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Biotech / Medical : Infinity Pharmaceuticals -- Ignore unavailable to you. Want to Upgrade?

To: idos who wrote (127)	11/19/2006 1:59:44 PM
From: tuck	Read Replies (3) \| Respond to of 210

Are you saying I write incomprehensibly or that the abstracts I post are a challenge for you to understand? Hopefully the latter, both for my ego and because I'm unlikely to change before the horse race is over. But you have plenty of time to learn, because as Praveen points out, I am making a comparison between the two Hsp90 inhibitors --DMAG and IPI-504 --very early. Praveen is very likely correct in saying that the DMAG AML trial was stopped because of the cardiac events. They might be drug related, but given the comorbidities of the patients who had the events, I have my doubts about that. Side effects observed in the preclinical tox studies don't seem to get published; often it seems only the FDA gets that as part of the IND package. All we see is the efficacy and PK/PD results, which always warrant further development. So we have no animal baseline to predict the drug's toxicity, just what one might expect/extrapolate from its mechanism of action, and what we have seen in small PI trials. I won't categorically say the drug didn't cause the cardiac events, because overexpression of Hsp90 is implicated in protecting the myocardium in reperfusion, so inhibiting it there might not be a good thing at first glance. However, Kamal et. al. (Nature 425, 407-410 (2003)) found that HSP90 in tumour cells is found in multimolecular complexes with higher affinity for 17AAG than the largely uncomplexed HSP90 found in normal cells. That paper showed why a useful therapeutic index might exist for HSP90 inhibitors, and suggests that GA analogs are unlikely to interfere with expression of normal Hsp90 molecules such as I presume are found in the normal myocardium (not sure of that presumption). The patients in the DMAG PI may not have had normal Hsp90 in their myocardium; it may have been aggregated into multimolecular complexes due to their pre-existing myocardial issues, causing DMAG to go after it there. One patient had already had an MI for sure, and the other had elevated troponin (an indicator of MI). Median patient age in the trial was 72, fwiw. In any case, if there is really cardiotoxicity with DMAG, it'll be a class effect, IMO. Here's a primer on Hsp90 inhibitors from Medscape. You'll need to register, I think, but it's free. medscape.com Here's a more recent look, but more superficial, and with company biases showing up everywhere (see my comments about this on the Kosan thread): pharmadd.com Praveen or anyone, has Infinity detailed the strategy Ms. Perkins refers to that will get their Hsp90 inhibitor to market first? IMO, it must involve doing a registrational PII trial in GIST, it's the only way they'd beat the Velcade/17-AAG combo. TIA & Cheers, Tuck