Re: What am I missing (repro tox)? by: jeskell 04/06/06 12:14 am Msg: 27974 of 28312
Mentioned it since the 10K did seem to imply those had been started in preparation for the phIIb in humans and since cx717 is delivered via blood after absorption, you would want to wonder whether it could cross the placenta into the fetus and what sort of effect or accumulation it would have there. Perhaps some of the current preclinical data shows some effect outside of the CNS.
Did a search on placenta and glutamateric and it does seem that there are glutamateric systems outside of the CNS. Perhaps CX717 has shown some effect there that COR didn't think was meaningful but where the FDA wants more info before continuing with human trials.
I'm presuming that all this is well known to COR and that they would have reviewed the effects of CX717 outside the CNS and I would think that if they saw anything unusual, they would have done a lot more testing to satisfy themselves as well as anticipating the FDA. However, it's possible that they may have rushed things, overlooked something or considered something insignificant that the FDA considers otherwise.
The first article I found was from 'Expert Opinion' journal Dec 2004 Vol 14 no 12. Here's the summary and link
The glutamatergic system outside the CNS and in cancer biology Niki Kalariti, ÂNikos Pissimissis & ÂMichael Koutsilieris​‌ Department of Experimental Physiology, Medical School, University of Athens, 75 Micras Asias, Goudi-Athens, Greece. mkouts@medscape.com †Author for correspondence
Glutamate is a major excitatory neurotransmitter in the CNS. The signalling machinery consists of: glutamate receptors, which are responsible for signal input; plasma glutamate transporters, which are responsible for signal termination; and vesicular glutamate transporters for signal output through exocytic release. Recently, data have suggested that the glutamatergic system plays an important role in non-neuronal tissues. In addition, the expression of glutamatergic system has been implicated in tumour biology. This review outlines the evidence, which suggests that the glutamatergic system may have an important role in cancer biology.
Re: What am I missing (repro tox)? by: jeskell 04/06/06 12:20 am Msg: 27975 of 28312
Another article: (This is all outside my expertise so this may not be relevant to the hold placed on the trials.)
Glutamate uptake.
Danbolt NC.
Department of Anatomy, Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1105, Blindern, N-0317, Oslo, Norway.
Brain tissue has a remarkable ability to accumulate glutamate. This ability is due to glutamate transporter proteins present in the plasma membranes of both glial cells and neurons. The transporter proteins represent the only (significant) mechanism for removal of glutamate from the extracellular fluid and their importance for the long-term maintenance of low and non-toxic concentrations of glutamate is now well documented. In addition to this simple, but essential glutamate removal role, the glutamate transporters appear to have more sophisticated functions in the modulation of neurotransmission. They may modify the time course of synaptic events, the extent and pattern of activation and desensitization of receptors outside the synaptic cleft and at neighboring synapses (intersynaptic cross-talk). Further, the glutamate transporters provide glutamate for synthesis of e.g. GABA, glutathione and protein, and for energy production. They also play roles in peripheral organs and tissues (e.g. bone, heart, intestine, kidneys, pancreas and placenta). Glutamate uptake appears to be modulated on virtually all possible levels, i.e. DNA transcription, mRNA splicing and degradation, protein synthesis and targeting, and actual amino acid transport activity and associated ion channel activities. A variety of soluble compounds (e.g. glutamate, cytokines and growth factors) influence glutamate transporter expression and activities. Neither the normal functioning of glutamatergic synapses nor the pathogenesis of major neurological diseases (e.g. cerebral ischemia, hypoglycemia, amyotrophic lateral sclerosis, Alzheimer's disease, traumatic brain injury, epilepsy and schizophrenia) as well as non-neurological diseases (e.g. osteoporosis) can be properly understood unless more is learned about these transporter proteins. Like glutamate itself, glutamate transporters are somehow involved in almost all aspects of normal and abnormal brain activity.
