Enlicitide Decanoate Demonstrates Meaningful Reductions in LDL-C

Results from the phase 3 CORALreef HeFH (NCT05952869) and CORALreef AddOn (NCT06450366) clinical trials indicate that enlicitide decanoate, an investigational, oral PCSK9 inhibitor, induced statistically significant and clinically meaningful reductions in low-density lipoprotein cholesterol (LDL-C). Further, enlicitide decanoate showed greater reductions compared with both placebo and other oral nonstatin therapies. Across each trial, there were no clinically meaningful differences in the incidence of adverse events (AEs) or serious AEs.^1-3

Hyperlipidemia puts patients at risk for adverse cardiovascular outcomes. | Image Credit: © Chopang.studio - stock.adobe.com

PCSK9 inhibitors are a standard of care cholesterol-lowering medicine, and the positive trial results from the CORALreef clinical development program demonstrate the strong potential of enlicitide to become an additional PCSK9 inhibitor approved for use in patients with hyperlipidemia.⁴

“We are thrilled to bring forward the first phase 3 results from our clinical development program evaluating enlicitide, which, if approved, would be the first marketed oral PCSK9 inhibitor in the US,” Dean Y. Li, MD, PhD, president of Merck Research Laboratories, said in a news release. “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.”¹

The CORALreef HeFH Trial

The randomized, double-blind, placebo-controlled, multicenter phase 3 CORALreef HeFH trial was designed to evaluate the safety and efficacy of enlicitide compared with placebo in patients with heterozygous familial hypercholesterolemia (HeFH) who have a history of or are at risk for atherosclerotic cardiovascular disease (ASCVD) and are being treated with a statin. HeFH is a genetic disorder that increases LDL-C, with levels reaching as high as 190 mg/dL or more.^1,5

Primary end points were mean percent change from baseline in LDL-C at week 24, number of participants with 1 or more AEs, and the number of participants who discontinued the study drug due to an AE. Key secondary end points included changes in LDL-C at week 52 and mean percent change from baseline in non–high-density lipoprotein cholesterol (non–HDL-C). Investigators reported statistically significant reductions in LDL-C for patients with HeFH using enlicitide vs placebo.¹

The CORALreef AddOn Trial

CORALreef AddOn, a phase 3, randomized, double-blind, multicenter trial, compared the efficacy and safety of enlicitide with other standard-of-care statins, including ezetimibe (Zetia; Merck), bempedoic acid, and ezetimibe and bempedoic acid. The participants included those with hypercholesterolemia who had a history of a major ASCVD event or were at risk for a major ASCVD event and were treated with a statin.¹

The primary end point of the trial was mean percent change from baseline in LDL-C at week 8, with secondary end points including mean percent change from baseline in non–HDL-C and apoprotein B. Building on the original CORALreef HeFH trial results, investigators reported clinically meaningful reductions in LDL-C for enlicitide use vs bempedoic acid and vs ezetimibe and bempedoic acid. Results from both trials provided a significant trove of evidence, demonstrating the effectiveness of enlicitide in multiple patient populations.¹

Enlicitide Could Become a Valuable Option for Pharmacists and Providers

Enlicitide could become the first oral PCSK9 inhibitor designed to lower LDL-C in a daily pill form, as opposed to the currently available monoclonal antibody injectable PCSK9s. By regulating levels of the LDL receptor, PCSK9 plays a major role in cholesterol homeostasis. Enlicitide is a novel oral macrocyclic peptide designed to bind to PCSK9 and inhibit the interaction of PCSK9 with LDL receptors, thereby providing a cholesterol-lowering effect.¹

Even with adjustments to a patient’s diet or lifestyle routines, many with hyperlipidemia will still have difficulty reaching recommended lipid levels and require medication to manage their condition. Enlicitide could become a new, valuable option for pharmacists and health care providers to use for patients with hyperlipidemia or associated conditions that cause high cholesterol.¹

“Despite available treatment options, cardiovascular-related deaths remain the leading cause of death worldwide and continue to rise,” Christie M. Ballantyne, MD, principal investigator of the CORALreef HeHF study, said in the news release. Ballayntyne is director of the Center for Cardiometabolic Disease Prevention and a professor of medicine and molecular and human genetics at Baylor College of Medicine in Houston, Texas.

Ballantyne added, “LDL-C is a major modifiable risk driver for atherosclerosis, and prioritization of LDL-C management should be a cornerstone of cardiovascular risk prevention. Early intervention and intensification of lipid treatment would allow more patients to achieve LDL-C goals.”¹

REFERENCES

1. Merck announces positive topline results from the last two phase 3 CORALreef trials evaluating enlicitide decanoate for the treatment of adults with hyperlipidemia. Merck. News release. June 9, 2025. Accessed June 12, 2025. https://www.merck.com/news/merck-announces-positive-topline-results-from-the-first-two-phase-3-coralreef-trials-evaluating-enlicitide-decanoate-for-the-treatment-of-adults-with-hyperlipidemia/

2. A study of enlicitide decanoate (MK-0616 oral PCSK inhibitor) in adults with heterozygous familial hypercholesterolemia (MK-0616-017) CORALreef HeFH. National Library of Medicine. ClinicalTrials.gov. Updated May 13, 2025. Accessed June 12, 2025. https://clinicaltrials.gov/study/NCT05952869

3. A study to evaluate the efficacy and safety of enlicitide decanoate (MK-0616, oral PCSK9 inhibitor) compared with ezetimibe or bempedoic acid or ezetimibe and bempedoic acid in adults with hypercholesterolemia (MK-0616-018) CORALreef AddOn. . ClinicalTrials.gov. Updated May 23, 2025. Accessed June 12, 2025. https://clinicaltrials.gov/study/NCT06450366

4. Cleveland Clinic. PCSK9 inhibitors. Updated February 17, 2022. Accessed June 12, 2025. https://my.clevelandclinic.org/health/drugs/22550-pcsk9-inhibitors

5. American Heart Association. What is familial hypercholesterolemia? Updated February 19, 2024. Accessed June 12, 2025. https://www.heart.org/en/health-topics/cholesterol/genetic-conditions/familial-hypercholesterolemia-fh#:~:text=Heterozygous%20FH%20(HeFH).,early%20as%2030%20years%20old