Upcoming Phase 3 Clinical Program Will Examine Efficacy of Oral PCSK9 Inhibitor MK-0616 in Patients With Hypercholesterolemia


The phase 3 clinical program, CORALreef, consists of 3 trials and is likely the first of its kind for an oral PCSK9 inhibitor, according to the study authors.

Merck recently announced the beginning of a phase 3 clinical program, CORALreef, to evaluate the efficacy of MK-0616, an investigational, oral proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, for the treatment of adults with hypercholesterolemia—a disorder in which there are elevated low-density lipoprotein (LDL) cholesterol levels in the blood.

3D illustration of human heart

Image credit: yodiyim | stock.adobe.com

PCSK9 has a significant role in cholesterol homeostasis due to its ability to regulate levels of the LDL receptor. The receptor is responsible for the uptake of cholesterol into cells, and the inhibition of PCSK9 prevents the interaction of PCSK9 with LDL cholesterol receptors. This results in a higher number of LDL receptors available on the cell surface to remove LDL cholesterol from the blood.

MK-0616 is a macrocyclic peptide that binds to PCSK9 and inhibits the interaction of PCSK9 with LDL receptors. According to the study authors, it is potentially the first oral PCSK9 inhibitor designed to lower LDL cholesterol by undergoing the same biological process as the injectable PCSK9 inhibitors; however, this version of treatment is in the form of a daily pill.

“Elevated LDL cholesterol is a major risk factor for cardiovascular disease, the leading cause of death worldwide. 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,” said Marc Sabatine, MD, chair of the Thrombolysis in Myocardial Infarction Study Group, Lewis Dexter distinguished chair in cardiovascular medicine at Brigham and Women’s Hospital, and professor of medicine at Harvard Medical School, in a press release.

PCSK9 is a validated target for lowering LDL cholesterol; however, there are currently no oral PCSK9 inhibitors available to physicians and patients. In the phase 2b trial, MK-0616 was overall well-tolerated: compared to placebo, all doses of MK-0616 were found to significantly reduce LDL cholesterol in patients with hypercholesterolemia with an extensive range 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. With its novel modality among PCSK9 inhibitors, MK-0616 could provide an important option for patients for the treatment of hypercholesterolemia,” Sabatine said in the press release.

The phase 3 CORALreef program follows results presented in a prior phase 2b trial. The phase 3 program consists of 3 studies to examine LDL cholesterol reduction when MK-0616 is used: CORALreef Lipids, CORALreef HeFH, and CORALreef.

CORALreef Lipids is a randomized, double-blind study enrolling a broad group of participants, including those with history of at least 1 major ASCVD event and those at intermediate to high risk for a first event. The study will evaluate the efficacy of MK-0616 compared with placebo on the mean percent change from baseline in LDL cholesterol at week 24.

The participants must be treated with stable lipid lowering therapies—including at least a moderate or high intensity statin—or have documented statin intolerance. Patients will receive 20 mg of MK-0616 orally once per day for up to 52 weeks, or placebo in addition to their background lipid lowering therapies. CORALreef HeFH is very similar, but it instead focuses on adult participants with heterozygous familial hypercholesterolemia who are being treated with stable lipid lowering therapies that include at least a moderate or high intensity statin.

Furthermore, the double-blind study CORALreef Outcomes will examine adult participants with high cardiovascular risk who are being treated with stable lipid lowering therapies, including at least a moderate or high intensity statin. The efficacy of MK-0616 in addition to background lipid therapies will be compared to placebo, in increasing time to the first occurrence of any of the following events: coronary heart disease death, ischemic stroke, myocardial infarction, acute limb ischemia or major amputation, or urgent revascularization.

“The initiation of a comprehensive phase 3 program is an important milestone in our 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,” said Joerg Koglin, MD, PhD, senior vice president of global clinical development at Merck Research Laboratories, in the press release. “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.”


Merck. Merck Initiates Phase 3 Clinical Program for Oral PCSK9 Inhibitor Candidate MK-0616. News release. August 25, 2023. Accessed August 29, 2023. https://bit.ly/47Rqb2W

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