COR Yahoo Message Board: Tue 4/4/2006
Re: SHO 3-31-06
by: gfp927z 04/04/06 01:44 am
Msg: 27667 of 27882
Biobetter, I had assumed that the recent reappearance of Cortex on that SHO list (indicating a high level of naked shorting) was somehow related to the recent availability of options on the stock (ie -some elaborate hedging strategy going on, possibly related to the warrants). However, in light of what happened today, who knows.
Well, Murphy's Law is certainly alive and well in this sector, and it seems that most of these bio stocks blow up at one time or another. What prompted me to finally abandon investing in these stocks (aside from my over-reliance on borrowed funds) was barely dodging similar meltdowns in PARS, CTIC, EPIX, plus watching GTCB's recent meltdowns. The way I see it, bottom line -- who the hell needs the aggravation, ulcers, and heartache of this sector? As a pure hobby though, the science is cool, there is suspense/intrigue, and the dramatic setbacks can be entertaining in a perverse sort of way, assuming one doesn't have any money riding on the results.
Anyway, my prediction from the sidelines is that after much angst and handwringing, this will only be a temporary setback for Cortex, and some additional animal studies will allay the FDA concerns, and the stock will eventually rise again from the ashes.
Recent warrant excercises=cash cushion
by: gfp927z 04/04/06 09:28 am
Msg: 27707 of 27882
As Neuro said, though we don't know for sure yet, Cortex will probably need to run some additional 3 month tox studies on larger populations of animals. If we assume that the BP deal will be on hold until after designing/running/analyzing/submitting these additional animal studies (perhaps 6-9 months?), then Cortex's relatively low cash level becomes a potential concern (approx $17 mil at year end 2005).
However, the recent excercising of some of the outstanding PIPE warrants should provide Cortex with a considerable amount of additional cash. Exactly how many warrants were excercised in the recent runup we don't know yet, but I figure at least 1/3 to 1/2 of them, which would equate to an additional $10-15 mil in cash or so. That extra cash cushion could make the difference between having to do an unfavorable PIPE or not, as well as keeping Cortex's important R+D activities (high impacts) fully funded while we await the data from the new animal studies.
The big question right now is what exactly was the problem that the FDA saw in the animal data (presumably it was in the longer term 3 month data that was recently completed)? The 3 month tox data was necessary in order to start running longer term human studies (up to now the longest human trial dosing was for 3 weeks in ADHD). While we're not privy to what's actually been going on in the BP negotiations, if BP interest has been as strong as we've been hearing in Cortex's presentations, then BP's must not have had any major concerns over CX-717's safety profile to date, either in its preclinical animal data, the human Phase 1, or the completed Phase 2a trials (UK Sleep Dep and the recent ADHD trial).
As Neuro said, the FDA has seen safety data on several other classes of AMPA modulators (Lilly's biarylpropylsulfonamide, which Lilly halted in Phase 2, apparently due to excitotoxocity problems), and Servier's current large S-18986 Phase 2 (S-18986 being a benzothiadiazide related compound), though I'd have to go back and check if the Servier study is enrolling in the US or only in Europe. Concerning Lilly, we don't know if they halted their Phase 2 trial voluntarily, or if the FDA was involved in the decision. As Dr. Rogers pointed out at the SHM several years ago, Lilly's high impacts have a far different (far worse) safety profile compared to Cortex's low impacts like CX-717. We have never heard of any excitotoxicity problem with CX-717 whatsoever. The problem concerning the FDA is more likely something other than excitotoxicity.
(continued)
Re: Recent warrant excercises=cash cushi
by: gfp927z 04/04/06 10:07 am
Msg: 27720 of 27882
So if the problem isn't likely excitotoxicity related, then what else might it be? Last year there was a paper published on the spectrin/calpain phenomenon (rumors at that time were that Dr. Lynch apparently had a falling out with the author over its publishing). This phenomenon reportedly occurs with some AMPA modulators, but not others, and is apparently more associated with the high impacts, as Dr. Mansbach discussed in a company presentation last year. I remember he said at that time that as far as they knew, CX-717 was not one of the compounds that produced the spectrin/calpain phenomenon. In this phenomenon, proteins are degraded/broken down, and it's been postulated that this protein breakdown which is usually associated with neural damage processes / neurodegeneration, might also occur during the process of normal LTP (long term potentiation) during memory formation (since proteins need to be broken down and then reassembled as part of memory formation/encoding). But the significance of the spectrin/calpain phenomenon as it pertains to AMPA modulation appears to still be a scientific grey area.
More likely, there may have been a change in liver enzymes, or something of that nature (just speculating here). We know that CX-717 reportedly doesn't produce somatic changes of any significance (changes in blood pressure, pulse/heart rate, etc). This is in contrast to non-specific stimulants like amphetamines. But at extremely high doses in animals, side effects may occur which might never show up in normal therapeutic doses. With the recent furor over the side effects of the current ADHD drugs, the FDA is probably being super-cautious at the moment (and thereby also covering their collective butts, a daunting task considering the sheer number of asses employed at the FDA :o)
Gfp's summary and comment
by: Neuroinv 04/04/06 11:01 am
Msg: 27741 of 27882
Gfp: 27720+27707 were a terrific summary--many thanks. The only addition I would make is: I would not assume that the BP deal will necessarily be put off until after the day that the FDA officially lifts the clinical hold.
Provided that the preclinical issue is solvable, which we both think is likely--but not certain, since the nature of the issue has yet to be divulged--I think the following will occur:
1) As soon as the issue is made public, both Cortex and a handful of the most interested companies (perhaps two or three) will independently address it in their own labs. A BP, having done its own DD thus far, will continue to do so.
2) BP has better contacts at the FDA than Cortex does. They will (and again, I am not buying into the paranoid model) be able to get a clear picture of exactly what the FDA wants to see. As soon as they believe they have that solution in their labs, they can be pretty confident that the hold will be lifted. At that point--and that point could differ from BP to BP--the offers go back on the table, perhaps amended, perhaps not.
3) There is also the possibility that the BPs with the most DD information may see the FDA's demand and decide that they already know the answer. In which case one of them might try to steal a march and make a deal with Cortex that might predicate part of the upfront money on the lifting of the clinical hold. That would probably take more time to work through the BP hierarchy, as each level would have to sign off on accepting the risk involved.
4) To be fair--there is the possibility that all involved might look at the FDA's demand and decide that it is not resolvable, no way to prove the negative, for example that there is no risk of Adverse Event X occurring. I do not expect that, the FDA is clumsy and slow, but that would be bizarrely arbitrary given what is already out there. But the climate now, particularly for ADHD drugs, has raised the bar.
NeuroInvestment
Re: Gfp's summary and comment
by: Neuroinv 04/04/06 03:30 pm
Msg: 27799 of 27882
The hold should have no bearing on the DARPA data--other than Cortex will be putting less pressure on DARPA to hurry up with its data analysis, since it will have much less impact now than it would have without the hold. But when the data is ready, it will be material, and DARPA and Cortex will negotiate the content of the press release.
NeuroInvestment
Even Cortex doesn'tknow the problem yet
by: ombowstring (56/M/Cape Cod, MA) 04/04/06 04:25 pm
Msg: 27805 of 27882
I e-mailed Dr. Stoll yesterday as follows:
Dr. Stoll,
Shareholders would like to know if the specific problem with CX717 was communicated to Cortex in the telephone call from the FDA.
Obviously, we are trying to gauge if this is a problem that can be rectified or if it is a death knell for CX717.
Thanks,
John Mackenzie
P.S. Can you say anything more than that which was contained in today's press release?
To which he replied:
John, I can’t say anything more except that when we have had the chance to assess the issues raised in the letter and communicated with the FDA about how we might be able to address their issues, we then could communicate a plan to shareholders. I can not at this time give you more clarity until we at Cortex are sure what we are up against. First we need to get the letter from the FDA. Roger
I then sent him a follow-up question:
Dr. Stoll,
Wasn't the FDA's problem with CX717 communicated to Cortex in the telephone call?
Thanks,
JM
To which he responded:
It was a short conversation between the division head and Hank Mansbach and we were told the specifics would be addressed in the letter to follow. Roger
Re: Even Cortex doesn'tknow (Ombow.)
by: Neuroinv 04/04/06 06:58 pm
Msg: 27824 of 27882
If Roger Stoll was going to go beyond what he'd said before, he wasnt going to do it in an email to an individual--that would be a big Reg FD problem. I have no doubt he knows more than he has told anyone publicly, but I also don't think he knows enough more to be able to make a reasonable public statement.
Someone just emailed me a question about how Stoll could not know all the details. Here is my scenario for how that could be :
<<I suspect that the liaison who called Mansbach is not the same person who reviews the preclinical data and decides on the hold. So--my hypothesis is:
The reviewer called the liaison and tells them: "Call Mansbach and tell them we're putting a hold on CX717. One of those three month dogs had elevated enzymes (or something of that ilk) , and based on what I've seen before
( Lilly, for example)....I'm not going to let them go ahead until we're sure that this isnt going to be a repetition of (Lilly, for example). The details will be in the letter, but I'm not going to get around to writing that until Tuesday." So the liaison did what he/she was told.
Which is how and why Mansbach would only get a little info, and not a sense of the context or details. And without the details, not much can be said by Stoll that would be useful guidance.
This is just a scenario--but if you think about how large bureaucracies behave, it could well be true.
