Anacetrapib Meets Primary Endpoint, But Its Future is Called into Question

MD Magazine Cardiology, August 2017, Volume 7, Issue 5

Pharmaceutical giant Merck is reporting positive results from its REVEAL (Randomized Evaluation of the Effects of Anacetrapib through Lipid modification) outcomes study of anacetrapib for the prevention of cardiovascular disease, but experts from Morgan Stanley and other firms don’t seem convinced the drug will ever be commercialized.

According to a Merck statement, anacetrapib significantly reduced major coronary events compared to placebo in patients at risk for cardiac events who are already receiving an effective LDL-C lowering regimen. Major coronary events were defined as the composite of coronary death, myocardial infarction, and coronary revascularization.

Anacetrapib is an 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 aged 50 or older at high risk of cardiovascular events. Merck’s statement said anacetrapib’s safety profile “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 trial results with external experts, and said it will consider whether to file new drug applications with the US Food and Drug Administration.

The REVEAL trial meeting its primary endpoint was a major turnaround for Merck, as many of those in the field had their doubts about the CETP inhibitor ever making it to market after the misfires it suffered in testing, and after many rival drugs — from Pfizer, Roche and Eli Lilly – had given up the task in Phase 3, due to safety issues.

According to Morgan Stanley Equity Analyst David Risinger, Merck’s “guarded statement” implies that anacetrapib is unlikely to be filed because of modest efficacy of safety concerns.

“Although Ph 3 succeeded, we wonder if the effect size is small and/or if there are safety questions. It is very unusual for a company to announce success of a phase 3 outcomes trial but not commit to filing the new drug candidate,” Risinger wrote in a statement. “We are maintaining our anacetrapib forecast of 5% odds of commercialization.”

Other have echoed the pessimism about the success of the drug. Stephen Nicholls, deputy director of the South Australian Health and Medical Research Institute in Adelaide, Australia, and lead investigator for the failed trial of Lilly’s drug said in 2016 that “Merck’s drug is the fourth shot on goal for CETP inhibitors, but with disappointment or lack of success for the other agents, you have to be increasingly pessimistic.”

“The cautious language in the release indicates an unclear risk:benefit in our view, which investors should pay attention to,” said analysts from Jeffries, a global analyst firm. "We have previously highlighted low expectations for REVEAL, given the prior failures of other products in the CETP class, only assigning a 25% probability of success in our model.”

Despite pessimism about Merck’s product making it to commercialization, there are possibilities as to why it could succeed where others failed. REVEAL contained double the patient population of the competitor’s trials, and the slower approach taken by Merck — the study was designed so that anacetrapib’s LDL-lowering effect would be enough to reach significance, while the other firms had bet on the benefits of raising HDL.

The REVEAL study began in June of 2011 and is expected to be completed by April of 2019. Full details on the drug’s performance are expected for the end of August at the European Society of Cardiology 2017 Congress, when many eyes will attempt to peel back the numbers to more fully examine its safety.

This is especially crucial considering that data on genetics have revealed that CTEP inhibition may increase macular degeneration, so the end-of-month information on anacetrapib will prove to be ever more important.

Timothy Anderson, an analyst at Bernstein Research, stated that anacetrapib is “not out of the woods” just yet, but if it can make it through reveal of the full results, forecasts sales of $1.6 billion.