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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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In the Pipeline: Don't miss Derek Lowe's excellent commentary on drug discovery and the pharma industry in general at In the Pipeline

In the Pipeline

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December 2, 2008

Torcetrapib: What Was the Problem? And Does It Matter?

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Posted by Derek

Ever since the catastrophic failure of Pfizer's HDL-raising CETP inhibitor torcetrapib in late 2006, everyone involved has wondered just what the problem was. There was a definitely higher cardiovascular-linked death rate in the drug-treatment group as opposed to placebo - which led to the screeching halt in Phase III, as well it might - but why? Is there something unexpectedly bad about raising HDL? Or just in raising it by inhibiting the CETP enzyme, which might well provide a different lipoprotein profile than other high-HDL ideas? Was it perhaps an off-target effect of the drug that had nothing to do with its mechanism? And for any of these possibilities, is there the possibility of a biomarker that could warn of approaching trouble?

There are now two analyses of clinical data that may shed some light on these questions (thanks to Heartwire for details and follow-up). The first, a new analysis from Holland of the RADIANCE trial data, shows an electrolyte imbalance (low potassium and higher sodium) in the treatment group. Measuring carotid wall thickness, they found no correlation between the degree of HDL elevation and progress of disease, which is disturbing. The only correlation was with lower LDL levels, and the authors point out that torcetrapib has unappreciated LDL-lowering activity. (Of course, there are easier and more proven ways to do that!)

The second, the ultrasound-monitored trial called ILLUSTRATE led by the Cleveland Clinic, actually did show a correlation between HDL levels and disease progression, as measured by PAV (per cent atheroma volume). This paper concludes that the drug did perform mechanistically, but that needs some qualification. Overall, there was no real significant change in PAV, but looking more closely, the individual changes did seem to correlate with the amount of HDL elevation each group of patients achieved. Only the very highest-responding group showed any regression, though.

Interestingly, this study also showed the same sort of electrolyte imbalance, and both teams seem to agree that torcetrapib is showing off-target mineralcorticoid effects. Steve Nissen of the Cleveland group is more optimistic (a phrase one doesn't get to write every day). He thinks that a CETP inhibitor that doesn't hit the adrenals might still find a place - but I have to say, looking over the data, that it sure won't be the place that the companies involved were hoping for. Instead of being world-conquering cardiovascular wonder drugs, perhaps the best this class of compounds can hope for is a niche, perhaps alongside statin therapy. I just don't see how this level of efficacy translates into something all that useful.

But we'll see. Merck's anacetrapib is still going along. The data we have so far suggest that the compound raises HDL without effects on blood pressure, as opposed to torcetrapib. So maybe (for whatever reason - blind luck, I'd say) this compound doesn't do anything to the aldosterone pathway. But does it do anything to atherosclerosis? That's the question, and that's what the big money will have to be spent on in Phase III to find out. A comment at the Wall Street Journal's Helath Blog has it right:

Welcome to the challenges of pharmaceutical research. Pharmacogenomic evidence originally led Pfizer to hope that elevating HDL through inhibiting CETP would be beneficial. A biomarker assessment in patients suggests that plaque reduction is associated with the highest HDL elevations. Yet, with torcetrapib, there appears to be a safety biomarker popping up. Are either the efficacy or safety signals really biomarkers of long term clinical outcome? You only need to ante up $800M to run mortality and morbidity trials for 5 or more years. Any investors?

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


COMMENTS

1. Hap on December 2, 2008 3:20 PM writes...

I didn't think that the safety issue was a biomarker, but a set of bad outcomes in the sample population - HDL levels may or may not be correlated with improvement in health (the biomarker's connection to outcomes isn't yet clear) but the level of heart problems is a direct influence on outcomes, rather than a conjectured one. Is this accurate?

Drug development seems to be analogous to a really expensive poker game, except no one knows what's in the deck, what the value of certain cards is, or what the odds and financial payoffs are.

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2. Mark on December 12, 2008 1:25 PM writes...

Many issues here. First, the evidence that CETP inhibition would be helpful is not mainly based on the human genetics; there aren't really enough human patients lacking the enzyme genetically for a good study I think. However, rodents lack the gene for CETP completely, but when humanized with a transgene do show the expected change in lipid profiles. Also, I may be misremembering but I thought there was evidence that the drug itself was helpful in a larger animal model.

Apparently the enzyme is difficult because it is very hydrophobic (not surprising given the biochemistry of the natural substrate) so the small molecule antagonists are also very sticky. If so, that would indeed be likely to increase the possibility of off-target effects.

More generally, I suspect that increasing HDL flux would be more productive than simply increasing equilibrium HDL levels. Unfortunately flux measurements can't really be used in a population wide ascertainment for new genes affecting HDL. It seems we are probably still stuck with simple HDL-C measurements. But there is no reason to think that all possible druggable targets for this variable have been identified.

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3. Gordon Ashworth on March 9, 2010 8:02 AM writes...

Has anyone looked at the Illuminate trial closely? Why were 20% of the patients diabetes type II patients who had to begin statin treatment, despite no cardiac disease history?

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