Merck’s oral PCSK9 inhibitor enlicitide delivered a 64.6% LDL-C reduction and outperformed oral non-statin therapies in the Phase 3 CORALreef AddOn trial, with strong efficacy and safety.
Written By: Karthik Teja Macharla, PharmD
Reviewed By: Pharmacally Editorial Team
Merck & Co. has reported detailed results from its Phase 3 CORALreef AddOn trial (NCT06450366), demonstrating that its investigational oral PCSK9 inhibitor, enlicitide decanoate, significantly outperforms existing oral non-statin therapies in lowering LDL cholesterol (LDL-C) in high-risk patients.
The late-breaking data, presented at the American College of Cardiology Annual Scientific Session and simultaneously published in the Journal of the American College of Cardiology, mark the third positive Phase 3 study for enlicitide, reinforcing its potential as a first-in-class oral PCSK9 inhibitor.
Enlicitide is a once-daily oral macrocyclic peptide designed to inhibit PCSK9, a key regulator of LDL receptor activity. By blocking PCSK9, the therapy increases the number of LDL receptors available to clear cholesterol from the bloodstream, mimicking the mechanism of injectable PCSK9 inhibitors in a convenient pill form.
In the CORALreef AddOn study, enlicitide delivered a 64.6% reduction in LDL-C from baseline at eight weeks when added to statin therapy. The drug also demonstrated statistically significant superiority over commonly used oral non-statin options. Compared with bempedoic acid, ezetimibe, and their combination, enlicitide achieved additional LDL-C reductions of 56.7%, 36.0%, and 28.1%, respectively (all p<0.001).
Beyond LDL-C, enlicitide showed robust improvements across key lipid markers. Apolipoprotein B (ApoB) levels were reduced by 54.6%, and non-HDL cholesterol decreased by 58.0%, both significantly outperforming comparator therapies. The drug also reduced lipoprotein(a) by 26.2%, while comparator groups showed minimal change or increases.
Enlicitide substantially improved goal attainment. At eight weeks, 78.2% of patients achieved both a ≥50% reduction in LDL-C and levels below 55 mg/dL, compared with just 2.0% to 20.0% across comparator arms.
The safety profile of enlicitide remained consistent with earlier studies, with no serious adverse events, no discontinuations due to drug-related events, and high adherence rates exceeding 96% across treatment groups.
According Alberico Catapano, a lead author of the study, these findings highlight the potential of enlicitide to address a major unmet need in lipid management. Despite available therapies, nearly 70% of patients with atherosclerotic cardiovascular disease fail to reach recommended LDL-C targets, leaving them at continued risk of cardiovascular events.
Dr. Joerg Koglin, senior vice president Merck emphasized that enlicitide is designed to combine “antibody-like efficacy with placebo-like tolerability,” and could become the first approved oral PCSK9 inhibitor if regulatory milestones are met.
In December 2025, the therapy received a Commissioner’s National Priority Voucher from the U.S. Food and Drug Administration, supporting accelerated development.
The CORALreef clinical program, which includes more than 19,000 participants across multiple trials including Phase 3 studies in broader hypercholesterolemia and heterozygous familial hypercholesterolemia populations is ongoing. A large cardiovascular outcomes study involving over 14,500 patients has completed enrolment and will further define the long-term clinical benefit of enlicitide.
References
Merck’s Enlicitide Decanoate, an Investigational Oral PCSK9 Inhibitor, Demonstrated Significantly Greater LDL-C Reductions at Eight Weeks Compared to Guideline-Recommended Oral Non-Statin Therapies When Added to Background Statins, 30 March 2026, https://www.merck.com/news/mercks-enlicitide-decanoate-an-investigational-oral-pcsk9-inhibitor-demonstrated-significantly-greater-ldl-c-reductions-at-eight-weeks-compared-to-guideline-recommended-oral-non-statin-ther/
A Study to Evaluate the Efficacy and Safety of Enlicitide (MK-0616, Oral PCSK9 Inhibitor) Compared with Ezetimibe or Bempedoic Acid or Ezetimibe and Bempedoic Acid in Adults with Hypercholesterolemia (MK-0616-018/CORALreef AddOn), ClinicalTrials.gov ID NCT06450366, https://clinicaltrials.gov/study/NCT06450366
About the Writer
Karthik Teja Macharla, PharmD is a Pharm.D. graduate with a strong interest in clinical research, pharmacovigilance, and medical writing. In his words, he is passionate about converting complex medical information into clear, evidence-based scientific communication, committed to contributing to patient safety and advancing healthcare through accurate and impactful medical content.