In November 2010, Merck presented Phase III results of its CETP inhibitor, anacetrapib. DEFINE was an 18-month study that included more than 1,600 patients with or at high risk for CHD who were already receiving statins and were at the guideline-established LDL-C goal. The study was designed to assess the lipid-modifying efficacy, safety, and tolerability of anacetrapib 100 mg daily added to ongoing statin therapy with or without other lipid-modifying agents.
According to the study results, LDL was reduced by 39.8% to 45 mg/dL in patients taking anacetrapib compared to those given placebo. The researchers also reported a 138.1% increase in HDL levels in the anacetrapib group to 101 mg/dL at 24 weeks. No changes in blood pressure nor in electrolyte or aldosterone levels were reported through the first 76 weeks.
Additionally, prespecified adjudicated cardiovascular events occurred in 16 patients in the anacetrapib group versus 21 in the placebo group. Researchers suggested that the event distribution in DEFINE yielded a predictive probability of 94% that anacetrapib would not be associated with a 25% increase in cardiovascular events seen with torcetrapib.
Merck will move forward with a four-year study to be launched in April 2011 and enroll 30,000 patients. If trial results are positive, anacetrapib may reach the market in 2015. Anacetrapib is part of a major commitment by Merck to cardiovascular disease drug development; when the large-scale study for anacetrapib is fully enrolled, the company will have some 120,000 patients in heart drug trials.
Some cardiologists believe, however, that the development of HDL therapies experienced a serious setback with termination of torcetrapib’s clinical development. Potentially because of off-target actions of torcetrapib, surrogate biomarkers intended to elucidate the impact of the drug on atherosclerosis provided an uninterpretable picture of actual effects, commented David Orloff, M.D., executive director of Medpace and the last director of the Division of Metabolism and Endocrinology at the Center for Drug Evaluation and Research, in the American Journal of Cardiology.
Pfizer’s failure in spite of spending big bucks on torcetrapib calls into question the merits of increasing HDL levels as well as lowering LDL levels. Ongoing clinical trials will certainly clarify some issues, but whether they will demonstrate success and bring a new cholesterol-lowering drug to the market remains to be seen.