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I can see low-impacts being used for heavily-medicated, hospitalized patients being treated for heart failure. I think that they'll have a hard time finding a partner to test ampakines for chronic CSA because of their robust sleep-disrupting effects. They backed into sleep as a consequence of their opioids work; a classic example of zebra's law.
I tend to think that the analgesia angle has more promise: Athero cited a statistic that there are now 110,000,000 generic opioid prescriptions being issued a year. In a recent JAMA artice the following appeared: "opioid overdose is now the second leading cause of accidental death in the United States and the prevalence is second only to marijuana,". Pharmas are making buckets of money on this class of drugs, but increasing death rates risk derailing the gravy train. For this reason, even though there may be a general aversion to new/old combo products, my hunch is that someone will pick it up.
The high-impacts (which I have generally been very leery of) may offer a breakthrough. If preliminary data are good, corx may be able to obtain ample funding from the MJFox foundation or others to advance this class of drugs to the clinic.
I'm not very optimistic about commercial partnerships because corx currently has no leverage.
So Varney's staying. So much for the rumor. I believed it and was wrong. We're probably still cooked, but in a different sauce.
This is my expectation here. I think we're done.
Cortex Pharmaceuticals, Inc. Venue Change August 5th, 2011
Fri, Aug 05, 2011 12:00 – Cortex Pharmaceuticals, Inc. (CORX: OTC Link/FINRA BB) – Venue Change – The symbol, CORX, no longer trades on OTC Link. As of Fri, Aug 05, 2011, CORX trades on OTC Link/FINRA BB. You may find a complete list of venue changes at otcmarkets.com.
http://pennystocksdotcom.com/otc-markets/cortex-pharmaceuticals-inc-corx-otc-linkfinra-bb-venue-change.html
If he's jumping ship to Neurolixis, he certainly isn't going to inform us here.
The only unambiguous signal would be "I'm not going anywhere". No response (which I expect) would lead me to lend more credence to the rumor of his departure. This is someone who in the past has responded promptly to some pretty inane emails, so the lack of a response is somewhat interpretable.
Stoll's response in post# 37334 gave me pause. If there was nothing to this story, he would have (and could have) said the whole thing was nonsense. Also look at that company's target indications. For a company with no pipeline, no staff and no building, it would certainly work out nicely for them if they got corx's IP. Also, look at where corx is at.
Neurolixis has no physical address, no molecules. I wonder whether the idea here is for Varney to jump ship to Neurolixis, then have Neurolixis buy corx or inlicence the whole caboodle.
I don't know how much money Neurolixis has on hand, or whether there are laws against what I outlined, but if they have the cash, and it's legal, this is a simple way to develop corx's IP without corx or its shareholders.
I've been following this board's traffic. My disappointment with corx is compounded by the lack of consideration that posters have shown one another. Almost everyone here is long, and we're all losing our shirts. That pain is real and personal, and possibly made worse by the knowledge that we've led others to this disaster. Since we're all trying to make our peace with this situation and get on with our lives, why turn the final weeks on this BB into a pissing contest? So you can walk away from this feeling you're right? We're all chumps here.
I didn't loose as much as some who post here, but what I lost was pretty much all I had. This is hard to deal with psychologically, and as a practical matter. It gives me some understanding of the situation of others on this board who bought the cortex story, and lost big too. My condolences to all of us.
If something surprising happens, and this story continues, I'll post here again. If the company folds in the coming weeks, know that my thoughts are with all of you here, accompanied by the hope that some good luck finds you soon.
Haven't some of the PIPE options expired? If you have the records of the PIPE terms from around 2007, I would be grateful if you would post them.
An alternative view is that these leaks are rigged to prop up the profits of a company that is trying to recoup its investment, developing a drug for a disease that is treated as well by a generic product.
I went to the study that Dew referred to, and found the evidence that avastin is more dangerous than lucentis to be weak. Both are anti-VEGF drugs, both are administered in very small doses. The worse health outcomes in patients treated with Avastin rather than Lucentis is just as likely a biproduct of their socio-economic status (the Lucentis cohort is likely better off and in better health).
