A Phase 2b Randomized, Double-Blind Placebo-Controlled, Multicenter Study to Evaluate the Efficacy and Safety of Efinopegdutide (MK-6024) in Adults with Precirrhotic Nonalcoholic Steatohepatitis

The primary objective of this Phase 2b randomized, double-blind, placebo-controlled, multicenter study is to evaluate the effect of **efinopegdutide** versus placebo on the proportion of individuals with resolution of non-alcoholic steatohepatitis (NASH) without worsening of fibrosis at Week 52. This is clinically relevant as NASH is a progressive liver disease that can lead to cirrhosis and liver failure, and effective treatment options are limited. Additionally, the study aims to assess the safety and tolerability of efinopegdutide, which is crucial for determining its potential as a therapeutic agent.

Secondary objectives include:

• Evaluating the effect of efinopegdutide versus placebo on the proportion of individuals with ≥1-stage improvement in fibrosis without worsening of steatohepatitis at Week 52.
• Assessing the effect of efinopegdutide versus placebo on the mean percent change from baseline in body weight at Week 52.

The clinical trial involves a total of **323 participants** diagnosed with **non-alcoholic steatohepatitis (NASH)**. The study population includes both male and female subjects, with an age range of 19 to 80 years. Participants were selected based on specific inclusion criteria, including histologic confirmation of NASH through liver biopsy, with a Nonalcoholic Fatty Liver Disease (NAFLD) Activity Score of 4 or higher, and a NASH Clinical Research Network (CRN) fibrosis score indicative of Stage 2 or 3. Individuals with a history of Type 2 diabetes mellitus (T2DM) are included only if their condition is controlled by diet or stable doses of antihyperglycemic agents. The trial does not involve a vulnerable population, and no specific lifestyle considerations such as diet or physical activity are highlighted in the selection process. The study aims to evaluate the effect of efinopegdutide versus placebo on NASH resolution without worsening fibrosis over a 52-week period, alongside assessing the safety and tolerability of the treatment.

The clinical trial is designed as a **randomized, double-blind, placebo-controlled** study to evaluate the efficacy and safety of **efinopegdutide** in adults with precirrhotic **non-alcoholic steatohepatitis** (NASH). The trial will span a duration of 52 weeks, with the primary objective being to assess the effect of efinopegdutide versus placebo on the proportion of individuals achieving NASH resolution without worsening of fibrosis. Secondary objectives include evaluating the safety and tolerability of efinopegdutide, as well as changes in body weight and fibrosis improvement.

Participants will be involved in the study for a total of 52 weeks, with the trial commencing with an inclusion (screening) visit to confirm eligibility based on histologic confirmation of NASH and other criteria. Following randomization, participants will receive subcutaneous injections of either efinopegdutide or placebo. Study visits will occur at regular intervals to monitor safety, efficacy, and any adverse events. The end-of-study visit will conclude the trial, assessing the primary and secondary endpoints.

Inclusion criteria require participants to have a histologic confirmation of NASH with a specific activity score and fibrosis stage, and either no history of type 2 diabetes mellitus or controlled diabetes. Participants from South Korea must be between 19 to 80 years of age. Conditions for early termination from the study include the occurrence of adverse events that necessitate discontinuation of the study medication. The trial is expected to end by December 2025, with recruitment having started in July 2023.

The clinical trial involves the administration of **efinopegdutide**, an experimental medication formulated as a **solution for injection in pre-filled syringe**. This investigational drug is administered via **subcutaneous injection**. The maximum daily dose is 10 mg, with a total maximum dose of 5200 mg over a treatment period of 52 weeks. Efinopegdutide is a protein-based substance, specifically categorized as "Protein - Other," and is developed by Merck & Co. Inc. The drug is identified by several synonyms, including HM12525A, HM-12525A, JNJ-64565111, and MK-6024. Participant compliance with the dosing schedule is monitored throughout the study.

In addition to the experimental treatment, the study includes a comparator treatment using **semaglutide**, which is also a **solution for injection**. Semaglutide is administered via **subcutaneous injection** with a maximum daily dose of 2.4 mg and a total maximum dose of 124.8 mg over the same 52-week treatment period. This comparator is a protein-based substance, similar to efinopegdutide, and is used to evaluate the efficacy and safety of the experimental drug. The semaglutide product is modified for clinical trial use by discarding the secondary package and replacing it with a clinical kit box, with clinical labels applied to both the primary container and the kit box. Each kit contains one pen for administration.

The trial also includes a **placebo** group, identified as MK-6024_PBO_0.5mL, to further assess the effects of efinopegdutide. The placebo is administered in a manner consistent with the active treatments, ensuring blinding and maintaining the integrity of the study design. The placebo is not associated with any active substance and serves as a control to evaluate the true efficacy of the experimental medication.

The efficacy of **efinopegdutide** in the clinical trial will be assessed primarily by evaluating the percentage of participants with Nonalcoholic Steatohepatitis (NASH) resolution without worsening of fibrosis at Week 52. Secondary efficacy endpoints include the percentage of participants with at least one stage improvement in fibrosis without worsening of steatohepatitis at Week 52 and the change from baseline in body weight at Week 52. These endpoints will be measured and collected at the specified timepoint of Week 52, utilizing histologic confirmation of NASH based on liver biopsy as a key assessment tool. The trial aims to determine the effect of efinopegdutide versus placebo on these parameters, ensuring a comprehensive evaluation of its efficacy in treating precirrhotic NASH.