Samyang's smart. If it gains control of the company, it may be able to bring the drugs to market in Asia. Aside from the problem of cronyism, the Chinese regulatory environment likely presents lower barriers to drug approval; I have no idea about Korea, but my guess is that if you've got big enough Chaebols, you can probably get things to happen.

It looks to me as though they are on a glide path to liquidate the company. Without the infrastructure for drug development, toxicology, or preclinical animal trials, they are reduced to licensing their IP. It's not obvious that you can come back from this.



>>>Subsequent to March 31, 2012, we executed an operating lease agreement for approximately 5,000 square feet of office space with a lease term beginning June 1, 2012 and ending May 31, 2015. The commitments under the new lease agreement for the seven months ending December 31, 2012, the years ending December 31, 2013 and 2014 and the five months ending May 31, 2015 are approximately $64,000, $103,000, $117,000 and $49,000, respectively. Provided that we are in compliance with the terms and conditions of the new lease, we have the option to terminate the lease at the expiration of the twelfth month or twenty-fourth month by providing four months prior written notice.

Samyang has invested in corx, and has the funds to solve corx's liquidity problem. Assuming that they still believe in the promise of ampakines, and want to protect their investment, couldn't they recapitalize corx in exchange for a larger ownership stake?

A more basic question is: what does corx have to do in order to increase the level of interest in low-impacts for opioid-induced RD? Back when they disastrously opted to pursue SA, there was talk of developing an IV version of the low-impact for post-operative use. Does this work require Street's expertise? What do you estimate the (pre-)clinical trials needed to increase the likelihood of a licencing agreement would cost? Is this even an option? Is it simply a matter of knocking on the same doors to see if someone has changed their mind?

Samyang took another bite:
http://xml.10kwizard.com/filing_raw.php?repo=tenk&ipage=8262925

Actually, I think what this doc states is that Samyang is unloading some shares. I'd be grateful for clarification.

By now that grant has been scored. I'm betting we haven't had an update because their proposal was rejected.

So it looks like these are 2 more LIs. The use patents suggest that Varney et al. still see hope in selling LIs to upregulate respiratory drive. I think this is a good development. I hope they didn't spell Cheyne-Stokes wrong on the patent docs. It's nice to be up to a dime.

Another reason for getting ampakines to market in the treatment of opioid-induced RD (free article from Nature, commenting on a paper in Science):

Has a cheap and effective treatment for chronic pain been lying under clinicians' noses for decades? Researchers have found that a very high dose of an opiate drug that uses the same painkilling pathways as morphine can reset the nerve signals associated with continuous pain — at least in rats.

If confirmed in humans, the procedure could reduce or eliminate the months or years that millions of patients spend on pain-managing prescription drugs. The results of the study are described today in Science1.

Higher than normal doses of opiates may be able to cure chronic pain.

“We have discovered a new effect of opiates when they are given, not constantly at a low dose, but at a very high dose,” says Jürgen Sandkühler, a neurophysiologist at the Center for Brain Research of the Medical University of Vienna, and a co-author of the paper.

Chronic pain is a nerve condition that lingers long after the immediate, or acute, pain-causing stimulus has receded. It can follow surgery or injury, and is also associated with conditions such as rheumatoid arthritis and cancer.

Sandkühler says that the original stimulus changes how the central nervous system deals with pain over time. In a model known as long-term potentiation, nerves carrying pain signals fire repeatedly, turning on a cellular pain amplifier that causes anything from exaggerated pain to outright agony on a long-term basis.


Opiates such as morphine and heroin remain the 'gold standard' in pain relief, but they work only temporarily for those with chronic pain. Sandkühler and his colleagues decided to push the boundaries of the opiates' action and measure whether the drugs could have any effect on the underlying problem.

The team induced long-term potentiation in 25 rats by exposing nerve fibres known to carry pain signals to low-frequency electrical stimulation. They subjected some of the rats to high-frequency electrical stimulation, or gave them injections of capsaicin, the pain-causing ingredient in chill peppers, as alternative stimuli.
Rapid relief

After the pain stimulus ceased, the researchers gave the rats a very high intravenous dose of the opiate remifentanil. As expected, the pain signals slumped at once — remifentanil is an extremely fast-acting painkiller, and was chosen because its effects tend to wear off in rats after just 10 minutes.

When the drug's effects did wear off, the chronic pain was significantly reduced in the rats treated with low-frequency stimulation. A second infusion of the drug an hour later abolished the long-term potentiation and restored these rats' pain levels to normal. A high dose of remifentanil was also effective in reducing the pain of the rats treated with capsaicin or high-frequency stimulation.

