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Biotech / Medical : Pharmos (PARS) -- Ignore unavailable to you. Want to Upgrade?

To: gfp927z who wrote (1323)	11/28/2004 3:33:49 PM
From: Clarksterh	Respond to of 1386

In the TBI Phase 2, during the initial 3 months, Dex provided a much more rapid rate of neurological recovery than placebo, but then the drug's benefit appears to trail off as they approach 6 months. Very good bet that that is only a measurement ceiling effect. The highest GOS score covers a lot of ground. So as people naturally improve they top out on the measurement even though they aren't yet anywhere near completely well. Moving to sicker patients and GOS-E will hopefully solve that. Even at 6 months however, the Dex arm still showed an advantage in neurological recovery of 47% vrs 32.4% for placebo (which would represent a 45% improvement over the placebo arm). Wouldn't a similar 6 month result in the larger 860 patient Phase 3 easily be considered statistically significant? Haven't run the numbers, but if it is repeated, yes it is probably stat sig. But the risk is that since the p was so low it won't repeat. At 6 months, the GCS 4-6 patients did phenomenally better than placebo, while the less seriously injured GCS 7-8 patients beat placebo, but a lot less dramatically. Let's say the Phase 3 has similar results, but the GCS 4-6 subgroup reaches statistical significance while the GCS 7-8 subgroup doesn't (and the combined GSC 4-8 group just misses). See my above comments on the ceiling effect. Is it possible that the FDA might still approve Dex, but with a label limiting its use to GCS 4-6 patients? Yes. But hopefully the use of GOSE and a larger trial will avoid that problem. 3) With the tapering off of measurable drug effect by 6 months, the suspicion might be that there may be only a very negligible drug effect by 9 or 12 months. Suspecting this, might the FDA want to see additional data going out a year? Possible I guess. But Pharmos had substantial conversations with the FDA when picking endpoints. For instance it is clear that Pharmos would have preferred to use GOAT instead of GOS. GOAT has (I believe) a higher ceiling than GOS. But the FDA appears to have forced GOS - albeit the extended version (GOS-E). But again, don't take the apparent 'tapering off' as a real tapering off - it is almost certainly a measurement effect. Clark

To: gfp927z who wrote (1323)	11/28/2004 6:02:21 PM
From: Tony van Werkhooven	Respond to of 1386

gfp - Please take the time to review that following document - in particular the references to the Dex Phase II trials. Based on your postings on the Cortex thread, I think you will find it most interesting. mayfieldclinic.com See p. 514 for discussion of Dex. Phase II trial. Tony PS You may want to consider membership on our Pharmos message board.

To: gfp927z who wrote (1323)	11/30/2004 6:52:47 PM
From: Clarksterh	Respond to of 1386

In the published Phase 2 results, they also break down neurological recovery based on the patient's GCS scores upon entry into the trial. At 6 months, the GCS 4-6 patients did phenomenally better than placebo, while the less seriously injured GCS 7-8 patients beat placebo, but a lot less dramatically. Let's say the Phase 3 has similar results, but the GCS 4-6 subgroup reaches statistical significance while the GCS 7-8 subgroup doesn't (and the combined GSC 4-8 group just misses). Ran the numbers and have to change my answer. No, it is unlikely that if they still use GOS Good Outcome as the top category that they will reach stat sig even if they multiplied the number of participants in this group proportional to the overall trial enrollment expansion. And we know that this group is actually being expanded less. However, offsetting this is that they may use the GOSE top category (the top half of GOS Good Outcome) and that will probably be more differentiated. Who knows how much? Probably still not enough to hit stat sig all by itself. BTW - Ran the numbers for the trial as a whole assuming exactly the same results as in the Phase II but with a different proportion of low GCS (more) to high GCS (fewer). Ridiculously low p values. Clark