Merck has announced that its investigational oral PCSK9 inhibitor, enlicitide decanoate, has successfully met all primary and key secondary endpoints in the pivotal CORALreef Lipids trial for managing hypercholesterolemia. The results were revealed on September 2, 2025, and demonstrate significant reductions in low-density lipoprotein cholesterol (LDL-C) compared to placebo over a period of 24 weeks.
The trial, which assessed the efficacy of enlicitide in adults at increased risk for atherosclerotic cardiovascular disease, showed not only a statistically significant decrease in LDL-C but also reductions in non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), and lipoprotein(a) [LP(a)]. Importantly, the study indicated no significant differences in the rates of adverse events, including serious ones, across the treatment and placebo groups.
Dr. Ann Marie Navar, an associate professor of medicine at UT Southwestern Medical Center and a lead investigator in the study, emphasized the implications of these findings: “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). Enlicitide has the potential to help more patients achieve guideline-recommended lipid goals and ultimately reduce atherosclerotic cardiovascular risk.”
Enlicitide is uniquely positioned as potentially the first oral PCSK9 inhibitor designed to lower LDL-C through the same biological mechanism as currently available monoclonal antibody injectable PCSK9 inhibitors, but in a convenient daily pill form. The drug is classified as a small molecule macrocyclic peptide that binds to PCSK9, inhibiting its interaction with LDL receptors.
Details of the CORALreef Lipids Study
The CORALreef Lipids study was a phase 3 randomized, placebo-controlled, double-blind trial involving 2,760 participants, all of whom had been on stable lipid-lowering therapies, including at least a statin, or had documented statin intolerance. The primary aim was to establish the superiority of enlicitide decanoate, administered at a dose of 20 mg daily, over placebo in reducing LDL-C, measured by mean percentage change from baseline at week 24.
Key secondary endpoints included the percentage of participants achieving LDL-C levels below 55 mg/dL and those showing a ≥50% reduction from baseline, alongside changes in non-HDL-C, ApoB, and LP(a) at week 24. The participants were randomly assigned in a 1:1 ratio to receive either enlicitide or placebo for a duration of up to 52 weeks. Blood samples were collected at baseline and at week 24 to assess lipid levels.
Future Implications and Ongoing Research
The safety and efficacy of enlicitide continue to be evaluated through the CORALreef Clinical Trial program, which encompasses a broader set of phase 3 clinical trials, of which CORALreef Lipids is a significant part.
Dr. Dean Y. Li, president of Merck Research Laboratories, remarked on the significance of these results: “This is the third Phase 3 trial to demonstrate clinically meaningful and statistically significant LDL-C lowering for enlicitide. 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.”
The findings from this trial represent a crucial step forward in cardiovascular health management, potentially benefiting numerous patients worldwide struggling with elevated cholesterol levels and associated cardiovascular risks.
