Phase 3 Evaluation of Pegozafermin Efficacy and Safety in Metabolic Dysfunction-Associated Steatohepatitis with Compensated Cirrhosis

The primary objective of this Phase 3 study is to evaluate the effect of **pegozafermin** compared to placebo on the regression of fibrosis at 24 months relative to baseline biopsy in subjects with compensated cirrhosis due to Metabolic Dysfunction-Associated Steatohepatitis (MASH). Additionally, at study completion, the study aims to assess the effect of pegozafermin in reducing the risk of clinical outcomes measured as a composite endpoint. These objectives are clinically relevant as they address the potential of pegozafermin to modify disease progression and improve clinical outcomes in patients with MASH-related cirrhosis, a condition with limited therapeutic options.

Secondary objectives include:

• At interim analysis: Evaluating the effect of pegozafermin compared to placebo on liver-related noninvasive tests after 24 months of treatment.
• At interim analysis: Assessing the safety and tolerability of pegozafermin compared to placebo after 24 months of treatment.
• At study completion: Evaluating the effect of pegozafermin compared to placebo on liver-related noninvasive tests.
• At study completion: Assessing the safety and tolerability of pegozafermin compared to placebo.

The clinical trial involves a total of **607 participants** diagnosed with **Metabolic Dysfunction-Associated Steatohepatitis (MASH) with Compensated Cirrhosis**. The study population includes both male and female subjects, aged between 18 and 75 years. Participants were selected based on the presence of at least one metabolic risk factor and a biopsy-confirmed fibrosis stage F4 MASH, as per the non-alcoholic steatohepatitis (NASH) Clinical Research Network (CRN) system, with compensated cirrhosis. The trial includes individuals with a body mass index (BMI) at screening of ≥25.0 (≥23.0 for Asian subjects) and <50.0 kg/m². The study population is characterized by a diverse range of ages and includes a vulnerable population, ensuring a comprehensive evaluation of the treatment's effects across different demographics. Lifestyle considerations such as diet and physical activity were not specified by the sponsor.

The clinical trial is a **Phase III**, randomized, double-blind, placebo-controlled study designed to evaluate the efficacy and safety of **pegozafermin** in subjects with **Metabolic Dysfunction-Associated Steatohepatitis (MASH)** with compensated cirrhosis. The primary objective is to assess the effect of pegozafermin compared to placebo on fibrosis regression at 24 months and to evaluate the reduction in the risk of clinical outcomes at study completion. The trial is expected to commence recruitment on December 1, 2024, and conclude by October 15, 2031.

Participants will be randomly assigned to receive either pegozafermin or a placebo, administered via a pre-filled syringe for subcutaneous use. The study will include several key visits: an initial screening visit to confirm eligibility based on criteria such as age, metabolic risk factors, and biopsy-confirmed fibrosis stage F4 MASH with compensated cirrhosis. Follow-up visits will occur at regular intervals to monitor the participants' health and response to treatment, with a focus on changes in fibrosis, ELF score, ALT levels, and FibroScan VCTE measurements. The end-of-study visit will assess the time to the first occurrence of disease progression and the proportion of subjects developing clinically significant portal hypertension (CSPH).

The expected duration of participant involvement is up to 60 months, with the possibility of early termination if significant adverse events occur or if the participant withdraws consent. The study will adhere to strict ethical guidelines, ensuring the safety and well-being of all participants throughout the trial duration.

The clinical trial involves the administration of **Pegozafermin**, a **solution for injection** developed by 89BIO INC. The active substance, BIO89-100, is a protein of other origin. Pegozafermin is administered via **subcutaneous use** using a pre-filled syringe. The dosing regimen includes a maximum daily dose of 30 mg, with a total maximum dose of 7200 mg over a treatment period of 60 days. The administration schedule and participant compliance are monitored to ensure adherence to the protocol.

The study also includes a **placebo** comparator, designed to match the administration method of Pegozafermin. The placebo is provided in a combined integral administration device, specifically a pre-filled syringe. Detailed information regarding the container closure system for the placebo is available in the IMPD Pegozafermin section 3.2.p.7. The placebo is used to evaluate the efficacy and safety of Pegozafermin by comparing the regression of fibrosis and reduction in clinical outcomes in subjects with compensated cirrhosis due to Metabolic Dysfunction-Associated Steatohepatitis (MASH).

The efficacy of Pegozafermin in subjects with compensated cirrhosis due to **Metabolic Dysfunction-Associated Steatohepatitis (MASH)** will be assessed through a series of primary and secondary endpoints. The primary endpoints include the proportion of subjects achieving fibrosis regression, defined as an improvement in fibrosis by at least one stage at the 24-month biopsy relative to the baseline biopsy, and the time to the first occurrence of disease progression as measured by a composite of protocol-specified clinical events at study completion.

Secondary endpoints will be evaluated both at interim analysis and study completion. These include changes from baseline in Enhanced Liver Fibrosis (ELF) score, alanine aminotransferase (ALT) levels, and FibroScan Vibration-Controlled Transient Elastography (VCTE) measurements. Additionally, at study completion, the proportion of subjects who develop clinically significant portal hypertension (CSPH) will be assessed. These efficacy parameters will be measured and collected at specified timepoints, with the primary focus on the 24-month mark for interim analysis and at the end of the study for final analysis.