Highlights 

  • Enlicitide decanoate lowered LDL-C by 59.4% at 24 weeks in adults with HeFH. 
  • Statistically significant decreases observed in ApoB, non-HDL-C, and Lp(a) at week 24. 
  • Safety profile similar to placebo; adherence to dosing and study intervention exceeded 95%. 

Merck (NYSE:MRK), known as MSD outside the U.S. and Canada, released results from the pivotal Phase 3 CORALreef HeFH trial at the American Heart Association Scientific Sessions 2025. The study assessed enlicitide decanoate, an investigational once-daily oral proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, in adults with heterozygous familial hypercholesterolemia receiving stable background lipid-lowering therapy, including moderate- or high-intensity statins. 

Treatment with enlicitide decanoate led to a statistically significant reduction in low-density lipoprotein cholesterol (LDL-C) of 59.4% at week 24 compared with placebo (95% CI: -65.6, -53.2; p<0.001). Secondary endpoints including non-HDL-C, apolipoprotein B (ApoB), and lipoprotein(a) (Lp(a)) also showed significant reductions. Adherence to the study intervention was 97%, with 96% adherence to dosing instructions. 

Sustained Efficacy and Safety Over One Year 

LDL-C reductions were observed from week 4 and sustained through one year, with a 61.5% reduction versus placebo at week 52 (95% CI: -69.4, -53.7; p<0.001). On week 24, enlicitide lowered non-HDL-C by 53.0%, ApoB by 49.1%, and Lp(a) by 27.5% versus placebo. Furthermore, 67.3% of patients achieved at least a 50% reduction in LDL-C and LDL-C <55 mg/dL (1.42 mmol/L), compared with 1.0% in the placebo group. The safety profile was comparable to placebo, with low and similar rates of adverse events and discontinuations. 

Management Commentary 

Dr. Christie M. Ballantyne, lead author of the CORALreef HeFH study and Professor of Medicine at Baylor College of Medicine, commented: 
“Data from CORALreef HeFH demonstrate the potential for enlicitide to help address critical unmet needs for adults with heterozygous familial hypercholesterolemia at risk for premature atherosclerotic cardiovascular events. Enlicitide was designed to provide efficacy comparable to anti-PCSK9 monoclonal antibodies and may assist adults with HeFH in reaching guideline-recommended LDL-C targets. Reducing elevated LDL-C levels helps lower the risk of atherosclerotic cardiovascular disease.” 

Dr. Dean Y. Li, president of Merck Research Laboratories, added: 
“Results from the CORALreef HeFH study showed statistically significant and sustained reductions in LDL-C, ApoB, non-HDL-C, and Lp(a) over one year across a diverse adult population. We look forward to sharing these findings with regulatory authorities and continuing enlicitide’s clinical development program.” 

About CORALreef HeFH and Enlicitide 

CORALreef HeFH (NCT05952869) is a Phase 3, randomized, double-blind, placebo-controlled study evaluating enlicitide in adults with HeFH at risk of major ASCVD events. Enlicitide is a small molecule macrocyclic peptide designed to inhibit PCSK9 interaction with LDL receptors, potentially providing oral PCSK9 inhibition with antibody-like efficacy.