MK-0616 Enlicitide chloride

MK-0616 (Enlicitide) is a novel, first-in-class oral macrocyclic peptide inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9), developed by Merck & Co. for the treatment of hypercholesterolemia .

Unlike currently approved PCSK9 inhibitors, which are administered via subcutaneous injection (monoclonal antibodies or siRNA), MK-0616 is designed as a once-daily oral tablet, offering a more convenient and patient-friendly alternative . Its molecular design, which incorporates a large macrocyclic peptide structure, enables it to resist gastrointestinal degradation and achieve sufficient oral bioavailability, a significant breakthrough for peptide therapeutics .

Mechanism of Action

The drug functions by binding to PCSK9 with high specificity, thereby blocking the interaction between PCSK9 and the low-density lipoprotein receptor (LDLR) on the surface of liver cells . By inhibiting this binding, it prevents the PCSK9-mediated degradation of LDLR. This increases the number of LDLRs available to clear circulating low-density lipoprotein cholesterol (LDL-C) from the bloodstream, resulting in potent lipid-lowering effects .

Clinical Efficacy

The efficacy and safety of MK-0616 have been demonstrated across the Phase 3 CORALreef clinical program. Key findings include:

• Potent LDL-C Reduction: The drug produces dose-dependent and substantial reductions in LDL-C. In clinical trials, a 20mg daily dose has been shown to lower LDL-C by approximately 56% to 62% from baseline, an effect comparable to that of injectable PCSK9 inhibitors .

• Broad Lipid Benefits: In addition to LDL-C, MK-0616 also significantly lowers other atherogenic lipids and lipoproteins, including non-HDL cholesterol, apolipoprotein B (ApoB), and modestly reduces lipoprotein (a) [Lp(a)] .

• Superiority to Other Oral Therapies: In a head-to-head Phase 3 study (CORALreef AddOn), MK-0616 demonstrated superior LDL-C reduction compared to other standard oral therapies like ezetimibe, bempedoic acid, and their combination .

• High Treatment Adherence: The oral, once-daily regimen has been associated with high patient adherence rates, with one study reporting a compliance rate of 98% .

Safety Profile

Data from clinical trials indicate that MK-0616 is generally well-tolerated, with a safety profile similar to placebo. The most commonly reported adverse events have been mild to moderate, such as upper respiratory tract infections and headache. Critically, no significant signals of muscle pain or liver enzyme elevations have been observed, which are common concerns with other lipid-lowering therapies .

Regulatory Status and Development

MK-0616 has completed its pivotal Phase 3 trials. In 2026, Merck filed for marketing authorization in China, and the drug is expected to be filed with the U.S. FDA in the same year. An ongoing Phase 3 outcomes trial (CORALreef Outcomes) is further evaluating its impact on reducing major adverse cardiovascular events (MACE) in high-risk patients