Oral PCSK9 Inhibitor Enlicitide Cuts LDL-C by 64.6% in Phase 3 Trial vs Nonstatin Therapies

An investigational once-daily oral proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, enlicitide decanoate, demonstrated significantly greater reductions in low-density lipoprotein cholesterol (LDL-C) compared with guideline-recommended oral nonstatin therapies when added to statins in adults with hypercholesterolemia, according to Phase 3 data presented at the American College of Cardiology’s Annual Scientific Session (ACC.26).

In the CORALreef AddOn trial (NCT06450366), enlicitide reduced LDL-C by 64.6% from baseline at 8 weeks when added to background statin therapy. Compared with active comparators, LDL-C reductions were significantly greater with enlicitide:

• –56.7% vs bempedoic acid (95% CI, –64.3 to –49.0; P<.001)
• –36.0% vs ezetimibe (95% CI, –41.8 to –30.2; P<.001)
• –28.1% vs combination therapy (95% CI, –33.6 to –22.6; P<.001)

The randomized, double-blind, multicenter study enrolled adults with hypercholesterolemia and either established atherosclerotic cardiovascular disease (ASCVD) or risk for a first major ASCVD event who were already receiving statins.

“Results from CORALreef AddOn demonstrate that enlicitide can significantly reduce LDL-C compared to established oral non-statin treatment options, reinforcing the practice-changing potential of an oral PCSK9 inhibitor,” said Alberico Catapano, a lead author of the study, professor of pharmacology and director of the center for the study of atherosclerosis at IRCCS Multimedica and University of Milan. “LDL-C is a major modifiable risk factor for ASCVD; ASCVD accounts for the majority of cardiovascular deaths and is a key driver of the ongoing CV epidemic. Nearly 70 percent of people with ASCVD who are treated with lipid-lowering therapies do not reach their target LDL cholesterol levels. Enlicitide, an investigational oral PSCK9 inhibitor, may help close gaps in lipid management by enabling robust LDL-C lowering among at-risk patients not at goal on statin therapy.”

Secondary Lipid Outcomes and Goal Attainment

Enlicitide also produced statistically significant improvements in key secondary endpoints at 8 weeks:

• Apolipoprotein B (ApoB): –54.6% vs baseline
• Non–high-density lipoprotein cholesterol: –58.0% vs baseline

Reductions in lipoprotein(a) were also observed (–26.2% vs baseline), whereas comparator therapies showed no change or increases.

Notably, 78.2% of patients receiving enlicitide achieved both ≥50% LDL-C reduction and LDL-C <55 mg/dL, compared with:

• 2.0% with bempedoic acid
• 8.0% with ezetimibe
• 20.0% with combination therapy

Safety and Adherence

The safety profile of enlicitide was consistent with prior Phase 3 trials, with no clinically meaningful differences in adverse events compared with comparator therapies.

There were no serious adverse events, no discontinuations due to drug-related adverse events, and adherence rates were high (98% for treatment; ≥96% for dosing instructions).

Clinical Context for Primary Care

Hypercholesterolemia affects approximately 86 million adults in the United States, and nearly 70% of patients with ASCVD do not achieve LDL-C targets despite existing lipid-lowering therapies.

Enlicitide is designed to inhibit PCSK9 through the same biologic pathway as injectable monoclonal antibodies but in an oral formulation.

Investigators noted that the therapy may address persistent gaps in lipid management, particularly among patients who require additional LDL-C lowering beyond statins and oral nonstatins.

The agent remains investigational, with additional evaluation ongoing in the large cardiovascular outcomes trial CORALreef Outcomes (NCT06008756).

References:

1. Merck. 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. News release. March 30, 2026. Accessed April 6, 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/