NeuroInvestment
Re: Inconceivable!
by: Neuroinv 04/04/06 08:42 pm
Msg: 27848 of 27883
A couple facts that are being overlooked by some:
1) The three month tox studies were completed after the Phase IIa program was started, patients enrolling. The three month tox studies are needed for longer-duration Phase IIb trials. Thus the assumption that the Company knew about some preclinical problem and went ahead anyways with clinical trials may or may not be true. A very important tranche of animal data went to the FDA recently--and if that is where the problem came from, Cortex was well into the clinical trials. Would they know there was a problem (or more than one?) Sure--but they might not have thought it was an important one. What they think to be a fluke might not be seen that way by the FDA--and the FDA's response clearly did blindside them.
2) Fbohn: Your post suggests that Lilly shares its preclinical data with Cortex, and that Cortex would thus be aware of problems therein. That is unrealistic. Lilly has to send it to the FDA, but competing companies tend to not freely share that kind of data on clinical-level drugs. It would be expected that the FDA would have a lot more info on the preclinical findings obtained by other companies than Cortex would.
NeuroInvestment
Re: Even Cortex doesn'tknow(meixatech)
by: ombowstring (56/M/Cape Cod, MA) 04/04/06 08:50 pm
Msg: 27849 of 27883
My impression is that the phone call came totally out of the blue to Cortex based on, again, what Dr. Stoll said about not knowing what we are up against.
What you say represents a possible scenario, but I don't think it's the actuality.
Therefore, I conclude, being invested in COR at this time is a dicey situation. If this problem with CX717 cannot be rectified to the satisfaction of the FDA and the drug is dead in the water, Cortex suffers a serious setback and the stock price plummets. If on the other hand, the problem can be resolved, the DARPA results are favorable, and the BP deal is consummated, the stock price soars. But at this point in time perhaps the very future of Cortex as a viable company hinges on the problem because of which the FDA has halted clinical trials of CX717, which seems to be a drastic step to take, a step that would not be taken without good reason. I'd have to say I'm very, very concerned about being invested in COR at this time because of the recent turn of events.
3 month tox studies
by: gfp927z 04/04/06 08:53 pm
Msg: 27851 of 27883
Thinking back, last year's 3 month tox studies in 2 species did take considerably longer than expected. I'm going from memory here, but I remember the studies were supposed to be completed around the end of the Summer, but then Dr. Stoll's estimates given at presentations for the completion date slipped several times, to around year end. I don't remember ever really hearing much about the final results themselves, other than some passing remarks that they were finally completed.
I remember us speculating at the time on what may have been causing the delay. One theory I recall was that the tox trials had been farmed out, and perhaps the lab doing them was simply slow/busy. Another theory was that they may have encountered a problem and had to repeat some of the tests. Maybe Neuro or others remember better, but I distinctly remember getting increasingly worried as the completion date for those tox studies kept getting pushed back (though the timelines for the Phase 2a trials were also getting pushed back too). Anyway, I suppose it's possible that whatever issue the FDA is currently concerned about might be the same issue that caused the delays in the 3 month tox studies last year (just speculating). Anyway, I guess we won't know much either way until next week or so.
I must admit to having lost a lot of faith in the regulatory process over the last several years. True, the FDA is underfunded and overwhelmed with drug data to evaluate, but the whole process seems to be fraught with the potential for abuse (with billions in profits hanging on every FDA decision). I watched the FDA screw Epix big time. And when the FDA panel discussion and vote for Celgene's Revlimid was webcast last year, to me these FDA panelists seemed anything but objective. Having a company's entire fate resting on the whim of some bozos at the FDA doesn't exactly inspire confidence.
10k
by: outsmiter (26/M/San Diego, CA) 04/04/06 08:58 pm
Msg: 27853 of 27883
"Additionally, we recently completed two separate three-month toxicology studies for CX717, one with a rodent species and one with a non-rodent species, as required by the guidelines of the FDA. Each study examined the effects of very high (toxicological) daily doses of CX717 for ninety consecutive days. Each study included extra animals to assess whether any observed toxicological effects were reversible once dosing was stopped. Full reports for each of these three-month toxicology studies have been submitted to the FDA for review. "
It does seem pretty likely that the FDA's concerns are over the 3 month tox studies and also, as Neuro speculated, whether the tox effects were reversible once dosing was stopped. Because the doses were "very high (toxicological) daily doses," the FDA probably has some concerns as well about long-term ampakine effects. I would assume these observed effects are far worse than the benefits an ADHD patient could receive from CX-717 and therefore drug development was stopped.
However, due to BDNF upregulation and the feedback loop, I'd guess that CX-717 when/if it comes to market, would have a spaced dosing regimen. So, I don't expect daily dosing for long-term treatment, which may reduce the probability of ever encountering these toxicological effects. Of course, I'm just speculating, but that's all we can do now.
One more thought - I believe that Ampakines simply enhance communication between the glutamate transmitted and the neuroreceptor, but does not increase the glutamate levels. If somehow CX-717 did increase glutamate levels, could it cause neurodegeneration? I picked this thought up from the I-Hub board. I think this is very unlikely, especially after what Rogers and Lynch and Neuro have said about the subject. But if very toxic doses did somehow increase glutamate levels, I could see how the FDA would be concerned. I'm not a science guy - anyone out there wish to tackle this possibility?
Re: 10k
by: gfp927z 04/04/06 09:30 pm
Msg: 27856 of 27883
Outsmiter, The low impacts like CX-717 don't upregulate BDNF to a large degree, though there is reportedly some modest BDNF upregulation during long term dosing (preclincical data on CX-727 was discussed at a Cortex presentation, and longer term it did upregulate BDNF modestly, approx 20-30% as I recall. High impacts can triple/quadruple BDNF levels however, so for these there would be the need for spaced dosing to bypass the feedback loop phenomenon, but probably not for the low impacts like CX-717).
Concerning increasing glutamate activity/levels, the excitotoxicity/seizure potential seen with high impacts (Lilly's biarylpropylsulfonamides for example) is apparently due to their overstimulation of the AMPA receptor, the end result being excess calcium in the synapse, and increased seizure potential. That has been the knock against the whole concept of AMPA upregulation all along. Everyone thought it would cause horrendous excitotoxicity, so it was largely ignored as an area of therapeutic research. The wide skepticism was what enabled Cortex to get all the key use patents in place - nobody thought they could upregulate AMPA receptors safely. Of course as we've seen, Cortex's low impacts like CX-717 strongly upregulate AMPA receptors (at a different binding site than the high impacts) with virtually no excitotoxicity.
This brings up an interesting topic though - the fact that even low impacts can upregulate neurotrophin levels modestly if dosed long enough. I've had a theory that it's the excitotoxicity induced by an AMPA upregulator that triggers the production of protective neurotrophins like BDNF (a response to the neural excitotoxic insult). The greater the excitotoxic potential of the Ampakine, the greater the degree of BDNF production in response.
(continued)
Re: Inconceivable!
by: mjxspxdr9248 04/04/06 09:44 pm
Msg: 27858 of 27883
As a scientist, I am also positive that Cortex either knows or has a damn good idea what the issue is. It's a shame no presentation exists that discusses the animal tox studies in detail. If this were available, I am sure we could come up with several reasons/places where the FDA might be interested in obtaining more data before proceeding with more clincial studies. All presentations that I have seen seem to focus mostly on the efficacy of the drug with a slide here and there dedicated to side effects. I bet that if we had the whole story (with each tox study graphed out), the picture wouldn't be as perfect. This is not to say that Cortex is hiding anything from us. My point here is that in science, alot of the data is up for interpretation. It is possible that cortex concluded that there was an insignificant trend in upregulation of liver enzymes, but the FDA concluded that there was a trend and given a higher sample size it may be significant.
So then why did this problem seem to pop up out of no where? I am definitely speculating. It is possible that Cortex began the application process for a phase II B trial in 100 ADHD patients to be conducted over several months. WIth these data, they probably sent the 3 month tox study results and there was some thing in these data that the FDA disliked. To be safe, the FDA stopped all ongoing trials (all of one, which no one was expecting data from any time soon). Cortex previously demonstrated that CX-717 was safe for short term use and was therefore approved for the Phase II a studies; however, the new tox data had a concern regarding long term use and to be safe the FDA put a halt to all use of this drug. It would have been unethical not to.
This may not even be how this was discovered and Cortex may not even be this far along in applying for the start of Phase IIB studies (although they said they were going to proceed with the paperwork ASAP back in early March). Just one possible explanation.
Re: 10k
by: Send me a message! horsetrader45
Long-Term Sentiment: Buy 04/04/06 09:46 pm
Msg: 27859 of 27884
All day long I have been questioning my mind and I keep coming up with the answer --Organon.They have been working with a "cousin" of CX717 for about six years.It is hard for me to believe that their ampakine is fine while ours that is safer and more stable has a problem.They have continued paying us milestones and have moved into depression with no inclinations about problems???
Maybe one of our scientific minds can explain this to me??
Andy C.
Re: 10k
by: gfp927z 04/04/06 09:51 pm
Msg: 27860 of 27884
(continued)
This theory would jive with what should theoretically be happening (neural response to insult), and what is observed with the various classes of AMPA upmodulators (those causing the greatest excitotoxocity also triggering the greatest production of BDNF).
Anyway, this all ties in with the spectrin/calpain topic, since my theory goes on to say that the excitotoxic insult not only triggers the production of protective BDNF, but also causes the neural degeneration that produces the breakdown of proteins (calpain mediated spectrin breakdown). This too jives with what's observed - that the high impacts trigger calpain/spectrin while low impacts don't (or do to a lesser degree). But therein lies the rub (or potential rub). Since low impacts also upregulate BDNF when dosed for longer periods (like 90 straight days for example), according to my theory the elevation of BDNF would be caused by a gradual, cumulative excitotoxicity, which while not enough to actually cause seizures could be enough to cause a degree of calpain mediated breakdown of spectrin/protein. That's potentially what was seen in the 3 month tox study, evidence of spectrin/protein breakdown (or some downstream indication of it). The FDA would then correlate this observation to what they probably saw with animal data on Lilly's compound (the one that was halted in Phase 2).