Re: Volume & messages by: gfp927z 04/06/06 11:34 am Msg: 27989 of 28312
Since it's a slow day, here are some of the high and low points we've seen with this stock over the last 5 years or so -
I started following Cortex right before the Shire CX-516/ADHD debacle dropped the stock to the sub-dollar level. Man, those were some dark days around here. CX-516 was a pathetically weak compound, and as longs will remember, Cortex got down to around 1/2 mil in cash before getting a new CEO (Stoll). The company was broke and in disarray, but there was some hope that the more potent Ampakine compounds might have promise (Cortex's CX-691/Org-24448 being advanced by partner Organon for example). Stoll was able to raise some money, just enough to advance a single potent compound toward the clinic - CX-717 (an even more potent compound than CX-691/Org-24448). With available funds severely limited, he was forced to essentially bet the farm on CX-717.
Then while CX-717 was being readied, we got the abysmal results from the ongoing CX-516 MCI trial with Servier, which put the nail in the CX-516 coffin for good. With everything riding on the potent CX-717 (50 times more potent than CX-516), we took it into Phase 1. Skepticism abounded that the GI problems seen with CX-516 might be a class effect for Ampakines, or that the big theoretical bugaboo haunting the AMPA upmodulation concept (excitotoxicity) might emerge as a platform buster. Adding to the angst, around that time we heard that Lilly's LY-451395 AD Phase 2 had been halted, apparently due to excitotoxicity related problems. And after the CX-516 MCI debacle, Servier seemed to be shelving plans for their own S-18986. Though these seemingly failed compounds were from totally different chemical families than Cortex's compounds, skepticism reigned.
Amazingly though, CX-717 had phenomenally great Phase 1 safety results (an understatement). They dosed up to a massive 1600 mg, but saw no potential for excitotoxicity whatsoever. No GI problems either. Cortex was clearly onto something, and this is when I really started getting interested in the stock.
There had been some phenomenally good primate data generated by Dr. Deadwyler using CX-717 in sleep deprived primates, returning their cogitive performance to better than baseline. So after raising some additional funds, we then took CX-717 into a Sleep Deprivation Phase 2a trial in the UK, and in spite of CRO restictions on the length/degree of sleep deprivation, we saw clear cognitive improvement and excellent safety.
Then 3 separate Phase 2a trials were started, in ADHD, Simulated Shift Work (DARPA), and a small AD PET scan study. ADHD would dose for 3 full weeks with the high dose being a very large 800 mg BID. I was concerned that very high BID dosing for 3 straight weeks might produce some side effects (headaches in particular), but the safety profile remained very good, and the efficacy results were far better than anyone could have expected, reaching statistical significance (P=0.05) in the hyperactivity portion of the endpoint, and a positive trend in the attention portion. We be cruisin folks!
Bringing developments up to date, the 3 month tox study data in 2 animal species which was performed in 2005, and which is required to do future longer clinical trials, was given to the FDA for their evaluation sometime in the last several months. Now we hear from the FDA that there was some problem noted in the animal data (presumably from the 3 month animal tox study), with details to come probably next week, and the FDA has put a clinical hold on CX-717.
While we need to see exactly what the FDA's concerns are, I say -- screw the damn FDA, because this is NOT the end of the story for CX-717 folks. In the words of George C. Scott in "Patton" --- CX-717 will be allowed to fulfill it's destiny!
Moose, Yes, and hopefully there is a good ending to the saga.
Looks like the bio sector is really getting creamed today. Of the 22 stocks on my watch list, only one is up (IDIX, rebounding from its recent severe drubbing), and many are down 3-5% (Vertex down over 7%). Oh well, at least my 5 yr CDs are churning along at a puny but reliable +0.014% today (5.1% annually).
Biotech is one crazy sector. After watching COR and GTCB recently crash, then rise, then crash again, and now DSCO get nailed undeservedly by the FDA, I'm happy to remain on the sidelines.
For me, Cortex's predicament still hasn't sunken in, partly because we really don't know much about the nature of the problem yet. I'm not even assuming that there is in fact a true science related issue at all yet. The FDA has shown itself to be an incompetent, petulant, capricious, vendictive, self-serving and polically charged bureaurcracy, especially in this post-Vioxx environment. They're currently under criticism with the various ADHD drug problems, and are in a circle the wagons / cover our butts mode. They recently shot down expanding the label of modafinil into ADHD on fairly flimsy grounds (one case of severe skin rash). Now they put the brakes on CX-717 just after it announces off-the-chart great results in ADHD. I have very little remaining faith in the objectivity or fairness of the FDA, and I had to be very naive to have had any faith in them previously.
