Merck (MSD) recently announced that its investigational oral PCSK9 inhibitor, Enlicitide Decanoate (MK-0616), has achieved positive results in two pivotal Phase III clinical trials, marking a significant step forward in the treatment of hyperlipidemia. This progress positions Enlicitide Decanoate to potentially become the first oral PCSK9 inhibitor approved by the U.S. FDA, offering a more convenient therapeutic option for the prevention and management of cardiovascular disease.

Hyperlipidemia is a common chronic metabolic disorder characterized by elevated levels of blood lipids, particularly low-density lipoprotein cholesterol (LDL-C). In the United States, more than 86 million adults are affected. For some patients, lifestyle modifications such as diet and exercise are not sufficient to reach optimal lipid levels, making pharmacological intervention necessary to reduce cardiovascular risk.

Enlicitide Decanoate is a once-daily oral macrocyclic peptide molecule, with a number of 2861205-06-1 and the structure shown in Formula I. Its mechanism of action is consistent with that of injectable PCSK9 inhibitors: by blocking the interaction between PCSK9 and the low-density lipoprotein receptor (LDL-R), it enhances receptor recycling and promotes the clearance of LDL-C from the bloodstream. What sets Enlicitide Decanoate apart is its oral formulation, which offers improved patient compliance and ease of use—especially appealing to individuals who are intolerant of or reluctant to use injectable therapies.

Formula I

The two recently announced Phase III trials—CORALreef HeFH and CORALreef AddOn—are both randomized, double-blind, controlled, multicenter clinical studies.

CORALreef HeFH primarily targeted patients with heterozygous familial hypercholesterolemia (HeFH) who also had a history or risk of atherosclerotic cardiovascular disease (ASCVD) and were receiving moderate- or high-intensity statin therapy. The study showed that Enlicitide Decanoate significantly reduced LDL-C levels at Week 24, and maintained favorable efficacy through Week 52. The incidence of adverse events was comparable to that observed in the placebo group.

The other study, CORALreef AddOn, focused on comparing the efficacy of Enlicitide Decanoate with ezetimibe, bempedoic acid, and their combination in adults with hypercholesterolemia already on statin therapy. Results similarly demonstrated that Enlicitide Decanoate achieved statistically and clinically meaningful reductions in LDL-C at Week 8, and also showed notable advantages on secondary endpoints such as non-HDL cholesterol (non-HDL-C) and apolipoprotein B (ApoB).

Together with the ongoing CORALreef Lipids and CORALreef Outcomes studies, these trials form the comprehensive Phase III development program for Enlicitide Decanoate. Merck stated that additional data on the drug’s long-term safety and cardiovascular outcomes will be released in the future.

Currently, the PCSK9 inhibitor market is dominated by injectable therapies, including Amgen’s evolocumab, Sanofi/Regeneron’s alirocumab, and Novartis’s long-acting siRNA therapy inclisiran. In 2024 alone, global sales of these three drugs exceeded $4.2 billion. If approved, Enlicitide Decanoate, with its oral administration advantage, is poised to challenge the current landscape, inject new momentum into hyperlipidemia treatment, and potentially drive further expansion of the global PCSK9 inhibitor market.

According to search results from the Patsnap database, there are currently two groups of published patents related to Enlicitide Decanoate. One group covers the compound, formulations, and uses, with the PCT publication number WO2023023245A1, filed on August 18, 2022. This application has entered the national phase in 16 countries or regions, all of which are currently in the publication or substantive examination stage. Among them, the Chinese counterpart, CN118159281A, was published on June 7, 2024, and is currently under substantive examination. The other group relates to crystalline forms, with the PCT publication number WO2024040125A1, filed on August 16, 2023. This application has entered the national phase in 8 countries or regions, all of which are also in the publication or substantive examination stage. The Chinese counterpart, CN119731194A, is currently at the publication stage, with a publication date of March 28, 2025.