Anyway, this is just a theory. We'll see what info we get from Dr. Stoll next week.
Re: 10k
by: aiming4_a_million (42/M)
Long-Term Sentiment: Strong Buy 04/04/06 10:04 pm
Msg: 27861 of 27885
Gfp - Dr. Stoll has mentioned several times that Cortex's scientists are making progress on developing a "safe" high impact Ampakine and hoped to have one in tox studies in 2006.
Does that maybe suggest that either the calpain/spectrin problem isn't serious, or they are confident they can engineer around it?
Thanks as always for your thoughts... Aiming4.
Re: 10k
by: bladerunner1717
Long-Term Sentiment: Hold 04/04/06 10:20 pm
Msg: 27862 of 27885
gfp et al,
If the problems you are talking about occured in a low-impact like CX717, then why haven't we seen anything like this in studies from Organon and especially Servier, which you have told us many times is more of a higher impact molecule than CX717. If this turns out to be a "platform" problem with Ampakines, then we're in serious trouble. I wonder what the animal tox studies from Organon and Servier looked like. And doesn't Organon have a high-impact in development that they got from COR? Are any of the Organon or Servier trials enrolling in the U.S.?
Bladerunner
Re: 10k
by: gfp927z 04/04/06 10:30 pm
Msg: 27863 of 27887
Aiming, The problem is that chronic medical conditions require long term dosing, for years and years. Side effects that wouldn't show up at all during short term dosing can become major problems after many months/years of daily dosing.
The entire platform is on shaky ground at the moment. One advantage the high impacts might theoretically have would be that in treating more serious medical conditions than the low impacts, a higher level of side effects would presumably be acceptable. But talking about the potential for the high impacts doesn't make much sense right at the moment, since we first need to get the low impacts back on some semblance of solid ground.
What we're experiencing here is the problem with investing in a brand new technology platform - we're in uncharted scientific waters, and anything can happen. I just hope the other shoe doesn't drop, when/if the FDA decides to dig into the animal data for Org-24448.
Re: 10k
by: gfp927z 04/04/06 10:50 pm
Msg: 27866 of 27887
Bladerunner, It could be that because longer term human trials involving AMPA upmodulators are a relatively new phenomenon, the FDA is still getting up to speed on what to look for as they evaluate the longer term animal data.
Concerning the Servier S-18986 trial, I can't remember if it's enrolling in the US. Unfortunately in deciding to no longer speculate on bio stocks several months ago, I foolishly threw out all my biotech related notebooks (a clean break seemed like the best thing at the time). But perhaps someone else has a link to the specific enrollment info on the Servier trial. Concerning Organon, the NIMH/TURNS study would obviously be based in the US, but I'm not sure about their own in-house monotherapy trial. Sorry, I shouldn't have tossed out all my notes.
Re: 10k
by: Neuroinv 04/04/06 11:28 pm
Msg: 27868 of 27887
Gfp:
1) Servier avoids having anything to do with US liability, so I am sure they do not have US sites.
2) I vaguely recall that we discussed the calpain-spectrin issue about a year ago. I have talked to at least three scientists who have worked with AMPA-modulators at various times, none of whom think that the calpain-spectrin-neurodegeneration hypothesis is valid.
3) I would bet that this has nothing to do with the FDA's current concerns and clinical hold. FWIW.
NeuroInvestment
Re: 10k
by: gfp927z 04/04/06 11:50 pm
Msg: 27870 of 27887
Neuro, The calpain/spectrin phenomenon is definitely real for at least some Ampakines. There have been several papers published on it, including one by Dr. Lynch himself (he said it occurs, but hypothesized that it is most likely associated with LTP, ie- proteins breaking down in order to be reassembled as part of memory formation/encoding, as opposed to breakdown resulting from neural damage / neurodegeneration caused by the Ampakine). When Dr. Mansbach was asked about it at the SHM Q+A in early December, he said it occurred with high impacts and wasn't a problem with low impacts like CX-717 as far as they knew at that time. I'm not sure if he had yet seen the full 3 month tox data yet though.
The FDA saw something they felt was serious enough to justify a clinical hold on CX-717, so we really can't rule it or anything else out until we get more info.
Re: 10k
by: bladerunner1717
Long-Term Sentiment: Hold 04/04/06 11:53 pm
Msg: 27871 of 27887
gfp,
You are making a leap here that may not be justified: Simply because a drug is dosed for longer term doesn't necessarily mean that there is a build up of toxicity. (Certain recent studies on HIV drugs has, in fact, shown just the opposite to be true, although, I admit, it goes against common sense thinking.) Extrapolating from animals given 10X the normal dose (from human beings) to human beings seems a dubious exercise. But, of course, that wouldn't stop the FDA from performing that exercise.
Of course, I don't know how COR could resolve a dilemma like that using only animal toxicology studies. But I guess that's what Stoll and Mansbach & Co. will have to figure out, if that is, in fact, what the FDA is concerned about because, as Dew implied, the FDA is not going to change its statistical rules in order to accommodate COR. Does anyone know here for certain that toxicology studies on animals dosed at extremely high dosages where certain toxicity issues show up always lead to a negative decision on allowing further clinical studies when the dosages used in the human trials is far lower? I mean if you give animals, or humans for that matter, high enough doses of virtually anything, they will get sick. So what are the parameters here? And what are the precedents? (Neuro?)
Bladerunner
Re: 10k
by: gfp927z 04/05/06 12:10 am
Msg: 27872 of 27887
Bladerunner, Yes, but bottom line it looks like in CX-717's case -
1) Something showed up after 3 month's dosing that wasn't seen after only one month's dosing, and
2) It was serious enough in the FDA's view to justify halting the trials.
Exactly what it was, we'll have to wait a week to find out. The Cortex saga has certainly been one long running soap opera. Relegating these bio stocks to "hobby" status has been a sound move, at least for me. Man, this is one crazy sector.
Toxicity
by: Neuroinv 04/05/06 12:26 am
Msg: 27875 of 27887
No--an adverse event in an animal at a high, sustained dose would not kill a drug. There are two possibilities--probably more, only two occur to me at the moment:
1) If the animal event was in just one, and the rest did not show--my bet, liver enzyme changes--Cortex would probably see that as a fluke. In that case, the FDA might make them repeat the 3 month animal study, same dose. If those liver changes are not seen in any of the animals, that would support the hypothesis that it was the animal, not the drug. Phase IIb would be permitted, but probably more frequent liver enzyme levels would be required. Right now--that's my candidate for most likely scenario.
2) If more than one animal showed significant liver enzyme changes, that would shift the burden of proof considerably. Then they might have to do more extended human safety studies now--to see if extended regular dosing indeed sets the stage for a similar impact on liver function.
3) That brings me to one final thought, per your apt observation that very high dosing can be expected to create negative effects. The number of times that the FDA has issued this kind of high-profile clinical hold--in the CNS area--is small. But I cannot count the number of times that I have been told by companies that something came up in Phase I or II that led them-at FDA 'suggestion'--to do another safety study of some kind. Phase IIs are often long-delayed beyond their projected dates--three, six months, a year. Yet there has not been a clinical hold--just a behind the scenes discussion with the FDA. And for the most part, those Phase II trials do eventually get underway.
This reinforces my belief that Cortex--because of the ADHD angle--may have been singled out for a more public 'citizen's arrest'--so that all of us can rest easy, knowing our FDA is on the job. There is nothing to be done about this, the congressional mood is for increased surveillance, and Cortex can never, ever complain about the process--unless they want all of their applications treated like a Middle Eastern male wearing brand new sneakers and carrying a Koran at an airport security check. It's one of those situations where you just have to comply.
NeuroInvestment
Calpain/Spectrin, Lynch abstract
by: gfp927z 04/05/06 12:27 am
Msg: 27876 of 27887
Here's the Lynch abstract concerning calpain/spectrin and Ampakines -
Effects of positive AMPA receptor modulators on calpain-mediated spectrin degradation in cultured hippocampal slices.
Jourdi H, Yanagihara T, Martinez U, Bi X, Lynch G, Baudry M.
Neuroscience Program, University of Southern California, Los Angeles, CA 90089-2520, USA.
Positive modulators of AMPA receptors (AMPAr), also known as ampakines, are allosteric effectors of the receptors and have been extensively studied in past years due to their potential use as treatment for various diseases and ailments of the central nervous system such as mild cognitive impairment, schizophrenia, and Alzheimer's disease. Ampakines have been shown to improve performance on memory tasks in animals and in human subjects, an effect linked to their ability to increase agonist-mediated ion influx through AMPAr, thus leading to enhanced synaptic responses and facilitation of long-term potentiation (LTP) induction at glutamatergic synapses. As LTP is associated with calpain activation and spectrin degradation, we determined the effects of ampakine treatment of cultured hippocampal slices on spectrin degradation. Calpain activation was evaluated by determining the levels of the 145-150kDa degradation products of spectrin. Our data indicated that incubation of hippocampal slices with some, but not all positive modulators of AMPA receptors resulted in enhanced spectrin degradation, an effect that was blocked by a calpain inhibitor. In addition, an antagonist of AMPAr but not of NMDAr blocked ampakine-induced spectrin degradation. These results indicate that prolonged treatment with selected ampakines leads to spectrin degradation mediated by activation of the calcium-dependent protease calpain.
