Merck recently announced detailed results from its CORALreef AddOn study, a Phase 3 trial evaluating enlicitide decanoate, an investigational oral PCSK9 inhibitor. The study compared enlicitide to other oral non-statin therapies like bempedoic acid, ezetimibe, or a combination of both, when added to statin treatments in adults with hypercholesterolemia who are at risk for atherosclerotic cardiovascular disease (ASCVD). This marks the third positive Phase 3 study for enlicitide decanoate.
Results showed that enlicitide achieved statistically significant and clinically meaningful reductions in low-density lipoprotein cholesterol (LDL-C) after eight weeks (56 days) of treatment. Enlicitide reduced LDL-C by 64.6% from baseline. This was significantly greater than the reductions seen with the comparators: a 56.7% reduction versus bempedoic acid, a 36.0% reduction versus ezetimibe, and a 28.1% reduction versus bempedoic acid with ezetimibe. All pairwise comparisons were statistically significant with a P-value of <0.001. The drug also led to greater achievement of LDL-C goals.
Enlicitide, an oral macrocyclic peptide PCSK9 inhibitor, functions by blocking PCSK9 binding to the LDL receptor, thereby reducing LDL receptor degradation and enhancing LDL-C clearance, similar to injectable monoclonal antibodies. Previous Phase 3 trials showed enlicitide reduced LDL-C by approximately 60% compared to placebo when added to statin therapy and was well-tolerated. It also reduced other atherogenic particles like apolipoprotein B (ApoB) and non-high-density lipoprotein cholesterol (nonHDL-C).
The development of an effective oral PCSK9 inhibitor addresses a significant unmet need in lipid management, as current injectable PCSK9 monoclonal antibodies, despite their efficacy in lowering LDL-C by about 60% beyond statins and reducing major adverse cardiovascular events, face limitations due to injection requirements, cost, and access barriers. The U.S. Food and Drug Administration (FDA) selected enlicitide for the Commissioner’s National Priority Voucher (CNPV) in December 2025, signaling the potential for it to be the first approved oral PCSK9 inhibitor, offering an easier-to-use option for millions.
