An Operationally Seamless Phase 2/3 Study to Evaluate the Safety, Efficacy, and Pharmacokinetics of Enlicitide Decanoate in Pediatric Participants with Heterozygous Familial Hypercholesterolemia

This study evaluates enlicitide in pediatric patients with heterozygous familial hypercholesterolemia. The primary objectives are: to evaluate the pharmacokinetics of enlicitide in Part A for Age Cohort 1 and Age Cohort 2 separately; to evaluate the efficacy of enlicitide compared with placebo on percent change from baseline in LDL-C at Week 24 in Part B for Age Cohort 1 and Age Cohort 2 combined; to evaluate the efficacy of enlicitide compared with placebo on percent change from baseline in LDL-C at Week 24 in Part B Age Cohort 1 specifically; and to evaluate the safety and tolerability of enlicitide across Part A, Part B, and the open-label extension. These objectives address the critical need to assess lipid-lowering efficacy and safety profile of this novel PCSK9 inhibitor in the pediatric population with this inherited lipid disorder, where early intervention may reduce long-term cardiovascular risk.

The secondary objectives include: • To evaluate the efficacy of enlicitide compared with placebo on percent change from baseline in ApoB, non-HDL-C, and Lp(a) at Week 24 in Part B. • To evaluate the efficacy of enlicitide compared with placebo on the proportion of participants achieving specific LDL-C goals at Week 24, including levels less than 130 mg/dL (3.37 mmol/L), at least 50% reduction from baseline, and levels less than 100 mg/dL (2.59 mmol/L) in Part B. • To evaluate the efficacy of enlicitide compared with placebo on change in ultrasound-determined mean carotid intima-media thickness at Week 24 in Part B.

This clinical trial enrolled a total of **149 participants** diagnosed with **heterozygous familial hypercholesterolemia**. The study population consisted of **pediatric patients** divided into two age cohorts: participants aged **12 to less than 18 years** (Age Cohort 1) and participants aged **6 to less than 12 years** (Age Cohort 2). Both **male and female** subjects were included in the trial. All participants were required to have a possible or definite diagnosis of heterozygous familial hypercholesterolemia based on a locally accepted diagnostic algorithm or genetic testing results. Eligible participants were receiving optimized treatment according to local guidelines and standard of care, which included a stable daily dose of **statin** therapy with or without non-statin **lipid-lowering treatment**, or non-statin lipid-lowering treatment alone in cases of documented statin intolerance or refusal. Participants were required to maintain stable doses of all background lipid-lowering therapies prior to screening and throughout the allocation or randomization phase, with no planned medication or dose changes. Additionally, participants needed to be able to take study medication orally and swallow the study intervention. The trial included a vulnerable population and comprised multiple parts, including Part A, Part B, and an open-label extension period, with specific eligibility criteria for continuation into the extension phase based on completion of prior study visits and receipt of at least one dose of study intervention.

This is an operationally seamless **Phase 2/3** clinical trial designed to evaluate the safety, efficacy, and **pharmacokinetics** of **enlicitide chloride** administered as a **film-coated tablet** via the **oral route** in pediatric participants diagnosed with **heterozygous familial hypercholesterolemia**. The investigational medicinal product MK-0616 contains enlicitide chloride as the active substance and will be compared against a matching placebo. The maximum daily dose is 20 mg, with a maximum total dose of 25,200 mg over a treatment period of up to 180 days.

The trial comprises three distinct phases: Part A, Part B, and an **open-label extension** (OLE) period. Part A is a pharmacokinetic evaluation phase conducted separately in two age cohorts: Age Cohort 1 includes participants aged 12 to less than 18 years, and Age Cohort 2 includes participants aged 6 to less than 12 years. Part B is a **randomized**, **placebo-controlled** efficacy phase in which participants from both age cohorts are combined and separately analyzed to assess the percent change from baseline in **low-density lipoprotein cholesterol** (LDL-C) at Week 24. The OLE period is available to participants from Part A who received at least one dose of study intervention and completed Visit 5 (Day 14), or to Part B participants who received at least one dose and completed Visit 7 (Week 24).

Eligible participants must have a possible or definite diagnosis of heterozygous familial hypercholesterolemia based on a locally accepted diagnostic algorithm or genetic testing results obtained before screening. All participants are required to be receiving optimized treatment per local guidelines and standard of care, which includes a stable dose of **statin** therapy with or without non-statin **lipid-lowering treatment**, or non-statin therapy alone in cases of documented statin intolerance or refusal. Background lipid-lowering medications must remain stable from screening through allocation or randomization. Participants must be able to take study medication orally and swallow the study intervention.

