Efficacy and Safety Evaluation of Enlicitide Chloride Versus Ezetimibe, Bempedoic Acid, and Their Combination in Hypercholesterolemia Patients

The primary objective of this study is to compare the **efficacy** of MK-0616 against three comparators: ezetimibe, bempedoic acid, and the combination of ezetimibe and bempedoic acid, focusing on the mean percent change from baseline in low-density lipoprotein cholesterol (LDL-C) at Day 56. This is clinically relevant as reducing LDL-C levels is a critical factor in managing **hypercholesterolemia**, which is associated with an increased risk of cardiovascular diseases.

Secondary objectives include:

• Comparing the efficacy of MK-0616 against the same comparators on mean percent change from baseline in Apolipoprotein B (ApoB) at Day 56.
• Assessing the efficacy on mean percent change from baseline in non-high-density lipoprotein cholesterol (non-HDL-C) at Day 56.
• Evaluating the efficacy on percent change from baseline in Lipoprotein(a) [Lp(a)] at Day 56.
• Determining the proportion of participants achieving an LDL-C level of less than 70 mg/dL and a reduction of at least 50% from baseline at Day 56.
• Determining the proportion of participants achieving an LDL-C level of less than 55 mg/dL and a reduction of at least 50% from baseline at Day 56.
• Evaluating the safety and tolerability of MK-0616.

The clinical trial involves a total of **250 participants** diagnosed with **hypercholesterolemia**. The study population includes individuals of any gender, aged 18 years and older, who are not part of a vulnerable population. Participants were selected based on specific criteria, including a history of a major atherosclerotic cardiovascular disease (ASCVD) event or an intermediate to high risk for developing a first major ASCVD event. Additionally, participants must have fasted lipid values meeting certain thresholds and be on a stable dose of statins, with or without non-statin lipid-lowering therapy, with no planned changes during the study. The trial does not impose specific lifestyle considerations such as diet or physical activity, focusing instead on the medical and treatment history of the participants.

The clinical trial is a **randomized, double-blind, controlled** study designed to evaluate the efficacy and safety of MK-0616 compared to **ezetimibe**, **bempedoic acid**, and a combination of ezetimibe and bempedoic acid in adults with **hypercholesterolemia**. The primary objective is to assess the mean percent change from baseline in low-density lipoprotein cholesterol (LDL-C) at Day 56. The trial is expected to commence recruitment on September 2, 2024, and conclude by September 21, 2025, with a total duration of 56 days for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a history of major atherosclerotic cardiovascular disease (ASCVD) events or intermediate to high risk for ASCVD, and specific LDL-C levels. Following the screening, participants will be randomly assigned to receive either MK-0616, ezetimibe, bempedoic acid, or their respective placebos, administered orally. The study will include follow-up visits to monitor the participants' health and response to the treatment, with the primary endpoint being the change in LDL-C levels at Day 56. Secondary endpoints include changes in ApoB, non-HDL-C, and Lp(a) levels, as well as the percentage of participants achieving specific LDL-C reductions.

The expected length of participant involvement is 56 days, during which they will be required to maintain a stable dose of all background lipid-lowering therapies. Conditions that may lead to early termination from the study include the occurrence of adverse events or the need for medication or dose changes. The trial will ensure that all participants are treated with a low, moderate, or high-intensity statin, with or without non-statin lipid-lowering therapy, as part of their background treatment regimen.

The clinical trial involves the administration of several treatments to evaluate their efficacy and safety in adults with **hypercholesterolemia**. The experimental medication **MK-0616** is a film-coated tablet containing the active substance **enlicitide chloride**. It is administered orally with a maximum daily dose of 20 mg and a total dose of 1120 mg over a treatment period of 56 days. The pharmaceutical form is specified as a film-coated tablet, and the medication is produced by Merck & Co. Inc.

**Ezetimibe** is used as a comparator treatment in the study. It is administered orally in a pharmaceutical form identified as PHF00245MIG. The maximum daily dose is 10 mg, with a total dose of 560 mg over the 56-day treatment period. Ezetimibe is classified under the ATC code C10AX09.

Another comparator treatment is **bempedoic acid**, which is also administered orally. The pharmaceutical form is PHF00082MIG, and the maximum daily dose is 180 mg, with a total dose of 10080 mg over the 56-day treatment period. Bempedoic acid is classified under the ATC code C10AX15. The medication undergoes over-encapsulation as part of the trial protocol.

Placebos are used in the study to maintain the double-blind design. These include placebos for MK-0616, ezetimibe, and bempedoic acid. The placebos are administered in a manner consistent with their respective active treatments, although specific pharmaceutical forms and active substances are not applicable.

The efficacy of the investigational product MK-0616 will be assessed in a Phase 3, randomized, double-blind clinical trial involving adults with **hypercholesterolemia**. The primary endpoint for evaluating efficacy is the mean percent change from baseline in low-density lipoprotein cholesterol (LDL-C) at Day 56. Secondary endpoints include mean percent changes from baseline in apolipoprotein B (ApoB), non-high-density lipoprotein cholesterol (non-HDL-C), and lipoprotein(a) [Lp(a)] at Day 56. Additionally, the trial will assess the percentage of participants achieving an LDL-C level of less than 70 mg/dL and a reduction of at least 50% from baseline, as well as those achieving an LDL-C level of less than 55 mg/dL with the same reduction criteria at Day 56.

Data collection will occur at specified timepoints, with the primary and secondary endpoints measured at Day 56. The trial will utilize laboratory tests to evaluate lipid levels, ensuring accurate and reliable data collection. The analysis will focus on comparing the efficacy of MK-0616 against three comparators: ezetimibe, bempedoic acid, and a combination of ezetimibe and bempedoic acid. The trial is designed to confirm the safety and efficacy of MK-0616 in the target population, with the estimated end date set for September 21, 2025.