Merck received FDA approval for 20 mg Lipfendra (enlicitide) tablets as an adjunct to diet and exercise to reduce LDL cholesterol in adults with hypercholesterolemia, including heterozygous familial hypercholesterolemia.

Lipfendra is a novel macrocyclic peptide and marks the first FDA-approved oral PCSK9 inhibitor, a class previously available only as injectable therapies, offering patients a once-daily pill option for lowering LDL-C, commonly referred to as bad cholesterol.¹

What is the approval based on?

The approval is based on results from two pivotal Phase III studies within the Coralreef clinical program: Coralreef Lipids and Coralreef HeFH.

In Coralreef Lipids, a randomized, double-blind, placebo-controlled study enrolling 2,904 patients with hypercholesterolemia and a history of or elevated risk for a major cardiovascular event, Lipfendra reduced LDL-C by 56% compared to placebo at week 24 (95% CI: -61, -51; p<0.001).² A post-hoc analysis applying revised data handling rules that removed biologically impossible baseline LDL-C values showed a 60% reduction compared to a 3% increase for placebo.

Secondary endpoints in the trial also showed meaningful reductions, with non-HDL-C falling by a mean of 54% and apolipoprotein B by 50%.² The safety profile of Lipfendra in this study remained similar to placebo, with similar discontinuation rates between arms.²

In Coralreef HeFH, which enrolled 303 patients with heterozygous familial hypercholesterolemia, Lipfendra reduced LDL-C by 59% compared to placebo at week 24 (95% CI: -66, -53; p<0.001).³ In the trial, non-HDL-C fell by a mean of 52% and ApoB by 48%, with the most common adverse reactions occurring at higher frequencies than placebo which include, diarrhea (7% vs 2%) and dizziness (9% vs 4%), though discontinuation rates were similar between arms.³

Ann Marie Navar, a lead author of the Coralreef Lipids study and associate professor of medicine in the division of cardiology at UT Southwestern Medical Center, placed the approval in the context of cardiovascular disease burden. "High LDL-C is a major risk factor for atherosclerotic cardiovascular disease, which is the leading cause of death globally," Navar said. "Now, for the first time, patients have an oral PCSK9 inhibitor for LDL lowering."

Why is this approval significant?

PCSK9 inhibitors have demonstrated strong LDL-lowering efficacy but have historically required subcutaneous injection, creating an access and adherence barrier for some patients. Lipfendra's macrocyclic peptide design enables oral delivery, addressing a longstanding gap in cardiovascular lipid management, and providing patients with another option.

"By harnessing the innovative science of PCSK9 inhibitors and novel macrocyclic peptide technology, Lipfendra was designed to significantly lower LDL-C in the form of a convenient once-daily pill," said Dean Y. Li, president of Merck Research Laboratories. "This is a pivotal moment as we bring the first U.S. FDA-approved oral PCSK9 inhibitor to adults with high LDL-C, offering patients an important new option."

Katherine Wilemon, CEO of the Family Heart Foundation, added: "We are encouraged by the approval of a new oral PCSK9 inhibitor option for adults who need additional LDL-C lowering."

What’s next for Lipfendra?

Despite FDA’s approval, it is not yet known whether Lipfendra reduces the risk of cardiovascular morbidity and mortality. That question is currently being addressed in Coralreef Outcomes, a large cardiovascular outcomes trial that has completed enrollment with over 14,500 participants.¹ Results from the study will be critical in determining how Lipfendra is positioned relative to established injectable PCSK9 inhibitors, which have demonstrated cardiovascular benefit in outcomes trials.

Sources

1. Merck’s Lipfendra (enlicitide) is the First and Only Once-Daily Oral PCSK9 Inhibitor Approved by the U.S. FDA to Reduce LDL-C in Adults with Hypercholesterolemia Merck July 16, 2026, https://www.merck.com/news/mercks-lipfendra-enlicitide-is-the-first-and-only-once-daily-oral-pcsk9-inhibitor-approved-by-the-u-s-fda-to-reduce-ldl-c-in-adults-with-hypercholesterolemia/
2. A Study of Enlicitide Decanoate (MK-0616 Oral PCSK9 Inhibitor) in Adults With Hypercholesterolemia (MK-0616-013) CORALreef Lipids National Library of Medicine September 10, 2025 https://clinicaltrials.gov/study/NCT05952856
3. A Study of Enlicitide Decanoate (MK-0616 Oral PCSK9 Inhibitor) in Adults With Heterozygous Familial Hypercholesterolemia (MK-0616-017/​CORALreef HeFH) National Library of Medicine February 24, 2026, https://clinicaltrials.gov/study/NCT05952869