Phase 2b Double-Blind, Placebo-Controlled Study of GSK4532990 for Efficacy and Safety in Adults with Nonalcoholic Steatohepatitis and Bridging Fibrosis

The primary objective of this study is to evaluate whether **GSK4532990** can induce fibrosis regression and/or resolution of Nonalcoholic Steatohepatitis (NASH) in participants with NASH and bridging (F3) fibrosis. This is clinically relevant as it addresses the potential therapeutic impact of GSK4532990 on reversing liver damage and improving liver function in patients with advanced stages of NASH, a condition associated with significant morbidity and mortality.

Secondary objectives include:

• Evaluating whether GSK4532990 can cause fibrosis regression and/or NASH resolution in participants with NASH and F3 and in participants with NASH and F4 fibrosis (pooled cohort).
• Assessing the treatment effects of GSK4532990 on blood-based and imaging markers of liver fat, liver injury, and liver fibrosis in participants with NASH and F3 fibrosis and in a pooled cohort of participants with NASH and F3 and NASH and F4 fibrosis.
• Assessing the safety and tolerability of GSK4532990 in participants with NASH and F3 fibrosis, in participants with NASH and F4 fibrosis, and in a pooled cohort of participants with NASH and F3 and NASH and F4 fibrosis.
• Evaluating GSK4532990 exposure parameters in participants with NASH and F3 fibrosis and in participants with NASH and F4 fibrosis.

The clinical trial involves a total of **200 participants** diagnosed with **Non-alcoholic Fatty Liver Disease** (NAFLD), specifically targeting those with NASH and bridging (F3) fibrosis. The study population includes both male and female subjects, aged between **18 to 75 years**. Participants were selected based on specific criteria, including a **Body Mass Index (BMI)** of 25 kg/m² or higher, with a lower threshold of 23 kg/m² for Asian participants. The trial excludes vulnerable populations and requires participants to have features of metabolic syndrome, such as type 2 diabetes mellitus, obesity, dyslipidemia, and hypertension, with NAFLD being the most likely cause of liver disease. Lifestyle considerations, such as diet and physical activity, are not explicitly detailed, but participants must be capable of providing informed consent and willing to comply with all study assessments. Female participants must adhere to strict contraceptive measures if of childbearing potential. The trial does not include pregnant or breastfeeding women. The selection process ensures that participants meet the necessary health criteria, including a liver biopsy showing a NAS of 4 or more, with specific points in steatosis, inflammation, and ballooning, confirmed by central scoring.

The clinical trial is designed to evaluate the efficacy and safety of **GSK4532990** in adults with **Nonalcoholic Steatohepatitis** (NASH) and bridging fibrosis. This is a randomized, double-blind, placebo-controlled Phase 2b study. The trial aims to determine whether the investigational product can achieve fibrosis regression and/or resolution of NASH. The study is expected to last until December 2025, with participant involvement spanning approximately 52 weeks from the initial screening to the end-of-study visit.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, body mass index, and liver biopsy results. The screening process ensures that participants have features of metabolic syndrome and that **Non-alcoholic Fatty Liver Disease** (NAFLD) is the most likely cause of liver disease. Following successful screening, participants will be randomized to receive either the investigational product or a placebo, administered via subcutaneous injection.

Throughout the trial, participants will attend regular follow-up visits to monitor safety and efficacy outcomes. These visits will include assessments such as liver function tests, imaging studies, and histological evaluations. The primary endpoints are achieving a one-stage improvement in histological fibrosis without worsening NASH and achieving NASH resolution without worsening fibrosis, both evaluated at 52 weeks. The end-of-study visit will conclude the trial, where final assessments will be conducted to gather comprehensive data on the investigational product's impact.

Participants are expected to adhere to the study protocol for the entire duration unless specific conditions necessitate early termination. Such conditions may include adverse events, non-compliance with study procedures, or withdrawal of consent. The trial is conducted under strict ethical guidelines, ensuring that all participants provide informed consent and are capable of complying with study assessments.

The clinical trial involves the administration of **GSK4532990A**, an experimental medication developed by GlaxoSmithKline. This investigational product is formulated as a **solution for injection** and is intended for **subcutaneous use**. The active substance, GSK4532990A, is of nucleic acid origin. The maximum total dose administered to participants is 200 mg/ml, with a treatment period extending up to 48 weeks. The dosing schedule and frequency of administration are determined by the study protocol, ensuring adherence to the specified maximum treatment period. Participant compliance is monitored throughout the trial to ensure accurate assessment of the medication's efficacy and safety in treating Nonalcoholic Steatohepatitis (NASH) with bridging fibrosis.

In addition to the experimental treatment, the study utilizes a **0.9% Sodium Chloride Injection** as a placebo comparator. This non-experimental treatment serves as a control to evaluate the efficacy of GSK4532990A. The placebo is administered in a manner consistent with the experimental medication to maintain the double-blind nature of the trial. The use of a placebo is critical in distinguishing the effects of the investigational drug from those of standard care or no treatment. The administration of the placebo follows the same route and frequency as the experimental treatment, ensuring that any observed effects can be attributed to the active substance under investigation.

The efficacy of the investigational product GSK4532990A in the treatment of **Nonalcoholic Steatohepatitis (NASH)** will be assessed through primary endpoints focused on histological improvements. The primary efficacy parameters include achieving a greater or equal to 1 stage improvement in histological fibrosis, as measured by the Clinical Research Network (CRN) scoring system, without any worsening of NASH. This is defined as no increase in the NAFLD Activity Score (NAS) for steatosis, ballooning, or inflammation at 52 weeks. Additionally, efficacy will be evaluated by achieving NASH resolution with no worsening of fibrosis, defined as no increase in the CRN fibrosis score. Resolution of NASH is characterized by a ballooning score of 0 and an inflammation score of 0-1.