Abstract Body (Do not enter title and authors here): Introduction: LDL-C lowering with anti PCSK9 monoclonal antibodies has been shown to prevent ASCVD events and to be well tolerated. Enlicitide decanoate, an oral macrocyclic peptide PCSK9 inhibitor demonstrated reduction of LDL-C by up to 60.9% over 8 weeks in a phase 2 trial. CORALreef Lipids (NCT05952856) is a phase 3, randomized, double-blind placebo-controlled trial that sought to assess the efficacy of enlicitide over 52 weeks in adults with elevated LDL-C and a history of a major ASCVD event or at intermediate to high-risk for a first major ASCVD event.
Hypothesis: The primary hypothesis was that enlicitide is superior to placebo on mean percent change in LDL-C from baseline at Week 24.
Methods: Adults with either 1) a prior major ASCVD event and an LDL-C≥55 mg/dL (1.42 mmol/L) or 2) at intermediate-to-high risk of a first major ASCVD event, and an LDL-C ≥70 mg/dL (1.81 mmol/L) were randomized in a 2:1 ratio to receive either 20 mg enlicitide or matching placebo daily for 52 weeks. Participants were on stable lipid lowering therapy (LLT) for ≥30 days, including at least a moderate or high intensity statin therapy (or had documented evidence of intolerance to statins) with or without other LLTs. After 52 weeks of treatment, participants either enrolled in an optional open-label extension or completed an 8-week safety follow-up (Figure). The primary endpoints were the percent change in LDL-C from baseline to week 24 and evaluation of adverse events (AEs) and discontinuations due to AEs. Multiplicity controlled secondary endpoints included percent change from baseline in LDL-C at week 52, and percent changes in non-HDL-C, ApoB, and Lp(a) at week 24.
Results: A total of 2912 participants were randomized at 167 sites across 14 countries. Mean age was 63 +/- 10.7 years, 39% were female, and 58% had a history of a major ASCVD event. At baseline, the mean ± SD LDL-C was 94 ± 37.4 mg/dL; 97% were on a statin (54% high-intensity), and 26% were on ezetimibe. Final trial results will be presented at the AHA Scientific Sessions 2025.
Conclusions: Pending.