Merck , known as MSD outside the United States and Canada, reported the first presentation of results from the pivotal Phase 3 CORALreef HeFH trial evaluating enlicitide decanoate—an investigational, once-daily oral PCSK9 inhibitor—in adults with heterozygous familial hypercholesterolemia (HeFH). The data, presented at the American Heart Association (AHA) Scientific Sessions 2025 and published in the Journal of the American Medical Association, demonstrated a 59.4% reduction in LDL-C at week 24 versus placebo (95% CI: -65.6, -53.2; p<0.001). The magnitude of LDL-C reduction and overall safety profile were consistent with findings from the CORALreef Lipids study.
The trial showed statistically significant and clinically meaningful improvements across primary and secondary endpoints, including LDL-C at one year, and reductions in non-HDL-C, ApoB, and Lp(a) at week 24. All participants were on stable background lipid-lowering therapy, including moderate or high-intensity statins. Treatment adherence was high, with 97% adherence to study drug and 96% adherence to dosing instructions.
“Data from CORALreef HeFH demonstrate the potential for enlicitide to help address critical unmet needs for adults with heterozygous familial hypercholesterolemia are at risk for premature atherosclerotic cardiovascular events yet a significant portion of patients do not achieve guideline-recommended LDL-C level despite available lipid-lowering therapies,” said Dr. Christie M. Ballantyne, lead study author. “As the potentially first approved oral PCSK9 inhibitor, enlicitide was designed to provide efficacy similar to anti-PCSK9 monoclonal antibodies and may be an important new treatment option to help adults with heterozygous familial hypercholesterolemia reach their guideline-recommended LDL-C goal. Lowering elevated LDL-C levels helps reduce the risk of atherosclerotic cardiovascular disease.”
“Results from the CORALreef HeFH study demonstrated statistically significant and sustained reductions in LDL-C, ApoB, non-HDL-C, and Lp(a) over one year in a diverse population of adults with heterozygous familial hypercholesterolemia receiving stable background lipid-lowering therapies,” added Dr. Dean Y. Li, president, Merck Research Laboratories. “We look forward to sharing the totality of the results from the CORALreef program presented at AHA with regulatory authorities and progressing enlicitide’s ongoing clinical development program to bring forward the potential first approved oral PCSK9 inhibitor to help address the growing CV epidemic.”
LDL-C reductions appeared by week 4 and sustained through one year, with a 61.5% reduction at week 52 (95% CI: -69.4, -53.7; p<0.001). At week 24, enlicitide reduced non-HDL-C by 53.0%, ApoB by 49.1%, and Lp(a) by 27.5%, all vs placebo. 67.3% of patients on enlicitide achieved ≥50% LDL-C reduction and LDL-C <55 mg/dL, compared with 1.0% on placebo.
Safety outcomes were comparable to placebo, with similar rates of adverse events, serious AEs, and low discontinuation rates. Merck plans to submit data from CORALreef HeFH, CORALreef Lipids, and CORALreef AddOn to global regulators.
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