Merck has launched the first Phase 3 clinical program for an oral PCSK9 inhibitor, potentially revolutionizing cholesterol treatment by offering patients a once-daily pill alternative to existing injectable therapies. The pharmaceutical giant announced the initiation of its CORALreef program for MK-0616, an investigational oral proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor being evaluated for treating adults with hypercholesterolemia.
The comprehensive Phase 3 program represents a significant milestone in cardiovascular medicine, as no oral PCSK9 inhibitors are currently available to physicians and patients. While companies like Amgen, Regeneron, and Novartis sell injectable PCSK9 inhibitors, MK-0616 would be the first in pill form if approved.
Robust Phase 2 Results Drive Advancement
The decision to advance MK-0616 to Phase 3 testing follows promising results from a Phase 2b study of 381 adults with hypercholesterolemia. Published in the Journal of the American College of Cardiology in April, the results demonstrated that MK-0616 significantly reduced LDL cholesterol by 40-60% after eight weeks of treatment compared to placebo across all doses studied. The drug was generally well-tolerated and showed efficacy in participants with a broad spectrum of atherosclerotic cardiovascular disease (ASCVD) risk, including those on high-intensity statin therapy.
"MK-0616 showed statistically significant LDL cholesterol lowering activity in the Phase 2 trial and has the unique aspect of being a once daily pill," said Dr. Marc Sabatine, Chair of the Thrombolysis in Myocardial Infarction (TIMI) Study Group and Professor of Medicine at Harvard Medical School. "With its novel modality among PCSK9 inhibitors, MK-0616 could provide an important option for patients for the treatment of hypercholesterolemia."
Three-Study CORALreef Program
The Phase 3 CORALreef program encompasses three studies designed to enroll approximately 17,000 participants globally. The first two registrational studies, CORALreef Lipids and CORALreef HeFH, are now enrolling participants and focus on LDL cholesterol reduction.
CORALreef Lipids is a randomized, double-blind study enrolling a broad group of participants, including those with a history of at least one major ASCVD event and those at intermediate to high risk for a first event. Participants must be on stable lipid-lowering therapies, including at least moderate or high-intensity statin therapy, or have documented statin intolerance. The study will evaluate the efficacy of 20 mg MK-0616 taken orally once daily for up to 52 weeks compared to placebo, with the primary endpoint being mean percent change from baseline in LDL cholesterol at Week 24.
CORALreef HeFH follows a similar design but focuses specifically on adult participants with heterozygous familial hypercholesterolemia, a genetic condition that causes high cholesterol. Both studies are expected to complete by September 2025.
Cardiovascular Outcomes Study
The third study, CORALreef Outcomes (TIMI 77), will begin by the end of 2023 and represents a crucial cardiovascular outcomes trial. This randomized, double-blind study will evaluate whether MK-0616 increases the time to first occurrence of major cardiovascular events, including 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 leading academic research organization for cardiovascular clinical trials, on this outcomes study. The estimated primary completion date is November 2029.
Addressing Unmet Medical Need
The development of MK-0616 addresses a significant unmet medical need in cardiovascular care. Hypercholesterolemia affects approximately 86 million adults in the United States, with nearly 25 million having very high total cholesterol above 240 mg/dL. Despite available lipid-lowering therapies, many patients with hypercholesterolemia do not reach or maintain their LDL cholesterol treatment goals as recommended by guidelines.
"Elevated LDL cholesterol is a major risk factor for cardiovascular disease, the leading cause of death worldwide," said Dr. Sabatine. "Despite several well-established lipid-lowering therapies, millions of people globally do not achieve and maintain their desired LDL cholesterol treatment goals, leaving them at risk for cardiac events."
Novel Mechanism of Action
MK-0616 is a macrocyclic peptide designed to lower LDL cholesterol via the same biological mechanism as currently approved injectable PCSK9 inhibitors but in a daily pill form. The drug binds to PCSK9 and inhibits its interaction with LDL receptors, resulting in greater numbers of LDL receptors available on the cell surface to remove LDL cholesterol from the blood.
PCSK9 plays a key role in cholesterol homeostasis by regulating levels of the LDL receptor, which is responsible for the uptake of cholesterol into cells. Inhibition of PCSK9 prevents this interaction, making it a validated target for lowering LDL cholesterol.
Commitment to Diverse Participation
Dr. Joerg Koglin, senior vice president of global clinical development at Merck Research Laboratories, emphasized the company's commitment to inclusive clinical trial participation. "In acknowledgment of the significant racial, ethnic and gender disparities in cardiovascular care, Merck is taking proactive measures to engage potential participants from populations that have historically been underrepresented in clinical trials of this type," he said.
The initiation of this comprehensive Phase 3 program represents an important milestone in Merck's goal to offer a highly effective oral medication that could be accessed by a broad population and potentially allow substantially more people to reach their LDL treatment goals.
