Merck’s Enlicitide Decanoate Shows LDL-C Reduction in Phase III

Merck has released new Phase III clinical trial results for enlicitide decanoate, an investigational oral PCSK9 inhibitor, showing significant reductions in low-density lipoprotein cholesterol (LDL-C) in adults with hypercholesterolemia. The data come from CORALreef Lipids, a randomized, double-blind, placebo-controlled Phase III study presented at the 2025 American Heart Association Scientific Sessions.

Merck also presented Phase III data from CORALreef HeFH during the same meeting, reporting a 59.4% LDL-C reduction at Week 24 in adults with heterozygous familial hypercholesterolemia receiving background statin therapy, with a safety profile consistent with CORALreef Lipids.

Merck is developing enlicitide as a once-daily oral therapy designed to block PCSK9 activity, a biological pathway targeted by currently approved injectable PCSK9 inhibitors.

Hypercholesterolemia, characterized by elevated LDL-C, is a major risk factor for atherosclerotic cardiovascular disease (ASCVD). People with ASCVD often use statins and additional lipid-lowering therapies but may still struggle to reach target LDL-C levels. Studies have shown that this may be due to due to high baseline levels, inconsistent treatment response and gaps in therapy optimization.

Injectable PCSK9 inhibitors help address this gap but require regular injections, which can affect long-term adherence.

The CORALreef Lipids trial enrolled more than 2,900 adults with hypercholesterolemia who were already on lipid-lowering treatment or had documented statin intolerance. Participants were randomized 2:1 to receive enlicitide or placebo once daily. The primary endpoint was LDL-C reduction at Week 24, with additional analyses at Week 52 and across other atherogenic lipids.

According to the primary analysis, enlicitide reduced LDL-C by 55.8% at Week 24 compared with placebo. A post-hoc reanalysis, which adjusted for issues related to missing data and biologically implausible baseline values, showed a 59.7% LDL-C reduction.

Simply put, the drug lowered “bad cholesterol” by more than half in most participants. Enlicitide also showed meaningful reductions in non-HDL-C, ApoB and lipoprotein(a).

Importantly, 67.5% of patients on enlicitide reached a predefined goal of at least a 50% LDL-C reduction and an absolute LDL-C level <55 mg/dL at Week 24, compared with 1.2% on placebo.

The safety profile of enlicitide was comparable to placebo. Rates of total adverse events, serious adverse events and deaths were similar between treatment groups.

Enlicitide is a small molecule macrocyclic peptide designed to block PCSK9, preventing the protein from binding LDL receptors. This inhibition allows more LDL receptors to remain active on the surface of liver cells to clear LDL-C from the bloodstream. The mechanism mirrors the biological effect of monoclonal antibody PCSK9 inhibitors, but in a pill form.

The CORALreef clinical program includes multiple Phase III studies. In addition to CORALreef Lipids, enlicitide met its primary endpoints in CORALreef HeFH and CORALreef AddOn. A larger cardiovascular outcomes trial, CORALreef Outcomes, has completed enrollment of more than 14,500 participants and will evaluate whether reductions in LDL-C translate into fewer cardiovascular events. Additional ongoing studies include CORALreef Extension, Pediatric and Combination trials.

Merck plans to share the full CORALreef Lipids dataset with regulatory authorities worldwide, along with results from other Phase III trials.

If approved, enlicitide may become the first oral PCSK9 inhibitor. However, confirmation of its clinical role will depend on regulatory evaluations, longer-term safety findings and results from cardiovascular outcomes trials.

Around the same time Merck broke their news, Amgen shared Phase III data on Repatha (evolocumab), an approved monoclonal antibody in the PCSK9 class. The drug reduced first major adverse cardiovascular events by 25% and first myocardial infarction by 36% versus placebo in the VESALIUS-CV trial among high-risk adults with no prior events.

AstraZeneca also shared Q3 2025 results spotlighting ongoing investment in metabolic and cardiovascular manufacturing, including development of its own oral PCSK9 candidate laroprovstat.

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