Merck has received FDA approval for Lipfendra (enlicitide), a once-daily oral tablet that becomes the first approved oral PCSK9 inhibitor for adults with high LDL cholesterol. The drug is cleared as an adjunct to diet and exercise to reduce LDL-C in adults with hypercholesterolemia, including those with heterozygous familial hypercholesterolemia (HeFH) — an inherited form of the condition that significantly elevates cardiovascular risk.
Lipfendra is a novel macrocyclic peptide, a molecular class distinct from both the small-molecule statins that have dominated cholesterol treatment for decades and the monoclonal antibody PCSK9 inhibitors — Amgen’s Repatha and Sanofi/Regeneron’s Praluent — that have been available as injections since 2015. By binding directly to the PCSK9 protein and blocking its interaction with LDL receptors on the liver, Lipfendra enables the liver to clear more LDL from the bloodstream, achieving LDL-C reductions comparable to injectable therapies in a once-daily pill.
The approval was based on two pivotal Phase 3 trials from Merck’s CORALreef clinical program. In CORALreef Lipids — a 2,904-patient multicenter study enrolling adults with hypercholesterolemia at elevated cardiovascular risk who were already on moderate- or high-intensity statin therapy — Lipfendra reduced LDL-C by 56% compared to placebo at week 24, with a 60% reduction observed when biologically anomalous baseline values were excluded in a post-hoc analysis. In CORALreef HeFH, a 303-patient study in patients with genetically confirmed or clinically diagnosed HeFH, LDL-C fell by 59% versus placebo at week 24. Both trials also showed statistically significant reductions in non-HDL-C and apolipoprotein B (ApoB), two additional markers of atherosclerotic cardiovascular disease risk. In CORALreef Lipids, the adverse event profile of Lipfendra was similar to placebo. In CORALreef HeFH, the most common adverse reactions occurring at higher frequencies than placebo were diarrhea (7% vs. 2%) and dizziness (9% vs. 4%), with similar discontinuation rates between treatment arms in both trials.
The CORALreef program encompasses more than 19,000 participants across multiple ongoing studies, including CORALreef Outcomes — a large cardiovascular outcomes trial with over 14,500 enrolled participants — which will evaluate whether Lipfendra reduces the risk of major adverse cardiovascular events such as heart attack and stroke. That data is not yet available, and the current approval is based solely on LDL-C reduction. Additional trials underway include a pediatric study and a combination therapy evaluation.
The drug carries a list price of $315 for a 30-day supply, roughly half the cost of existing injectable PCSK9 inhibitors, with Merck indicating insured patients will likely pay substantially less. Analysts have projected Lipfendra could generate peak annual revenues exceeding $5 billion, representing one of the more significant cardiovascular drug launches in years. The approval was granted under the FDA’s Commissioner’s National Priority Voucher program, which expedites review for medicines addressing major public health priorities. A cardiovascular outcomes trial — necessary to demonstrate reduction in heart attacks and strokes, not just cholesterol levels — remains ongoing.
KEY QUOTES:
“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. 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. We’re proud of our work with regulators on this rigorous and efficient review process.”
Dr. Dean Y. Li, President, Merck Research Laboratories
“High LDL-C is a major risk factor for atherosclerotic cardiovascular disease, which is the leading cause of death globally. In two Phase 3 trials, LIPFENDRA led to impressive reductions in LDL-C. Now, for the first time, patients have an oral PCSK9 inhibitor for LDL lowering.”
Dr. Ann Marie Navar, Lead Author, CORALreef Lipids Study, and Associate Professor of Medicine, Division of Cardiology, UT Southwestern Medical Center
“One of the greatest opportunities to help manage the risk of ASCVD lies in the timely identification and appropriate treatment of risk factors, such as LDL-C. We are encouraged by the approval of a new oral PCSK9 inhibitor option for adults who need additional LDL-C lowering.”
Katherine Wilemon, CEO, Family Heart Foundation
