REVEAL-ing the truth about CETP inhibitors?

OXFORD, U.K.—Despite a string of clinical trial failures over the last decade, the demise of the cholesteryl ester transfer protein (CETP) inhibitors has been greatly exaggerated. At least, that’s the hopeful take by pharmaceutical company Merck & Co. (known as MSD outside the United States and Canada) as it looks toward results later this year from REVEAL (Randomized Evaluation of the Effects of Anacetrapib through Lipid-modification), a study designed by investigators at the United Kingdom’s University of Oxford.

The REVEAL study is an international clinical trial that aims to find out if treating cholesterol with anacetrapib will drive down the risk of heart attacks, deaths from heart disease and other vascular diseases.

Merck’s decision to continue on with the trial has been based on a planned review of unblinded data by the study’s independent data monitoring committee, which included “an assessment of futility” after clinical trials of three previous CETP inhibitors by three different drug companies were discontinued.

First, and most spectacularly, Pfizer’s torcetrapib, which the company had hoped would preserve its cholesterol franchise, was found to have off-target negative effects. Expectations for the CETP inhibitor class were further damaged by the failure of Roche’s dalcetrapib and, more recently, Eli Lilly’s evacetrapib.

The failure of the trials prompted researchers to question the value of the HDL hypothesis. (Some experts argue that simply raising high-density lipoprotein may not be enough; instead, it may be necessary to enhance the purported benefit of HDL’s “reverse cholesterol transport” mechanism.) Merck seems to be pinning its hopes not on the HDL-raising properties of the drug, but on its LDL-lowering properties.

Robert Blaustein, executive director of clinical research for cardiovascular diseases at Merck, spoke to DDNews about previous failed and aborted trials with CETP inhibitators. “The ILLUMINATE trial in approximately 15,000 patients with pre-existing cardiovascular disease for torcetrapib was stopped prematurely in 2007 because of an excess risk of death among patients allocated to receive torcetrapib,” he notes. “Cardiovascular outcomes trials with two other CETP inhibitors were also terminated early due to lack of efficacy.”

The Dal-OUTCOMES trial of dalcetrapib in 16,000 patients with a recent acute coronary syndrome was stopped prematurely due to a lack of clinically meaningful reductions in cardiovascular events but with no significant safety concerns, he says, and the ACCELERATE trial of evacetrapib, which doubled HDL cholesterol and lowered LDL cholesterol by about one-quarter, enrolled about 12,000 patients and was stopped early due to insufficient evidence of efficacy.

“By contrast with the ACCELERATE trial, the REVEAL trial of anacetrapib has recruited more participants (30,000 vs. 12,092), including a lower proportion with ACS (15 percent vs. 31 percent), longer duration of follow-up (median at least four years vs. average about 2.5 years) and involves more primary cardiovascular events (anticipated 3,000 vs. 1,500),” Blaustein says.

The REVEAL trial “will provide a robust assessment of the efficacy and safety of anacetrapib among individuals at high risk of cardiovascular events who are receiving effective LDL-lowering treatment.”

The most compelling aspect of Merck's REVEAL study is that large-scale randomized trials have shown that lowering LDL cholesterol concentration by about 40 mg/dL for four to five years reduces the risk of coronary events (including myocardial infarction, coronary death and revascularization procedures) and stroke by about one-fifth—and that lowering LDL cholesterol more (either with more effective statin regimens or the addition of ezetimibe) produces further reductions in risk, Blaustein says.

“Nevertheless, among individuals who already have occlusive vascular disease, the risk of cardiovascular events remains high,” he adds.

The authors of a baseline paper for REVEAL—published recently by the American Heart Journal—note that REVEAL will provide a robust evaluation of the clinical efficacy and safety of adding anacetrapib to an effective statin regimen, and will access the efficacy and safety of anacetrapib among individuals at high risk of cardiovascular events who are receiving effective LDL-lowering treatment.

“Patients with prior vascular disease remain at high risk of cardiovascular events despite intensive statin-based treatment,” the authors state. “Inhibition of cholesteryl ester transfer protein by anacetrapib reduces LDL cholesterol by around 25 to 40 percent, and more than doubles HDL cholesterol. However, it is not known if these apparently favorable lipid changes translate into reductions in cardiovascular events.”

Back in 2015, an article in Forbes noted, “Merck is not putting any credence in the potential for the HDL-elevating properties of anacetrapib for reducing cardiovascular risk. They are resting all their hopes on the enhanced LDL cholesterol-lowering capacity of anacetrapib which, when combined with a statin, is superior to a statin alone.”

Only time will tell whether Merck succeeds with anacetrapib when three Big Pharma competitors did not.