Moose, For the sake of argument, let's assume that - 1) the FDA hasn't based its clinical hold on some BS reason, like trying to look "tough" on ADHD drugs generally, and 2) some BP hasn't bought off someone at the FDA, getting them to temporarily torpedo CX-717 so the BP can pick it up on the cheap.
So the FDA has therefore found a serious, bonafide "problem" somewhere in the animal data, serious enough to legitimately warrant a clinical hold. The question then is, if there is such a serious "problem" evident in the data, then why didn't Cortex and the BPs also notice it, with the BPs then simply walking away from negotiations?
I would have to reject the theory that "Cortex saw the problem, recognized it as very serious, but failed to disclose the problem publicly, and subsequently lied about the continued level of BP interest", since for one thing Cortex wouldn't benefit from such an approach anyway (the BPs see the problem too, walk away, no BP deal, and Cortex insiders face criminal charges for failure to reveal material events).
The other theory is that the data "problem" was noticed by both Cortex and the BPs, but wasn't deemed serious enough to be either disclosed by Cortex to shareholders, or be of much concern to the BPs either (at least not be a deal breaker).
Which begs the next question - how could the FDA consider a piece of data to be serious enough to justify a clinical hold, while neither Cortex nor the BPs considered it a major problem at all? That gets back to Neuro's discussion, that perhaps since the FDA had presumably seen more animal data on various types of AMPA modulators than have Cortex or the BPs, that the FDA recognized a problem that Cortex/BPs missed or didn't consider relevant. I don't know, I find it hard to believe that the morons at the FDA would know more about the tox profiles of AMPA modulators than Cortex, Lilly, Glaxo, Pfizer, Merck, etc.
I still think the basis of this clinical hold is most likely in the "BS" category, ie - damage control/butt covering behavior by the FDA. Sure, they'll have found "something" in the data to justify the clinical hold, but that something will then ultimately show itself to be a big nothing. Just a convenient excuse, manufactured to fit the FDA's self-serving agenda. Of course I could be wrong though, so we'll see.
Ruengies, If the "problem" is pure BS, it might be apparent to investors as soon as Dr. Stoll discusses it in the conf call (and BPs will quickly see if it's BS or not). While the FDA can erect a formidable barrier for any drug/company that they want to for any reason, in this case the BPs will probably still be interested in CX-717, figuring they can use their superior FDA contacts/influence to reverse the clinical hold in a timely way.
Man, from an investor's perspective, this sector really sucks. Not only do we have to deal with massive scientific risks / challenges, but also with a corrupt regulatory apparatus (just my opinion).
was cx717 efficacy ever reported? by: nerdseeksblonde 04/06/06 07:49 pm Msg: 28041 of 28316
The cx717 sleep-deprivation paper makes interesting reading- it sounds like the PET scans make sense except possibly for thalamic effects ( interesting to read about ARAS too).
I think someone mentioned possible toxicology issues but I wouldn't rule out delayed cns/behavioral effects in animal subjects or new animal data related to AMPA from an unrelated study. Several AMPA/glutamate animal results in the literature recently ( I'll try to post links when I get some of these sorted out).
Paranoia by: Neuroinv 04/06/06 08:41 pm Msg: 28045 of 28316
The paranoia is getting ridiculous. I believe that the FDA is slow, clumsy, nitpicky, and self-serving: they want to avoid looking bad, now more than ever. But the notion that they are aiding and abetting a BP's competitive scheme is just....absurd. Can I prove that it's not happening? No. Can I prove that it was not a mutant alien space dog from Betelguese that had an anomalous reaction to CX717 because its liver processes differently than terrestial dogs? No. Doesnt make that hypothesis likely either.
I had a conversation today with a physician who use to work for FDA. I asked him about the situation that COR is in. He informed me that they do that frequently because some of the preclinical toxicity studies used megadoses of the drug that are far beyond the equivalent doses that will be used in humans. He told me about what happened to Green Tea. The animal studies used megadoses in beagles and some of the animals eventually developed liver toxicity. This caused the FDA to put on hold any human study on green tea. Here is a substance that a lot of people had been drinking for years and is no exception.