CCHS is due to mutations to the phox2b transcription factor. Unlike most developmental transcription factors, phox2b has a narrow regulatory function: it specifies visceral afferents. Thus the name CCHS is a bit misleading, since it allows for the possibility that the syndrome is entirely or in part due to failure of networks to generate breathing rhythm. In fact, CCHS is associated quite specifically with inadequate chemosensory drive. This is a mutation with variable penetrance, so likely most people who suffer from CCHS go undiagnosed, and "ondine's curse" patients are at the far end of the CCHS spectrum.
All this to say that while it's possible that ampakines might provide enough drive to respiratory rhythm generating networks to allow blood gas homeostasis despite inadequate chemosensory drive, but it is unlikely that ampakines would counteract the specific deficit associated with CCHS, and upregulate chemosensory drive.
Thanks for your insights. It appears that ADHD may be a better indication to target, but my concern there is that it is a non-life-threatening indication for which other approved drugs exist, whose target population is in the main young and otherwise healthy. This never struck me as the best indication to pursue with a new class of drugs. Sickle-cell disease may be an attractive option because the barrier to approval may be somewhat lower since the need is great and alternatives don't exist. If it is established that ampakines are safe, the regulatory barrier will be less of a problem for other indications.
Is there any private sickle-cell foundation money that corx might go after? This might be an option to fund a clinical trial.
It should certainly occur to some company that targets pain management to explore the possibility of incorporating ampakines into their compounds.
The only thing we all have in common is the very mixed blessing of having our money tied up in corx. Given that we choose to be stuck in this boat, why can't we be nice to each other, or at least civil? All the bashing doesn't improve anything.
Again, my focus is in the regulatory aspect. I think the bar is lower for pain management in SCD, and it will increase the FDA's comfort level with ampakines for other indications.
I think you're complicating the picture; If opioids are administered at regular intervals (as your post indicates), then you'd have your within-patient control data during the same crisis, under blinded conditions.
The point is, unlike SA, where there are multiple subtypes, and multiple response profiles, here you have two read-outs: level of analgesia, and respiratory rate, impacted by the analgesic in a pretty generic, disease-independent way (I might be wrong, but SSD probably doesn't impact central respiratory rhythmogenic networks).
As a consequence, while there is likely to be considerable variability in the severity, duration, and location of the pain, the study will likely provide an accurate estimate of level of analgesia before and during ampakine administration (since opioid is delivered via a patient-controlled analgesia device), and respiratory variables are also straightforward to measure (since the patient will be hooked up to a spirometer already).
Neither of us are clinicians, so this is really pretty uninformed opinion on both sides, but for my part, I think this is much simpler than the SA trial.
the SSD indication is all about pain management. If the clinical trial shows that excruciating pain that cannot safely be controlled with existing meds becomes manageable and that the risk to patient is reduced, does anyone here think that the companies whose business is built around pain management won't notice?
Sorry about the double negatives here. My point is that pain management is a huge indication, for which ampakines are perfectly suited. If ampakines become an obligatory additive to every narcotic or benzodiazepine pain med out there, corx won't need to develop another drug. We'll be fine.
I'm talking about getting an IND approved. They need to get INDs approved to meaningfully do anything, and that's not years away.
The bottom line for me is that the drugs have shown efficacy in 2 potentially huge areas (ADHD, RD). There are orphan-like indications that will facilitate clinical trials in RD, which will give the FDA greater confidence about ampakines' safety. With this in place, getting the IND for ADHD will be easier.
I think the situation is ugly but not hopeless. There are likely some dilutive financings ahead of us, but at least now I know what corx's strategy is, and I think it's a pretty good one. I don't think this company will go under, but I think that we're at least 2 years away from being in the clear.
How many times have we deluded ourselves with that line of thinking?
The point I was making is that the sickle-cell trial would be simpler than controlling RD in a post-operative context, not that the trial would be simple. That said, The sickle-cell trial will basically boil down to increasing analgesia while monitoring respiration; it's essentially the same trial as was carried out for RD, so of all the things corx has undertaken, this is the closest to a known quantity. Finally, you're over-generalizing. The only clinical trial that turned into a disaster was the SA trial. The RD trial had its bumps, but was complete within 6 months of its target.
