Evaluation of Pegozafermin Efficacy and Safety in Patients with Metabolic Dysfunction-Associated Steatohepatitis and Fibrosis: A Phase 3 Clinical Trial

The primary objective of this Phase 3 study is to evaluate the effect of **pegozafermin** compared to placebo on liver histology at 52 weeks relative to baseline biopsy in subjects with Metabolic Dysfunction-Associated Steatotic Liver Disease (MASH) and fibrosis. This is clinically relevant as it aims to assess the potential of pegozafermin in improving liver histological features, which are critical indicators of disease progression in MASH. Additionally, at study completion, the study seeks to evaluate the effect of pegozafermin in reducing the risk of a clinical outcome composite endpoint, which is significant for understanding the long-term benefits of the treatment in preventing adverse clinical outcomes.

Secondary objectives include: - At interim analysis, evaluating the effect of pegozafermin compared to placebo on liver-related noninvasive tests (NITs), additional liver histology endpoints, additional NITs, metabolic effects, and the safety and tolerability of pegozafermin after 52 weeks of treatment. - At study completion, demonstrating the effect of pegozafermin compared to placebo in reducing the risk of progression to cirrhosis, and evaluating its effect on liver-related NITs, additional liver histology endpoints, additional liver-related NITs, metabolic effects, and the safety and tolerability of pegozafermin. These objectives are crucial for a comprehensive understanding of the therapeutic profile of pegozafermin, including its efficacy, safety, and potential impact on liver function and disease progression.

The clinical trial involves a total of **784 participants** diagnosed with **Metabolic Dysfunction-Associated Steatotic Liver Disease (MASH)** or **Nonalcoholic Steatohepatitis (NASH) with fibrosis**. The study population includes both male and female subjects, aged between 18 and 75 years. Participants were selected based on specific criteria, including a biopsy-confirmed diagnosis of MASH with fibrosis stage F2 or F3, and a body mass index (BMI) of 25.0 kg/m² or higher (23.0 kg/m² for Asian subjects) but less than 50.0 kg/m². The trial population is characterized by individuals who are not pregnant and have a confirmed liver condition, with a focus on evaluating the effect of pegozafermin compared to placebo. The study also considers lifestyle factors such as BMI, which may influence the progression of liver disease. The trial includes a vulnerable population, ensuring comprehensive representation of the affected demographic.

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 Steatotic Liver Disease (MASH)** and fibrosis. The trial aims to assess the effect of Pegozafermin compared to placebo on liver histology at 52 weeks and to evaluate its impact on reducing the risk of clinical outcome composite endpoints by the study's completion. The trial is expected to commence recruitment in September 2024 and conclude by October 2026, with a total duration of approximately 36 months.

Participants will be involved in the study for up to 36 months, with the primary endpoint measured at 52 weeks. The study will include several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor progress and safety, and an end-of-study visit to assess final outcomes. The inclusion criteria require participants to be males or non-pregnant females aged 18 to 75 years, with biopsy-confirmed MASH and fibrosis stage F2 or F3, and a body mass index (BMI) of 25.0 to 50.0 kg/m². Participants will be randomly assigned to receive either Pegozafermin or a placebo, administered via subcutaneous injection using a pre-filled syringe.

Study visits will be structured to ensure comprehensive monitoring and data collection. The screening visit will involve a detailed assessment to confirm eligibility, including a liver biopsy if not previously conducted within six months. Follow-up visits will occur at regular intervals to evaluate liver fat changes, alanine aminotransferase (ALT) levels, and any disease progression. The end-of-study visit will focus on the primary and secondary endpoints, including the proportion of participants achieving improvement in fibrosis and resolution of MASH without worsening. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or non-compliance with study procedures.

The clinical trial involves the administration of **Pegozafermin**, an investigational medicinal product developed by 89BIO INC. Pegozafermin is formulated as a **solution for injection** and is administered via **subcutaneous use**. The active substance, BIO89-100, is a protein of other origin. The maximum daily dose of Pegozafermin is 44 mg, with a total maximum dose of 4320 mg over a treatment period of 36 weeks. The medication is delivered using a pre-filled syringe, as detailed in the IMPD Pegozafermin section 3.2.P.7 container closure system. The trial aims to evaluate the efficacy and safety of Pegozafermin in subjects with Metabolic Dysfunction-Associated Steatohepatitis (MASH) and fibrosis.

The study also includes a **placebo** group for comparison. The placebo is designed to match the administration device of Pegozafermin, utilizing a pre-filled syringe. This placebo is used to assess the effect of Pegozafermin on liver histology and clinical outcomes by providing a baseline for comparison. The placebo does not contain any active substance and is administered in the same manner as the investigational product to ensure blinding and maintain the integrity of the trial results.

The efficacy of **Pegozafermin** in the treatment of Metabolic Dysfunction-Associated Steatohepatitis (MASH) with fibrosis will be assessed in a Phase 3 clinical trial. The primary endpoints for evaluating efficacy include the proportion of participants achieving co-primary endpoints at 52 weeks: improvement in fibrosis by at least one stage without worsening of MASH/NASH, and resolution of MASH/NASH without worsening of fibrosis. Secondary endpoints include changes from baseline in liver fat as assessed by Magnetic Resonance Imaging - Proton Density Fat Fraction (MRI-PDFF) at Week 52, changes from baseline in Alanine Aminotransferase (ALT) levels at Week 52 and Month 36, and the time to the first occurrence of disease progression as measured by a composite of protocol-specified clinical events up to Month 36.

The efficacy parameters will be measured and collected at specified timepoints, including Week 52 and Month 36, using validated scales and laboratory tests. The analysis will focus on comparing the effects of Pegozafermin to placebo on liver histology at 52 weeks relative to baseline biopsy, and on reducing the risk of clinical outcome composite endpoints at study completion. The trial is designed as a randomized, double-blind, placebo-controlled study, ensuring rigorous assessment of the treatment's efficacy.