Merck Reveals Positive Findings For Its CETP Inhibitor

–Surprising success after 3 previous drugs in the class failed.

Merck announced on Tuesday that the REVEAL trial with anacetrapib had met its primary endpoint, significantly reducing the rate of coronary death, MI, and coronary revascularization in high risk patients already taking statins. Full results of REVEAL will be presented on August 29 at the European Society of Cardiology meeting in Barcelona, Spain.

The announcement contained no details about the results, though the company said that “the safety profile of anacetrapib in the early analysis was generally consistent with that demonstrated in previous studies of the drug, including accumulation of anacetrapib in adipose tissue.”

REVEAL is by far the largest and longest trial to study a cholesteryl ester transfer protein (CETP) inhibitor. 30,000 patients were randomized to anacetrapib or placebo and followed for 4 years. The CETP inhibitor class originally raised hopes because the drugs raise HDL levels, the so-called good cholesterol, but they also lower LDL cholesterol and can have other off-target effects. It is now believed that any benefits of the drugs are likely a result of the effect on LDL.

The REVEAL announcement came as an enormous surprise, since three previous large trials with different drugs in the same  class had been unsuccessful, sparking broad skepticism about all drugs in 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.

Given the history of CETP inhibitors it is not clear whether Merck will have a success on its hands, even with a positive trial under its belt. “The challenge is given the null or negative results of 3 previous trials within the class, are the results of REVEAL credible?” asked Sanjay Kaul (Cedars-Sinai).

Merck said it “plans to review the results of the trial with external experts, and will consider whether to file new drug applications.” This might mean that the results, though statistically significant, are not very robust, particularly in the context of a mature cholesterol lowering market with statins, ezetimibe and PCKS9 inhibitors.

“Why would the sponsor wait to consider whether to file or not? Perhaps the data are not robust enough to warrant approval on the basis of a single trial,” Kaul speculated.




  1. Dr Steve Nissin on Dr Fred Feit’s Sirius XM show talked about this and indicated best not to give much hope to this study. The reason being the study size was so large so they met their end point goal with a statistical factor but not necessarily a clinical factor. Secondly he mention the drug remained in your system after 4 years which is definitely not a good profile for a drug particularly if you are found to be allergic to it. In fact he mentioned that the company behind the drug itself is not sure whether to take it forward because they too probably recognize the fact that a statistical clinical benefit is missing.

  2. James Stein says

    Excellent coverage. Thanks, Larry.

Speak Your Mind