The US FDA has approved Merck’s LIPFENDRA (enlicitide) tablets, the first and only once-daily oral PCSK9 inhibitor approved to reduce low-density lipoprotein cholesterol (LDL-C) in adults with hypercholesterolemia.
The approval marks a major milestone in cholesterol treatment, giving patients an oral alternative in the PCSK9 inhibitor class, which has historically relied on injectable therapies. LIPFENDRA is a novel macrocyclic peptide designed to block PCSK9 from interacting with LDL receptors, helping lower levels of LDL-C, commonly known as “bad cholesterol.”
Phase 3 results from Merck’s CORALreef clinical program showed significant LDL-C reductions. In the CORALreef Lipids trial, LIPFENDRA reduced LDL-C by 56% compared with placebo at week 24. In the CORALreef HeFH trial, the treatment reduced LDL-C by 59% compared with placebo at the same time point.
“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, 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. We’re proud of our work with regulators on this rigorous and efficient review process.”
The approval was supported by two pivotal Phase 3 trials involving thousands of patients with elevated cholesterol and cardiovascular risk factors.
In CORALreef Lipids, which enrolled 2,904 patients, LIPFENDRA achieved a statistically significant 56% placebo-adjusted reduction in LDL-C at week 24. The treatment also reduced other cholesterol-related risk markers, including non-high-density lipoprotein cholesterol (non-HDL-C) by 54% and apolipoprotein B (ApoB) by 50%.
In CORALreef HeFH, a trial involving 303 patients with inherited high cholesterol, LIPFENDRA delivered a 59% placebo-adjusted LDL-C reduction at week 24, along with reductions in non-HDL-C and ApoB of 52% and 48%, respectively.
"High LDL-C is a major risk factor for atherosclerotic cardiovascular disease, which is the leading cause of death globally,” said Dr. 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.
“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.”