Treating the rats with half the dose of remifentanil did not produce the same effect. Sandkühler suggests that a threshold level of the drug is needed to disrupt the movement of calcium signalling ions between nerves and neutralize the long-term potentiation.

“The dose of drugs we use is very high, probably 2–4 times higher than used for normal pain control,” says Sandkühler. “The animals almost stop breathing, which is probably one reason why this was not discovered before.”

But he adds that the equivalent amount of the opiate for a human is well below a fatal dose. He and his colleagues have conducted pre-clinical experiments that have shown that people can tolerate it.

Michael Serpell, a consultant anaesthetist and pain doctor at the University of Glasgow School of Medicine, UK, is impressed with the paper's methodology. He says the idea has always been that if you hit acute pain hard enough, then you can reduce the chance of it becoming chronic. “It would be appropriate to try this. It could be rolled out into the clinical arena in high-risk patients first,” he says.

However, Serpell cautions that a similar approach, applying a pre-emptive analgesic before surgery that was likely to cause chronic pain, produced promising results in animal studies but later trials in humans were “a complete failure”.

Treatments are certainly needed for chronic pain, which may affect up to one in six adults across the world; Serpell says that 3–5% of the adult population in the United Kingdom is prevented from working by pain. The condition is the second most common reason for claiming incapacity benefit.

Nature
doi:10.1038/nature.2012.9796

In the event of a good outcome, what is the role that MJFF plays? Can they come in as VC? Given the investment they're making to bring HIs closer to the clinic, wouldn't they be interested in profiting from their investment? Alternatively, given the capriciousness of BP, wouldn't MJFF want to ensure that clinical development of a promising drug not be blocked by the bureaucracy of a BP?

On the LI / HI story, I don't think anybody knows what a disease-modifying in vivo BDNF dose is. UCI is mainly in vitro I think, and it would be hard to execute or justify long-term studies assessing the benefits of the small BDNF upregulation seen with LIs.

This whole discussion is moot anyway, because if the HIs upregulate BDNF and are safe, corx won't step on their successful compounds by assessing the extent to which LIs can emulate the effect, and if HIs fail, it is unclear that corx will be doing much of anything other than selling off furniture.

I still think it's nuts that the LIs aren't being picked up for RD. The benefit to public health that is being lost here is enormous.

The physiological consequences of BDNF up-regulation are likely non-linear, and we don't know much about the long-term effects of chronic modest BDNF upregulation. A sustained small increase in BDNF might be more important than a steeper HI-induced upregulation that is accompanied by seizure risk.



That isn't what I was proposing, only that there is this accepted wisdom that LIs don't upregulate BDNF, and there is evidence to suggest that they may, which would change the therapeutic profile of safer LIs.


The artifact was observed at 50X clinically effective dose. If the FDA imposes that kind of nuttiness on HI toxicology, how likely are they to get through?



Minor problem: the strongest effect of ampakines in the SA trial was that they made it difficult for subjects to fall asleep.



I think you're getting way ahead of the science here. One of the biggest challenges in the field of neurodegeneration is that so little is known about how or why neurodegeneration occurs. Most slow disease processes arise out of the gradual disregulation of multiple interacting metabolic processes. It's possible that a single compound could reverse neurodegenerative diseases, but unlikely.

All the discussion of high-impacts focuses on efficacy and potential benefits. Absent is any discussion of the regulatory hurdles corx will face getting the drugs to market. Corx is comatose from its bungled effort in bringing CX717 forward to treat ADHD. While it is true that the FDA's risk-reward calculation for PD would be substantially different than for ADHD, I think it's likely that the safe dosage window for HIs is substantially smaller than for LIs. If effective HI dosages approach seizure threshold, all the promise of the HI platform is gone.

The clinical and strategic importance of LIs are being understated here. There is anecdotal evidence that LIs upregulate BDNF, they are very likely safer than the HIs, and they are closer to the clinic.

What I see as a fundamental strategic problem for corx is their indication-based licensing. At this point, a viable way to bring in the money they need to go forward would be to outlicence the whole LI platform, forget about indications or molecules. I believe neuro posted reasons for why indication-based licensing is the norm, but it strikes me as greatly complicating partnerships.

This is way too long. The basic point I wanted to make is that in assessing corx's prospects, the blunder we have all made is focusing on the science. The regulatory environment and the priorities of the sector have historically been a big part of the problem.

