Abstract Body (Do not enter title and authors here): Introduction: Heterozygous familial hypercholesterolemia (HeFH) is a common genetic disorder characterized by elevated low-density lipoprotein cholesterol (LDL-C) levels from birth and premature atherosclerotic cardiovascular disease (ASCVD). Many HeFH patients do not achieve guideline-recommended LDL-C goals with currently available lipid lowering therapies (LLT). Enlicitide decanoate, an oral PCSK9 inhibitor, has been shown to lower LDL-C in a phase 2 clinical trial. CORALreef HeFH (NCT05952869) was a pivotal phase 3, randomized, double-blind, placebo-controlled, multi-center trial to evaluate enlicitide over 52 weeks of treatment in participants with HeFH.
Hypothesis: The primary hypothesis was that enlicitide is superior to placebo on mean percent change in LDL-C from baseline at Week 24 in HeFH participants.
Methods: Participants were ≥ 18 years of age, met clinical criteria for HeFH, were on a stable background of optimized LLT with at least moderate or high intensity statin (with or without additional LLT), and had LDL-C of ≥ 55 mg/dL (1.42 mmol/L) for participants with a history of a major ASCVD event or ≥ 70 mg/dL (1.81 mmol/L) for those without a history of a major ASCVD event. Participants were randomized to receive enlicitide or placebo (2:1 ratio) for 52 weeks followed by an 8-week safety follow-up or enrollment into an optional open-label extension (Figure). The primary efficacy endpoint was mean percent change in LDL-C from baseline at Week 24. Secondary efficacy endpoints included mean percent change in LDL-C at Week 52, mean percent changes in ApoB and non-HDL-C at Week 24, and percent change in Lp(a) at Week 24. Safety and tolerability were evaluated over 52 weeks.
Results: The mean age of participants (N=303) was 52.0 ± 13.5 years, 51% were female, 26% had a history of a major ASCVD event, and all participants were on a statin (18% moderate, 82% high intensity) with 64% also receiving ezetimibe. Enlicitide compared to placebo demonstrated statistically significant and clinically meaningful reductions in LDL-C in this participant population. There were no clinically meaningful differences in incidences of adverse events or serious adverse events. Final results will be presented at the American Heart Association Scientific Sessions in November 2025.
Conclusions: Data from this trial will inform on the efficacy, safety, and tolerability of enlicitide in HeFH adult patients who require further LDL-C lowering to reach guideline-based goals.