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January 31, 2011
Sanofi's PARP1 Inhibitor Misses
Past results, they tell you, are no guarantee of future performance. Sanofi-Aventis is ready to tell you all about that after the results of a Phase III trial of their recently acquired oncology drug, iniparib (BSI-201). This had shown very strong results in Phase II against "triple-negative" breast cancer, but it appears to have missed two survival endpoints in a larger trial. Sanofi bought BiPar, the company that had been developing the drug, a little less than two years ago.
Iniparib's a small molecule indeed - small enough that its systematic name can be immediately parsed by any sophomore chemistry student. It's 4-iodo-3-nitrobenzamide; it's the sort of thing you can order out of a catalog. But it's also an inhibitor of poly-(ADP-ribose) polymerase I (PARP1), and it's the first compound of that class to get this far in the clinic. PARP1 is part of a DNA repair pathway, although it's not on the front line. That would be homologous recombination, which is the pathway that needs the well-known BRCA to function. The idea has been that since so many aggressive breast cancers are deficient in BRCA, that they'd be especially sensitive to something that targeted PARP as well - they should accumulate so many DNA breaks that they'd be unable to replicate.
That's a perfectly reasonable theory. But it doesn't seem to have yielded perfectly reasonable results in this case. Problem is, PARP1 has a lot of functions in the cell, and inhibiting the lot of them all at once may not be such a good idea. One possibility is that effects on the Akt pathway might boomerang and reduce the effectiveness of therapy.
More broadly, this is yet another illustration of the perils of Phase II data. And it does make a person think about the idea of tightening up the endpoints of such trials even more. Problem is, you often don't get good survival numbers until Phase III, anyway, by which time you've spent the money. Like Sanofi-Aventis is spending it now. Let's hope that one of the other indications for the drug works out better.
Update: here's a rundown on competition in this field. The next round of clinical data will be quite interesting. . .
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