Merck’s Oral PCSK9 Inhibitor Enlicitide Decanoate Shows Significant LDL-C Reduction in Phase 3 CORALreef Lipids Trial

11/08/2025 – 02:30 PM

Enlicitide, designed to deliver antibody-like efficacy, has the potential to be the first approved oral PCSK9 inhibitor to lower LDL-C with a safety profile comparable to placebo

Enlicitide may help address unmet needs in ASCVD, a key driver of the ongoing cardiovascular (CV) epidemic

RAHWAY, N.J. – Merck (MRK), known as MSD outside of the United States and Canada, today unveiled findings from its pivotal Phase 3 CORALreef Lipids trial, showcasing the potential of enlicitide decanoate, an investigational, once-daily oral proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor. The study demonstrated a statistically significant and clinically meaningful reduction of 55.8% in low-density lipoprotein cholesterol (LDL-C) levels (primary analysis; 95% CI: -60.9, -50.7; p<0.0001) with enlicitide. A post-hoc reanalysis further reinforced these results, showing a 59.7% reduction (95% CI: -62.3, -57.1; p<0.0001).

The CORALreef Lipids trial focused on adults with or at risk for atherosclerotic cardiovascular disease (ASCVD) already undergoing lipid-lowering therapies or those with documented statin intolerance. Participants receiving once-daily oral enlicitide experienced statistically significant and clinically meaningful LDL-C reductions at week 24 (primary endpoint), with these reductions sustained through one year (week 52). Secondary endpoints also showed significant improvements, including reductions in non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), and lipoprotein(a) (Lp(a)) at week 24. Importantly, the overall safety profile remained comparable to placebo, with high adherence to both the study intervention (97%) and dosing instructions (≥97%) across treatment groups.

“The data underscores the promise of enlicitide as a potential game-changer in lipid management,” said analysts following the data release. “An oral PCSK9 inhibitor with a safety profile mirroring placebo could significantly improve patient compliance and accessibility, addressing a critical unmet need in ASCVD management.” Currently, PCSK9 inhibitors are primarily administered via injection, posing a barrier for some patients.

Merck’s approach with Enlicitide leverages a novel macrocyclic peptide platform aimed at delivering the efficacy and specificity typically associated with PCSK9 antibody treatments, but in a more convenient oral form. The key technical challenge lies in achieving sufficient bioavailability of the peptide after oral administration, which Merck appears to have successfully addressed with the decanoate formulation. This is a significant advancement in medicinal chemistry, potentially opening doors for oral delivery of other peptide-based therapeutics.

At one year, the study demonstrated sustained, statistically significant LDL-C reductions with enlicitide: 47.6% (primary analysis; 95% CI: -52.7, -42.5; p<0.0001), 52.4% (post-hoc reanalysis; 95% CI: -55.1, -49.7; p<0.0001), 53.4% (95% CI: -55.5, -51.2; p<0.0001), 50.3% (95% CI: -52.1, -48.5; p<0.0001) and 28.2% (95% CI: -30.3, -26.0; p<0.0001). Furthermore, 67.5% of patients treated with enlicitide achieved at least a 50% reduction in LDL-C, compared to only 1.2% in the placebo arm at week 24, demonstrating a clear clinical benefit.

The safety data is crucial for market acceptance. The incidence of adverse events (AEs), serious AEs, and deaths showed no significant differences between the enlicitide and placebo groups. Discontinuations due to AEs were low and similar across both groups (3.1% with enlicitide vs. 4.1% with placebo).

Merck’s next steps involve sharing the data from CORALreef Lipids, as well as data from the CORALreef HeFH and CORALreef AddOn trials, with regulatory bodies globally, setting the stage for potential market approval.

The CORALreef clinical trial program is evaluating approximately 19,000 participants who have hypercholesterolemia. Enlicitide is also being evaluated in the large cardiovascular outcomes trial, CORALreef Outcomes, which has completed enrollment with over 14,500 participants.

The market for cholesterol-lowering drugs is substantial, driven by the high prevalence of hypercholesterolemia and ASCVD globally. The introduction of an oral PCSK9 inhibitor could reshape the competitive landscape, potentially capturing significant market share from existing injectable therapies. Investors will be closely watching the outcomes of the CORALreef Outcomes trial, as positive results could solidify enlicitide’s position as a leading treatment option and significantly impact Merck’s long-term revenue projections.