Replies to post #1717 on RespireRx Pharmaceuticals Inc (fka RSPI)

[bladerunner1717]

Neuro,

Did I hear correctly that the AD trials were being "re-started?" Why "re-started?" I thought they were continuing, even as the FDA issues in ADHD were being addressed.

Also, did I hear correctly the cellular abnormalities showed up in the 7-day rat study, but not in the longer rat and monkey studies? Is this the reason that Stoll thinks that the histo procedure might be the cause of the cellular abnormalities. (He seemed to backtrack from that position by saying that the abnomalities still showed up, but not to the same extent, when a different histo procedure was used. These points were very unclear to me.)

Stoll semed to indicate that other company's studies could impact COR's Ampakine platform, but yet seemed assured that this was not a platform-wide problem. There seems to me to be a contradiction here. I don't see how Stoll can be so sure this is not a platform-related problem.

How important do you think it is to the FDA's decision-making bodies that the tox studies are clean, but COR can't identify the root cause of the histo problem?

The sense I got from Stoll on the CC is that he thought CX717 development in ADHD was really a thing of the past. What COR learned was important and there was some "proof of principle," but this molecule really had to give way to a more powerful molecule that could be delivered at lower dosages.


Bladerunner

[gfp927z]

Neuro, Dr. Stoll said the histopathologists had never seen anything like the cellular changes caused by CX-717 (and the fact that they were caused by the drug and were not an artifact was confirmed by their dose dependent reappearance in the rat study). That may be why the FDA apparently didn't notice the cellular changes originally, before the Phase 2as - no one had seen anything like it before, so they weren't looking for it. What we really need to worry about now, along with everything else, is what a thorough tox reexamination of Org-24448 might reveal.

Unfortunately, one can now start to make an argument that Cortex may belong in the "broken biotech" portion of one's portfolio, ie - the seriously flawed companies. I don't know, to me this feels considerably worse than the Shire rejection of CX-516. CX-516 was merely a very weak compound, and everyone already knew that. The question now is whether there is a fatal class wide problem with the low impacts generally. Think I need a beer...

[upndown1313]

You cannot say that FDA is holding CX 717 to a higher therapeutic index standard since you don't know the PK profiles at these "ultra-high" doses. It could be that the AUC's at these g/kg doses are not much higher than say at 20 mg/kg doses. Quite often in these type of tox studies, there is dose limited absoprtion and the bioavaibility decreases significantly as the dose increases, resulting in only a fractional increase in exposure with a several-fold increase in dose. Therefore, the therapeutic index based on AUC exposure is quite small. Another possibility, is that at these ultra high doses, toxicity can be caused by an impurity in the API that is present at say < 0.x% level. Under this scenario, the API itself is fine, but obviously a separate dosing of the toxic impurity would need to be done to confirm the tox finding.

Based on what I read in this forum about the cc, I would recommend pursuing AZ ASAP and close the BP deal, even if at less money. ADHD will require a squeaky clean drug, and obviously, CX 717 is not it.

[Market_Fest4]

Thanks Neuro,
This is what I understood also. So at a dose that's 75 times higher than the highest dose that gave positive ADHD results (800mG), they noticed some non-permanent cellular changes in one species.

The animal didn't die, suffer a stroke or anything else life threatening and everyone is acting like CX-717 is dead. I don't get it? Who's gonna take 75 hits of CX-717 at the same time? I bet if you took 30 hits of codiene at the same time, you'd OD. But you can take 2.5 times that much CX-717 and after a few weeks of daily overdosing, you develop some temporary cellular changes. Maybe those changes correlate to a better brain? Stoll had to treat the results with care for the FDA, so he didn't belittle them, but it sounds like in normal doses, this stuff is pretty darn safe!!!! Am I missing something???

Is there any sanity left on this board?

Yes, the continually expanding schedule for a green light is disappointing, but does it justify the inevitable haircut we will see Friday on huge volume? It doesn't appear so.......

MF4