Key Takeaways
- Robust Efficacy Results: Enlicitide achieved statistically significant and clinically meaningful LDL-C reductions in both familial and non-familial hyperlipidemia populations.
- Favorable Safety Profile: Both CORALreef trials met primary and key secondary endpoints with no clinically meaningful differences in adverse events.
- Potential First-in-Class Option: If approved, enlicitide would become the first orally administered PCSK9 inhibitor available in the United States, offering a convenient alternative to injectable therapies.
Results from the Phase III CORALreef HeFH and CORALreef AddOn trials show that enlicitide decanoate, Merck’s investigational oral PCSK9 inhibitor for adults with hyperlipidemia already on lipid-lowering therapies, produced statistically significant and clinically meaningful reductions in low-density lipoprotein cholesterol (LDL-C) levels. According to the company, full results from the CORALreef clinical development program will be presented at a future scientific congress.1
How Did Enlicitide Perform in the CORALreef Trials?
“We are thrilled to bring forward the first Phase III results from our clinical development program evaluating enlicitide, which, if approved, would be the first marketed oral PCSK9 inhibitor in the US,” said Dean Y. Li, president, Merck Research Laboratories, in a press 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. We are working with urgency to make this oral therapy available to patients worldwide.”
Significant LDL-C Reductions in HeFH Population
The randomized, double-blind, placebo-controlled, multicenter CORALreef HeFH trial evaluated the safety and efficacy of enlicitide versus placebo in 303 adults with heterozygous familial hypercholesterolemia (HeFH) who had a history of or were at risk for major atherosclerotic cardiovascular disease (ASCVD) events. All participants were treated with a moderate- or high-intensity statin, with or without additional lipid-lowering therapies.
The trial’s three primary endpoints included the mean percent change from baseline in LDL-C at week 24, the number of participants experiencing one or more adverse events (AEs), and the number of participants who discontinued treatment due to an AE. Key secondary endpoints included mean percent change from baseline in LDL-C at week 52, mean percent change in non-high density lipoprotein cholesterol (HDL-C), and percent change in Lp(a) at week 24. Results showed that enlicitide led to notable and clinically relevant reductions in LDL-C compared to placebo in statin-treated patients.1,2
Enlicitide Outperforms Non-Statin Oral Therapies
The randomized, double-blind, multicenter CORALreef AddOn trial evaluated the efficacy and safety of enlicitide compared to ezetimibe, bempedoic acid, and their combination in 301 adult patients. The primary endpoint was the mean percent change from baseline in LDL-C at eight weeks, with secondary endpoints that included mean percent change in non-HDL-C and ApoB. Results showed that enlicitide delivered statistically significant and clinically meaningful reductions in LDL-C compared to all three treatment arms.1,3
Both trials showed no clinically meaningful differences in AEs or serious AEs.1
Cardiovascular Burden Underscores Treatment Need
According to a study published in the American Journal of Preventive Medicine hyperlipidemia is prevalent in the United States, affecting 32.8% of males and 36.2% of females with total cholesterol ≥200 mg/dL and LDL-C ≥130 mg/dL. However, the number of deaths for which hyperlipidemia is considered the primary cause remains unknown.4
“Atherosclerotic cardiovascular disease accounts for 85 percent of cardiovascular deaths,” said Christie M. Ballantyne, principal investigator of the CORALreef HeFH study, professor of medicine, Baylor College of Medicine, in the press release. “Despite available treatment options, cardiovascular-related deaths remain the leading cause of death worldwide and continue to rise. 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.”
Phase III Program Extends to Larger Populations
The CORALreef development program is ongoing and aims to enroll approximately 17,000 patients. It also includes the additional studies CORALreef Lipids and CORALreef Outcomes.1
References
1. Merck Announces Positive Topline Results From the First Two Phase 3 CORALreef Trials Evaluating Enlicitide Decanoate for the Treatment of Adults With Hyperlipidemia. Merck. June 9, 2025. Accessed June 9, 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 PCSK9 Inhibitor) in Adults With Heterozygous Familial Hypercholesterolemia (MK-0616-017) CORALreef HeFH. Clinicaltrials.gov. Accessed June 9, 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. Accessed June 9, 2025. https://clinicaltrials.gov/study/NCT06450366
4. Hyperlipidemia-Attributed Deaths in the U.S. in 2018–2021. AJPM. Accessed June 9, 2025. https://www.ajpmonline.org/article/S0749-3797(24)00068-0/abstract#:~:text=However%2C%20hyperlipidemia%20is%20common%20in,)%20%E2%89%A5130%20mg/dL.
