FDA approves enlicitide, first oral PCSK9 inhibitor, for hypercholesterolemia

The once-daily tablet reduced LDL-C by more than half compared with placebo across two phase 3 trials in the CORALreef program, providing clinicians with an oral alternative to injectable PCSK9-targeting therapies.

The FDA has approved enlicitide (LIPFENDRA®; Merck, Rahway, NJ, USA) tablets, 20 mg, 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 press release from Merck.¹ Enlicitide is a novel macrocyclic peptide and the first FDA-approved oral proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor for lowering LDL-C.

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Elevated LDL-C, often described as bad cholesterol, is a major modifiable risk factor for atherosclerotic cardiovascular disease (ASCVD), which remains a leading cause of death worldwide. Many patients do not reach guideline-recommended LDL-C targets despite treatment with statins and other lipid-modifying therapies. Existing PCSK9-targeting therapies are administered by subcutaneous injection, and an oral option may be preferable for some patients who wish to avoid injectable treatment.¹

Enlicitide binds to PCSK9 and inhibits its interaction with LDL receptors, preventing PCSK9-mediated degradation of the receptors and increasing hepatic clearance of circulating LDL particles. Unlike currently available PCSK9-targeting therapies, which are administered by subcutaneous injection, enlicitide is taken orally once daily.¹

The approval was based on two phase 3 trials in the CORALreef clinical trial program: CORALreef Lipids (NCT05952856) and CORALreef HeFH (NCT05952869).^1-3

CORALreef Lipids was a multicenter, double-blind, randomized, placebo-controlled trial that enrolled 2,904 adults with hypercholesterolemia, with or without HeFH, who had a history of a major ASCVD event or were at increased risk of a first major ASCVD event. Patients required additional LDL-C lowering despite stable treatment with moderate- or high-intensity statins, unless statin intolerance was documented, with or without other lipid-modifying therapy. Patients taking PCSK9 inhibitors were excluded.

Participants were randomized 2:1 to enlicitide 20 mg orally once daily (n=1,935) or placebo (n=969) for 52 weeks. The primary endpoint was the mean percentage change in LDL-C from baseline to Week 24.

At Week 24, enlicitide reduced LDL-C by 56% compared with placebo (95% confidence interval [CI]: −61 to −51; p<0.001). LDL-C decreased by 57% from baseline in the enlicitide group, compared with a 3% increase in the placebo group. Enlicitide also reduced non-high-density lipoprotein cholesterol by 54% and apolipoprotein B by 50% from baseline, with both reductions statistically significant compared with placebo.¹

CORALreef HeFH enrolled 303 adults with HeFH, diagnosed using clinical criteria or genotyping, who required additional LDL-C lowering despite stable statin therapy with or without other lipid-modifying agents. Patients were randomized 2:1 to enlicitide 20 mg orally once daily (n=202) or placebo (n=101) for 52 weeks.

At Week 24, enlicitide reduced LDL-C by 59% compared with placebo (95% CI: −66 to −53; p<0.001). LDL-C decreased by 58% from baseline in the enlicitide group, compared with a 3% increase in the placebo group. Non-high-density lipoprotein cholesterol and apolipoprotein B were reduced by 52% and 48%, respectively, compared with placebo.¹

In CORALreef Lipids, the frequency of adverse reactions was similar between the enlicitide and placebo groups, and discontinuation rates due to adverse reactions were comparable between the treatment arms.

In CORALreef HeFH, the most common adverse reactions occurring more frequently with enlicitide than placebo were diarrhea, reported in 7% versus 2% of patients, and dizziness, reported in 9% versus 4%. Discontinuation rates due to adverse reactions were again similar between groups, and the overall safety profile was otherwise consistent with that observed in CORALreef Lipids.¹

“In two phase 3 trials, [enlicitide] led to impressive reductions in LDL-C,” said Dr Ann Marie Navar of UT Southwestern Medical Center, Dallas, TX, USA, a lead author of the CORALreef Lipids study, in the press release. “Now, for the first time, patients have an oral PCSK9 inhibitor for LDL lowering.”¹

The effect of enlicitide on cardiovascular morbidity and mortality is being evaluated in the ongoing CORALreef Outcomes trial (NCT06008756), which has completed enrollment of more than 14,500 participants. It is not yet known whether enlicitide reduces cardiovascular morbidity or mortality.

The CORALreef program has enrolled more than 19,000 participants with hypercholesterolemia overall and also includes the CORALreef Extension (NCT06492291), CORALreef Pediatric (NCT07058077) and CORALreef Combination (NCT07216482) trials.

Clinicians managing patients with persistently elevated LDL-C despite statin therapy now have an oral PCSK9 inhibitor option. Full prescribing information should be consulted for complete dosing, administration, safety and monitoring guidance.¹

References

1. Merck & Co., Inc. Merck’s LIPFENDRA® (enlicitide) is the First and Only Once-Daily Oral PCSK9 Inhibitor Approved by the U.S. FDA to Reduce LDL-C in Adults with Hypercholesterolemia [Press release]. July 15, 2026.
2. ClinicalTrials.gov. Study to Evaluate the Effect of Enlicitide Decanoate (MK-0616) on the Reduction of Low-Density Lipoprotein Cholesterol in Participants With Hypercholesterolemia (CORALreef Lipids). ClinicalTrials.gov Identifier: NCT05952856.
3. ClinicalTrials.gov. Study to Evaluate the Effect of Enlicitide Decanoate (MK-0616) on the Reduction of Low-Density Lipoprotein Cholesterol in Participants With Heterozygous Familial Hypercholesterolemia (CORALreef HeFH). ClinicalTrials.gov Identifier: NCT05952869.