGluR5. The players currently willing to pursue Fragile X already have their mechanistic 'horses.' If Cortex gets money for one of their other programs, Fragile X might be a good place to invest it in terms of getting their preclinical work done inhouse.
NeuroInvestment
The level of disinformation and/or ignorance in your posts never ceases to exceed even my maximal expectations.
Zero tolerance.
NeuroInvestment
Interesting trifecta scenario. Here's a variant on the theme:
1) A Central Sleep Apnea partner, perhaps for CSA in congestive heart failure. The reason? Ampakines sound like very very old news in CNS, where old news is interpreted as a lack of potential. They are new to the cardiac area, just as they are new to the respiratory area. It does not make this probable, just possible.
The only other ways to maintain independent function and prospects would be either: a) a RD partnership with a pain company, but there's a lot of resistance to combo products where one component has a very short track record; b) as you mention, a broader acquisition or partnering of their low-impacts. Servier would be the most likely interested party, above and beyond the existing $2 million option.
Other than that--So far as low impacts are concerned: ADHD has fallen off the cliff in terms of licensing interest, and they are so far back in the mechanistic queue for Alzheimer's that they could not get back in the game without some Phase II data--and even then, the risks are really high with the disease-modifiers already in Phase III, and the multiple other approaches already in Phase II. Just finding patients to enroll would be a challenge, given the many programs in the clinic. So without either a CSA, RD, or high-impact deal, I would think they'd sell the company, and no one will be happy with the pricing.
IF they can obtain a CSA deal: They might hope for enough preclinical data in PD to get more MJF funding for PhI human testing. But an interesting other option would be for either a more potent 'low-impact' or (perhaps more likely) a high-impact going after Fragile X/autism. CX516 was a failure in Fragile X, but Elizabeth Berry-Kravis herself said that a more potent Ampakine would be worth testing. With Novartis and Roche both in or approaching Phase III with mGluR5 drugs, (Seaside is too, with arbaclofen, but they aren't a bellwether), alternate mechanisms will be of interest, since Fragile X is seen as a possible proxy for for the large market of autism.
P.S. Oldies, I don't know of any association between PD and CSA. Doesn't mean there couldn't be, but I don't know anything about it.
NeuroInvestment
I now have a zero tolerance policy for stupidity.
Cordially,
NeuroInvestment
Oh, I'm back, but in looking over the past week or two of posts, it's mostly the same ignorant regression to whiny personal denigration that has polluted this thread for at least the past year. It's like watching Michelle Bachmann reconstruct American history without ever learning it, substituting information with a disturbingly entrenched emphasis upon self-congratulatory and repetitive certainty; If you say it often and loud enough, it must be true.
It's not.
NeuroInvestment