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

To: Mike McFarland who wrote (122)	11/17/2006 6:30:53 PM
From: tuck	Read Replies (1) \| Respond to of 210

Combo of Hsp90 inhibitors with other drugs is indeed where it's at; I doubt that DMAG or IPI-504, despite their improved PK/PD versus 17-AAG, are so much better that they will beat the 17-AAG combos by themselves. Combo of Hsp90 and proteasome inhibition accomplishes similar ends to combo of Hsp90 and 70 inhibition. No good inhibitors of HSP70 are yet available, whereas we already have the geldanamycin analogs and an approved proteasome inhibitor in the form of Velcade. This combo causes OVERproduction of Hsp70 in the tumor cells. It grabs so many client proteins that insoluble complexes form, and are sealed off into big vacuoles that are toxic to the cell. Then the tumor cell bursts. The downside to the proteasome/hsp90 approach might be worse tumor lysis syndrome (already a bit of an issue with Velcade). It seems to cause even more glop in the tumor cells, so that when they burst, that additional glop will be in the bloodstream. Direct inhibition of Hsp70 might get around that, but it's years away in humans. Kosan is doing exactly this combination of Velcade with 17-AAG, and they are well ahead of Infinity in clinical development. They will likely do this combo with DMAG, too. The race in this second generation area is closer, but DMAG has done PI, and PII with Velcade is likely coming, too. IPI-504 is still a monotherapy, and whether it's better than DMAG -- or enough to be clinically relevant -- remains to be seen. Studies of these combos indicate that basically any proteasome inhibitor and any Hsp90 inhibitor will do the job described in the above paragraph. So will the bioavailability, solubility, etc., of IPI-504 or DMAG make much difference? Probably some, but such combos are way behind 17-AAG combos. It will take less drug, so that may reduce the side effect profile, but I'd expect IPI-504 to be similar to DMAG in that respect. But if my suspicions about tumor lysis syndrome are correct, neither DMAG nor IPI-504 will show better than 17-AAG in that respect. Has Infinity said much about their clinical development program for IPI-504? Have they said they are going to do combo trials with something? I can't find much help on their website, which seems very out of date and skimpy. I'm thinking that if MLNM still wants to munch someone, now that they've had their AnorMed candy taken away from them (at least they were paid), they might well be looking at Kosan. Cheers, Tuck