Oral PCSK9 Inhibitor Enlicitide Decanoate Shows Promise in HeFH Phase 3 Trial

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11/09/2025 – 05:00 PM

Enlicitide has the potential to be the first approved oral PCSK9 inhibitor designed to deliver antibody-like efficacy and help address critical unmet needs for patients with HeFH to help combat the ongoing CV epidemic

Results were presented today at AHA Scientific Sessions 2025 and simultaneously published in the Journal of the American Medical Association

RAHWAY, N.J. – Merck (MRK), known as MSD outside of the United States and Canada, today unveiled promising results from its pivotal Phase 3 CORALreef HeFH trial, showcasing the potential of enlicitide decanoate, an investigational, once-daily oral proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor. The data demonstrates a statistically significant and clinically meaningful reduction in low-density lipoprotein cholesterol (LDL-C) of 59.4% compared to placebo at week 24 (95% CI: -65.6, -53.2; p<0.0001) in adults with heterozygous familial hypercholesterolemia (HeFH). These findings were revealed at the American Heart Association (AHA) Scientific Sessions 2025 and simultaneously published in the Journal of the American Medical Association.

The CORALreef HeFH trial highlights enlicitide’s ability to achieve significant LDL-C reductions at week 24, meeting its primary endpoint. Furthermore, the study showed significant improvements in key secondary endpoints, including LDL-C levels at one year (week 52), as well as reductions in non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), and lipoprotein(a) (Lp(a)) at week 24. These results were observed in adults with HeFH already receiving stable background lipid-lowering therapy, including at least moderate or high-intensity statins. Notably, the safety profile of enlicitide was comparable to placebo, with high adherence to the study intervention (97%) and dosing instructions (96%) across treatment groups.

“The CORALreef HeFH data underscore the potential of enlicitide to address crucial unmet needs in adults with heterozygous familial hypercholesterolemia. These individuals face a heightened risk of premature atherosclerotic cardiovascular events, yet a significant portion fails to achieve guideline-recommended LDL-C levels despite existing lipid-lowering therapies,” stated Dr. Christie M. Ballantyne, a lead author of the CORALreef HeFH study and Professor of Medicine at Baylor College of Medicine. “Enlicitide, as a potentially first-in-class oral PCSK9 inhibitor, is designed to provide efficacy comparable to anti-PCSK9 monoclonal antibodies, offering a potentially significant new treatment option for adults with HeFH to reach their target LDL-C goals. Lowering elevated LDL-C levels is fundamental to reducing the risk of atherosclerotic cardiovascular disease.”

Dr. Dean Y. Li, president of Merck Research Laboratories, emphasized the broader implications of the findings. “The CORALreef HeFH study demonstrated statistically significant and sustained reductions in LDL-C, ApoB, non-HDL-C, and Lp(a) over one year in a diverse patient population with HeFH receiving stable background lipid-lowering therapies,” said Li. “We anticipate sharing the comprehensive results from the CORALreef program presented at AHA with regulatory bodies and advancing enlicitide’s clinical development program, aiming to introduce the potential first approved oral PCSK9 inhibitor to combat the escalating cardiovascular epidemic.”

Beyond the primary endpoint, the study showed that LDL-C reductions with enlicitide were evident as early as week 4 and sustained through the one-year mark. Specifically, treatment with enlicitide resulted in a statistically significant reduction in LDL-C of 61.5% compared to placebo (95% CI: -69.4, -53.7, p<0.0001) at one year. Additional improvements were observed in key lipid parameters, with enlicitide demonstrating significant reductions in ApoB of 53.0% (95% CI: -58.5, -47.4, p<0.0001), non-HDL-C of 49.1% (95% CI: -54.0, -44.3, p<0.0001), and Lp(a) of 27.5% (-95% CI: -34.3, -20.6, p<0.0001). Furthermore, 67.3% of patients treated with enlicitide achieved at least a 50% reduction in LDL-C, compared to only 1.0% in the placebo arm at week 24.

From a safety perspective, enlicitide boasted a profile mirroring placebo. The incidence of adverse events (AEs), serious AEs, and discontinuations due to AEs were similar across treatment groups. Discontinuations attributed to AEs remained low and comparable between enlicitide (2.0%) and placebo (3.0%).

Merck’s next steps involve sharing these findings, alongside data from the CORALreef Lipids and CORALreef AddOn trials, with regulatory agencies worldwide.

The Broader Context: Market Implications and Technological Advancement

The potential approval of enlicitide marks a significant shift in the treatment landscape for hypercholesterolemia. Currently, PCSK9 inhibitors are primarily administered via injection, posing a barrier to patient adherence and market penetration. An oral PCSK9 inhibitor could significantly broaden access to this effective class of drugs.

From a market perspective, analysts predict that an approved oral PCSK9 inhibitor could capture a substantial share of the lipid-lowering market, potentially reaching billions of dollars in annual sales. However, key factors such as pricing, reimbursement strategies, and long-term cardiovascular outcomes data from the ongoing CORALreef Outcomes trial will ultimately determine enlicitide’s commercial success.

Technologically, enlicitide represents a significant advancement in peptide drug delivery. Oral administration of large molecules like peptides is notoriously challenging due to enzymatic degradation and poor absorption in the gastrointestinal tract. Merck’s development of a macrocyclic peptide with enhanced stability and bioavailability is a testament to the company’s expertise in drug design and formulation.

The CORALreef Clinical Trial program encompasses multiple ongoing studies, including the large cardiovascular outcomes trial, CORALreef Outcomes (NCT06008756), which has completed enrollment with over 14,500 participants.

In conclusion, the CORALreef HeFH trial results are an encouraging step forward in the fight against cardiovascular disease. Enlicitide’s potential as an oral PCSK9 inhibitor could revolutionize lipid-lowering therapy, offering a more convenient and accessible option for patients with HeFH and potentially impacting the wider cardiovascular health landscape.

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