Oral PCSK9 Inhibitor Enlicitide Meets All Endpoints in Phase 3 Hypercholesterolemia Trial

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The investigational oral proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor enlicitide decanoate achieved all primary and key secondary endpoints in the pivotal Phase 3 CORALreef Lipids study of adults with hypercholesterolemia, according to a Merck news release.¹

At week 24, patients receiving once-daily enlicitide demonstrated statistically significant and clinically meaningful reductions in low-density lipoprotein cholesterol (LDL-C) compared with placebo, according to the company. Significant improvements were also observed in non–high-density lipoprotein cholesterol, apolipoprotein B, and lipoprotein(a).¹

Enlicitide showed a favorable safety profile, with rates of adverse events and discontinuations comparable to placebo.¹

“This is the third Phase 3 trial to demonstrate clinically meaningful and statistically significant LDL-C lowering for enlicitide,” said Dean Y. Li, MD, PhD, president, Merck Research Laboratories, in the news release. "The advent of injectable PCSK9 inhibitors has enabled a new approach to controlling LDL-C and reducing the risk of atherogenic cardiovascular events. 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.¹

“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,” Yi added.¹

Ann Marie Navar, MD, PhD, associate professor of medicine in the Division of Cardiology at UT Southwestern Medical Center and a lead investigator, noted that enlicitide could help more patients achieve guideline-recommended lipid targets. “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,” she said in the release.¹

CORALreef Lipids (NCT05952856) was a randomized, double-blind, placebo-controlled trial enrolling adults with hypercholesterolemia and either prior atherosclerotic cardiovascular disease (ASCVD) events or elevated risk for a first event. Participants were required to be on stable lipid-lowering therapy, including at least a moderate- or high-intensity statin, or have documented statin intolerance.¹

The findings add to results from 2 previous Phase 3 trials—CORALreef HeFH and CORALreef AddOn—in which enlicitide demonstrated LDL-C lowering efficacy. Merck is also conducting CORALreef Outcomes, a cardiovascular outcomes trial that has completed enrollment of more than 14 500 participants.¹

According to the latest data from the American Heart Association, hypercholesterolemia affects approximately 86 million adults in the US and is a major driver of ASCVD, which accounts for the majority of cardiovascular deaths.² Despite widespread use of lipid-lowering therapies, nearly 70% of patients with ASCVD do not achieve guideline-recommended LDL-C targets.¹

“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,” Nevar said.¹

References:

1. Merck & Co., Inc. Merck’s investigational oral PCSK9 inhibitor enlicitide decanoate met all primary and key secondary endpoints in adults with hypercholesterolemia in pivotal CORALreef Lipids study. Merck News Releases. Published September 2, 2025. Accessed September 2, 2025. https://www.merck.com/news/mercks-investigational-oral-pcsk9-inhibitor-enlicitide-decanoate-met-all-primary-and-key-secondary-endpoints-in-adults-with-hypercholesterolemia-in-pivotal-coralreef-lipids-study/
2. Tsao CW, Aday AW, Almarzooq ZI, et al. Heart disease and stroke statistics-2023 update: A report from the American Heart Association. Circulation. 2023;147:e93-e621. doi:10.1161/CIR.0000000000001123