Merck Provides Update on REVEAL Outcomes Study of Anacetrapib

KENILWORTH, N.J.–(BUSINESS WIRE)–Merck (NYSE:MRK), known as MSD outside of the United States and Canada, today announced that the REVEAL (Randomized EValuation of the Effects of Anacetrapib through Lipid modification) outcomes study of anacetrapib met its primary endpoint, significantly reducing major coronary events (defined as the composite of coronary death, myocardial infarction, and coronary revascularization) compared to placebo in patients at risk for cardiac events who are already receiving an effective LDL-C lowering regimen. 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, as has been previously reported. Merck plans to review the results of the trial with external experts, and will consider whether to file new drug applications with the U.S. Food and Drug Administration (FDA) and other regulatory agencies. The results of the REVEAL study will be presented at the European Society of Cardiology meeting on Aug. 29, 2017.

Anacetrapib is Merck’s investigational cholesteryl ester transfer protein (CETP) inhibitor. The REVEAL study is a randomized, double-blind placebo-controlled clinical trial to assess the efficacy and safety of adding anacetrapib to effective LDL-lowering treatment with atorvastatin for a median duration of at least 4 years among approximately 30,000 patients at high risk of cardiovascular events. REVEAL was designed and independently conducted by investigators at the Clinical Trial Service Unit (CTSU) at the University of Oxford, the trial’s regulatory sponsor, in collaboration with the TIMI Study Group based at Brigham and Women’s Hospital in Boston and Merck. Merck provided funding for REVEAL. Details on the REVEAL study design are available at

Source:  Business Wire  June 27, 2017


Although low concentrations of high-density lipoprotein cholesterol HDL-C (<40 mg/dL) have been recognized as a risk factor for coronary heart disease [Troth 2004], it is not clear whether increased HDL-C levels confer additional risk reduction, independent of lowering LDL-C levels [Sing 2007].  Raising HDL-C with diet and lifestyle modifications has proven challenging [Troth 2004].  Niacin and fibrates were shown to raise HDL-C but outcome studies did not show long-term benefits in terms of reduced CV mortality [Keene 2014].  More recently, small molecule inhibitors of CETP have been discovered that are able to raise HDL-C levels with or without a reduction of LDL-C. Their development was predicated on the inverse relationship between HDL-C levels and risk of atherosclerosis and the theoretical possibility that higher HDL-C levels may protect against cardiovascular disease and its complications in humans. Unfortunately, this once promising class of drugs has not produced the anticipated results.  The development of torcetrapib was discontinued due to higher incidence of hypertension and increased mortality observed in the torcetrapib-treated subjects compared to the placebo group [Barter 2007].  This was found to be an off-target effect specific to torcetrapib and not observed with dalcetrapib or anacetrapib [Joy & Hegele 2009].  Despite an adequate safety profile, the development of dalcetrapib was also discontinued in phase 3 due to lack of beneficial effects on cardiovascular outcomes [Schwartz 2012]. The latest CTEP inhibitor to fail in phase 3 due to lack of benefit on cardiovascular outcomes is evacetrapib [see here and here]. The failure of dalcetrapib and evacetrapib raise the question whether plasma HDL-C is a good biomarker of HDL-C functionality or whether other biomarkers of anti-atherogenic properties of HDL-C particles may need to be developed [Kontush 2006; Joy & Hegele 2009, Mohammadpour 2013].  HDL-C may protect against atherosclerosis by promoting reverse cholesterol transport (RCT), and potentially through anti-inflammatory, antioxidative and anti-thrombotic effects [Duffy 2009; Khera 2011]. Therefore, determination of cholesterol efflux capacity may be a better measure of HDL function than plasma HDL-C levels [Khera 2011].  Unless future trials of drugs aimed at raising HDL-C address these issues, the likelihood of reaching the required hard efficacy endpoints will remain elusive. One could also question whether CTEP inhibitors confer any measurable benefits over and above those obtained with statins, and whether the costs of conducting very large clinical trials with this class of drugs can be justified [see commentary in FB].

Currently, anacetrapib remains the only small molecule CETP inhibitor in late phase development.  Judging by the recent news release from Merck, it appears that anacetrapib is well-tolerated and, if further analysis confirms the top down information given by Merck, it is likely that anacetrapib may become the first CETP inhibitor to be approved.  However, longer term observations will be needed to definitively assess the benefits of increasing HDL-C via CETP inhibition on cardiovascular outcomes in the Real-World setting. The medical community is anxiously awaiting the results of REVEAL trial in late August of this year.


The results of the REVEAL study were presented at the  European Society of Cardiology Congress on August 29, 2017 (see Merck press release) and simultaneously published online in the New England Journal of Medicine (see here).  This is the first phase 3 trial of a CETP inhibitor, which has reached its primary endpoint, but the effect size was relatively small and it is still not clear whether the difference can be attributed solely to the rise in HLD-C or to some other effect of anacetrapib that may differentiate it from other CETP inhibitors (see also commentary).  It remains to be seen whether Merck will proceed with submission of the dossier for FDA approval and if approved, the pricing would justify the small additional benefit of anacetrapib on top of intensive statin therapy.

Keywords: atherosclerosis; Cholesteryl ester transfer protein; reverse cholesterol transport;

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