More generally, I think you are mistaken in focusing on the biology side of the equation. Corx's biggest hurdle is regulatory. Getting approval for pain management in sickle cell opens the door. Further, you're conflating RD and SA. RD is straightforward, and of direct relevance to every pharma that targets pain management; this is potentially a bigger market than ADHD. SA is a more difficult problem, and should definitely be postponed.
the Biovail negotiations took so long because they (Biovail) were apparently the only seriously interested party.
That was then, this is now. There are fewer in-licencing opportunities for BPs, the same or greater need, and less uncertainty.
RD is a very attractive outlicencing candidate. Any company that has drugs for pain management understands the significance of cx-717's broad-spectrum efficacy in alleviating RD without affecting analgesia. The fact that corx is planning a clinical trial to alleviate sickle-cell anemia-induced pain indicates that the company is targeting pain management.
Incidentally, I think that the clinical trial for sickle-cell will be more straight-forward than the clinical trial for post-operative RD.
As for extrapolating from the past, in biotech, that works beautifully until it doesn't.
Based on the odd things corx has done over the last few months (no ADHD IND filing, long delay in SA results release, minimal communications), I think it is quite possible that they are well along on a more comprehensive deal that needed the RD piece to get resolved before being closed. I think that a deal in the near term may obviate the need to raise funds.
Who says management is unable to do anything with RD? They can outlicence it again.
FDA is going to be extremely cautious about approving a new compound class for an indication that has many millions of patients. The approach that Varney is taking is one that corx would have done well to pursue years ago. It lowers the payoff and delays the payoff, but comes with a lower risk of failure. I think this is a good choice.
Before ampakines are approved for chronic use in any indication, drug safety has to be established in the clinic for other intdications requiring one-time (or intermittent) use.
If sickle-cell treatment can establish ampakine safety, it greatly facilitates ADHD approval. Although the sample size was tiny, efficacy in central apnea is particularly important because CPAP is useless. For this particular subset of SA patients, ampakines may be the only option.
Overall, I like the tactic of advancing drugs for relatively small patient populations for which alternative treatments don't exist. The barrier that corx has to overcome is the FDA's reservations about ampakine safety. My sense is that they will be more willing to see ampakines in clinical trials for these indications, than for an indication for which drugs are already approved.
Thanks for the clarification. In light of this, it looks like a very good choice: orphan indication will accelerate approval, as will the fact that the only treatment options are either dangerous or inadequate. I am happy with this, since efficacy is likely, and it establishes POC for the much broader market of pain management, and not just post-operative pain. It looks good.
Did anyone sit through this thing? I looked at the slides. Did V explain the ADHD delay? Is sickle-cell a zebra indication? Was there any discussion of partnerships? Was there anything here at all?
Athero,
I absolutely think you're right. Fatality rates associated with chronic use of opioids in pain management keep going up, and incorporating a low impact could mitigate this risk. By regaining the RD rights, this kind of drug development is possible.
Fantastic news. This creates options that didn't exist before. There is a definite path forward now.
If they regain the RD rights, they'd be in a position to outlicence the entire low impact platform, to generate funds for development of the high impacts. This is something I've suggested for some time now, and may be one of the better options, but still a bad one.
This would bring in money, but the high impacts are at an earlier stage of development so they'd have to do a lot of things right to get them to the point where they could be outlicenced before the money runs out again.
I have a feeling that the low impacts are the most valuable IP that corx holds. My concern with the high impacts is that the dosage at which some clinical benefit is had will overlap with the dosage at which some animals or people suffer seizures.
Let's see what they do. On the no-dog-barking front, I am heartened that JerryDylan has gone silent. He in the past has had good lines of communication with management, but a while back, it appears that he pissed them off by sharing some of what they told him here. If he's stopped posting, but is still lurking, it may be because what he knows can't be disseminated.
