A phase 3 randomized clinical trial demonstrated that enlicitide—an oral small-molecule macrocyclic peptide inhibitor of PCSK9—produced a mean percentage change in LDL-C at 24 weeks of −58.2% compared with 2.6% with placebo. Enlicitide binds circulating PCSK9 and prevents its interaction with the LDL receptor, a mechanism analogous to that of PCSK9 monoclonal antibodies. A prior placebo-controlled phase 2 trial showed up to 60.9% LDL-C reduction over 8 weeks with similar rates of adverse and serious adverse events between groups.
Trial Design and Population
The CORALreef HeFH trial enrolled 303 adults with genetically or clinically confirmed HeFH across 59 sites in 17 countries. All participants were taking at least moderate- or high-intensity statins, and 64% were on ezetimibe. The mean baseline LDL-C level was 119 mg/dL. Participants were randomized 2:1 to 20 mg of enlicitide or placebo once daily for 52 weeks. The enlicitide formulation contained the sodium caprate, a permeation enhancer; placebo did not. Participants took the study drug fasting and waited 30 minutes before eating. Treatment and fasting adherence exceeded 96%.
Primary and Secondary Efficacy Outcomes
At 24 weeks, the mean absolute LDL-C change was −69.5 mg/dL with enlicitide versus 0.3 mg/dL with placebo. LDL-C reductions were evident by week 4 and sustained through 52 weeks (−55.3% vs 8.7%). Multiplicity-controlled secondary outcomes showed mean percentage reductions at week 24 of −52.3% in non–HDL-C, −48.2% in apolipoprotein B, and a median −24.7% in lipoprotein(a), compared with minimal changes in the placebo group.
LDL-C goal attainment at 24 weeks showed that 70.8% of enlicitide-treated participants achieved 50% or greater LDL-C reduction and less than 70 mg/dL, and 67.3% achieved 50% or greater reduction with LDL-C less than 55 mg/dL (vs 1% for each threshold with placebo).
Safety
The incidence of adverse events was similar between the enlicitide and placebo groups (77.7% vs 76.2%), and most events were mild. Serious adverse events occurred in 4.5% vs 4.0%, respectively, with no investigator-assessed intervention-related events. One participant in the enlicitide group died after ischemic stroke and cardiovascular death; neither was deemed treatment-related.
Laboratory evaluations, including liver, kidney, hematologic, and ECG parameters, showed no clinically meaningful differences between groups. New-onset or worsening diabetes occurred in 2% of enlicitide-treated participants and 3% of those receiving placebo.
Subgroups and Additional Observations
LDL-C reductions were generally consistent across prespecified subgroups defined by sex, race, baseline statin intensity, and history of atherosclerotic cardiovascular disease. Genetic variants associated with HeFH were identified in 58.4% of participants, most commonly LDLR.
Limitations
The trial enrolled only adults with HeFH and was not powered to evaluate cardiovascular outcomes. A separate outcomes trial is ongoing.
Funding and Disclosures
The study was funded by Merck Sharp & Dohme LLC. Full disclosures are available in the published manuscript.
Source: JAMA