The primary objectives of the trial are to evaluate the pharmacokinetics of enlicitide in Part A for each age cohort separately, to assess the efficacy of enlicitide compared with placebo on percent change from baseline in LDL-C at Week 24 in Part B participants (both combined cohorts and Age Cohort 1 separately), and to evaluate the safety and tolerability of enlicitide across all trial phases including the OLE period. Primary endpoints include **maximum plasma concentration** (Cmax) and **area under the concentration-time curve** from 0 to 24 hours (AUC0-24) of enlicitide in Part A, percent change from baseline in LDL-C at Week 24 in Part B participants, and the number of participants experiencing one or more **adverse events** or discontinuing study treatment due to an adverse event.

Secondary endpoints include percentage change from baseline in **apolipoprotein B** (ApoB), **non-high-density lipoprotein cholesterol** (non-HDL-C), and **lipoprotein (a)** [Lp(a)] at Week 24 in Part B participants. Additional secondary endpoints assess the proportion of participants achieving LDL-C levels below 130 mg/dL (3.37 mmol/L), a reduction of at least 50% from baseline, or levels below 100 mg/dL (2.59 mmol/L) at Week 24. Change in ultrasound-determined mean **carotid intima-media thickness** (cIMT) at Week 24 is also evaluated as a secondary endpoint in Part B participants.

The trial is expected to commence recruitment in February 2026 and is estimated to conclude in January 2037. The duration of participant involvement varies depending on the trial phase. Part A participants complete assessments through Day 14 (Visit 5), while Part B participants complete assessments through Week 24 (Visit 7). Participants who enter the open-label extension period will have extended involvement beyond the initial treatment phases. Early termination from the study may occur due to adverse events, participant or legally acceptable representative withdrawal of consent, protocol violations, investigator decision, or other conditions as specified in the trial protocol.

The experimental medication **MK-0616** is a **film-coated tablet** containing **enlicitide chloride** as the active substance of chemical origin. The product is administered via the **oral route**. The maximum daily dose is **20 mg**, with a maximum total dose of **25200 mg** over a treatment period of up to **180 days**. The sponsor product code for this investigational medicinal product is MK-0616, manufactured by Merck & Co. Inc.

A **placebo** matching MK-0616 is utilized as the comparator treatment in this clinical trial. The placebo is administered to participants in the control group to evaluate the efficacy of enlicitide compared with placebo on percent change from baseline in low-density lipoprotein cholesterol at Week 24. Specific details regarding the pharmaceutical form, dosage, and route of administration for the placebo are designed to match the experimental medication to maintain blinding integrity throughout the study.

The study comprises multiple parts including Part A, Part B, and an open-label extension, with treatment allocation and dosing schedules determined according to the study protocol for pediatric participants with **heterozygous familial hypercholesterolemia**. Participant compliance monitoring and safety assessments are conducted throughout all phases of the trial to evaluate the safety, tolerability, efficacy, and pharmacokinetics of enlicitide.

Efficacy will be assessed through multiple parameters addressing lipid levels and cardiovascular markers in pediatric participants with **heterozygous familial hypercholesterolemia**. In Part A, the pharmacokinetics of enlicitide will be evaluated separately for Age Cohort 1 and Age Cohort 2, with measurement of maximum plasma concentration (Cmax) and area under the concentration-time curve from 0 to 24 hours (AUC0-24) of enlicitide. In Part B, the primary efficacy endpoint is the percent change from baseline in **low-density lipoprotein cholesterol** (LDL-C) at Week 24, assessed for Age Cohort 1 and Age Cohort 2 combined, as well as for Age Cohort 1 separately, comparing enlicitide with placebo.

Secondary efficacy endpoints in Part B include percentage change from baseline at Week 24 in **apolipoprotein B** (ApoB), **non-high-density lipoprotein cholesterol** (non-HDL-C), and **lipoprotein (a)** [Lp(a)]. Additional efficacy measures include the proportion of participants achieving LDL-C levels below 130 mg/dL (3.37 mmol/L), below 100 mg/dL (2.59 mmol/L), or a reduction of at least 50% from baseline at Week 24. Change in ultrasound-determined mean carotid intima-media thickness (cIMT) at Week 24 will also be assessed as a secondary endpoint in Part B participants.