In corx-world, absence is the proof of substance, and I appear to be loosing my marbles here.
what brass ring? Even with a PIPE, they won't have the money for an ADHD trial. They don't even have an IND filed.
This isn't the case for PD, fragile-X, or even Rett's Syndrome, for which pretty good animal models exist, where the physiological or genetic mechanism are known, and where patient heterogeneity is better. These are all diseases that corx could have gone after.
ADHD is better than SA, but not by much. We've been over this so many times that I'll resort to shorthand: non-life-threatening, healthy subjects, chronic use, huge patient pool, existing (bad but approved) drugs.
You've got to be kidding. Academia is the oasis of rationality?
I didn't write that. Researchers do stupid things all the time; they pay a very high price for blunders though.
It's actually one of the strengths of academic research that people can obtain funding to chase 'wild geese' in order to see if there is any value there
This is out of step with the current realities of federally funded research. Long-ball research strategies are no longer viable, and won't be for the foreseeable future.
When I walk around SFN, half the time I am shaking my head in disbelief that discredited hypotheses are still being funded.
SFN is an example of the hasidic saying "those who know don't say and those who say don't know". The really interesting stuff rarely gets presented at SFN, because people don't want to get scooped; much of what is presented is half-baked, and never finds its way to publication (there's plenty of half-baked stuff in print too though).
You think that Cortex did not read the literature and get SA expert input?
Here's an abstract from a 2008 review, obtained by entering "osa trial" as a search term in pubmed:
Pharmacological treatment of sleep apnea: current situation and future strategies.
Hedner J, Grote L, Zou D.
Sleep Laboratory, Department of Pulmonary Medicine and Allergology, Sahlgrenska University Hospital, 413 45 Gothenburg, Sweden. jan.hedner@lungall.gu.se
Abstract
Current forms of mechanical treatment in obstructive sleep apnea (OSA) are generally effective in eliminating sleep and breathing disorders. However, they do have drawbacks, such as incomplete tolerability and non-compliance. Several attempts have been made to identify pharmacological treatments for OSA, but no drug has consistently reduced the severity of the condition by more than 50%. OSA, in most cases, is a condition characterized by considerable comorbidity, including hypertension, obesity, metabolic derangement and hormonal dysfunction. Daytime sleepiness and cognitive dysfunction represent common, but not consistent, findings in people with this nocturnal sleep and breathing disorder. Hence, future pharmacological treatments for OSA may need to take aspects other than the nocturnal breathing events alone into consideration. Drug research into OSA has been hampered by the lack of useful experimental systems and animal models for drug screening. In addition, the phenotypic characterization of OSA seems to be incomplete, and this limits the possibility of using stringent criteria for patient selection in drug studies. Finally, the criteria for defining the severity of OSA and disease impact seem to be insufficient for adequate definition of efficacy end points in clinical trials. This review will list some potential shortcomings and possibilities of pharmacological treatment in OSA, and discuss some of the already attempted modes of treatment.
The whole point of my post was that if they had consulted the literature, and talked to people in the field, they would have learned that SA is an extremely complicated condition, arising from an interaction between biomechanical factors (adipose tissue leading to airway collapse; adipose tissue leading to smaller lung volume, thereby decreasing the delay in gas exchange [less dead space], and thereby increasing plant gain) peripheral chemoreceptor sensitivity, central chemoreceptor sensitivity, and central modulatory pathways (5-HT, orexin, acetylcholine,...), not to mention interaction effects with related cardiovascular variables such as hypertension, with some or all factors present in any given patient. Because of the variety of paths to SA, and interaction effects, they could have expected a heterogeneous patient population, and a tough clinical trial. Then there was the little detail that ampakines make it difficult to sleep.
All this to say, this isn't 20-20 hindsight. They didn't operate as scientists. Their ignorance led them to believe that because ampakines worked in opiate-induced RD, it would also work in SA, and they didn't test that hunch at a time when they had just one last shot at a clinical trial. SA was an avoidable, foreseeable disaster, and it has left the company undone.
Their main failure was not as businessmen, but as scientists. People on this board have no inkling about how brutally scientists are punished for failures of judgement. We eat what we kill, and if we don't kill, we die. There are no PIPEs for research scientists, and NIH only funds people who are productive. You chase the wild goose, you're gone.
