FDA APPROVAL

FDA Approves Lipfendra as First Oral PCSK9 Inhibitor for Adults With High Cholesterol

Edited by:
Anthony Calabro, MA

Key Highlights

  • Enlicitide is the first oral therapy that blocks PCSK9 to reduce LDL-C.
  • The treatment is indicated for use with diet and exercise in adults with high cholesterol or heterozygous familial hypercholesterolemia.
  • In 2 randomized, double-blind, placebo-controlled trials, mean LDL-C changes from baseline to Week 24 were -56% and -59% in the Lipfendra groups compared with placebo.
  • The most common adverse reactions reported at higher frequencies than placebo in adults with HeFH were diarrhea and dizziness.

On July 16, the FDA approved enlicitide (Lipfendra, Merck Sharp & Dohme, LLC) for use with diet and exercise to reduce low-density lipoprotein cholesterol (LDL-C) in adults with high cholesterol or heterozygous familial hypercholesterolemia (HeFH), an inherited form of high cholesterol. Enlicitide is the first oral therapy that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9) and is administered as a once-daily tablet.

The approval was supported by 2 randomized, double-blind, placebo-controlled trials, NCT05952856 and NCT05952869, that evaluated the efficacy and safety of enlicitide in 3,207 adults with severe hypercholesterolemia, including patients with and without HeFH, who were already receiving maximally tolerated statin therapy. The primary endpoint in both trials was percent change from baseline to Week 24 in LDL-C compared with placebo.

In the first trial, which included adults with a history of atherosclerotic cardiovascular disease (ASCVD) or who were at high risk for ASCVD, the average baseline LDL-C level was 96 mg/dL. The average percentage change in LDL-C from baseline to Week 24 was -56% in the enlicitide group compared with placebo. In the second trial, which enrolled only adults with HeFH, the average baseline LDL-C level was 119 mg/dL. The average percentage change in LDL-C from baseline to Week 24 was -59% in the enlicitide group compared with placebo.

In the first trial, adverse reaction rates were similar between patients treated with enlicitide and those who received placebo. In the second trial, the most common adverse reactions in adults with HeFH treated with enlicitide that occurred at higher frequencies than placebo were diarrhea and dizziness. Across both trials, similar proportions of patients in the enlicitide and placebo groups discontinued treatment because of adverse reactions.

Reference
US Food and Drug Administration. FDA approves first oral therapy that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9) to lower bad cholesterol in adults with high cholesterol. Published July 16, 2026. Accessed July 16, 2026. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-first-oral-therapy-inhibits-proprotein-convertase-subtilisinkexin-type-9-pcsk9-lower