Unwinding torcetrapib

Despite some talk in the general media that last week's failure of Pfizer Inc.'s torcetrapib CETP inhibitor could be the death knell for a novel approach to cholesterol management, the available evidence hints that the pharma company's problem was more likely the compound than the target. Nevertheless, the target itself has some contradictory properties that could prove vexing.

Beyond the profound impact torcetrapib was expected to have on PFE's aging blockbuster portfolio, the compound was more broadly tipped as the bellwether of a potential new class of heart drugs that would boost plasma levels of high density lipoprotein (HDL), a molecule known to have an atheroprotective effect by inhibiting the activity of cholesteryl ester transfer protein (CETP).

Unchecked, CETP moves cholesteryl ester (CE) from HDL into very low density lipoprotein (VLDL) and LDL particles, and thus lowers plasma HDL, while increasing proatherogenic vLDL-cholesterol and LDL-cholesterol (see "Elevating HDL," A2).

While lowering LDL via statins is a well-established treatment, the search for additional therapeutic targets has shifted the emphasis to boosting HDL based on epidemiologic findings that low HDL is a strong and independent risk factor for chronic heart disease (CHD).

On Saturday, Dec. 2, only two days after hailing torcetrapib as its next breakthrough product, PFE (New York, N.Y.) announced that it was stopping all clinical trials involving the compound

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