I have no problem with RD. I wrote about SA.
The point that is being missed in this discussion is that corx is in trouble not because corx management has lacked basic business skills.
The company has squandered its promise because of basic errors in scientific judgement. A minimum of research would have made it obvious that SA was an incredibly complicated indication to attempt to run clinical trials in. Further, the most statistically significant outcome of the trial (i.e. that ampakines disrupted sleep) should have been foreseen, given earlier clinical trials in sleep deprivation, and in ADHD (loss of sleep was the most common side-effect from that trial). Every scientific endeavour has to start with an exhaustive cost-benefit analysis. They skipped this step, and we've paid the price.
This isn't to say that corx management aren't also lousy business people. They've missed every timeline, and handled communications in an absolutely amateurish and unethical manner: if the private channel communications with people on this BB had the remotest connection with reality, they would have been guilty of abetting insider trading.
I've been trying to stay on the wagon, ignoring this miserable company, but I can't take the Rumsfeldian revisionism that has cropped up lately here. Bad luck has played a part in this company's fortunes, it always does in everything. In my opinion though, management ineptitude has played a much more important role.
Is the inaction on ADHD consistent with preparations to sell the company? By minimizing ongoing projects, it could be that they are leaving the options of buyers unencumbered by pre-existing commitments.
fragile X syndrome for starters. Probably Rett's syndrome too.
I don't have a chem background.
As for corx's prospects, the problems here are structural: getting a compound across the valley of death (see the link a few posts back to the advocacy group FasterCures and their position paper entitled "valley of death" I think)requires much more capital than microcaps have on hand, and big pharma doesn't have much appetite for this process either. As a consequence, while corx has some very exciting preclinical results and a range of compounds, they have historically been completely unable to shepherd compounds to a late enough stage to make them of interest to BPs.
Right now, the most optimistic position that can be held for corx is that they will form a partnership that will generate enough funds to bring one compound to market for one indication. The earliest home-run that I can see for corx would be efficacy in ADHD trials (getting the IND will be important, but I don't think it will significantly affect SP). The earliest I see this happening is 2 years out. From the standpoint of accelerating the rate at which their compounds are developed, the best thing that could happen then is that the company be bought out. On this view, things aren't all that bad, although all this is a chain of wishful thinking.
The next 6 months are decisive: without the funds to move their compounds forward in any meaningful way, corx has to close some kind of a deal. As gfp pointed out, they could raise capital through a PIPE and/or a reverse split, but these actions will only buy them at most a year, and if they take this action, they will henceforth be negotiating from a position of extreme weakness, since they will have shot their last bullet. The complete lack of communication from corx, and the absence of any forward movement (IND filing, etc.) all suggest that corx is in negotiations. This doesn't mean a deal will be struck.
Developing a shortcut in the manufacture of a desirable class of compounds also reduces the barrier of entry for other entities to develop novel compounds and carry out pre-clinical efficacy screens.
While corx stagnates, their IP is melting away. Corx patented a number of new compounds about 2 years ago, and since then, nothing has been brought closer to the clinic in a meaningful way. If a deal were inked tomorrow, and everything went perfectly, a drug for any indication might reach patients in 5 years. Assuming they don't go belly up, corx will progress towards this goal at a much slower pace. In another year or two, interest in these compounds will decline, because of the short patent life left on compounds that are all years away from the clinic. Who is going to spend millions on trials when less than 5 years are left on the IP?
The more general point this finding raises is that the world isn't standing still. Corx is.
They can call it something different. It isn't as though corx has had much success making "ampakine" a household word. They've developed a technology to build ampakine analogs. They built cx-614 to show that they could do it, but nothing would impede them or another party to use their general approach to build novel compounds that aren't under patent.
I'm not a chemist, so I can't make the stuff. My bet is that with a bit of digging, you could find an outfit in China who would crank this out for you with no problem whatsoever. The important thing about this report is that they've greatly simplified the process by which ampakines are synthesized.