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Will Merck Seek FDA Filing For Heart Drug After Lackluster Results?

Xconomy New York — 

News from Merck this morning on a large trial known as Reveal might signal the end of the road for a once-promising group of cholesterol-lowering medicines.

It all depends on what New York drug giant Merck (NYSE: MRK) intends to do now that it has the results of the four-year, 30,449-patient trial, which tested a drug known as anacetrapib. The Merck drug met its main goal, but questions regarding the magnitude of the benefit, combined with some worrisome side effects and the availability of other cholesterol agents, leave anacetrapib’s future up in the air. Merck says this morning that it is “reviewing the results of the trial with external experts and will consider whether to file new drug applications with the [FDA] and other regulatory agencies.”

Anacetrapib is what’s known as a CETP inhibitor, a type of drug once seen as a potentially big advance in heart medicine. These drugs are designed to inhibit a protein called CETP (cholesterolylester transfer protein) and, in the process, raise levels of HDL, also known as “good” cholesterol. Thus, the drugs were a bet that raising levels of “good” cholesterol might be more effective at preventing heart disease than lowering LDL-C, or “bad” cholesterol.

CETP inhibitors, however, have turned out to be colossal flops for several large pharma companies over the years. One by one, CETP blockers from Pfizer (torcetrapib), Roche (dalcetrapib), and Eli Lilly (evacetrapib) failed massive clinical trials, and in some cases produced serious side effects along the way. Merck’s anacetrapib was the last of the group standing, pending the results of the Reveal study.

So it was a surprise when Merck said two months ago—without providing details—that the Reveal study had met its primary goal. The drug helped lower the rates of heart attacks when given to people along with the widely prescribed statins that are the standard of care for people with high cholesterol levels. That hinted that CETP inhibitors might still have a future, depending on the size of anacetrapib’s benefit, and Merck’s drug might represent a threat to the new, expensive class of cholesterol-lowering medicines called PCSK9 inhibitors. Yet at the time, Merck was noncommittal about the results, saying, as it did today, that it would consult with experts and decide whether to file for FDA approval.

That half-hearted announcement lowered expectations for the results, which were published this morning in the New England Journal of Medicine and presented at a medical meeting in Europe. The key findings from the study:

When added to a course of statins for patients with atherosclerotic vascular disease, a daily dose of anacetrapib reduced the risk of major cardiac events—like heart attacks—by 9 percent compared to those on statins and a placebo. Patients on the Merck drug and statins had a total of 1,640 cardiac events (10.8 percent), compared to 1,803 events (11.8 percent) for those on statins and a placebo. A relative risk reduction benefit was the study’s main goal.

Anacetrapib had just a one point absolute difference over placebo, however. It also failed a secondary study goal, showed no effect on the rate of heart attacks or death from heart disease, and Merck flagged a new potential safety concern—an accumulation of the drug in fat tissue after prolonged use. The drug is already tied to potential side effects on the kidneys and higher blood pressure.

Taken together, the study results, while better than previous CETP inhibitors, leave Merck in a tough spot. Should it file for approval of a drug that will compete in a crowded market, in which payers are already pushing back against other high-priced cholesterol medicines? Or write off anacetrapib’s long journey as a lesson learned?

“I think clinical adoption will be a challenge,” says Sekar Kathiresan, the director of preventative cardiology at Massachusetts General Hospital in Boston. Kathiresan says there may be a potential role for anacetrapib in patients who can’t tolerate statins or need an additional LDL-C lowering boost, but another Merck pill, ezetimibe (Zetia), already helps treat these people. And side effects on blood pressure and kidney function, along with the drug’s “very, very long half-life” are concerns.

Pushback from payers might be a problem as well. Insurers and their agents have already taken a hard line stance against PCSK9 inhibitors. Amgen (NASDAQ: AMGN), a PCSK9 drug developer, has been battling payers for a few years,  in an effort to prove its evolocumab (Repatha) is worth the high price. Referring to the PCSK9 blockers, Jefferies analyst Jeffrey Holford noted anacetrapib’s modest benefit will likely limit its commercial upside, particularly given payers are fighting back against drugs that have shown a stronger impact on cardiovascular disease.

“It would not be a surprise if Merck eventually decides not to file anacetrapib, given the likely heavy marketing expenditure that would be required to deliver only a modest return,” Holford wrote.

Here’s more on the new wave of cholesterol-lowering medicines, and payers’ response to them.