FDA approves Lipfendra, first oral PCSK9 inhibitor

The FDA has approved Merck’s Lipfendra (enlicitide), an oral PCSK9 inhibitor, as an adjunct to diet and exercise to reduce LDL cholesterol in adults with hypercholesterolemia, including those with heterozygous familial hypercholesterolemia (HeFH), according to a news release.

The once-daily pill is the first and only oral PCSK9 inhibitor the FDA has approved to lower LDL-C, also known as bad cholesterol. Enlicitide is a novel macrocyclic peptide that binds to PCSK9 and blocks its interaction with LDL receptors.

"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," Dean Y. Li, M.D., president of Merck Research Laboratories, said in a news release. "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 is based on two Phase 3 trials in Merck's CORALreef program. CORALreef Lipids enrolled 2,904 patients with hypercholesterolemia and a history of, or increased risk for, a major atherosclerotic cardiovascular disease (ASCVD) event. Participants were randomized 2:1 to Lipfendra or placebo for 52 weeks; patients included in the trial needed additional LDL-C lowering despite stable statin treatment, and those already on a PCSK9 inhibitor were excluded.

At week 24, Lipfendra reduced LDL-C by 56% compared with placebo, a reduction from baseline of 57% versus a 3% increase for placebo. Lipfendra also produced a 54% mean reduction in non-HDL-C and a 50% mean reduction in apolipoprotein B (ApoB), both secondary endpoints.

In CORALreef HeFH, 303 patients with the inherited condition were randomized 2:1 to Lipfendra or placebo for 52 weeks. At week 24, Lipfendra reduced LDL-C by 59% versus placebo — a 58% reduction from baseline compared with a 3% increase for placebo — along with a 52% mean reduction in non-HDL-C and a 48% mean reduction in ApoB. Safety in CORALreef Lipids was similar to placebo. In CORALreef HeFH, diarrhea (7% versus 2% for placebo) and dizziness (9% versus 4%) occurred more often with Lipfendra, but similar proportions of patients in each arm discontinued treatment because of an adverse reaction.

"High LDL-C is a major risk factor for atherosclerotic cardiovascular disease, which is the leading cause of death globally," said Ann Marie Navar, M.D., a lead author of the CORALreef Lipids study and an 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."

An ongoing trial, CORALreef Outcomes, is evaluating Lipfendra's effect on cardiovascular morbidity and mortality; Merck said it is not yet known whether the drug reduces that risk. The trial has completed enrollment of more than 14,500 participants. The broader CORALreef program has enrolled more than 19,000 people with hypercholesterolemia and includes additional studies: CORALreef Extension, CORALreef Pediatric, and CORALreef Combination.

Katherine Wilemon, CEO of the Family Heart Foundation, said in a statement that timely identification and treatment of risk factors such as LDL-C remains one of the greatest opportunities to manage ASCVD risk. "We are encouraged by the approval of a new oral PCSK9 inhibitor option for adults who need additional LDL-C lowering," she said.