ACCELERATE Shows Third Time’s No Charm for CETP Inhibitors
Newly presented data from the phase 3 trial of evacetrapib reveal why development of this lipid-modifying agent was discontinued — and why hopes for CETP inhibitors are waning.
Lingering hopes for the CETP inhibitor class of lipid-modifying drugs were dealt a major blow last October when the phase 3 ACCELERATE trial of evacetrapib was terminated early due to failure to reduce cardiovascular events after a preliminary analysis. Now ACCELERATE investigators have shared data at ACC.16, the American College of Cardiology’s 65th Annual Scientific Session, showing just how stark the disconnect is between evacetrapib’s effect on lipids and its lack of impact on clinical events.
Cleveland Clinic is a non-profit academic medical center. Advertising on our site helps support our mission. We do not endorse non-Cleveland Clinic products or services Policy
Among the ACCELERATE findings presented at ACC.16:
“Here we’ve got an agent that more than doubles HDL cholesterol and lowers LDL cholesterol as much as many statins, yet it has no effect on clinical events,” says ACCELERATE co-principal investigator Stephen Nicholls, MBBS, PhD, who presented the findings at an April 3 late-breaking clinical trials session. Dr. Nicholls is a professor at the South Australian Health and Medical Research Institute and a consultant to the Cleveland Clinic Coordinating Center for Clinical Research (C5Research), which served as the study’s coordinating center.
“We were certainly hoping for different results and are trying to understand why we didn’t see a clinical benefit from this drug,” adds co-principal investigator A. Michael Lincoff, MD, a Cleveland Clinic cardiologist and Director of C5Research. “The trial raises questions about the benefits of raising HDL cholesterol and the future of the CETP inhibitor class of drugs.”
“These findings illustrate the importance of performing large, high-quality outcome trials,” notes ACCELERATE steering committee chair Steven Nissen, MD, Chairman of Cardiovascular Medicine at Cleveland Clinic. “Just looking at the effects a therapy has on cholesterol levels doesn’t always translate into clinical benefits.”
ACCELERATE enrolled 12,092 patients at more than 540 sites who were at high cardiovascular risk due to one or more of the following:
Patients were randomized to at least 18 months of therapy with either the CETP inhibitor evacetrapib 130 mg/day or placebo in addition to standard medical therapy, which in a large majority of patients included statins or other cholesterol-lowering drugs. The data reported at ACC.16 reflect an average of 25 months on study drug and follow-up through all patients’ end-of-study visit.
The events included in the composite primary end point were cardiovascular death, myocardial infarction, stroke, coronary revascularization and hospitalization for unstable angina. Notably, there were no significant differences between the evacetrapib and placebo groups on any of these individual end points. Although a reduction in all-cause mortality in the evacetrapib group approached statistical significance (P = .06), it was not driven by a decrease in cardiovascular death.
The study raised no safety concerns with evacetrapib, and no major side effects emerged, but Eli Lilly has announced that it is discontinuing development of the agent.
This marks the demise of the third agent to emerge from the class of cholesteryl ester transfer protein (CETP) inhibitors, which act by disrupting the process by which HDL cholesterol is converted to LDL cholesterol. Development of these agents was predicated on the notion, supported by animal and genetic studies, that CETP deficiency is cardioprotective.
Yet the first CETP inhibitor, torcetrapib, was abandoned after it was shown to increase rates of cardiovascular events and death in late-stage trials, and development of the second agent, dalcetrapib, was discontinued after phase 2 clinical testing found it ineffective.
The ACCELERATE results are particularly disappointing because evacetrapib was believed to offer potent CETP inhibition without the toxicity of torcetrapib. “These findings continue to challenge the hope that CETP inhibition might successfully address residual cardiovascular risk,” says Dr. Nicholls. He notes that while the lack of clinical benefit remains a mystery, at least several theoretical explanations have been posited:
To help sort out these and other theories, the ACCELERATE trial leaders and Eli Lilly are making the trial database available to independent investigators. Review of research proposals and governance will be coordinated by Cleveland Clinic’s C5Research group.
Click here to view more late-breaking trials and clinical research from ACC.16