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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: derekb.lowe@gmail.com Twitter: Dereklowe

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« Write It Down, Write it Down | Main | Fast Plaques in a Slow Disease »

February 8, 2008

A Look Under the Hood

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Posted by Derek

There’s an excellent article in Nature Reviews Drug Discovery that summarizes the state of the HDL-raising drug world. It will also serve as an illustration, which can be repeated across therapeutic areas, of What We Don’t Know, and How Much We Don’t Know It.

The last big event in this drug space was the catastrophic failure of Pfizer’s torcetrapib, which wiped out deep into Phase III, taking a number of test patients and an ungodly amount of money with it. Ever since then, people have been frantically trying to figure out how this could have happened, and whether it means that the other drug candidates in this area are similarly doomed. There’s always the chance that this was a compound-specific effect, but we won’t know until we see the clinical results from those others. Until that day, if you want to know about HDL therapies, read this review.

I’d guess that if you asked a thousand random people about that Pfizer drug, most wouldn’t have heard about it, the same as with most other scientific news. But many that had might well have thought it was a cholesterol-lowering drug. Cholesterol = bad; if there’s one thing that the medical establishment has managed to get into everyone’s head, that’s it. The next layer of complexity (two kinds of cholesterol, one good, one bad) has penetrated pretty well, but not as thoroughly. A small handful of our random sample might have known, though, that torcetrapib was designed to raise HDL (“good cholesterol”).

And that’s about where knowledge of this field stops among the general population, and I can understand why, because it gets pretty ferocious after that point. As with everything else in living systems, the closer you look, the more you see. There are, for starters, several subforms of HDL, the main alpha fraction and at least three others. And there are at least four types of alpha. At least sixteen lipoproteins, enzymes, and other proteins are distributed in various ratios among all of them. We know enough to say that these different HDL particles vary in size, shape, cholesterol content, origin, distribution, and function, but we don’t know anywhere near as much as we need to about the details. There’s some evidence that instead of raising HDL across the board, what you want to do is raise alpha-1 while lowering alpha-2 and alpha-3, but we don’t really know how to do that.

How does HDL, or its beneficial fraction(s) help against atherosclerosis? We’re not completely sure about that, either. One of the main mechanisms is probably reverse cholesterol transport (RCT), the process of actually removing cholesterol from the arterial plaques and sending it to the liver for disposal. It’s a compelling story, currently thought to consist of eight separate steps involving four organ systems and at least six different enzymes. The benefits (or risks) of picking one of those versus the others for intervention are unknown. For most of those steps, we don’t have anything that can selectively affect them yet anyway, so it’s going to take a while to unravel things. Torcetrapib and the other CETP inhibitors represent a very large (and very risky) bet on what is approximately step four.

And HDL does more than reverse cholesterol transport. It also prevents platelets from aggregating and monocytes from adhering to artery walls, and it has anti-inflammatory, anti-thrombotic, and anti-oxidant effects. The stepwise mechanisms for these are not well understood, their details versus all those HDL subtypes are only beginning to be worked out, and their relative importance in HDL’s beneficial effects are unknown.

At this point, the review article begins a section titled “Further Complications”. I’ll spare you the details, but just point out that these involve the different HDL profiles (and potentially different effects) of people with diabetes, high blood pressure, and existing cardiovascular disease. If you’re thinking “But that’s exactly the patient population most in medical need”, you are correct. And if it’s occurred to you that this could mean that an HDL drug candidate’s safety profile might be even more uncertain than usual, since you won’t see these mechanisms kick in until you get deep into the clinical trials, right again. (And if you thought of that and you don’t already work in the industry, please consider coming on down and helping us out).

Much of the rest of the article is a discussion of what might have gone wrong with torcetrapib, and suffice it to say that there are many possibilities. The phrases “conflicting findings”, “remain to be elucidated”, “would be important to understand” and “will require careful analysis” feature prominently, as they damn well should. As I said at the time, we’re going to learn a lot about human lipidology from its failure, but it sure is a very painful way to learn it.

And that is the state of the art. This is exactly what the cutting edge of medical knowledge and drug discovery looks like, except for the fact that cardiovascular disease is relative well worked out compared to some of the other therapeutic areas. (Try central nervous system diseases if you want to see some real black boxes). This is what we’re up against. And if anyone wants to know how come we don’t have a good therapy yet for Disease A or Syndrome B. . .well, this is why.

Comments (3) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Drug Development | Toxicology


COMMENTS

1. samir roy on February 8, 2008 9:35 PM writes...

The problem is that high LDL/triglyceride levels or low HDL are a proxy of something that happens in the liver. They are not the cause, rather a by product of the same mechanism that promotes atherosclerosis.

There have been large studies that show that reactive protein C (itself a surrogate for measuring chronic inflammation) is better correlated with the risk of developing macro-vascular disease than any type of cholesterol values.

The problem is that too many people have too much to loose by abandoning the 'cholesterol hypothesis'.

Statins are the only cholesterol drugs that reliably reduce the risk of CV disease in large populations. The reduction in CV disease risk due to statins is better correlated with their ability to reduce reactive protein C's levels than increase in HDL levels or decrease in LDL/triglyceride levels.

Neither niacin, fibrates, resins etc have ever been shown to decrease risk in anything other than small "controlled" trials.

Alcohol consumption (30-50 g/ day)on the other hand can decrease C-reactive protein levels, fasting and postprandial blood glucose, increase adiponectin levels. There have been some population based studies that show that moderate alcohol consumption decrease the rates of CV disease, renal microvascular damage and Type 2 diabetes by more than half, without increasing total mortality from other causes - The J curve.

I think a couple of glasses of wine a day will do one more good than everything except probably statins. In any case 8 bottles of wine cost less than a months prescription of vytorin or zetia.

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2. Anonymous BMS Researcher on February 10, 2008 8:20 PM writes...


In the aftermath of the Great Plavix Disaster, one of my colleagues headed for Groton -- but between the day he accepted Pfizer's offer and his start date, torcetrapib got killed off. I had been wondering whether I was making a mistake staying at BMS myself; I chose to stay and so far am glad I did...

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3. tom bartlett on February 12, 2008 8:29 AM writes...

"In any case 8 bottles of wine cost less than a months prescription of vytorin or zetia."

Cheers!

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