Merck has commenced the Phase 3 clinical program, named CORALreef, for MK-0616. MK-0616 is an investigational oral proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor aimed at treating hypercholesterolemia in adults. This marks the first Phase 3 clinical initiative for an oral PCSK9 inhibitor. The program aims to enroll approximately 17,000 participants across three global studies.
The first phase involves enrolling participants in two registrational Phase 3 studies, CORALreef Lipids and CORALreef HeFH, focused on assessing the reduction of low-density lipoprotein (LDL) cholesterol. By the end of 2023, Merck plans to initiate a Phase 3 cardiovascular outcomes study, CORALreef Outcomes.
PCSK9 is an established target for lowering LDL cholesterol, but no oral PCSK9 inhibitors are available for patients. The Phase 3 CORALreef program builds on the strong results from Phase 2b trials presented at ACC 23, demonstrating MK-0616's significant reduction of LDL cholesterol compared to placebo in participants with hypercholesterolemia and varying risks of atherosclerotic cardiovascular disease (ASCVD), including those on high-intensity statin therapy. The safety profile of MK-0616 was generally favorable.
CORALreef Lipids (NCT05952856) is a randomized, double-blind study encompassing a diverse participant group, including those with a history of major ASCVD events and those at intermediate to high risk for a first event. Participants must be on stable lipid-lowering therapies, including at least a moderate or high-intensity statin, or have documented statin intolerance. The study aims to evaluate the effectiveness of MK-0616 compared to the placebo in terms of the mean percent change from baseline in LDL cholesterol at Week 24. Individuals will be administered a daily oral quantity of 20 mg MK-0616 for a duration of 52 weeks, or they will receive a placebo alongside their continuous lipid-lowering therapies. Similarly, the CORALreef HeFH (NCT05952869) trial is centered around adult participants afflicted with heterozygous familial hypercholesterolemia, who are under stable lipid-lowering regimens, encompassing at minimum a moderate or high-intensity statin. The anticipated culmination for both the CORALreef Lipids and CORALreef HeFH studies is set for September 2025.
CORALreef Outcomes (TIMI 77) (NCT06008756) is a randomized, double-blind study involving adult participants with high cardiovascular risk who are on stable lipid-lowering therapies, including at least a moderate or high-intensity statin. The primary objective of the study is to compare the efficacy of MK-0616 to placebo, in addition to background lipid-lowering therapies, in extending the time until the first occurrence of specific events like coronary heart disease death, ischemic stroke, myocardial infarction, acute limb ischemia or major amputation, or urgent arterial revascularization. Merck is collaborating with the TIMI Study Group, a renowned academic research organization specializing in cardiovascular clinical trials, on the CORALreef Outcomes study. The primary completion date is anticipated to be in November 2029.
Regarding PCSK9 and MK-0616, PCSK9's role in cholesterol homeostasis involves regulating LDL receptor levels and facilitating cholesterol uptake into cells. Inhibiting PCSK9 prevents its interaction with LDL receptors, leading to increased availability of LDL receptors on cell surfaces, thereby aiding in removing LDL cholesterol from the bloodstream.
MK-0616, the investigational oral PCSK9 inhibitor, is designed to lower LDL cholesterol using the same biological mechanism as currently approved injectable PCSK9 inhibitors but in the form of a daily pill. MK-0616 is a macrocyclic peptide that binds to PCSK9, inhibiting its interaction with LDL receptors.
Hypercholesterolemia, characterized by elevated LDL cholesterol levels in the blood, affects about 86 million adults in the U.S., with nearly 25 million having very high total cholesterol levels exceeding 240 mg/dL. This condition significantly increases the risk of ASCVD, a leading cause of mortality in the U.S. and worldwide. Despite dietary adjustments and statin therapies, many individuals with hypercholesterolemia struggle to achieve or maintain recommended LDL cholesterol reduction goals. Left untreated, high LDL cholesterol can substantially elevate the risk of ASCVD events like heart attacks and strokes.