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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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April 1, 2007

The HDL Compost Pile

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Posted by Derek

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.

Comments (8) + TrackBacks (0) | Category: Cardiovascular Disease | Drug Development


1. milkshake on April 2, 2007 12:33 AM writes...

You have to come up with a plausible hypothesis of how some protein works so that you can do a medchem project on it - but often it turns out that the initial understanding was too simplistic and things work difrently - and sometimes this happens in a lucky way also.

For example, developing psychoactive drugs is a complete hunt in the dark. (SSRI probably work by indirect mechanism that is not dependent on serotonin.)

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2. Morten on April 2, 2007 2:19 AM writes...

Exercise will raise HDL levels, won't it?

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3. RKN on April 2, 2007 7:34 AM writes...

Nice link.

I didn't realize HDL was such a "chameleon" particle. Nor did I know the medical community is now back to square one on the LDL/HDL/triglyceride debate. In fact, I thought it was only matter of time before statins would be added to our drinking water.

Kind of disconcerting, especially for someone like myself in a PhD pharmacology program. I'm begining to think we don't really understand what biological changes many of these drugs are causing over an exended period of use.

Maybe I'll return to a regimen of fish oil, niacin, resveratrol, & exercise, and hope for the best.

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4. Jonadab the Unsightly One on April 2, 2007 7:53 AM writes...

The nature of research and development (in any field, not just drugs) is that not everything you try to develop pans out. Nonetheless, if you view this as shredding money, you are missing the bigger picture. If you don't do any R&D, your competitors will always be coming out with new stuff you can't match.

What you really want, of course, is to know ahead of time which R&D efforts will pan out well. But if you could predict the future, there would be more luctrative ways to exploit that ability than by directing where to spend R&D money.

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5. Derek Lowe on April 2, 2007 8:40 AM writes...

True, that money has bought us some valuable information about what (not) to do, which is what a lot of research spending ends up doing. But my shredding comment was meant to emphasize that the sunk-cost aspect of things. Many people outside the area don't realize how many expensive blind alleys get followed (and how what works has to pay for them).

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6. dearieme on April 2, 2007 8:54 AM writes...

We could, of course, agree to stop using the word "science" for any topic where we can't perform properly controlled experiments.

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7. david on April 2, 2007 10:23 AM writes...

Everyone seems to be focused on the idea that raising HDL doesn't work. Perhaps the problem is that the drugs raising HDL levels are doing other things as well, stuff that markedly increases the death rate. I'm not saying I know what that "side effect" is, just that the HDL hypothesis shouldn't be dismissed so glibly. Side effects have been the bain of the pharma houses since before I can remember. Why should this instance be different?

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8. Norman Yarvin on April 3, 2007 5:53 PM writes...

Meanwhile, those of us who think heart disease is primarily an infection are looking at this and saying to ourselves "Of course that didn't work; to work, it'd have to kill some bacteria, like statins do and like niacin does."

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