CORALreef Lipids: Enlicitide Achieves All Endpoints in Hypercholesterolemia Trial

Enlicitide decanoate, an oral PCSK9 inhibitor for the treatment of hypercholesterolemia in adults with increased risk for atherosclerotic cardiovascular disease in development by Merck, met all primary and key secondary endpoints in the pivotal CORALreef Lipids study.1

Announced by Merck on September 2, 2025, treatment with enlicitide during the trial resulted in statistically significant and clinically meaningful reduction in low-density lipoprotein cholesterol (LDL-C) compared to placebo after 24 weeks. Enlicitide also saw reductions in non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), and lipoprotein(a) [LP(a)] versus placebo. There were no clinically meaningful differences in proportions of patients with adverse events, including serious adverse events, between treatment groups.1

“These data add to the growing body of evidence supporting the safety and efficacy profile of enlicitide to lower LDL cholesterol and other key atherogenic lipids including ApoB and Lp(a),” said Ann Marie Navar, associate professor of medicine in the division of cardiology at UT Southwestern Medical Center and a lead investigator in the CORALreef Lipids study. “Enlicitide has the potential to help more patients achieve guideline-recommended lipid goals and ultimately reduce atherosclerotic cardiovascular risk, which is currently being evaluated in an ongoing cardiovascular outcomes trial.”1

Enlicitide is potentially the first oral PCSK9 inhibitor designed to lower LDL-C cholesterol via the same biological mechanism as currently approved monoclonal antibody injectable PCSK9 inhibitors, but in a daily pill form. Enlicitide is a small molecule macrocyclic peptide that binds to PCSK9 and inhibits its interaction with LDL receptors.1

CORALreef Lipids was a phase 3 randomized, placebo-controlled, double-blind study, including patients who had been treated with stable lipid lowering therapies, including at least a statin, or who had documented statin intolerance. The study’s primary goal was to assess whether enlicitide decanoate was superior to placebo in reducing LDL-C, as measured by mean percent change from baseline at week 24. Key secondary endpoints included change from baseline in LDL-C at week 52 and change from baseline in other key atherogenic lipids at week 24, such as non-HDL-C, ApoB, and Lp(a).1

The trial included a total of 2760 participants, who were randomly assigned in a 1:1 ratio to either enlicitide decanoate 20mg or placebo, both daily for up to 52 weeks. Investigators collected blood samples at baseline and week 24 to assess the percentage of participants with LDL-C <55 mg/dL and ≥50% reduction from baseline, as well as mean percent change in LDL-C, non-HDL-C, and ApoB.2

The safety and efficacy of enlicitide is being actively investigated via the CORALreef Clinical Trial program, the larger set of phase 3 clinical trials of which CORALreef Lipids is a part.1

“This is the third Phase 3 trial to demonstrate clinically meaningful and statistically significant LDL-C lowering for enlicitide,” said Dean Y. Li, president of Merck Research Laboratories. “Enlicitide, designed to deliver antibody-like efficacy, is the first oral macrocyclic peptide PCSK9 inhibitor with clinically meaningful and statistically significant LDL-C lowering in Phase 3 trials. If approved, it has the potential to change the way we think about managing LDL levels, giving patients the possibility of a new option to help them meet their treatment goals.”1

References

1. Merck Sharp & Dohme LLC. Merck’s Investigational Oral PCSK9 Inhibitor Enlicitide Decanoate Met All Primary and Key Secondary Endpoints in Adults with Hypercholesterolemia in Pivotal CORALreef Lipids Study. Businesswire. September 2, 2025. Accessed September 2, 2025. https://www.businesswire.com/news/home/20250902024418/en/Mercks-Investigational-Oral-PCSK9-Inhibitor-Enlicitide-Decanoate-Met-All-Primary-and-Key-Secondary-Endpoints-in-Adults-with-Hypercholesterolemia-in-Pivotal-CORALreef-Lipids-Study

2. Merck Sharp & Dohme LLC. A Study of Enlicitide Decanoate (MK-0616 Oral PCSK9 Inhibitor) in Adults with Hypercholesterolemia (MK-0616-013) CORALreef Lipids. ClinicalTrials.gov identifier: NCT05952856. Updated November 18, 2024. Accessed September 2, 2025. https://clinicaltrials.gov/study/NCT05952856?id=NCT05952856&rank=1