Neuro, Just wondering where you first heard about the finding being seen in a *single* monkey? During the May SHM conf call most of the Q+A was not audible for those of us listening at home, so I assume Stoll said it there? I don't remember him publicly saying it was a single monkey at any other time, and I've taped every presentation/conf call that has been webcast over the internet or has been available over the phone. Or perhaps Stoll mentioned the "single monkey" topic during a private conversation?
The other thing I don't remember him saying (prior to the recent October conf call) was that the finding was seen in the longer term 13 week primate study. Before the October conf call, I didn't even know Cortex had done a 13 week primate study. We (or at least I) were under the impression that Cortex had originally only done 3 month studies in rats and dogs (and shorter term studies in rats and primates). So we/I assumed the finding was seen in one of the shorter term studies, based on the "acute" phrase used in the original press release (Piros also seemed to be under this false impression). Had I known that the finding was seen in a longer term 13 week study, that would have changed my analysis of the situation (for what that's worth).
I remember you said that you had brought up the calpain/spectrin topic to someone at Cortex, and they said they didn't think it was a problem (this was prior to the clinical hold). However, since neither Cortex nor their histopathologists now seem to have the foggiest idea what's causing the cellular changes, we really can't rule out the calpain/spectrin phenomenon as the cause. Reading the full text of the two major calpain papers, it doesn't look like this phenomenon is definitively limited to high impacts as we had previously thought (Dr. Rogers suggested it was a high impact phenomenon at the 12-05 SHM Q+A). A large component of CX-614's mode of action involves inhibition of receptor deactivation, as do the low impact Ampakines. The impression I had previously was that the high impact mode of action involved primarily inhibition of desensitization (as in Lilly's compounds, and also the benzothiadiazines). But the prototypical high impact cyclothiazide doesn't cause calpain/spectrin activity (!) Instead, calpain activity appears to be possibly linked to the deactivation mode of action, which is exactly the opposite of what one might have expected (since inhibiting desensitization is clearly linked to excitotoxicity, which is/should be linked to calpain/spectrin activity). At the time the calpain papers came out (last year), they apparently hadn't yet tested low impacts like CX-717 for calpain activity.
FWIW, I think it's way too early to rule out calpain/spectrin as the cause of our mysterious cellular finding, although since Cortex hasn't even disclosed if the finding was seen in CNS tissue or not, we're essentially groping in the dark. It would fit on some levels - causing microscopically visible cellular changes, occurring at higher doses, and being partially reversible after cessation of the drug. Why calpain activity wouldn't occur with cyclothiazide is a real mystery, since one would have expected it theoretically to occur most with that compound. Bottom line I guess, is that bio science (and investing) is full of surprises.
