The US FDA approved enlicitide (Lipfendra; Merck), the first oral PCSK9 inhibitor, to reduce LDL-C in adults with hypercholesterolemia, including HeFH.
The US Food and Drug Administration has approved enlicitide (Lipfendra®; Merck) 20-mg tablets as an adjunct to diet and exercise to reduce low-density lipoprotein cholesterol (LDL-C) in adults with hypercholesterolemia, including heterozygous familial hypercholesterolemia (HeFH), according to a company announcement.
The approval makes enlicitide the first FDA-approved oral proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor shown to lower LDL-C. The once-daily oral agent is a novel macrocyclic peptide that binds to PCSK9 and inhibits its interaction with LDL receptors.
The approval was supported by results from 2 pivotal phase 3 trials in the CORALreef clinical program: CORALreef Lipids and CORALreef HeFH. At week 24, enlicitide reduced LDL-C by 56% compared with placebo in CORALreef Lipids and by 59% compared with placebo in CORALreef HeFH.
In CORALreef Lipids, treatment with enlicitide resulted in a 57% reduction from baseline in LDL-C compared with a 3% increase with placebo at week 24, for a placebo-adjusted reduction of 56% (95% CI, –61 to –51; P<.001). In a post hoc analysis excluding biologically impossible baseline LDL-C values according to revised data handling rules, enlicitide reduced LDL-C by 60% compared with placebo at week 24.
Enlicitide was also associated with a reduction in other atherogenic lipoproteins associated with atherosclerotic cardiovascular disease (ASCVD) risk in CORALreef Lipids. At week 24, investigators reported a 54% mean reduction in non–high-density lipoprotein cholesterol and a 50% mean reduction in apolipoprotein B compared with a 3% increase for placebo.
In CORALreef HeFH, enlicitide reduced LDL-C by 58% from baseline compared with a 3% increase with placebo, for a placebo-adjusted reduction of 59% (95% CI, –66 to –53; P<.001). Secondary end points also favored enlicitide, with a 52% mean reduction in non-HDL-C and a 48% mean reduction in ApoB compared with a 2% increase for placebo.
“High LDL-C is a major risk factor for atherosclerotic cardiovascular disease, which is the leading cause of death globally,” Ann Marie Navar, MD, PhD, lead author of the CORALreef Lipids study and associate professor of medicine in the Division of Cardiology at UT Southwestern Medical Center, said in the announcement. “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.”
CORALreef Lipids was a multicenter, double-blind, randomized, placebo-controlled trial that included 2904 adults with hypercholesterolemia, with or without HeFH, who had a history of a major ASCVD event or were at increased risk for a first major ASCVD event. Participants required additional LDL-C reduction despite stable lipid-lowering treatment with moderate- or high-intensity statins, unless statin intolerance was documented, with or without other lipid-modifying therapy. Patients receiving PCSK9 inhibitors were excluded. Participants were randomly assigned 2:1 to 20 mg orally once daily or placebo for 52 weeks.
CORALreef HeFH was a multicenter, double-blind, randomized, placebo-controlled trial that included 303 patients with HeFH. Participants required additional LDL-C reduction despite stable lipid-lowering treatment with moderate- or high-intensity statins, with or without other lipid-modifying therapy, and were randomly assigned 2:1 to once-daily enlicitide 20 mg or placebo for 52 weeks.
The safety profile of enlicitide in CORALreef Lipids was similar to placebo. In CORALreef HeFH, the most common adverse reactions occurring more frequently with enlicitide than placebo were diarrhea (7% vs 2%) and dizziness (9% vs 4%). In both trials, similar proportions of enlicitide-treated and placebo-treated patients discontinued treatment because of an adverse reaction.
Merck noted that an ongoing clinical trial is evaluating the effect of enlicitide on cardiovascular morbidity and mortality. It is not yet known whether enlicitide reduces the risk of cardiovascular morbidity and mortality.
