FDA Approves First Oral PCSK9 Inhibitor for High Cholesterol

Traditionally, managing high LDL cholesterol has meant a combination of diet, exercise and, for many patients, daily statin medications. For those who needed additional LDL lowering beyond what statins could provide, PCSK9 inhibitors offered a powerful option but came with a significant catch: They required injections, either every two weeks or once monthly. That landscape just changed.

Merck has announced that the U.S. Food and Drug Administration (FDA) has approved Lipfendra, known generically as enlicitide, as the first oral PCSK9 inhibitor cleared in the United States. The once-daily tablet is approved as an adjunct to diet and exercise to reduce LDL cholesterol in adults with hypercholesterolemia, including those with heterozygous familial hypercholesterolemia (HeFH), a genetic condition that causes persistently high LDL levels from birth.

What Is a PCSK9 Inhibitor and Why Does It Matter?

PCSK9 is a protein that degrades the receptors on liver cells responsible for clearing LDL cholesterol from the bloodstream. By blocking PCSK9, these medications allow more LDL receptors to remain active, dramatically increasing the liver’s ability to remove LDL from circulation.

PCSK9 inhibitors have been available as injectable medications since 2015 and have shown impressive LDL-lowering results, but their delivery format has limited adoption for many patients who are unwilling or unable to self-inject.

Lipfendra works through a novel mechanism as a macrocyclic peptide that binds directly to PCSK9 and prevents it from interacting with LDL receptors, achieving similar results through a pill taken once a day.

What the Clinical Trials Showed

The FDA approval is based on results from two Phase 3 trials in the CORALreef clinical program. In the CORALreef Lipids trial, which enrolled 2,904 patients with hypercholesterolemia who required additional LDL reduction despite being on stable statin therapy, Lipfendra reduced LDL cholesterol by 56% compared with placebo at Week 24.

The drug also produced meaningful reductions in non-HDL cholesterol, down 54%, and apolipoprotein B, down 50%, both of which are associated with cardiovascular disease risk.

In the CORALreef HeFH trial, which enrolled 303 patients with heterozygous familial hypercholesterolemia, Lipfendra reduced LDL cholesterol by 59% compared with placebo at Week 24, with similar reductions in non-HDL cholesterol and apolipoprotein B. Meanwhile, patients in the placebo group had a 3% increase in these secondary end points.

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

Safety Profile

In the CORALreef Lipids trial, the frequency of adverse reactions was similar between patients taking Lipfendra and those taking placebo, a notably clean safety profile. In the CORALreef HeFH trial, the most common side effects occurring at higher rates than placebo were diarrhea, affecting 7% of Lipfendra patients versus 2% on placebo, and dizziness, affecting 9% versus 4%, respectively. In both trials, similar proportions of patients in the treatment and placebo groups discontinued because of a side effect.

What Comes Next

An ongoing cardiovascular outcomes trial called CORALreef Outcomes has completed enrollment with more than 14,500 participants. Additional trials are evaluating Lipfendra in pediatric populations, in combination with other therapies and in extended follow-up settings.

“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, M.D., Ph.D., 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.”