Merck's Investigational Oral PCSK9 Inhibitor Enlicitide Decanoate Met All Primary and Key Secondary Endpoints in Adults with Hypercholesterolemia in Pivotal CORALreef Lipids Study

Enlicitide is the first oral PCSK9 inhibitor to demonstrate statistically significant and clinically meaningful reductions in LDL-C compared to placebo in Phase 3 trials

Enlicitide had a favorable safety profile, with comparable rates of discontinuation between treatment groups

Merck (NYSE:MRK), known as MSD outside of the United States and Canada, today announced positive topline results from the Phase 3 CORALreef Lipids trial evaluating the safety and efficacy of enlicitide decanoate, an investigational, once-daily oral proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor being evaluated for the treatment of adults with hypercholesterolemia on a moderate or high intensity statin (or with documented statin intolerance).

The CORALreef Lipids trial successfully met all primary and key secondary endpoints. Treatment with enlicitide resulted in statistically significant and clinically meaningful reduction in low-density lipoprotein cholesterol (LDL-C) compared to placebo at Week 24. Statistically and clinically significant reductions were also seen for enlicitide versus placebo across all key secondary endpoints including in non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), and lipoprotein(a) [Lp(a)]. There were no clinically meaningful differences in proportions of participants with adverse events (AE), including serious adverse events (SAE), between treatment groups. Discontinuations due to adverse events were low and comparable between treatment groups.

CORALreef Lipids represents the largest completed Phase 3 study evaluating enlicitide in a broad range of participants with elevated LDL-C and a history of or increased risk for major atherosclerotic cardiovascular disease events despite treatment with at least a moderate or high intensity statin (or with documented statin intolerance). Merck plans to share these results with regulatory authorities worldwide and will present the data at a future scientific congress.

"This is the third Phase 3 trial to demonstrate clinically meaningful and statistically significant LDL-C lowering for enlicitide," said Dr. Dean Y. Li, president, Merck Research Laboratories. "The advent of injectable PCSK9 inhibitors has enabled a new approach to controlling LDL-C and reducing the risk of atherogenic cardiovascular events. Enlicitide, designed to deliver antibody-like efficacy, is the first oral macrocyclic peptide PCSK9 inhibitor with clinically meaningful and statistically significant LDL-C lowering in Phase 3 trials. If approved, it has the potential to change the way we think about managing LDL levels, giving patients the possibility of a new option to help them meet their treatment goals."

"These data add to the growing body of evidence supporting the safety and efficacy profile of enlicitide to lower LDL cholesterol and other key atherogenic lipids including ApoB and Lp(a)," said Dr. Ann Marie Navar, a lead trial investigator of the study and Associate Professor of Medicine in the Division of Cardiology at UT Southwestern Medical Center. "Enlicitide has the potential to help more patients achieve guideline-recommended lipid goals and ultimately reduce atherosclerotic cardiovascular risk, which is currently being evaluated in an ongoing cardiovascular outcomes trial."

About CORALreef Lipids

CORALreef Lipids (NCT05952856) was a Phase 3 randomized, double-blind, placebo-controlled study designed to evaluate the efficacy, safety and tolerability of enlicitide decanoate in adults with hypercholesterolemia and a history of a major atherosclerotic cardiovascular disease (ASCVD) event or increased risk for a first event. Participants were required to be treated with stable lipid lowering therapies including at least a statin (or have documented statin intolerance). The study's primary objective was to assess whether enlicitide decanoate was superior to placebo in reducing LDL-C, as measured by mean percent change from baseline at Week 24. Key secondary efficacy endpoints included: change from baseline in LDL-C at week 52 and change from baseline in other key atherogenic lipids at week 24 (non-HDL-C, apolipoprotein B, lipoprotein(a) [Lp(a)]).

The efficacy and safety of enlicitide are being evaluated through the comprehensive CORALreef Clinical Trial program, including the large cardiovascular outcomes trial, CORALreef Outcomes, which has completed enrollment with over 14,500 participants. As previously announced, enlicitide demonstrated statistically significant and clinically meaningful reductions in LDL-C in both the Phase 3 CORALreef HeFH and CORALreef AddOn trials. The CORALreef program reflects Merck's commitment to advancing research to help address the global burden of atherosclerotic cardiovascular disease.

About enlicitide and PCSK9

Enlicitide is an investigational, potentially first oral PCSK9 inhibitor designed to lower LDL-C via the same biological mechanism as currently approved monoclonal antibody, injectable PCSK9 inhibitors but in a daily pill form. Enlicitide is a novel small molecule macrocyclic peptide that binds to PCSK9 and inhibits the interaction of PCSK9 with LDL receptors.

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 is designed to prevent the interaction of PCSK9 with LDL receptors. This results in greater numbers of LDL receptors available on the cell surface to remove LDL cholesterol from the blood.

About hypercholesterolemia

Hypercholesterolemia, a type of hyperlipidemia, is a disorder in which there are elevated LDL cholesterol levels in the blood. It affects approximately 86 million adults in the U.S and is a major risk driver for ASCVD, accounting for 85% of cardiovascular deaths. Nearly 70% of people with ASCVD who are treated with lipid lowering therapies do not reach target low-density lipoprotein cholesterol. High LDL-C, if left untreated, can lead to ASCVD events such as heart attacks and strokes.

Merck's focus on cardiovascular disease

Merck has a long history of developing treatments for cardiovascular disease. More than 60 years ago, we introduced our first cardiovascular therapy—and our scientific efforts to understand and treat cardiovascular-related disorders have continued. Cardiovascular disease continues to be one of the most serious health challenges of the 21st century and is the leading cause of death worldwide. Approximately 18 million people across the globe die from cardiovascular disease every year; in the United States, one person dies every 36 seconds from cardiovascular disease.

Advancements in the treatment of cardiovascular disease can make a critical difference for patients and health systems around the world. At Merck, we strive for scientific excellence and innovation in all stages of research, from discovery through approval and life cycle management. We work with experts throughout the cardiovascular and pulmonary community to advance research that can help improve the lives of patients globally.

Information for other currently enrolling cardiovascular studies can be found by visiting: https://www.merckclinicaltrials.com/cardiovascular.

About Merck

At Merck, known as MSD outside of the United States and Canada, we are unified around our purpose: We use the power of leading-edge science to save and improve lives around the world. For more than 130 years, we have brought hope to humanity through the development of important medicines and vaccines. We aspire to be the premier research-intensive biopharmaceutical company in the world—and today, we are at the forefront of research to deliver innovative health solutions that advance the prevention and treatment of diseases in people and animals. We foster a diverse and inclusive global workforce and operate responsibly every day to enable a safe, sustainable, and healthy future for all people and communities. For more information, visit www.merck.com and connect with us on X (formerly Twitter), Facebook, Instagram, YouTube and LinkedIn.

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