FDA Approves Lipfendra, Merck’s First Oral PCSK9 Inhibitor, to Lower LDL in Adults

The U.S. Food and Drug Administration on Friday approved Lipfendra, known generically as enlicitide, to lower low-density lipoprotein cholesterol, or LDL-C, in adults with hypercholesterolemia, including people with heterozygous familial hypercholesterolemia, an inherited form of high cholesterol. The drug, approved for Merck Sharp & Dohme LLC, is the first oral inhibitor of PCSK9 cleared by the FDA.

That matters because PCSK9 has already been validated as a powerful cholesterol-lowering target, but U.S. treatments in the class until now have been injections. Lipfendra offers a once-daily pill alternative and, in late-stage trials, delivered large reductions in LDL, often called “bad” cholesterol.

Under the label, Lipfendra is approved as an adjunct to diet and exercise. It comes as a 20-milligram oral film-coated tablet, with a labeled dose of one tablet once daily. Patients are instructed to take it in the morning on an empty stomach with water, black coffee or plain tea, then wait at least 30 minutes before eating or drinking anything else. The tablet should be swallowed whole, not split, crushed or chewed.

The approval was supported by two randomized, double-blind, placebo-controlled Phase 3 trials involving a combined 3,207 adults who were already on maximally tolerated statin therapy. In the larger CORALreef Lipids trial, which enrolled 2,904 participants, Lipfendra cut LDL-C by about 56% versus placebo at 24 weeks. In CORALreef HeFH, a 303-patient trial in adults with heterozygous familial hypercholesterolemia, the placebo-adjusted LDL reduction was about 59% at 24 weeks. The FDA and the prescribing information say LDL response can be assessed as early as four weeks after starting treatment.

“Cardiovascular disease remains the leading cause of death in the United States, and elevated LDL cholesterol is one of its most important modifiable risk factors. This approval provides an additional treatment option for adults with hypercholesterolemia and reflects the FDA’s broader commitment to supporting meaningful advances in patient access and tackling chronic diseases,” said Dr. Michael Davis, acting director of the FDA’s Center for Drug Evaluation and Research.

Enlicitide works by blocking PCSK9 from interacting with LDL receptors, which increases receptor recycling and helps clear more LDL from the bloodstream. On safety, adverse reaction rates in CORALreef Lipids were similar to placebo. In the smaller HeFH study, diarrhea was reported in 7% of Lipfendra patients versus 2% on placebo, while dizziness was reported in 9% versus 4%, respectively. Discontinuation rates due to adverse reactions were comparable to placebo across the studies.

The novelty here is the pill form, not the target itself. Existing FDA-approved PCSK9 therapies include injectable monoclonal antibodies such as Repatha and Praluent, as well as Leqvio, a twice-yearly injected small interfering RNA drug. Those medicines have already shown they can reduce major cardiovascular events in outcomes trials.

Lipfendra’s approval, by contrast, rests on its ability to sharply lower LDL cholesterol, not on proof yet that it reduces heart attacks, strokes or cardiovascular death. Merck’s ongoing CORALreef Outcomes trial, which has enrolled more than 14,500 participants, is designed to answer that question and has an estimated primary completion date of Nov. 29, 2029. The application received Priority Review and was reviewed under the FDA commissioner’s National Priority Voucher pilot program. Separately, trade and business outlets citing Merck spokespersons reported a U.S. list price of about $10.50 a day, or roughly $315 for a 30-day supply, and said the company expected the drug to be available within weeks of the approval.