Re: Calpain/Spectrin, Lynch abstract
by: biobetter2 04/05/06 12:31 am
Msg: 27877 of 27887
This is recent study on cx614 and calpain--http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstra ct&list_uids=15784649&query_hl=2&itool=pubmed_docsum
Text for above link inserted… Aiming4.
J Pharmacol Exp Ther. 2005 Jul;314(1):16-26. Epub 2005 Mar 22.
Prolonged positive modulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors induces calpain-mediated PSD-95/Dlg/ZO-1 protein degradation and AMPA receptor down-regulation in cultured hippocampal slices.
Jourdi H, Lu X, Yanagihara T, Lauterborn JC, Bi X, Gall CM, Baudry M.
Neuroscience Program and Department of Biology, University of Southern California, Los Angeles, CA 90089-2520, USA.
Prolonged exposure of cultured hippocampal slices to CX614 [2H,3H,6aH-pyrrolidino[2'',1''-3',2']1,3-oxazino[6',5'-5,4]-benzo[e]1,4-dioxan 10-one], a positive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (AMPAr) modulator, decreases receptor response to synaptic stimulation, an effect that could reflect reduced receptor expression. The present study investigates this down-regulation and its underlying mechanisms using cultured rat hippocampal slices. Chronic treatment with CX614 gradually reduced levels of glutamate receptor (GluR)1 and GluR2/3 AMPAr subunits and of their anchoring proteins synapse-associated protein 97 (SAP97) and glutamate receptor interacting protein 1 (GRIP1) through 48 h. Decline in SAP97 and GRIP1 levels was associated with increased abundance of lower molecular weight bands, suggesting degradation of these proteins. CX614 effects were partially reversible after drug removal. GluR1 and GluR2/3 down-regulation and their slow recovery were associated with similar changes in SAP97 and GRIP1 levels. Treatment with CX614 for 48 h significantly reduced AMPAr mRNA levels in hippocampus, whereas 8-h exposure did not. Blockade of ionotropic glutamate receptors prevented CX614-induced decrease in AMPAr subunits and mRNA, with regional selectivity, although an AMPAr blocker was more efficacious than an N-methyl-D-aspartate receptor blocker. Blockade of calpain activity reduced CX614-induced degradation of SAP97 and GRIP1 and prevented decreases in AMPAr subunit but not mRNA levels. Treatment with CX614 alone or in combination with glutamate receptor blockers or calpain inhibitor III did not modify lactate dehydrogenase release into culture medium, implying the absence of cell toxicity. We conclude that CX614-induced AMPAr protein loss is primarily mediated by AMPAr activation and involves calpain-dependent proteolysis of SAP97 and GRIP1. CX614-induced suppression of AMPAr gene expression is, however, calpain-independent, and all these effects are not associated with cell damage.
PMID: 15784649 [PubMed - indexed for MEDLINE]
Re: Calpain/Spectrin, Lynch abstract
by: Neuroinv 04/05/06 12:35 am
Msg: 27879 of 27887
Gfp:
It's kind of odd that this Lynch abstract is being presented as evidence for a possible Ampakine-neurodegeneration link when--as you know--Lynch does not believe that Ampakines lead to in vivo neurodegeneration--as he confirmed directly to me last year around this time when it came up on the YMB. Keep in mind that they have done numerous in vivo tests of Ampakines in neurodegeneration models--e.g. stroke--and Ampakines were neuroprotective. Add to that the Lilly Parkinson's data where Ampakines were protective/neuroprotective in a PD model--and I feel as certain as one can without knowing what the FDA said--that has nothing to do with calpain-induced degeneration.
But we'll all know at some point in the next week or two.
NeuroInvestment
Re: Calpain/Spectrin, Lynch abstract
by: gfp927z 04/05/06 12:38 am
Msg: 27880 of 27887
Here's another calpain/spectrin/Ampakine related abstract. CX-614 is one of Cortex's earlier high impact compounds -
Prolonged positive modulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors induces calpain-mediated PSD-95/Dlg/ZO-1 protein degradation and AMPA receptor down-regulation in cultured hippocampal slices.
Jourdi H, Lu X, Yanagihara T, Lauterborn JC, Bi X, Gall CM, Baudry M.
Neuroscience Program and Department of Biology, University of Southern California, Los Angeles, CA 90089-2520, USA.
Prolonged exposure of cultured hippocampal slices to CX614 [2H,3H,6aH-pyrrolidino[2'',1''-3',2']1,3-oxazino[6',5'-5,4]-benzo[e]1,4-dioxan 10-one], a positive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (AMPAr) modulator, decreases receptor response to synaptic stimulation, an effect that could reflect reduced receptor expression. The present study investigates this down-regulation and its underlying mechanisms using cultured rat hippocampal slices. Chronic treatment with CX614 gradually reduced levels of glutamate receptor (GluR)1 and GluR2/3 AMPAr subunits and of their anchoring proteins synapse-associated protein 97 (SAP97) and glutamate receptor interacting protein 1 (GRIP1) through 48 h. Decline in SAP97 and GRIP1 levels was associated with increased abundance of lower molecular weight bands, suggesting degradation of these proteins. CX614 effects were partially reversible after drug removal. GluR1 and GluR2/3 down-regulation and their slow recovery were associated with similar changes in SAP97 and GRIP1 levels. Treatment with CX614 for 48 h significantly reduced AMPAr mRNA levels in hippocampus, whereas 8-h exposure did not. Blockade of ionotropic glutamate receptors prevented CX614-induced decrease in AMPAr subunits and mRNA, with regional selectivity, although an AMPAr blocker was more efficacious than an N-methyl-D-aspartate receptor blocker. Blockade of calpain activity reduced CX614-induced degradation of SAP97 and GRIP1 and prevented decreases in AMPAr subunit but not mRNA levels. Treatment with CX614 alone or in combination with glutamate receptor blockers or calpain inhibitor III did not modify lactate dehydrogenase release into culture medium, implying the absence of cell toxicity. We conclude that CX614-induced AMPAr protein loss is primarily mediated by AMPAr activation and involves calpain-dependent proteolysis of SAP97 and GRIP1. CX614-induced suppression of AMPAr gene expression is, however, calpain-independent, and all these effects are not associated with cell damage.
PMID: 15784649 [PubMed - indexed for MEDLINE]
Re: Calpain/Spectrin, Lynch abstract
by: Neuroinv 04/05/06 12:43 am
Msg: 27882 of 27887
Exactly:
<<Treatment with CX614 alone or in combination with glutamate receptor blockers or calpain inhibitor III did not modify lactate dehydrogenase release into culture medium, IMPLYING THE ABSENCE OF CELL TOXICITY . We conclude that CX614-induced AMPAr protein loss is primarily mediated by AMPAr activation and involves calpain-dependent proteolysis of SAP97 and GRIP1. CX614-induced suppression of AMPAr gene expression is, however, calpain-independent, and ALL THESE EFFECTS ARE NOT ASSOCIATED WITH CELL DAMAGE.
(capitalization mine)
Those who are not convinced can continue to debate this. I'm done.
NeuroInvestment
Re: Toxicity
by: bladerunner1717
Long-Term Sentiment: Hold 04/05/06 01:03 am
Msg: 27883 of 27887
Thanks, Neuro. I agree with all of your conclusions/speculations...for whatever my opinions are worth.
You made a point earlier about COR not having--and perhaps not being able to afford--a "regulatory"/clinical affairs person as a liaison to the FDA. It may interest you that another company I own alot of shares in, Genvec(GNVC), seemed to be stuck in a kind of limbo world with its drug for pancreatic cancer in a Phase II trial. The company then went out and hired a "pure" regulatory affairs person from Baxter in Nita Patel and a clincal/drug development guy from NIH in Dr. Thomas Davis. Very recently, in a rather surprise move, IMO, the FDA allowed the company to change the Phase II into a Phase III trial!!!
I'm sure you've read the FDA's (read: McClellan's) position paper on the "Critical Path," a paper that Gottlieb has publicly embraced. The emphasis in the "critical path" paper is to try to make sure there are more successful Phase III trials by having the FDA get involved more in the Phase II trials, which McClelllan deemed crucial for getting more drugs successfully through trials.
It's possible that in the long run, the situation for COR could turn out for the best, if the FDA decisions do not turn out to be fatal for CX717, which I don't believe they will. (I admit the short term consequences for shareholders have been and could well be into the future quite unnerving.) Because getting the FDA more involved now may prove fruitful for the upcoming Phase II's, not to mention the possible Phase III's with a BP partner. In light of the above, I should mention that Stoll vaguely implied to me in conversation that the days of COR not being able to afford a regulatory affairs person/FDA liaison may have turned into a situation where COR cannot afford to be without one.
Bladerunner
Re: Calpain/Spectrin, Lynch abstract
by: gfp927z 04/05/06 01:10 am
Msg: 27884 of 27887
Neuro, We know that some higher impact Ampakines (CX-614) are associated with calpain mediated spectrin protein degradation. All I'm saying is that if evidence of such protein breakdown is measurable in animal tox studies, that might conceivably justify a clinical hold by the FDA (one possibility).
What we don't know are - 1) whether this protein degradation is the result of a harmful neurodegeneration process, or merely from increased LTP activity, or 2) if a similar protein breakdown that occurs with CX-614 can also occur with a low impact like CX-717 when dosed over long periods.
As you said, only time will tell. All we know for now is that we have some type of problem. Other than excitotoxicity, the calpain/spectrin phenomenon is the other potential problem we've previously heard about being associated with Ampakines.