There are 3 possible favorable outcomes in cortex's future:
1. Some pharma decides to run with opioid-induced respiratory depression. This is a no-brainer, and the fact that it's not happening is an indication of how disfunctional the sector is. There is no way to put a time-frame on this, but if I were forced to, I'd guess "never". Everybody who might be interested in the RD indication knows about corx's results, so it's not obvious why somebody who hasn't been interested over the last 2 years would suddenly gain interest. The clinical need is and has been huge, so I don't think Whitney or Michael or the next celeb are going to make a difference.

2. The Michael J. Fox foundation gets some very nice results with ampakines in the treatment of Parkinson's. I don't know the details of when this study was started, but it seems that it's been over a year, so I'd expect some data in the next 6-9 months. Early data looked too good to be true, so there might be something favorable on that front.

3. Servier finds a sweet spot for the high-impact, where seizures are absent and BDNF is upregulated. In the past Servier has done nothing with the corx molecules they had inlicensed, so aside from the scientific uncertainties, there is also a decent likelihood of Servier non-performance.

Meanwhile corx is slowly running out of funds, with no obvious way to raise more.

I'm not very optimistic.

thanks for the update.

This is good news, but it's a drop in the bucket. The NIH total budget is ~$30B, so this is a tiny increase against a background of stagnation in funding levels, which because of inflation, translates as cuts. The general consensus is that for the coming FY, NIH will be cut by 5%. Even if it stays at current levels, US science will continue to be decimated. The bottom line for researchers is the cutoff percentile at which research is funded. Right now it's at about 12%. An explicit directive for NIH is to protect new researchers; an implicit policy is to sustain research at elite institutions and/or cronies, when you factor these 2 elements in, you're left with something closer to a 6% cutoff for everybody else.

If you talk to people who sit on NIH study sections, the task is an impossible one: the committee is given 50 grants to review, and 3 are funded. Every review cycle, study section participants report that multiple excellent proposals weren't funded because of lack of funds.

Another way of looking at this is that $50M have been added to NIH's funds. This will support 50 small research grants that will fund 50 researchers for 4 years. Leaving aside other branches of biomedical research, the Society for Neuroscience has 41,000 members. Conservatively, a third are PIs competing for NIH funds. So there are ~14,000 neuroscientists competing for the fraction of NIH dollars going to neuroscientists, 50 more of whom now will get funded.

I woke up thinking about what you wrote. The problem with your analogy is that refining is a mature technology, in the sense that obsolescent solutions work reasonably well, so that a shift in market conditions can lead to a dramatic change in the industry, as funds are reallocated to building a well-understood infrastructure.
Biotech is different. It takes about a decade to complete undergraduate and graduate education, then in most cases another decade to develop a deeper understanding of one's subject of specialization. Similarly, it takes time to put together a productive research team.
As has been extensively documented here, big pharma has dismantled its research division. NIH funding is inadequate to maintain the academic research community. The cohort of students who might consider a career in research are opting for other professions out of pragmatism.
Finally, the regulatory environment is very different. While energy sector regulation is likely strict, the guidelines are clear, and addressing regulatory challenges is straight-forward. In biotech, the regulatory environment is opaque, arbitrary, and risk-averse in a space where some level of risk is unavoidable.
Taken together, the problems facing biotech are of a different order. The research teams that have been dismantled will be difficult to reconstitute, and the work-force is disappearing: those being pushed out move into new professions and rapidly loose their competence as the field advances, and those who might have entered the profession are choosing different careers.

All this in the context of the FB IPO...

Thanks to all of you for the informative updates. The emphasis on translational research at NIH is in my opinion another way to aid big pharma, at the cost of NIH's core mission, which should be to fund pre-clinical basic research.

Given the looming costs of AD, the federal government better come up with a viable path to drug development. It's first-world malaria.

They're still doing research at cortex. I apologize if this has already been posted.


Bioorg Med Chem Lett. 2011 Oct 15;21(20):6170-5. Epub 2011 Aug 12.
Benzotriazinone and benzopyrimidinone derivatives as potent positive allosteric AMPA receptor modulators.
Mueller R, Rachwal S, Lee S, Zhong S, Li YX, Haroldsen P, Herbst T, Tanimura S, Varney M, Johnson S, Rogers G, Street LJ.
Source

Cortex Pharmaceuticals Inc., 15231 Barranca Parkway, Irvine, CA 92618, USA. rudolfmueller@yahoo.com
Abstract

AMPA receptors (AMPARs) have been demonstrated to be an important therapeutic CNS target. A series of substituted benzotriazinone and benzopyrimidinone derivatives were prepared with the aim to improve in vivo activity over the previously reported bis-benzoxazinone based AMPAKINE series from our laboratory. These compounds were shown to be potent, positive allosteric AMPAR modulators that have better in vivo activity and improved metabolic stability over the analogous benzoxazinone derivatives.

