Merck (MSD) has announced positive topline results from the first two Phase III trials of enlicitide decanoate, an investigational oral PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor for the treatment of adults with hyperlipidemia.
The CORALreef HeFH (NCT05952869) and CORALreef AddOn (NCT06450366) trials both met their primary and key secondary endpoints, demonstrating statistically significant and clinically meaningful reductions in low-density lipoprotein cholesterol (LDL-C). Importantly, enlicitide’s safety profile appeared favorable, with no meaningful differences in adverse events or serious adverse events compared to control groups.
“These first Phase III results offer compelling evidence of enlicitide’s potential,” said Dr. Dean Y. Li, president of Merck Research Laboratories. “This novel macrocyclic peptide could become the first oral PCSK9 inhibitor, offering the efficacy of antibody-based therapies in a convenient pill form.”
Enlicitide clinical development
The CORALreef clinical program is expected to enroll approximately 17,000 patients. The program includes the ongoing CORALreef Lipids (NCT05952856) and CORALreef Outcomes (NCT06008756) trials, which will provide further data on efficacy, safety, and cardiovascular outcomes.
In the CORALreef HeFH trial, enlicitide was tested in adults with heterozygous familial hypercholesterolemia (HeFH) already on statin therapy. Compared to placebo, the drug significantly reduced LDL-C at both 24 and 52 weeks. Secondary measures such as non-HDL cholesterol, ApoB, and lipoprotein(a) also showed favorable changes.
The CORALreef AddOn trial assessed enlicitide in patients with hyperlipidemia at risk of or with established atherosclerotic cardiovascular disease (ASCVD), already receiving statins. Enlicitide outperformed existing oral non-statin therapies—ezetimibe, bempedoic acid, and their combination—in lowering LDL-C by week 8.
Dr. Christie M. Ballantyne, principal investigator of the CORALreef HeFH trial and a professor at Baylor College of Medicine, emphasized the importance of early and aggressive LDL-C management. “Atherosclerotic cardiovascular disease accounts for 85 percent of cardiovascular deaths globally. LDL-C is a major modifiable risk driver. Prioritizing its control is essential to prevention strategies,” he said.
Results from all three CORALreef trials, including the third study not yet reported, are expected to be presented at an upcoming scientific congress.
Hyperlipidemia treatment landscape
Hyperlipidemia remains a widespread health issue, affecting over 86 million adults in the US alone. While lifestyle changes help some, many patients require medication to control their lipid levels and reduce cardiovascular risk.
Enlicitide works by inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9), a validated target for cholesterol-lowering therapies. PCSK9 plays a role in cholesterol regulation by modulating LDL receptors on liver cells, which are responsible for removing LDL-C from the blood. Blocking this interaction increases the number of receptors available to clear LDL-C, thus reducing cholesterol levels.
Currently available injectable PCSK9 inhibitors include monoclonal antibodies like Amgen’s Repatha (evolocumab) and Sanofi-Regeneron’s Praluent (alirocumab). Novartis’ Leqvio, another competitor in the field, uses siRNA technology to suppress PCSK9 production.
