Pfizer, torcetrapib, and HDLs

It's time to spill some ink on torcetrapib. Everyone knows this drug by now--"son of Lipitor" which couldn't make it to an NDA. In a late Phase 3 trial, persons taking torcetrapib had higher mortality than those not taking it. Definitely not a good thing. (Some years back, Bristol-Myers Squibb had an antibiotic, desquin, which had higher mortality associated with its use among persons with abdominal abscesses. After the company finally realized it would never get the drug to market (it also had a slight hypoglycemia problem), it gave the drug back to its Japanese discoverer, which promptly licensed it to Schering-Plough. Lord only knows what Fred Hassan was thinking when he made the deal. But I digress...) The idea with torcetrapib was to raise HDLs. Data from Framingham and lots of other epidemiologic data suggested that HDLs were important to reduce cardiovascular risk. Some suggested it was even more important than LDLs, which are the target of the omnipresent statins like Lipitor. Niacin, which raises HDLs (if you can tolerate the hot flashes), doesn't appear to raise mortality; on the contrary, it lowers it, enough for Abbott Labs to buy Kos Pharmaceuticals just to get into the niacin market. So what gives with torcetrapib?

It turns out it might not be a matter of increasing levels of HDL per se. It turns out HDL molecules carry lots of stuff inside beside lipoproteins. For example, protease inhibitors, which might help stabilize atherosclerotic lesions, aka plaque. That's just an example. There are lots of others. I doubt torcetrapib does anything about this other stuff. It works to increase HDL levels, period. While Pfizer shareholders will likely not be heartened by this fact, for the rest of us, this realization carries two messages: first, raising HDL alone may not be the best path to reducing cardiovascular disease (and identifying a potential blockbuster), and second, pharmacological approaches are often not as compelling as we first thought.

On the other hand, one wonders why the good folks at Pfizer didn't try pairing Lipitor with niacin (which is generic, I think). Maybe there's a patent issue, but I doubt it. It certainly would have been safer than torcetrapib. In any case, one of the lessons from the torcetrapib is that not all drug safety issues are post-marketing (after marketing approval has been obtained), and not all of drug safety is sturm and drang. While Pfizer shareholders didn't benefit much from torcetrapib, the rest of us did.

To CET: Many thanks.