Merck & Co., known as MSD outside the United States and Canada, has reported positive Phase III results for its investigational oral PCSK9 inhibitor, enlicitide decanoate.
The once-daily therapy, designed to lower cholesterol in adults with hypercholesterolemia, successfully met all primary and key secondary endpoints in the pivotal CORALreef Lipids trial (NCT05952856).
“This is the third Phase III trial to demonstrate clinically meaningful LDL-C lowering for enlicitide,” said Dr. Dean Y. Li, president of Merck Research Laboratories. He highlighted that while injectable PCSK9 inhibitors have already transformed cholesterol management, enlicitide’s oral formulation could be a game-changer. “If approved, it has the potential to change the way we think about managing LDL levels, giving patients a new option to meet their treatment goals.”
Phase III Trial Results
The CORALreef Lipids study demonstrated that enlicitide produced statistically significant and clinically meaningful reductions in low-density lipoprotein cholesterol (LDL-C) compared to placebo at 24 weeks. Additional benefits were seen across secondary measures, including reductions in non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), and lipoprotein(a) [Lp(a)].
Importantly, the therapy was well tolerated. The rate of discontinuation due to adverse events was low and comparable to placebo, with no clinically meaningful differences observed in serious adverse events between treatment groups.
The CORALreef Lipids study is the largest completed Phase III trial to date of enlicitide. It enrolled adults with elevated LDL-C and a history of, or increased risk for, major atherosclerotic cardiovascular disease (ASCVD) events despite being on moderate or high-intensity statins or having documented statin intolerance.
The trial’s primary endpoint was the mean percent change in LDL-C from baseline at 24 weeks. Secondary measures included LDL-C change at 52 weeks, as well as changes in other atherogenic lipids at 24 weeks. Results exceeded expectations across all measures, as per Merck.
Dr. Ann Marie Navar, a lead investigator from UT Southwestern Medical Center, emphasized that enlicitide may help more patients achieve guideline-recommended lipid goals and reduce cardiovascular risk. She noted that outcomes are being further evaluated in the large-scale CORALreef Outcomes trial, which has enrolled over 14,500 participants.
How Enlicitide Works
Enlicitide is a novel small molecule macrocyclic peptide designed to block PCSK9, a protein that plays a key role in cholesterol regulation. By preventing PCSK9 from binding to LDL receptors, enlicitide increases the number of receptors available to clear LDL cholesterol from the blood.
This mechanism is the same as that used by injectable PCSK9 inhibitors, such as Amgen’s Repatha (evolocumab) and Sanofi-Regeneron’s Praluent (alirocumab).
Hypercholesterolemia remains a major public health issue, affecting more than 86 million adults in the US alone. Elevated LDL-C is a leading driver of ASCVD, which accounts for 85% of cardiovascular deaths. Despite treatment with statins and other therapies, nearly 70% of patients with ASCVD fail to reach target cholesterol levels.
Cardiovascular disease is the world’s leading cause of death, responsible for an estimated 18 million deaths annually. In the US, one person dies every 36 seconds from cardiovascular-related conditions. With such a large unmet need, new therapies like enlicitide could significantly change patient outcomes.
The company’s ongoing CORALreef clinical program, expected to involve roughly 17,000 patients across multiple trials, underscores its investment in addressing cardiovascular disease.
With enlicitide now demonstrating consistent success across three Phase III trials, CORALreef HeFH (NCT05952869), CORALreef AddOn (NCT06450366), and CORALreef Lipids, Merck is preparing to engage with regulators worldwide. Full results are expected to be presented at an upcoming scientific congress.
