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April 1, 2007
The HDL Compost Pile
There's a good article at Forbeson the various attempts to improve cardiac outcomes by raising HDL levels. Matthew Herper and Robert Langreth round up the latest disappointing results, starting with Pfizer's torcetrapib and going on from there. It isn't an appealing sight.
You'd have thought that raising HDL would be a lot more effective than this, wouldn't you? Think of all the associated evidence that's piled up over the years saying that high HDL levels are cardioprotective. We in the industry have been betting hundreds and hundreds of millions of dollars on the hope that we knew enough to make useful drugs out of this information, and by golly, we appear to have been wrong.
This is just one more example, in what appears to be a literally endless series, of how scientific issues get more complicated the more you learn about them. There is clearly an awful lot that we just don't understand about HDL and cardiac risk, for example. Trying to treat the varying distributions of the many different sorts of HDL particles as if they were all one unit has not been fruitful, to put it mildly, so right in front of us the field divides, branches, and fans out into fuzziness: How many different sorts of HDL are there, and how do we tell them apart? What causes different types to be produced or eliminated? What time scale does this happen on, and how do all these things vary between individuals and populations? What do the various HDL species do, individually and in concert, to affect atherosclerosis and other cardiovascular conditions? How on earth can we come up with drugs to differentiate among them, assuming we ever figure out which ones to go after? We are remarkably far away from answers to any of these questions.
Our business is already dependent to an unnerving degree on rolls of invisible dice. If anyone gets an HDL-directed therapy to work in the next few years, their success will surely have an even greater share of plain good luck in it than usual. We're all going to have to know a lot more about lipoproteins before we can safely reach for our wallets in this area. For now, an awful lot of development money has been irrevocably shredded, and earning it back will be quite the job.
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