Merck Drops Development Of Once Promising CETP Inhibitor

–Despite positive results in the REVEAL trial anacetrapib is dead.

Merck announced on Wednesday that it would not seek regulatory approval for its cholesterol drug anacetrapib.

The decision did not surprise most observers, despite the fact that investigators recently reported positive results for the drug in the enormous 30,000+ patient REVEAL trial.

The trial was by far the largest and longest CETP inhibitor trial. It revealed a modest 9% reduction in the risk of a major coronary event with anacetrapib when compared to placebo. This seemed to suggest that at best Merck had only a small potential market for the drug.

“We are deeply grateful to the researchers and patients who participated in the anacetrapib clinical development program, and in particular the REVEAL outcomes study. Unfortunately, after comprehensive evaluation, we have concluded that the clinical profile for anacetrapib does not support regulatory filings,” said Roger M. Perlmutter, M.D., Ph.D., president, Merck Research Laboratories.

Anacetrapib is the latest, and nearly the last, in the once highly promising class of CETP inhibitors. The drugs originally attracted enormous interest because of of their HDL-raising properties, which, it was hoped, would complement and perhaps enhance the established benefits of LDL-lowering statins. Some CETP inhibitors also possessed significant LDL-lowering properties, and this eventually became the source for renewed hope in the drugs, anacetrapib in particular because of its large LDL-lowering effect.

Three previous large trials with different CETP inhibitors were unsuccessful, sparking broad skepticism about the class. First, and most spectacular, was the failure of Pfizer’s torcetrapib in the ILLUMINATE trial. It is now widely believed that the failure was due to the off-target effects of the drug. Subsequently, the trial with Roche’s dalcetrapib was stopped for futility, likely a result of the drug’s relatively weak LDL-lowering effect. The third drug, evacetrapib, may have suffered because Lilly rushed the trial and didn’t allow enough time to demonstrate benefit.

One Remaining CETP Inhibitor

But the CETP inhibitor story isn’t quite over yet. A startup company, DalCor, acquired dalcetrapib from Roche and is betting that it can snatch victory from the jaws of defeat. DalCor is pinning its hopes on a genetic substudy of dal-OUTCOMES, the Roche phase 3 study, which found a single genetic polymorphism that appeared to identify trial patients who were likely to benefit from the drug.

Although dalcetrapib was not found to be effective in dal-OUTCOMES, it was shown to be safe. This allowed the company to jump immediately into a large phase 3 trial. In Augst DalCor announced that it had enrolled more than half of an anticipated 5,000 patients into this trial.


  1. “the established benefits of LDL-lowering statins”: for many people these benefits would appear to be microscopic if they exist at all. You get all the adverse side effects, though, whether or not there’s any useful CVD benefit.

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