Topline Findings
- Oral PCSK9 Inhibitor Innovation: Enlicitide decanoate is the first oral macrocyclic peptide PCSK9 inhibitor to reach Phase III development, offering a potential new option for managing high cholesterol.
- Broad Lipid-Lowering Impact: The CORALreef Lipids trial showed meaningful reductions in LDL-C, non-HDL cholesterol, apolipoprotein B, and lipoprotein(a), supporting enlicitide’s efficacy in patients on statins or with statin intolerance.
- Favorable Safety Profile: Enlicitide demonstrated comparable adverse events to placebo and low discontinuation rates, reinforcing its potential as a well-tolerated cholesterol-lowering therapy.
Results from the Phase III CORALreef Lipids trial (CT05952856) showed that Merck’s enlicitide decanoate demonstrated statistically significant and clinically meaningful reductions in LDL cholesterol (LDL-C), particularly in patients with hypercholesterolemia on moderate- or high-intensity statins or with documented statin intolerance.
According to the company, enlicitide decanoate represents the first oral macrocyclic peptide PCSK9 inhibitor to advance through Phase III development, offering a potential new therapeutic option for managing elevated cholesterol levels. Merck plans to share the full study findings with regulatory authorities worldwide and present the data at upcoming scientific congresses.1
How does Enlicitide Compare to Existing Cholesterol-Lowering Treatments?
“This is the third Phase III trial to demonstrate clinically meaningful and statistically significant LDL-C lowering for enlicitide,” said Dean Y. Li, president, Merck Research Laboratories, in a press release. "The advent of injectable PCSK9 inhibitors has enabled a new approach to controlling LDL-C and reducing the risk of atherogenic cardiovascular events.
“Enlicitide, designed to deliver antibody-like efficacy, is the first oral macrocyclic peptide PCSK9 inhibitor with clinically meaningful and statistically significant LDL-C lowering in Phase III trials. If approved, it has the potential to change the way we think about managing LDL levels, giving patients the possibility of a new option to help them meet their treatment goals.”
Overview of the CORALreef Lipids Trial
- The randomized, double-blind, placebo-controlled CORALreef Lipids trial evaluated the efficacy, safety, and tolerability of enlicitide decanoate in 2,912 adults with hypercholesterolemia and a history of a major atherosclerotic cardiovascular disease (ASCVD) event or increased risk for a first event.
- Enrollment criteria required participants to be on consistent lipid-lowering treatment that included a statin or have a documented intolerance to statins.
- The primary endpoint of the trial was to assess whether enlicitide decanoate was superior to placebo in reducing LDL-C, as measured by mean percent change from baseline at week 24.
- Key secondary endpoints included change from baseline in LDL-C at week 52 and change from baseline in other key atherogenic lipids at week 24.
- The trial met all primary and key secondary endpoints, showing meaningful improvements in key atherogenic lipids, including non-HDL cholesterol, apolipoprotein B, and lipoprotein(a).
- Safety was favorable, with adverse events (AEs) and serious AEs comparable to placebo, with low discontinuation rates.1
Additional Context and Ongoing Studies
The latest results from the CORALreef program provide additional data on the safety and efficacy of enlicitide in adults with hypercholesterolemia. In June, data from the Phase III CORALreef HeFH and CORALreef AddOn trials showed that enlicitide decanoate produced statistically significant and clinically meaningful reductions in LDL-C levels for adults with hyperlipidemia already on lipid-lowering therapies.3
According to the Centers for Disease Control and Prevention (CDC), 10% of adults aged 20 years and older had hypercholesterolemia between 2017 and 2020. Notably, an estimated 25 million adults in the United States had hypercholesterolemia during this period.
The CDC also suggested that 54.5% of people in the United States could benefit from taking medication for cholesterol.4
Expert Perspectives
“These data add to the growing body of evidence supporting the safety and efficacy profile of enlicitide to lower LDL cholesterol and other key atherogenic lipids including ApoB and Lp(a),” CORALreef Lipids lead trial investigator Ann Marie Navar, associate professor of Medicine in the Division of Cardiology at UT Southwestern Medical Center, said in the press release. “Enlicitide has the potential to help more patients achieve guideline-recommended lipid goals and ultimately reduce atherosclerotic cardiovascular risk, which is currently being evaluated in an ongoing cardiovascular outcomes trial.”
References
- Merck’s Investigational Oral PCSK9 Inhibitor Enlicitide Decanoate Met All Primary and Key Secondary Endpoints in Adults with Hypercholesterolemia in Pivotal CORALreef Lipids Study. Merck. September 2, 2025. Accessed September 3, 2025. https://www.merck.com/news/mercks-investigational-oral-pcsk9-inhibitor-enlicitide-decanoate-met-all-primary-and-key-secondary-endpoints-in-adults-with-hypercholesterolemia-in-pivotal-coralreef-lipids-study/
- A Study of Enlicitide Decanoate (MK-0616 Oral PCSK9 Inhibitor) in Adults With Hypercholesterolemia (MK-0616-013) CORALreef Lipids. Clinicaltrials.gov. Accessed September 3, 2025. https://clinicaltrials.gov/study/NCT05952856?intr=MK-0616&rank=5&utm_source=chatgpt.com
- Phase III Trials Show Merck’s Oral PCSK9 Inhibitor Significantly Reduces LDL-Cholesterol in Hyperlipidemia. PharmExec. June 9, 2025. Accessed September 3, 2025. https://www.pharmexec.com/view/phase-iii-trials-show-merck-oral-pcsk9-inhibitor-significantly-reduces-ldl-cholesterol-hyperlipidemia
- High Cholesterol Facts. CDC. Accessed September 3, 2025. https://www.cdc.gov/cholesterol/data-research/facts-stats/index.html#:~:text=High%20total%20cholesterol%20in%20the,3