Re: SHO 3-31-06
by: gfp927z 04/04/06 01:44 am
Msg: 27667 of 27882
Biobetter, I had assumed that the recent reappearance of Cortex on that SHO list (indicating a high level of naked shorting) was somehow related to the recent availability of options on the stock (ie -some elaborate hedging strategy going on, possibly related to the warrants). However, in light of what happened today, who knows.
Well, Murphy's Law is certainly alive and well in this sector, and it seems that most of these bio stocks blow up at one time or another. What prompted me to finally abandon investing in these stocks (aside from my over-reliance on borrowed funds) was barely dodging similar meltdowns in PARS, CTIC, EPIX, plus watching GTCB's recent meltdowns. The way I see it, bottom line -- who the hell needs the aggravation, ulcers, and heartache of this sector? As a pure hobby though, the science is cool, there is suspense/intrigue, and the dramatic setbacks can be entertaining in a perverse sort of way, assuming one doesn't have any money riding on the results.
Anyway, my prediction from the sidelines is that after much angst and handwringing, this will only be a temporary setback for Cortex, and some additional animal studies will allay the FDA concerns, and the stock will eventually rise again from the ashes.
Recent warrant excercises=cash cushion
by: gfp927z 04/04/06 09:28 am
Msg: 27707 of 27882
As Neuro said, though we don't know for sure yet, Cortex will probably need to run some additional 3 month tox studies on larger populations of animals. If we assume that the BP deal will be on hold until after designing/running/analyzing/submitting these additional animal studies (perhaps 6-9 months?), then Cortex's relatively low cash level becomes a potential concern (approx $17 mil at year end 2005).
However, the recent excercising of some of the outstanding PIPE warrants should provide Cortex with a considerable amount of additional cash. Exactly how many warrants were excercised in the recent runup we don't know yet, but I figure at least 1/3 to 1/2 of them, which would equate to an additional $10-15 mil in cash or so. That extra cash cushion could make the difference between having to do an unfavorable PIPE or not, as well as keeping Cortex's important R+D activities (high impacts) fully funded while we await the data from the new animal studies.
The big question right now is what exactly was the problem that the FDA saw in the animal data (presumably it was in the longer term 3 month data that was recently completed)? The 3 month tox data was necessary in order to start running longer term human studies (up to now the longest human trial dosing was for 3 weeks in ADHD). While we're not privy to what's actually been going on in the BP negotiations, if BP interest has been as strong as we've been hearing in Cortex's presentations, then BP's must not have had any major concerns over CX-717's safety profile to date, either in its preclinical animal data, the human Phase 1, or the completed Phase 2a trials (UK Sleep Dep and the recent ADHD trial).
As Neuro said, the FDA has seen safety data on several other classes of AMPA modulators (Lilly's biarylpropylsulfonamide, which Lilly halted in Phase 2, apparently due to excitotoxocity problems), and Servier's current large S-18986 Phase 2 (S-18986 being a benzothiadiazide related compound), though I'd have to go back and check if the Servier study is enrolling in the US or only in Europe. Concerning Lilly, we don't know if they halted their Phase 2 trial voluntarily, or if the FDA was involved in the decision. As Dr. Rogers pointed out at the SHM several years ago, Lilly's high impacts have a far different (far worse) safety profile compared to Cortex's low impacts like CX-717. We have never heard of any excitotoxicity problem with CX-717 whatsoever. The problem concerning the FDA is more likely something other than excitotoxicity.
(continued)
Re: Recent warrant excercises=cash cushi
by: gfp927z 04/04/06 10:07 am
Msg: 27720 of 27882
So if the problem isn't likely excitotoxicity related, then what else might it be? Last year there was a paper published on the spectrin/calpain phenomenon (rumors at that time were that Dr. Lynch apparently had a falling out with the author over its publishing). This phenomenon reportedly occurs with some AMPA modulators, but not others, and is apparently more associated with the high impacts, as Dr. Mansbach discussed in a company presentation last year. I remember he said at that time that as far as they knew, CX-717 was not one of the compounds that produced the spectrin/calpain phenomenon. In this phenomenon, proteins are degraded/broken down, and it's been postulated that this protein breakdown which is usually associated with neural damage processes / neurodegeneration, might also occur during the process of normal LTP (long term potentiation) during memory formation (since proteins need to be broken down and then reassembled as part of memory formation/encoding). But the significance of the spectrin/calpain phenomenon as it pertains to AMPA modulation appears to still be a scientific grey area.
More likely, there may have been a change in liver enzymes, or something of that nature (just speculating here). We know that CX-717 reportedly doesn't produce somatic changes of any significance (changes in blood pressure, pulse/heart rate, etc). This is in contrast to non-specific stimulants like amphetamines. But at extremely high doses in animals, side effects may occur which might never show up in normal therapeutic doses. With the recent furor over the side effects of the current ADHD drugs, the FDA is probably being super-cautious at the moment (and thereby also covering their collective butts, a daunting task considering the sheer number of asses employed at the FDA :o)
Gfp's summary and comment
by: Neuroinv 04/04/06 11:01 am
Msg: 27741 of 27882
Gfp: 27720+27707 were a terrific summary--many thanks. The only addition I would make is: I would not assume that the BP deal will necessarily be put off until after the day that the FDA officially lifts the clinical hold.
Provided that the preclinical issue is solvable, which we both think is likely--but not certain, since the nature of the issue has yet to be divulged--I think the following will occur:
1) As soon as the issue is made public, both Cortex and a handful of the most interested companies (perhaps two or three) will independently address it in their own labs. A BP, having done its own DD thus far, will continue to do so.
2) BP has better contacts at the FDA than Cortex does. They will (and again, I am not buying into the paranoid model) be able to get a clear picture of exactly what the FDA wants to see. As soon as they believe they have that solution in their labs, they can be pretty confident that the hold will be lifted. At that point--and that point could differ from BP to BP--the offers go back on the table, perhaps amended, perhaps not.
3) There is also the possibility that the BPs with the most DD information may see the FDA's demand and decide that they already know the answer. In which case one of them might try to steal a march and make a deal with Cortex that might predicate part of the upfront money on the lifting of the clinical hold. That would probably take more time to work through the BP hierarchy, as each level would have to sign off on accepting the risk involved.
4) To be fair--there is the possibility that all involved might look at the FDA's demand and decide that it is not resolvable, no way to prove the negative, for example that there is no risk of Adverse Event X occurring. I do not expect that, the FDA is clumsy and slow, but that would be bizarrely arbitrary given what is already out there. But the climate now, particularly for ADHD drugs, has raised the bar.
NeuroInvestment
Re: Gfp's summary and comment
by: Neuroinv 04/04/06 03:30 pm
Msg: 27799 of 27882
The hold should have no bearing on the DARPA data--other than Cortex will be putting less pressure on DARPA to hurry up with its data analysis, since it will have much less impact now than it would have without the hold. But when the data is ready, it will be material, and DARPA and Cortex will negotiate the content of the press release.
NeuroInvestment
Even Cortex doesn'tknow the problem yet
by: ombowstring (56/M/Cape Cod, MA) 04/04/06 04:25 pm
Msg: 27805 of 27882
I e-mailed Dr. Stoll yesterday as follows:
Dr. Stoll,
Shareholders would like to know if the specific problem with CX717 was communicated to Cortex in the telephone call from the FDA.
Obviously, we are trying to gauge if this is a problem that can be rectified or if it is a death knell for CX717.
Thanks,
John Mackenzie
P.S. Can you say anything more than that which was contained in today's press release?
To which he replied:
John, I can’t say anything more except that when we have had the chance to assess the issues raised in the letter and communicated with the FDA about how we might be able to address their issues, we then could communicate a plan to shareholders. I can not at this time give you more clarity until we at Cortex are sure what we are up against. First we need to get the letter from the FDA. Roger
I then sent him a follow-up question:
Dr. Stoll,
Wasn't the FDA's problem with CX717 communicated to Cortex in the telephone call?
Thanks,
JM
To which he responded:
It was a short conversation between the division head and Hank Mansbach and we were told the specifics would be addressed in the letter to follow. Roger
Re: Even Cortex doesn'tknow (Ombow.)
by: Neuroinv 04/04/06 06:58 pm
Msg: 27824 of 27882
If Roger Stoll was going to go beyond what he'd said before, he wasnt going to do it in an email to an individual--that would be a big Reg FD problem. I have no doubt he knows more than he has told anyone publicly, but I also don't think he knows enough more to be able to make a reasonable public statement.
Someone just emailed me a question about how Stoll could not know all the details. Here is my scenario for how that could be :
<<I suspect that the liaison who called Mansbach is not the same person who reviews the preclinical data and decides on the hold. So--my hypothesis is:
The reviewer called the liaison and tells them: "Call Mansbach and tell them we're putting a hold on CX717. One of those three month dogs had elevated enzymes (or something of that ilk) , and based on what I've seen before
( Lilly, for example)....I'm not going to let them go ahead until we're sure that this isnt going to be a repetition of (Lilly, for example). The details will be in the letter, but I'm not going to get around to writing that until Tuesday." So the liaison did what he/she was told.
Which is how and why Mansbach would only get a little info, and not a sense of the context or details. And without the details, not much can be said by Stoll that would be useful guidance.
This is just a scenario--but if you think about how large bureaucracies behave, it could well be true.
