Investigational Oral PCSK-9 Inhibitor Reduces LDL-C by 60% in Late Stage HeFH Trial

The investigational oral PCSK9 inhibitor enlicitide decanoate reduced LDL-C by 59.4% compared to placebo at 24 weeks in adults with heterozygous familial hypercholesterolemia (HeFH) receiving stable background lipid-lowering therapy, including at least moderate or high intensity statins, according to results from the phase 3 CORALreef HeFH trial.¹ The findings were presented November 9 at the American Heart Association (AHA) Scientific Sessions 2025 and published simultaneously in the Journal of the American Medical Association.²

The reduction (95% CI, -65.6 to -53.2; P <.001) represents the primary endpoint in a study of 303 participants who were randomly assigned to receive either 20 mg of enlicitide orally once daily or placebo. At one year, treatment with enlicitide resulted in a sustained reduction in LDL-C of 61.5% compared to placebo (95% CI, -69.4 to -53.7, P <.001), according to the study. Both effect size and the enlicitide safety profile were comparable to those observed in the pivotal phase 3 CORALreef Lipids study, also presented during the AHA meeting, during a late-breaking sicence news briefing.¹

Strong Secondary Endpoints

Enlicitide also demonstrated significant reductions in secondary endpoints vs placebo at 24 weeks, including¹:

• Non-HDL-C of 53.0% (95% CI, -58.5 to -47.4, P <.001)
• Apolipoprotein B of 49.1% (95% CI, -54.0 to -44.3, P <.001)
• Lipoprotein(a) of 27.5% (95% CI, -34.3 to -20.6, P <.001)

Among CORALreef HeFH participants treated wtih enclicitide, 67.3% achieved at least a 50% reduction in LDL-C as well as LDL-C of less than 55 mg/dL (1.42 mmol/L) compared to 1.0% in the placebo arm at 24 weeks.¹

"Data from CORALreef HeFH demonstrate the potential for enlicitide to help address critical unmet needs for adults with heterozygous familial hypercholesterolemia who are at risk for premature atherosclerotic cardiovascular events," Christie M. Ballantyne, a lead author of the CORALreef HeFH study and professor of medicine at Baylor College of Medicine, said in a statement.² A "significant portion of patients do not achieve guideline-recommended LDL-C level despite available lipid-lowering therapies," he continued. "As the potentially first approved oral PCSK9 inhibitor, enlicitide was designed to provide efficacy similar to anti-PCSK9 monoclonal antibodies," Ballantyne added and would add an important treatment option for adults with HeFH and their clinicians.²

The enlicitide safety profile was similar to the profile observed for treatment with placebo. The incidence of adverse events and serious adverse events were similar between groups, according to study findings. Discontinuations due to adverse events were low and also similar between enlicitide (2.0%) and placebo (3.0%). Ballentyne and colleagues reported high adherence with the study intervention (97%) and dosing instructions (96%) across treatment groups.¹

A Small Molecule Macrocyclic Peptide

Enlicitide is a novel small molecule macrocyclic peptide candidate that lowers LDL-C through a similar mechanism as monoclonal antibodies against PCSK9.³ The peptiede binds to PCSK9 and inhibits the interaction of the protein with LDL receptors, protecting them from degradation and increasing their concentration on the the hepatocyte surface, which optimizes removal of LDL-C from the blood.¹

Significant Treatment Gap

HeFH affects approximately 1 in 250 individuals and is characterized by elevated levels of LDL-C cholesterol from birth. Individuals with the genetic mutation are at increased risk of premature atherosclerotic cardiovascular disease (ASCVD) as a result of cumulative lifetime exposure to LDL-C, study authors wrote. Despite the prevalence of HeFH and the excellent efficacy and safety profiles of the injectable PCSK9 inhibitors, the medications are markedly underused.⁴ This leaves those who are not at recognized LDL-C goals at a 13-fold higher risk for coronary artery disease compared with the general population, according to currently published data.⁵

Enlicitide safety and efficacy is being evaluated through the CORALreef Clinical Trial program, which has enrolled more than 19,000 participants who have hypercholesterolemia. Cardiovascular outcomes are being studied in CORALreef Outcomes (NCT06008756), with enrollment of approximately 14,500 participants completed, Merck stated. The company plans to present data from both the CORALreef HeFH, CORALreef Lipids, and CORALreef AddOn trials, with regulatory authorities worldwide.¹

"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," Dean Y. Li, MD, PhD, president, Merck Research Laboratories, said in the Merck statement. "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."

References

1. Ballantyne CM, Gellis L, Tardif J-C, et al. Efficacy and safety of oral PCSK9 inhibitor enlicitide in adults with heterozygous familial hypercholesterolemia: a randomized clinical trial. JAMA. Published online November 9, 2025. doi: 10.1001/jama.2025.20620
2. Merck's enlicitide decanoate, an investigational oral PCSK9 inhibitor, significantly reduced LDL-C in adults with heterozygous familial hypercholesterolemia (HeFH) in phase 3 CORALreef HeFH trial. News release. Merck. November 9, 2025. Accessed November 10, 2025. https://www.merck.com/news/mercks-enlicitide-decanoate-an-investigational-oral-pcsk9-inhibitor-significantly-reduced-ldl-c-in-adults-with-heterozygous-familial-hypercholesterolemia-hefh-in-phase-3-coralreef-hefh-tr/
3. Johns DG, Campeau LC, Banka P, et al. Orally bioavailable macrocyclic peptide that inhibits binding of PCSK9 to the low density lipoprotein receptor. Circulation. 2023;148(2):144-158. doi:10.1161/CIRCULATIONAHA.122.063372
4. MacDougall DE, Baum SJ, Ahmed CD, McGowan MP, Wilemon KA. Trends in patient access to and utilization of prescribed PCSK9 inhibitors in a large US claims database from 2015 to 2021. Circ Cardiovasc Qual Outcomes. 2024;17(2):e009988. doi:10.1161/CIRCOUTCOMES.123.009988
5. Nordestgaard BG, Chapman MJ, Humphries SE, et al. European Atherosclerosis Society Consensus Panel. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur Heart J. 2013;34(45):3478-3490. doi:10.1093/eurheartj/eht273