Phase 3 results of oral PCSK9 inhibitor enlicitide in HeFH

In the CORALreef HeFH trial, the oral PCSK9 inhibitor enlicitide significantly reduced LDL-c compared with placebo in adults with HeFH receiving background lipid-lowering therapy. Other atherogenic lipoproteins such as non-HDL-c, apoB and Lp(a) were also reduced.

This summary is based on the publication of Ballantyne CM, Gellis, L, Tardif J, et al. - Efficacy and Safety of Oral PCSK9 Inhibitor Enlicitide in Adults With Heterozygous Familial Hypercholesterolemia A Randomized Clinical Trial. JAMA. 2026 Jan 13;335(2):129-139. doi: 10.1001/jama.2025.20620.

Introduction and methods

Background

Heterozygous familial hypercholesterolemia (HeFH) is a common genetic disorder associated with lifelong elevation of LDL-c and a high risk of premature ASCVD [1,2]. Many patients with HeFH do not achieve guideline-recommended LDL-c targets despite maximally tolerated statins and ezetimibe. Injectable PCSK9-targeted therapies efficiently reduce LDL-c in patients with HeFH but remain underused [3-7]. Enlicitide decanoate is an oral small molecule macrocyclic peptide PCSK9 inhibitor designed to address this treatment gap. The CORALreef HeFH trial evaluated the efficacy and safety of enlicitide in adults with HeFH requiring additional LDL-c lowering despite background statin therapy.

Aim of the study

The aim of the study was to evaluate the efficacy and safety of enlicitide versus placebo in adults with HeFH on background statin therapy.

Methods

CORALreef HeFH was a phase 3, randomized, double-blind, placebo-controlled trial conducted at 59 sites in 17 countries. A total of 303 adults with HeFH on stable lipid-lowering therapy (moderate- or high-intensity statin) and with LDL-c ≥55 mg/dL (with ASCVD) or ≥70 mg/dL (without ASCVD) were randomized 2:1 to enlicitide 20 mg once daily or placebo for 52 weeks.

Outcomes

The primary outcome was the mean percentage change in LDL-c at week 24. Secondary outcomes included the mean percentage change in LDL-c at week 52, the mean percentage change in non-HDL-c and apoB at week 24, and the median percentage change in Lp(a) at week 24. Secondary outcomes were controlled for multiplicity.

Main results

• At 24 weeks, the mean percentage change in LDL-c was −58.2% in the enlicitide group compared with 2.6% in the placebo group (between-group difference: −59.4%; 95%CI: −65.6 to −53.2; P<0.001).
• In the enlicitide group, reductions in LDL-c occurred at week 4 and were sustained through 52 weeks (between-group difference at 52 weeks: −61.5%; 95%CI: −69.4 to −53.7; P<0.001).
• At 24 weeks, non-HDL-c, apoB, and Lp(a) levels were also reduced in the enlicitide group compared with the placebo group (−52.3% vs. 2.1% for non-HDL-c; −48.2% vs. 1.8% for apoB; and Lp(a): −24.7% vs. −1.6%; all P<0.001).
• The rates of adverse events, serious adverse events, and treatment discontinuation due to adverse events were comparable between the two groups.

Conclusion

In adults with HeFH receiving background lipid-lowering therapy, treatment with oral enlicitide resulted in significant reductions in LDL-c and other atherogenic lipoproteins compared with placebo.

Find this article online at JAMA

References

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