NeuroInvestment
Re: Inconceivable!
by: Neuroinv 04/04/06 08:42 pm
Msg: 27848 of 27883
A couple facts that are being overlooked by some:
1) The three month tox studies were completed after the Phase IIa program was started, patients enrolling. The three month tox studies are needed for longer-duration Phase IIb trials. Thus the assumption that the Company knew about some preclinical problem and went ahead anyways with clinical trials may or may not be true. A very important tranche of animal data went to the FDA recently--and if that is where the problem came from, Cortex was well into the clinical trials. Would they know there was a problem (or more than one?) Sure--but they might not have thought it was an important one. What they think to be a fluke might not be seen that way by the FDA--and the FDA's response clearly did blindside them.
2) Fbohn: Your post suggests that Lilly shares its preclinical data with Cortex, and that Cortex would thus be aware of problems therein. That is unrealistic. Lilly has to send it to the FDA, but competing companies tend to not freely share that kind of data on clinical-level drugs. It would be expected that the FDA would have a lot more info on the preclinical findings obtained by other companies than Cortex would.
NeuroInvestment
Re: Even Cortex doesn'tknow(meixatech)
by: ombowstring (56/M/Cape Cod, MA) 04/04/06 08:50 pm
Msg: 27849 of 27883
My impression is that the phone call came totally out of the blue to Cortex based on, again, what Dr. Stoll said about not knowing what we are up against.
What you say represents a possible scenario, but I don't think it's the actuality.
Therefore, I conclude, being invested in COR at this time is a dicey situation. If this problem with CX717 cannot be rectified to the satisfaction of the FDA and the drug is dead in the water, Cortex suffers a serious setback and the stock price plummets. If on the other hand, the problem can be resolved, the DARPA results are favorable, and the BP deal is consummated, the stock price soars. But at this point in time perhaps the very future of Cortex as a viable company hinges on the problem because of which the FDA has halted clinical trials of CX717, which seems to be a drastic step to take, a step that would not be taken without good reason. I'd have to say I'm very, very concerned about being invested in COR at this time because of the recent turn of events.
3 month tox studies
by: gfp927z 04/04/06 08:53 pm
Msg: 27851 of 27883
Thinking back, last year's 3 month tox studies in 2 species did take considerably longer than expected. I'm going from memory here, but I remember the studies were supposed to be completed around the end of the Summer, but then Dr. Stoll's estimates given at presentations for the completion date slipped several times, to around year end. I don't remember ever really hearing much about the final results themselves, other than some passing remarks that they were finally completed.
I remember us speculating at the time on what may have been causing the delay. One theory I recall was that the tox trials had been farmed out, and perhaps the lab doing them was simply slow/busy. Another theory was that they may have encountered a problem and had to repeat some of the tests. Maybe Neuro or others remember better, but I distinctly remember getting increasingly worried as the completion date for those tox studies kept getting pushed back (though the timelines for the Phase 2a trials were also getting pushed back too). Anyway, I suppose it's possible that whatever issue the FDA is currently concerned about might be the same issue that caused the delays in the 3 month tox studies last year (just speculating). Anyway, I guess we won't know much either way until next week or so.
I must admit to having lost a lot of faith in the regulatory process over the last several years. True, the FDA is underfunded and overwhelmed with drug data to evaluate, but the whole process seems to be fraught with the potential for abuse (with billions in profits hanging on every FDA decision). I watched the FDA screw Epix big time. And when the FDA panel discussion and vote for Celgene's Revlimid was webcast last year, to me these FDA panelists seemed anything but objective. Having a company's entire fate resting on the whim of some bozos at the FDA doesn't exactly inspire confidence.
10k
by: outsmiter (26/M/San Diego, CA) 04/04/06 08:58 pm
Msg: 27853 of 27883
"Additionally, we recently completed two separate three-month toxicology studies for CX717, one with a rodent species and one with a non-rodent species, as required by the guidelines of the FDA. Each study examined the effects of very high (toxicological) daily doses of CX717 for ninety consecutive days. Each study included extra animals to assess whether any observed toxicological effects were reversible once dosing was stopped. Full reports for each of these three-month toxicology studies have been submitted to the FDA for review. "
It does seem pretty likely that the FDA's concerns are over the 3 month tox studies and also, as Neuro speculated, whether the tox effects were reversible once dosing was stopped. Because the doses were "very high (toxicological) daily doses," the FDA probably has some concerns as well about long-term ampakine effects. I would assume these observed effects are far worse than the benefits an ADHD patient could receive from CX-717 and therefore drug development was stopped.
However, due to BDNF upregulation and the feedback loop, I'd guess that CX-717 when/if it comes to market, would have a spaced dosing regimen. So, I don't expect daily dosing for long-term treatment, which may reduce the probability of ever encountering these toxicological effects. Of course, I'm just speculating, but that's all we can do now.
One more thought - I believe that Ampakines simply enhance communication between the glutamate transmitted and the neuroreceptor, but does not increase the glutamate levels. If somehow CX-717 did increase glutamate levels, could it cause neurodegeneration? I picked this thought up from the I-Hub board. I think this is very unlikely, especially after what Rogers and Lynch and Neuro have said about the subject. But if very toxic doses did somehow increase glutamate levels, I could see how the FDA would be concerned. I'm not a science guy - anyone out there wish to tackle this possibility?
Re: 10k
by: gfp927z 04/04/06 09:30 pm
Msg: 27856 of 27883
Outsmiter, The low impacts like CX-717 don't upregulate BDNF to a large degree, though there is reportedly some modest BDNF upregulation during long term dosing (preclincical data on CX-727 was discussed at a Cortex presentation, and longer term it did upregulate BDNF modestly, approx 20-30% as I recall. High impacts can triple/quadruple BDNF levels however, so for these there would be the need for spaced dosing to bypass the feedback loop phenomenon, but probably not for the low impacts like CX-717).
Concerning increasing glutamate activity/levels, the excitotoxicity/seizure potential seen with high impacts (Lilly's biarylpropylsulfonamides for example) is apparently due to their overstimulation of the AMPA receptor, the end result being excess calcium in the synapse, and increased seizure potential. That has been the knock against the whole concept of AMPA upregulation all along. Everyone thought it would cause horrendous excitotoxicity, so it was largely ignored as an area of therapeutic research. The wide skepticism was what enabled Cortex to get all the key use patents in place - nobody thought they could upregulate AMPA receptors safely. Of course as we've seen, Cortex's low impacts like CX-717 strongly upregulate AMPA receptors (at a different binding site than the high impacts) with virtually no excitotoxicity.
This brings up an interesting topic though - the fact that even low impacts can upregulate neurotrophin levels modestly if dosed long enough. I've had a theory that it's the excitotoxicity induced by an AMPA upregulator that triggers the production of protective neurotrophins like BDNF (a response to the neural excitotoxic insult). The greater the excitotoxic potential of the Ampakine, the greater the degree of BDNF production in response.
(continued)
Re: Inconceivable!
by: mjxspxdr9248 04/04/06 09:44 pm
Msg: 27858 of 27883
As a scientist, I am also positive that Cortex either knows or has a damn good idea what the issue is. It's a shame no presentation exists that discusses the animal tox studies in detail. If this were available, I am sure we could come up with several reasons/places where the FDA might be interested in obtaining more data before proceeding with more clincial studies. All presentations that I have seen seem to focus mostly on the efficacy of the drug with a slide here and there dedicated to side effects. I bet that if we had the whole story (with each tox study graphed out), the picture wouldn't be as perfect. This is not to say that Cortex is hiding anything from us. My point here is that in science, alot of the data is up for interpretation. It is possible that cortex concluded that there was an insignificant trend in upregulation of liver enzymes, but the FDA concluded that there was a trend and given a higher sample size it may be significant.
So then why did this problem seem to pop up out of no where? I am definitely speculating. It is possible that Cortex began the application process for a phase II B trial in 100 ADHD patients to be conducted over several months. WIth these data, they probably sent the 3 month tox study results and there was some thing in these data that the FDA disliked. To be safe, the FDA stopped all ongoing trials (all of one, which no one was expecting data from any time soon). Cortex previously demonstrated that CX-717 was safe for short term use and was therefore approved for the Phase II a studies; however, the new tox data had a concern regarding long term use and to be safe the FDA put a halt to all use of this drug. It would have been unethical not to.
This may not even be how this was discovered and Cortex may not even be this far along in applying for the start of Phase IIB studies (although they said they were going to proceed with the paperwork ASAP back in early March). Just one possible explanation.
Re: 10k
by: Send me a message! horsetrader45
Long-Term Sentiment: Buy 04/04/06 09:46 pm
Msg: 27859 of 27884
All day long I have been questioning my mind and I keep coming up with the answer --Organon.They have been working with a "cousin" of CX717 for about six years.It is hard for me to believe that their ampakine is fine while ours that is safer and more stable has a problem.They have continued paying us milestones and have moved into depression with no inclinations about problems???
Maybe one of our scientific minds can explain this to me??
Andy C.
Re: 10k
by: gfp927z 04/04/06 09:51 pm
Msg: 27860 of 27884
(continued)
This theory would jive with what should theoretically be happening (neural response to insult), and what is observed with the various classes of AMPA upmodulators (those causing the greatest excitotoxocity also triggering the greatest production of BDNF).
Anyway, this all ties in with the spectrin/calpain topic, since my theory goes on to say that the excitotoxic insult not only triggers the production of protective BDNF, but also causes the neural degeneration that produces the breakdown of proteins (calpain mediated spectrin breakdown). This too jives with what's observed - that the high impacts trigger calpain/spectrin while low impacts don't (or do to a lesser degree). But therein lies the rub (or potential rub). Since low impacts also upregulate BDNF when dosed for longer periods (like 90 straight days for example), according to my theory the elevation of BDNF would be caused by a gradual, cumulative excitotoxicity, which while not enough to actually cause seizures could be enough to cause a degree of calpain mediated breakdown of spectrin/protein. That's potentially what was seen in the 3 month tox study, evidence of spectrin/protein breakdown (or some downstream indication of it). The FDA would then correlate this observation to what they probably saw with animal data on Lilly's compound (the one that was halted in Phase 2).
