Enlicitide Reduces LDL-C in People With Hyperlipidemia, HeFH, Against Placebo and Non-Statins

Two phase 3 clinical trials of enlicitide decanoate have met their primary end points of significantly reducing low-density lipoprotein cholesterol (LDL-C) in people with hyperlipidemia compared to placebo and other oral non-statin therapies.1

“We are thrilled to bring forward the first Phase 3 results from our clinical development program evaluating enlicitide, which, if approved, would be the first marketed oral PCSK9 inhibitor in the U.S.,” Dean Y. Li, MD, PhD, president, Merck Research Laboratories, said in a statement.1 “Enlicitide is a novel macrocyclic peptide that has the potential to deliver antibody-like efficacy and specificity for the validated PCSK9 mechanism in the form of a daily oral pill. We are working with urgency to make this oral therapy available to patients worldwide.”

Enlicitide decanoate is an investigational, oral proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor being evaluated in people with hyperlipidemia and heterozygous familial hypercholesterolemia (HeFH) on lipid-lowering therapies, including at least a statin. In addition to meeting primary endpoints, Merck shared that there were no clinically meaningful differences in incidences of adverse events (AE) and serious AEs in either trial.

The 2 trials, CORALreef HeFH (NCT05952869) and CORALreef AddOn (NCT06450366) randomized, double-blind, placebo-controlled, multicenter trials, are the first 2 in a program of pivotal trials evaluating enlicitide decanoate in a population of approximately 17,000 patients. Further results from the HeFH and AddOn trials, as well as the CORALreef Lipids and CORALreef Outcomes trials, will be presented at a future scientific conference.2

CORALreefHeFH enrolled adults with HeFH who have a history of or were at risk for a major ASCVD event and are treated with a moderate or high intensity statin with or without other lipid-lowering therapies. The primary endpoints were mean percent change from baseline in LDL-C at week 24, number of participants who experienced at least 1 AE, and number of participants who discontinued study drug due to an AE. Secondary endpoints included mean percent change from baseline in LDL-C at week 52, mean percent change from baseline in non—high-density lipoprotein cholesterol (HDL-C), Apolipoprotein B (ApoB), and percent change in lipportoein [Lp(a)] at week 24.

CORALreef AddOn evaluated the efficacy and safety of enlicitide compared to ezetimibe, to bempedoic acid, and to ezetimibe and bempedoic acid, in patients with hypercholesterolemia who had a history of a major ASCVD event or were at risk for a major ASCVD event and are treated with a statin. The primary endpoint was the mean percent change from baseline in LDL-C at week 8. Secondary endpoints included mean percent change from baseline in non-HDL-C and ApoB.

“Atherosclerotic cardiovascular disease accounts for 85 percent of cardiovascular deaths. Despite available treatment options, cardiovascular-related deaths remain the leading cause of death worldwide and continue to rise,” principal investigator Christie M. Ballantyne, MD, Professor of Medicine at Baylor College of Medicine, added.1 “LDL-C is a major modifiable risk driver for atherosclerosis and prioritization of LDL-C management should be a cornerstone of cardiovascular risk prevention. Early intervention and intensification of lipid treatment would allow more patients to achieve LDL-C goals.”

REFERENCES

1. Merck Announces Positive Topline Results From the First Two Phase 3 CORAL reef Trials Evaluating Enlicitide Decanoate for the Treatment of Adults With Hyperlipidemia. News release. Merck. June 9, 2025. http://businesswire.com/news/home/20250609545552/en/Merck-Announces-Positive-Topline-Results-From-the-First-Two-Phase-3-CORALreef-Trials-Evaluating-Enlicitide-Decanoate-for-the-Treatment-of-Adults-With-Hyperlipidemia

2. Enlicitide Decanoate MK-0616 Oral PCSK9 Inhibitor Phase 3 Clinical Trials Program. Webpage. Merck. 2025. https://www.merck.com/wp-content/uploads/sites/124/2025/06/CORALreef_Clinical_Trial_Explainer.pdf