There's still some research being carried out on ampakines. Here is one study that gives a bit of information about sleep-disrupting effects of CX-717 at 1g dosage, which may be of some relevance to the RD angle:


J Psychopharmacol. 2011 Sep 22. [Epub ahead of print]
Acute sleep deprivation: the effects of the AMPAKINE compound CX717 on human cognitive performance, alertness and recovery sleep.
Boyle J, Stanley N, James LM, Wright N, Johnsen S, Arbon EL, Dijk DJ.
Source

Surrey Clinical Research Centre, Division of Clinical Medicine, Faculty of Health and Medical Sciences University of Surrey, Guildford, Surrey, UK.
Abstract

AMPA receptor modulation is a potential novel approach to enhance cognitive performance. CX717 is a positive allosteric modulator of the AMPA receptor that has shown efficacy in rodent and primate cognition models. CX717 (100 mg, 300 mg and 1000 mg) and placebo were studied in 16 healthy male volunteers (18-45 years) in a randomized, crossover study. Cognitive function, arousal and recovery sleep (by polysomnography) were assessed during the extended wakefulness protocol. Placebo condition was associated with significant decrements in cognition, particularly at the circadian nadir (between 03:00 and 05:00). Pre-specified primary and secondary analyses (general linear mixed modelling, GLMM) at each separate time point did not reveal consistent improvements in performance or objective alertness with any dose of CX717. Exploratory repeated measures analysis, a method used to take into account the influence of individual differences, demonstrated an improvement in attention-based task performance following the 1000 mg dose. Analysis of the recovery sleep showed that CX717 1000 mg significantly reduced stage 4 and slow-wave sleep (p = 0.05) with evidence of reduced electroencephalogram (EEG) slow-wave and spindle activity. The study suggests that CX717 only at the 1000 mg dose may counteract effects of sleep deprivation on attention-based tasks and that it may interfere with subsequent recovery sleep.

This is indisputably the case. Sleep-disordered breathing and the resulting intermittent hypoxia drives obesity, diabetes, hypertension, and neurodegeneration.

FWIW: I think that the people left at corx are doing everything they can to get out of the hole they are in. I remain confident about the efficacy of low-impacts for opioid- or propofol- induced RD, and I think this is a big deal. I am making every effort to forget about this company, but haven't lost hope.

All the best to everyone here in the new year.

You've proved his point.

Happy thanksgiving to everybody who still glances at this board.

I am thankful because the pain caused by my foolish purchase of this stock has receded almost as completely as the stock valuation.

I think the user fees are borne by those who buy the meds. From the doc you posted:
"Since the enactment of the Prescription
Drug User Fee Act (PDUFA) in 1992, FDA has
steadily increased the speed of Americans’
access to important new drugs compared to
the EU and the world as a whole. As shown in
Figure 1, the United States now leads the world
in the first introduction of new active drug
substances."

This has its own problems, but at least it doesn't tilt the playing field to BP's advantage.

there was a recent piece in the NYT about a new commitment at the FDA to speed up drug approval.

http://www.nytimes.com/2011/11/04/health/policy/drug-approvals-rise-for-fda.html?_r=1&scp=2&sq=FDA&st=cse

Then there was this piece outlining the changing strategy at the FDA, raising the bar for me-too drugs:

http://seekingalpha.com/article/292260-fda-approval-process-sets-higher-bar-for-what-s-treatable

Taken together, these changes may lead to a slightly more favorable climate for ampakines in the treatment of conditions for which there are currently untreated or badly treated (opioid RD, parkinson's).

These really are hard times.

How do you pump and dump an illiquid low-priced stock traded OTC?

If this is an intraday play, then even if they were the sellers of all the 800k shares traded today, purchased over a few weeks at ~ $0.06, they made all of ~$15K. That's pretty labor-intensive.

I'm not saying this didn't happen; as scams go though, it's stupid.

Did I read it right? It looks like they've invested ~$600K. Not a lot, but it helps.

http://xml.10kwizard.com/filing_raw.php?repo=tenk&ipage=7866943

If Stoll or others in management aren't willing to go along with Varney's plan, this could end badly for Varney, since he'd need their support, and the support of the BOD.

This looks like a really stupid idea. I don't think the scenario I've been describing is going to happen.