Anyway, this is just a theory. We'll see what info we get from Dr. Stoll next week.
Re: 10k
by: aiming4_a_million (42/M)
Long-Term Sentiment: Strong Buy 04/04/06 10:04 pm
Msg: 27861 of 27885
Gfp - Dr. Stoll has mentioned several times that Cortex's scientists are making progress on developing a "safe" high impact Ampakine and hoped to have one in tox studies in 2006.
Does that maybe suggest that either the calpain/spectrin problem isn't serious, or they are confident they can engineer around it?
Thanks as always for your thoughts... Aiming4.
Re: 10k
by: bladerunner1717
Long-Term Sentiment: Hold 04/04/06 10:20 pm
Msg: 27862 of 27885
gfp et al,
If the problems you are talking about occured in a low-impact like CX717, then why haven't we seen anything like this in studies from Organon and especially Servier, which you have told us many times is more of a higher impact molecule than CX717. If this turns out to be a "platform" problem with Ampakines, then we're in serious trouble. I wonder what the animal tox studies from Organon and Servier looked like. And doesn't Organon have a high-impact in development that they got from COR? Are any of the Organon or Servier trials enrolling in the U.S.?
Bladerunner
Re: 10k
by: gfp927z 04/04/06 10:30 pm
Msg: 27863 of 27887
Aiming, The problem is that chronic medical conditions require long term dosing, for years and years. Side effects that wouldn't show up at all during short term dosing can become major problems after many months/years of daily dosing.
The entire platform is on shaky ground at the moment. One advantage the high impacts might theoretically have would be that in treating more serious medical conditions than the low impacts, a higher level of side effects would presumably be acceptable. But talking about the potential for the high impacts doesn't make much sense right at the moment, since we first need to get the low impacts back on some semblance of solid ground.
What we're experiencing here is the problem with investing in a brand new technology platform - we're in uncharted scientific waters, and anything can happen. I just hope the other shoe doesn't drop, when/if the FDA decides to dig into the animal data for Org-24448.
Re: 10k
by: gfp927z 04/04/06 10:50 pm
Msg: 27866 of 27887
Bladerunner, It could be that because longer term human trials involving AMPA upmodulators are a relatively new phenomenon, the FDA is still getting up to speed on what to look for as they evaluate the longer term animal data.
Concerning the Servier S-18986 trial, I can't remember if it's enrolling in the US. Unfortunately in deciding to no longer speculate on bio stocks several months ago, I foolishly threw out all my biotech related notebooks (a clean break seemed like the best thing at the time). But perhaps someone else has a link to the specific enrollment info on the Servier trial. Concerning Organon, the NIMH/TURNS study would obviously be based in the US, but I'm not sure about their own in-house monotherapy trial. Sorry, I shouldn't have tossed out all my notes.
Re: 10k
by: Neuroinv 04/04/06 11:28 pm
Msg: 27868 of 27887
Gfp:
1) Servier avoids having anything to do with US liability, so I am sure they do not have US sites.
2) I vaguely recall that we discussed the calpain-spectrin issue about a year ago. I have talked to at least three scientists who have worked with AMPA-modulators at various times, none of whom think that the calpain-spectrin-neurodegeneration hypothesis is valid.
3) I would bet that this has nothing to do with the FDA's current concerns and clinical hold. FWIW.
NeuroInvestment
Re: 10k
by: gfp927z 04/04/06 11:50 pm
Msg: 27870 of 27887
Neuro, The calpain/spectrin phenomenon is definitely real for at least some Ampakines. There have been several papers published on it, including one by Dr. Lynch himself (he said it occurs, but hypothesized that it is most likely associated with LTP, ie- proteins breaking down in order to be reassembled as part of memory formation/encoding, as opposed to breakdown resulting from neural damage / neurodegeneration caused by the Ampakine). When Dr. Mansbach was asked about it at the SHM Q+A in early December, he said it occurred with high impacts and wasn't a problem with low impacts like CX-717 as far as they knew at that time. I'm not sure if he had yet seen the full 3 month tox data yet though.
The FDA saw something they felt was serious enough to justify a clinical hold on CX-717, so we really can't rule it or anything else out until we get more info.
Re: 10k
by: bladerunner1717
Long-Term Sentiment: Hold 04/04/06 11:53 pm
Msg: 27871 of 27887
gfp,
You are making a leap here that may not be justified: Simply because a drug is dosed for longer term doesn't necessarily mean that there is a build up of toxicity. (Certain recent studies on HIV drugs has, in fact, shown just the opposite to be true, although, I admit, it goes against common sense thinking.) Extrapolating from animals given 10X the normal dose (from human beings) to human beings seems a dubious exercise. But, of course, that wouldn't stop the FDA from performing that exercise.
Of course, I don't know how COR could resolve a dilemma like that using only animal toxicology studies. But I guess that's what Stoll and Mansbach & Co. will have to figure out, if that is, in fact, what the FDA is concerned about because, as Dew implied, the FDA is not going to change its statistical rules in order to accommodate COR. Does anyone know here for certain that toxicology studies on animals dosed at extremely high dosages where certain toxicity issues show up always lead to a negative decision on allowing further clinical studies when the dosages used in the human trials is far lower? I mean if you give animals, or humans for that matter, high enough doses of virtually anything, they will get sick. So what are the parameters here? And what are the precedents? (Neuro?)
Bladerunner
Re: 10k
by: gfp927z 04/05/06 12:10 am
Msg: 27872 of 27887
Bladerunner, Yes, but bottom line it looks like in CX-717's case -
1) Something showed up after 3 month's dosing that wasn't seen after only one month's dosing, and
2) It was serious enough in the FDA's view to justify halting the trials.
Exactly what it was, we'll have to wait a week to find out. The Cortex saga has certainly been one long running soap opera. Relegating these bio stocks to "hobby" status has been a sound move, at least for me. Man, this is one crazy sector.
Toxicity
by: Neuroinv 04/05/06 12:26 am
Msg: 27875 of 27887
No--an adverse event in an animal at a high, sustained dose would not kill a drug. There are two possibilities--probably more, only two occur to me at the moment:
1) If the animal event was in just one, and the rest did not show--my bet, liver enzyme changes--Cortex would probably see that as a fluke. In that case, the FDA might make them repeat the 3 month animal study, same dose. If those liver changes are not seen in any of the animals, that would support the hypothesis that it was the animal, not the drug. Phase IIb would be permitted, but probably more frequent liver enzyme levels would be required. Right now--that's my candidate for most likely scenario.
2) If more than one animal showed significant liver enzyme changes, that would shift the burden of proof considerably. Then they might have to do more extended human safety studies now--to see if extended regular dosing indeed sets the stage for a similar impact on liver function.
3) That brings me to one final thought, per your apt observation that very high dosing can be expected to create negative effects. The number of times that the FDA has issued this kind of high-profile clinical hold--in the CNS area--is small. But I cannot count the number of times that I have been told by companies that something came up in Phase I or II that led them-at FDA 'suggestion'--to do another safety study of some kind. Phase IIs are often long-delayed beyond their projected dates--three, six months, a year. Yet there has not been a clinical hold--just a behind the scenes discussion with the FDA. And for the most part, those Phase II trials do eventually get underway.
This reinforces my belief that Cortex--because of the ADHD angle--may have been singled out for a more public 'citizen's arrest'--so that all of us can rest easy, knowing our FDA is on the job. There is nothing to be done about this, the congressional mood is for increased surveillance, and Cortex can never, ever complain about the process--unless they want all of their applications treated like a Middle Eastern male wearing brand new sneakers and carrying a Koran at an airport security check. It's one of those situations where you just have to comply.
NeuroInvestment
Calpain/Spectrin, Lynch abstract
by: gfp927z 04/05/06 12:27 am
Msg: 27876 of 27887
Here's the Lynch abstract concerning calpain/spectrin and Ampakines -
Effects of positive AMPA receptor modulators on calpain-mediated spectrin degradation in cultured hippocampal slices.
Jourdi H, Yanagihara T, Martinez U, Bi X, Lynch G, Baudry M.
Neuroscience Program, University of Southern California, Los Angeles, CA 90089-2520, USA.
Positive modulators of AMPA receptors (AMPAr), also known as ampakines, are allosteric effectors of the receptors and have been extensively studied in past years due to their potential use as treatment for various diseases and ailments of the central nervous system such as mild cognitive impairment, schizophrenia, and Alzheimer's disease. Ampakines have been shown to improve performance on memory tasks in animals and in human subjects, an effect linked to their ability to increase agonist-mediated ion influx through AMPAr, thus leading to enhanced synaptic responses and facilitation of long-term potentiation (LTP) induction at glutamatergic synapses. As LTP is associated with calpain activation and spectrin degradation, we determined the effects of ampakine treatment of cultured hippocampal slices on spectrin degradation. Calpain activation was evaluated by determining the levels of the 145-150kDa degradation products of spectrin. Our data indicated that incubation of hippocampal slices with some, but not all positive modulators of AMPA receptors resulted in enhanced spectrin degradation, an effect that was blocked by a calpain inhibitor. In addition, an antagonist of AMPAr but not of NMDAr blocked ampakine-induced spectrin degradation. These results indicate that prolonged treatment with selected ampakines leads to spectrin degradation mediated by activation of the calcium-dependent protease calpain.