Could this be the same thing that happened with COR? I think Dr. Stoll mentioned in the past that they still have to find the maximum dose to see significant side effects.
Yes. When we ran out of goats, we had to import dogs from Betelguese in a hurry. Who knew one of them would volunteer for a CX717 study ('Earn $250 or your weight in puppy chow for participating in an experimental drug study') and mess up the results.
BTW: Fbohn--the absolutely worst thing one can do in the eyes of the FDA is to preempt private discussions with them by taking the topic out into a public venue. If he asserts CX717 is safe before the FDA agrees it is--he'd be asking for a world of hurt. So he won't.
P.S. Pfizer and Rinat. Rinat is the spinoff of Genentech's neuro protein programs. Very good science--some overlap perhaps in terms of both addressing neurodegeneration. The only implication for us is that this may reduce the likelihood that Pfizer is a frontline player for Cortex's partnership--though their large molecule and Cortex's small molecule approaches could be seen as complementary. They certainly have the money to make multiple deals/acquisitions in the neuro area--do they have the will?
NeuroInvestment
Avoiding the perception of hubris by: Neuroinv 04/06/06 10:16 pm Msg: 28060 of 28316
Even a show of confidence might be interpreted as hubris. I think Stoll has to walk very carefully here- and the truth is, it's more important at this time that he make the FDA happy, than try to make shareholders happy. If he accomplishes the former, then the latter will be assured.
NeuroInvestment
Re: Avoiding the perception of hubris by: gfp927z 04/06/06 10:52 pm Msg: 28063 of 28316
Neuro, As we sit here cowering and prostrate before the omnipotent FDA, I was wondering what the chances are that the FDA will now start digging through the animal data for Org-24448? Or would finding something there be too embarrassing for them since the government (NIMH) has already selected Org-24448 for the TURNS Schizo trials?
Reality check, this is now an 07' story by: mitch_blood_green (M/Catskill, NY) 04/06/06 11:26 pm Msg: 28068 of 28316
This will be resolved favorably in Dec 2006 It will take 9 months to clean up. Dead money for the next 9 months as new tox tests will need to be set up, then processed to generate new safety data sets to address concerns and disprove FDA potential red flags.I think that later this year there will be the need to do a bridge PP to get to where they need to get with agency. In early 2007 when the dust clears, BP interest should resurface.Everything is on hold now.NO BP deal,no inlicensing until resolution Tough business.A hold but dead $ and could go lower later in year with tax-selling. This is the way I see this now
Org-24448 by: gfp927z 04/06/06 11:45 pm Msg: 28071 of 28316
In discussing the development of CX-717 at a presentation, Dr. Stoll explained some of the shortcomings of earlier Ampakines. CX-516 was not only extremely weak, with a very short halflife (under an hour), but it also had some poor metabolic characteristics. He said that CX-691 (Org-24448) was far better than CX-516, but it too also showed some metabolic characteristics that left something to be desired. So they continued to modify the structures, arriving at CX-717. The resulting compound CX-717 is not only more potent than CX-691 (50 times the potency of CX-516 vrs 30 times for CX-691), but also has a longer halflife (9-10 hours vrs 6-7 hours), and has better metabolic properties.
It's the superior metabolic characteristics of CX-717 vrs CX-691/Org-24448 that are relevant to the current situation. Since CX-717 has the cleaner metabolic profile of the two compounds, but still (presumably) had animal tox problems sufficient to justify an FDA clinical hold, then couldn't one reasonably expect Org-24448 to potentially have even more animal tox problems than CX-717?
Something doesn't jive here. Either - 1) the serious tox related problem encountered with CX-717 don't occur with Org-24448, or 2) they do occur but the FDA previously missed it in their evaluation of Org-24448, or 3) the FDA was just looking for an excuse to derail CX-717 development for some reason and invented a tox "problem" that isn't really a problem.
Without further info, it's impossible to figure out what's really going on. Unfortunately we can't assume that the FDA is being honest/objective in its treatment of CX-717, or that they were thorough in their evaluation of Org-24448. So, we sit and wait, "cowering and prostrate before the omnipotent FDA".
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