It worries me that you had the same idea. Do you think this would be legal? A CEO of one company sets up another company, sells his company to the new company, and then moves to the new company as CEO. This is sort of like screwing it forward. The fact that Stoll isn't quashing it, and Varney isn't responding gives this thing some credence.
Newman-Tancredi operates out of France, and the only pharma with a stake in corx right now is Servier, which has a bad reputation in france, where they face charges of fraud:
http://www.latribune.fr/entreprises-finance/industrie/chimie-pharmacie/20110926trib000651801/en-attendant-son-proces-servier-rassure-ses-employes-.html

Along with an extensive track-record of hiding dangerous/lethal side effects of their drugs (the attached article translates as "Servier: the shame of french pharma")
http://cpolitic.wordpress.com/2007/11/20/laboratoire-servier-la-honte-de-lindustrie-pharmaceutique-francaise/
the details are pretty hair-raising, particularly a weight-loss drug Isomeride, which caused heart damage.

So Neurolixis may be focusing on delivering corx to Servier, perhaps with Servier's collusion.

I don't buy the roomie angle. Corx has valuable IP, thus arguably undervalued stock. If neurolixis were to buy corx, current shareholders would be eliminated, and VCs could finance (and reap the profits from) bringing the pipeline to the clinic via partnerships.

The only problem with this scenario is that it's likely illegal.

If it isn't, it should be.

Here's a link:
http://kepler.sos.ca.gov/cbs.aspx

and type in neurolixis.

Varney's name is definitely associated with the company.

He appears to have filed this paperwork using his home address.

It's possible that he did this as a favor for Newman-Tancredi, who may not have had a CA address for the filing.

I'd be curious to know what Neuro has to say about this.

The house associated with Varney's name was purchased on 3/29/2011. Nice to see how the other half lives...

There's also a neurolixis address, missing from the Neurolixis website: 525 B ST STE 2200 San Diego
This is actually the address of a law firm:
Procopio, Cory, Hargreaves & Savitch LLP
525 B Street, Suite 2200
San Diego, CA 92101
619-238-1900

Go figure.

Extreme pain, not managed at safe opioid dosages. People dumped on this, but I thought it was a good idea. Pain management drugs are under scrutiny because they are killing people every day, and the market is huge (I think Athero posted some jaw-dropping stats on the number of generic opioid prescriptions written in the US).

If another entity wants to prevent the eventual absorption of corx and its IP into Servier, this would be the time to do a low-cost partnership.

Somebody out there has to see the value of corx as a drug against respiratory depression. The data are pretty good, and that's worth a good deal of money.

Another partnership would bump this thing up. If the company has enough to ensure > 1y of viability, the company's prospects and valuation could change qualitatively.

Well, there you have it... This might explain yesterday's volume.
Does this impact the MJF project?
This should get us to $0.13

Servier's decision should come along soon.

Correction: they have a month.

On or before October 31, 2011, Servier may exercise its option to acquire sole ownership of the global patent rights to CX1632, along with a sub-license of Cortex's rights to all indications licensed from the University of California for use with CX1632.

Unbelievable that they will relinquish all the IP associated with this high impact for $2M!

If it boosts the credibility of their other molecules, it may be a good thing.

JD welcome back. Since you left the paint has dried and started to peel in spots. We'll see what Servier does.

FWIW, it appears that corx has locked up the RD indication when treated with allosteric AMPAR modulators (even non-ampakines).

http://www.naturalremedyfordepression.org/2352/cortex-receives-u-s-patent-for-the-use-of-ampakine-molecules-to-treat-respiratory-depression-news-press-release

The corx website has the update, but their server isn't working, so this is a mirror.

You're assuming rationality on the part of the buyer; all this buying may just be the activity of a fool or fools. Anyone who bought this stock in the last 3 years is arguably a bigger fool than whoever is paying more for the transaction than for the stock now.

I think this one is current:
DJ Holder SAMYANG OPTICS Registers 788,581 Of CORTEX PHARMACEUTICALS-Amended 18/08/2011 03:47

http://www.morningstar.co.uk/uk/markets/newsfeeditem.aspx?id=155144956475850

It looks like Samyang is cutting its losses. From the accompanying text:

Corx has also released its 2nd quarter operating results:

http://www.marketwatch.com/story/cortex-reports-second-quarter-operating-results-2011-08-18?reflink=MW_news_stmp

It isn't just Varney who gets criticized, but anybody who takes a more nuanced position of what's going on with this company. A lot of what goes on at this BB is ranting at other posters. We need to agree to disagree and move on.

The unfortunate thing that is missed is that when you control the debate, everybody else has stopped listening. I think that most people who browse this BB simply ignore the ranters. I know I do.