Re: Calpain/Spectrin, Lynch abstract
by: biobetter2 04/05/06 12:31 am
Msg: 27877 of 27887
This is recent study on cx614 and calpain--http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstra ct&list_uids=15784649&query_hl=2&itool=pubmed_docsum
Text for above link inserted… Aiming4.
J Pharmacol Exp Ther. 2005 Jul;314(1):16-26. Epub 2005 Mar 22.
Prolonged positive modulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors induces calpain-mediated PSD-95/Dlg/ZO-1 protein degradation and AMPA receptor down-regulation in cultured hippocampal slices.
Jourdi H, Lu X, Yanagihara T, Lauterborn JC, Bi X, Gall CM, Baudry M.
Neuroscience Program and Department of Biology, University of Southern California, Los Angeles, CA 90089-2520, USA.
Prolonged exposure of cultured hippocampal slices to CX614 [2H,3H,6aH-pyrrolidino[2'',1''-3',2']1,3-oxazino[6',5'-5,4]-benzo[e]1,4-dioxan 10-one], a positive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (AMPAr) modulator, decreases receptor response to synaptic stimulation, an effect that could reflect reduced receptor expression. The present study investigates this down-regulation and its underlying mechanisms using cultured rat hippocampal slices. Chronic treatment with CX614 gradually reduced levels of glutamate receptor (GluR)1 and GluR2/3 AMPAr subunits and of their anchoring proteins synapse-associated protein 97 (SAP97) and glutamate receptor interacting protein 1 (GRIP1) through 48 h. Decline in SAP97 and GRIP1 levels was associated with increased abundance of lower molecular weight bands, suggesting degradation of these proteins. CX614 effects were partially reversible after drug removal. GluR1 and GluR2/3 down-regulation and their slow recovery were associated with similar changes in SAP97 and GRIP1 levels. Treatment with CX614 for 48 h significantly reduced AMPAr mRNA levels in hippocampus, whereas 8-h exposure did not. Blockade of ionotropic glutamate receptors prevented CX614-induced decrease in AMPAr subunits and mRNA, with regional selectivity, although an AMPAr blocker was more efficacious than an N-methyl-D-aspartate receptor blocker. Blockade of calpain activity reduced CX614-induced degradation of SAP97 and GRIP1 and prevented decreases in AMPAr subunit but not mRNA levels. Treatment with CX614 alone or in combination with glutamate receptor blockers or calpain inhibitor III did not modify lactate dehydrogenase release into culture medium, implying the absence of cell toxicity. We conclude that CX614-induced AMPAr protein loss is primarily mediated by AMPAr activation and involves calpain-dependent proteolysis of SAP97 and GRIP1. CX614-induced suppression of AMPAr gene expression is, however, calpain-independent, and all these effects are not associated with cell damage.
PMID: 15784649 [PubMed - indexed for MEDLINE]
Re: Calpain/Spectrin, Lynch abstract
by: Neuroinv 04/05/06 12:35 am
Msg: 27879 of 27887
Gfp:
It's kind of odd that this Lynch abstract is being presented as evidence for a possible Ampakine-neurodegeneration link when--as you know--Lynch does not believe that Ampakines lead to in vivo neurodegeneration--as he confirmed directly to me last year around this time when it came up on the YMB. Keep in mind that they have done numerous in vivo tests of Ampakines in neurodegeneration models--e.g. stroke--and Ampakines were neuroprotective. Add to that the Lilly Parkinson's data where Ampakines were protective/neuroprotective in a PD model--and I feel as certain as one can without knowing what the FDA said--that has nothing to do with calpain-induced degeneration.
But we'll all know at some point in the next week or two.
NeuroInvestment
Re: Calpain/Spectrin, Lynch abstract
by: gfp927z 04/05/06 12:38 am
Msg: 27880 of 27887
Here's another calpain/spectrin/Ampakine related abstract. CX-614 is one of Cortex's earlier high impact compounds -
Prolonged positive modulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors induces calpain-mediated PSD-95/Dlg/ZO-1 protein degradation and AMPA receptor down-regulation in cultured hippocampal slices.
Jourdi H, Lu X, Yanagihara T, Lauterborn JC, Bi X, Gall CM, Baudry M.
Neuroscience Program and Department of Biology, University of Southern California, Los Angeles, CA 90089-2520, USA.
Prolonged exposure of cultured hippocampal slices to CX614 [2H,3H,6aH-pyrrolidino[2'',1''-3',2']1,3-oxazino[6',5'-5,4]-benzo[e]1,4-dioxan 10-one], a positive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (AMPAr) modulator, decreases receptor response to synaptic stimulation, an effect that could reflect reduced receptor expression. The present study investigates this down-regulation and its underlying mechanisms using cultured rat hippocampal slices. Chronic treatment with CX614 gradually reduced levels of glutamate receptor (GluR)1 and GluR2/3 AMPAr subunits and of their anchoring proteins synapse-associated protein 97 (SAP97) and glutamate receptor interacting protein 1 (GRIP1) through 48 h. Decline in SAP97 and GRIP1 levels was associated with increased abundance of lower molecular weight bands, suggesting degradation of these proteins. CX614 effects were partially reversible after drug removal. GluR1 and GluR2/3 down-regulation and their slow recovery were associated with similar changes in SAP97 and GRIP1 levels. Treatment with CX614 for 48 h significantly reduced AMPAr mRNA levels in hippocampus, whereas 8-h exposure did not. Blockade of ionotropic glutamate receptors prevented CX614-induced decrease in AMPAr subunits and mRNA, with regional selectivity, although an AMPAr blocker was more efficacious than an N-methyl-D-aspartate receptor blocker. Blockade of calpain activity reduced CX614-induced degradation of SAP97 and GRIP1 and prevented decreases in AMPAr subunit but not mRNA levels. Treatment with CX614 alone or in combination with glutamate receptor blockers or calpain inhibitor III did not modify lactate dehydrogenase release into culture medium, implying the absence of cell toxicity. We conclude that CX614-induced AMPAr protein loss is primarily mediated by AMPAr activation and involves calpain-dependent proteolysis of SAP97 and GRIP1. CX614-induced suppression of AMPAr gene expression is, however, calpain-independent, and all these effects are not associated with cell damage.
PMID: 15784649 [PubMed - indexed for MEDLINE]
Re: Calpain/Spectrin, Lynch abstract
by: Neuroinv 04/05/06 12:43 am
Msg: 27882 of 27887
Exactly:
<<Treatment with CX614 alone or in combination with glutamate receptor blockers or calpain inhibitor III did not modify lactate dehydrogenase release into culture medium, IMPLYING THE ABSENCE OF CELL TOXICITY . We conclude that CX614-induced AMPAr protein loss is primarily mediated by AMPAr activation and involves calpain-dependent proteolysis of SAP97 and GRIP1. CX614-induced suppression of AMPAr gene expression is, however, calpain-independent, and ALL THESE EFFECTS ARE NOT ASSOCIATED WITH CELL DAMAGE.
(capitalization mine)
Those who are not convinced can continue to debate this. I'm done.
NeuroInvestment
Re: Toxicity
by: bladerunner1717
Long-Term Sentiment: Hold 04/05/06 01:03 am
Msg: 27883 of 27887
Thanks, Neuro. I agree with all of your conclusions/speculations...for whatever my opinions are worth.
You made a point earlier about COR not having--and perhaps not being able to afford--a "regulatory"/clinical affairs person as a liaison to the FDA. It may interest you that another company I own alot of shares in, Genvec(GNVC), seemed to be stuck in a kind of limbo world with its drug for pancreatic cancer in a Phase II trial. The company then went out and hired a "pure" regulatory affairs person from Baxter in Nita Patel and a clincal/drug development guy from NIH in Dr. Thomas Davis. Very recently, in a rather surprise move, IMO, the FDA allowed the company to change the Phase II into a Phase III trial!!!
I'm sure you've read the FDA's (read: McClellan's) position paper on the "Critical Path," a paper that Gottlieb has publicly embraced. The emphasis in the "critical path" paper is to try to make sure there are more successful Phase III trials by having the FDA get involved more in the Phase II trials, which McClelllan deemed crucial for getting more drugs successfully through trials.
It's possible that in the long run, the situation for COR could turn out for the best, if the FDA decisions do not turn out to be fatal for CX717, which I don't believe they will. (I admit the short term consequences for shareholders have been and could well be into the future quite unnerving.) Because getting the FDA more involved now may prove fruitful for the upcoming Phase II's, not to mention the possible Phase III's with a BP partner. In light of the above, I should mention that Stoll vaguely implied to me in conversation that the days of COR not being able to afford a regulatory affairs person/FDA liaison may have turned into a situation where COR cannot afford to be without one.
Bladerunner
Re: Calpain/Spectrin, Lynch abstract
by: gfp927z 04/05/06 01:10 am
Msg: 27884 of 27887
Neuro, We know that some higher impact Ampakines (CX-614) are associated with calpain mediated spectrin protein degradation. All I'm saying is that if evidence of such protein breakdown is measurable in animal tox studies, that might conceivably justify a clinical hold by the FDA (one possibility).
What we don't know are - 1) whether this protein degradation is the result of a harmful neurodegeneration process, or merely from increased LTP activity, or 2) if a similar protein breakdown that occurs with CX-614 can also occur with a low impact like CX-717 when dosed over long periods.
As you said, only time will tell. All we know for now is that we have some type of problem. Other than excitotoxicity, the calpain/spectrin phenomenon is the other potential problem we've previously heard about being associated with Ampakines.
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