Oral PCSK9 Inhibitor Enlicitide Reduces LDL Cholesterol in Phase 3 Trial

Enlicitide decanoate has demonstrated its efficacy in reducing low-density lipoprotein cholesterol (LDL-C) levels compared to placebo in patients with a history of or at risk for a major atherosclerotic cardiovascular disease (ASCVD) event, according to data from the phase 3 CORALreef Lipids trial.

Enlicitide is an oral macrocyclic peptide, designed to inhibit proprotein convertase subtilisin-kexin type 9 (PCSK9) and prevent it from binding to LDL-C receptors. In prior phase 1 and 2 trials, enlicitide demonstrated its efficacy in lowering LDL-C levels over the short term; the CORALreef Lipids trial examined the drug's efficacy over a 52-week period.

CORALreef Lipids was a multinational, double-blind, randomized, placebo-controlled trial conducted across 168 sites in 14 countries worldwide. Patients were eligible for inclusion if they were aged ≥18 years and had a history of a major ASCVD event and an LDL-C level ≥55 mg/dL, or if they were at risk for a first ASCVD event and had an LDL-C ≥70 mg/dL. Major ASCVD events were defined as acute coronary syndrome, coronary revascularization, myocardial infarction, and ischemic stroke, among others.

A total of 2912 patients were enrolled and randomly assigned in a 2:1 ratio to receive either enlicitide 20 mg or matching placebo for 52 weeks. Investigators instructed participants to take enlicitide or placebo in the morning on an empty stomach and to withhold food and beverages other than water for 30 minutes. The team conducted follow-up visits at baseline and at weeks 4, 8, 16, 24, 36, and 52.

The study's primary endpoint was the mean percentage change in LDL-C from baseline to week 24. Key secondary endpoints included the mean change in LDL-C by week 52 and the mean percent change in levels of non-high-density lipoprotein cholesterol (non-HDL-C) and apolipoprotein B.

Ultimately, 1831 participants in the enlicitide arm and 918 in the placebo arm completed the trial. Adherence to the full regimen was high and consistent across both arms, with an overall mean adherence of 97.2%. The mean LDL-C level was 95 +/- 38.8 mg/dL in the enlicitide group and 98.3 +/- 39.2 mg/dL in the placebo group. By week 24, the enlicitide group had reached a mean LDL-C level of 38.7 +/- 35.6 mg/dL, while the placebo group rose to 98.6 +/- 42.5 mg/dL. The mean percent change in the enlicitide group was -57.1% (95% CI, -61.8 to -52.5%) and 3% (95% CI, 0.9 to 5.1%) in the placebo group.

Due to the substantial treatment adherence documented in the study, investigators hope that the comparative simplicity of oral enlicitide will overcome the notorious prescription inertia present in dyslipidemia management.