Replies to post #2258 on RespireRx Pharmaceuticals Inc (RSPI)

[neuroinv]

Obviously, I don't think CX717 should be scrapped: but here is the rationale on the part of the FDA that puts it at risk:

1) If you don't have a lot of headroom between the clinical dose and the potentially risky dose, there is the possibility that over millions of patient exposures, more vulnerable individuals might experience adverse effects that were thought to only occur with much higher doses.
2) In a population like adult ADHD, where use is going to be daily and longterm, the odds of #1 are higher, and one is trying to extrapolate from three months of use to years of use.
3) Adult ADHD patients are, for the most part, a healthy population relatively speaking. Any adverse medical effect would thus be in the context of what otherwise would have been physical health.
4) If #3 occurs, even to a small number of individuals, this will be interpreted as the FDA not doing its job. Which would lead to more congressional grandstanding. Very little--indeed no--price is paid by the FDA for excessive constraint and caution. A high price will be paid if anything unexpected sneaks through.

Gfp: One thought about the 200mg and 800mg doses. Stoll gave a hint regarding their thinking during the last CC. He referenced their belief--based on animal models--that 10-20mg/kg would be necessary for the treatment of hyperactivity, one of the two main domains of ADHD symptoms (inattention being the other). That translates into 750-1500mg on average. Thus the 800mg was near the bottom of what they thought they needed to show an effect on hyperactivity, whereas 200mg was probably near the bottom of what they thought they needed for inattention. A nonstimulant that addresses both is far more valuable as a competitor to stimulants (really the only drugs at present that address hyperactivity with any consistency) than one that only treats inattention.
Thus a mid-range dose would have been seen as superfluous--more than one needs for inattention, less than one needs for hyperactivity.

NeuroInvestment

[gfp927z]

MarketFest, Part of the FDA's concern is due to the fact that the cellular effect being seen is as yet unexplained. In the conf call Dr. Stoll said that the FDA's general view is that "until we can get better explanations, we're going to have to stay conservative". One gets the impression that neither Cortex's histopathologists nor the FDA have seen cellular changes quite like this before (which is one reason why one might suspect the changes to be in the brain itself and not in say the liver, kidney, etc). So with the uncertainty over the causes of the cellular changes, the FDA is setting the safety bar for CX-717 higher than usual. Plus AMPA upmodulation is a brand new neurological approach, and the FDA probably remembers Lilly's difficulties with LY-451395 also.

Part of our problem in figuring the odds for CX-717 is that we have very little solid info to go on. Not only don't we know what the histo finding is, or in what organ it's seen, we have no idea what human dosing level is currently allowed by the FDA over various durations (1 month, 3 months). Is it 100 mg for 1 month, or 200 mg, or 500 mg or what? How about BID doses? Without this info we can't get a handle on how much dose liberalization we'll need to get from the FDA for CX-717 to be viable for further studies and for partnering/outlicensing.

Concerning 800 mg BID specifically, this was the highest BID dose given in the Phase 1, in effect the "MTD", though they never did get any serious adverse events, only an increased frequency of headaches (1600 mg was called the single dose MTD). With the dosing of CX-717 being restricted by the FDA (how restricted we don't know), it seems very unlikely that the FDA would allow BID dosing for any length of time at the MTD.