Merck announced positive topline results from two pivotal Phase 3 trials evaluating enlicitide decanoate, an investigational oral PCSK9 inhibitor that could become the first approved oral therapy in this class. The CORALreef HeFH and CORALreef AddOn trials successfully met their primary and all key secondary endpoints, demonstrating statistically significant and clinically meaningful reductions in low-density lipoprotein cholesterol (LDL-C) compared to placebo and existing oral therapies.
Trial Results Demonstrate Superior Efficacy
The CORALreef HeFH trial evaluated enlicitide versus placebo in adults with heterozygous familial hypercholesterolemia (HeFH) who have a history of or are at risk for atherosclerotic cardiovascular disease (ASCVD) and are treated with a statin. The study achieved statistically significant and clinically meaningful reductions in LDL-C for enlicitide compared to placebo.
In the CORALreef AddOn trial, enlicitide demonstrated superior efficacy compared to ezetimibe, bempedoic acid, and the combination of ezetimibe and bempedoic acid in adults with hyperlipidemia who have a history of or are at risk for ASCVD and are treated with a statin. Both trials showed no clinically meaningful differences in incidences of adverse events (AE) and serious adverse events (SAE).
Novel Mechanism of Action
Enlicitide is a novel oral macrocyclic peptide that binds to PCSK9 and inhibits the interaction of PCSK9 with LDL receptors. This mechanism prevents PCSK9 from degrading LDL receptors, resulting in greater numbers of LDL receptors available on the cell surface to remove LDL cholesterol from the blood. The drug is designed to deliver the same biological mechanism as currently approved monoclonal antibody injectable PCSK9 inhibitors but in a daily pill form.
"Enlicitide is a novel macrocyclic peptide that has the potential to deliver antibody-like efficacy and specificity for the validated PCSK9 mechanism in the form of a daily oral pill," said Dr. Dean Y. Li, president, Merck Research Laboratories. "We are working with urgency to make this oral therapy available to patients worldwide."
Addressing Cardiovascular Disease Burden
The clinical need for improved cholesterol management remains substantial. According to the study investigators, atherosclerotic cardiovascular disease accounts for 85 percent of cardiovascular deaths, and cardiovascular-related deaths remain the leading cause of death worldwide. Hyperlipidemia affects approximately 86 million adults aged 20 and older in the U.S.
"LDL-C is a major modifiable risk driver for atherosclerosis and prioritization of LDL-C management should be a cornerstone of cardiovascular risk prevention," said Dr. Christie M. Ballantyne, principal investigator of the CORALreef HeFH study and Professor of Medicine at Baylor College of Medicine. "Early intervention and intensification of lipid treatment would allow more patients to achieve LDL-C goals."
Comprehensive Clinical Development Program
The CORALreef Phase 3 clinical development program aims to enroll approximately 17,000 patients across several trials. Beyond the two completed studies, the program includes two large ongoing trials: CORALreef Lipids and CORALreef Outcomes. Results from all three Phase 3 trials will be presented at a future scientific congress.
The CORALreef HeFH trial (NCT05952869) was designed as a randomized, double-blind, placebo-controlled, multicenter study with primary endpoints including mean percent change from baseline in LDL-C at week 24, number of participants with adverse events, and number of participants who discontinued study drug due to an adverse event. Secondary endpoints included mean percent change from baseline in LDL-C at week 52, non-HDL-C, ApoB, and percent change in Lp(a) at week 24.
The CORALreef AddOn trial (NCT06450366) was a randomized, double-blind, multicenter study with a primary endpoint of mean percent change from baseline in LDL-C at week 8. Secondary endpoints included mean percent change from baseline in non-HDL-C and ApoB.
