Merck announced new Phase 3 results from the CORALreef Lipids trial showing that enlicitide decanoate, an investigational once-daily oral PCSK9 inhibitor, achieved substantial reductions in LDL-C levels in adults with or at risk for atherosclerotic cardiovascular disease. The therapy demonstrated a 55.8% reduction in LDL-C in the primary analysis and a 59.7% reduction in a post-hoc reanalysis at week 24 compared to placebo. These results are being presented at the American Heart Association Scientific Sessions 2025 as part of Late-Breaking Science.
The study enrolled patients on background lipid-lowering therapies, including those with documented statin intolerance. Enlicitide demonstrated statistically significant reductions in LDL-C at week 24 and maintained reductions through week 52. Additional improvements were observed in non-HDL-C, apolipoprotein B, and lipoprotein(a). The treatment profile was comparable to that of the placebo, with low discontinuation rates and high adherence.
At one year, enlicitide maintained LDL-C reductions of 47.6% in the primary analysis and 52.4% in the post-hoc reanalysis. At week 24, reductions included 53.4% in non-HDL-C, 50.3% in ApoB, and 28.2% in Lp(a) compared to placebo. Nearly 68% of patients receiving the therapy achieved at least a 50% reduction in LDL-C and an LDL-C level below 55 mg/dL. Only 1.2% of patients in the placebo group reached that target.
Safety outcomes showed no meaningful differences between enlicitide and placebo in overall adverse events, serious adverse events or deaths. Discontinuations due to adverse events were low in both groups. Merck intends to share the results from this study and additional trials in the CORALreef program with regulatory authorities globally.
Enlicitide is designed as a small molecule macrocyclic peptide that inhibits PCSK9 activity through the same biological mechanism as currently approved injectable PCSK9 inhibitors, but in oral form. If approved, enlicitide may become the first oral PCSK9 inhibitor available. The CORALreef clinical trial program includes more than 19,000 participants across multiple Phase 3 studies, including a significant cardiovascular outcomes trial that has completed enrollment.
Hypercholesterolemia remains a widespread condition affecting approximately 86 million adults in the United States, with many patients not achieving treatment targets even with current therapies. ASCVD continues to drive cardiovascular morbidity and mortality globally. Merck highlighted its long-term commitment to improving cardiovascular outcomes through therapeutic research and development.
KEY QUOTES:
“Enlicitide demonstrated impressive LDL-C reductions with placebo-like safety in the CORALreef Lipids study, underscoring the practice-changing potential of an oral PCSK9 inhibitor. Despite the availability of lipid-lowering therapies such as statins and injectable PCSK9 inhibitors, the majority of patients with atherosclerotic cardiovascular disease do not reach their LDL-C goal. Enlicitide has the potential to help close gaps in achievement of lipid goals in patients with and at risk for cardiovascular events and ultimately help address the ongoing CV epidemic.”
Dr. Ann Marie Navar, Associate Professor of Medicine in the Division of Cardiology at UT Southwestern Medical Center
“Enlicitide was designed to deliver PCSK9 antibody-like efficacy and specificity in an easy-to-use pill. Enlicitide, if approved, adds to physicians’ armamentarium to lower LDL-C. This moment is the result of Merck’s legacy and commitment to researching ways to help improve ASCVD outcomes for millions worldwide and our strength in medicinal chemistry using our novel macrocyclic peptide platform. Cardiovascular disease is the leading cause of death globally, and we look forward to bringing a potential new option to help address the CV epidemic.”
Dr. Dean Y. Li, President, Merck Research Laboratories
