Phase 2b Study of GSK4532990 in Adults With NASH

Study Overview
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Brief Summary
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The purpose of this study is to measure improvements in liver fibrosis and inflammation with GSK4532990 compared with placebo in participants with NASH and advanced (F3) fibrosis. The study duration will be up to 76 weeks including the screening period. The treatment duration will be up to 52 weeks.

Official Title
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17 β-Hydroxysteroid Dehydrogenase Type 13 Minimization for the Treatment of NASH (HORIZON): A Double-Blind, Placebo-Controlled Phase 2b Study to Evaluate the Efficacy and Safety of GSK4532990 in Adults With Pre-Cirrhotic Nonalcoholic Steatohepatitis

Conditions
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Nonalcoholic Fatty Liver Disease

Intervention / Treatment
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* Drug: GSK4532990
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Body Mass Index (BMI) ≥25 kilogram per meter square (kg/m^2) (all ethnic origins) except for Asian participants who qualify for the study with BMI ≥23 kg/m2 at Screening. In the opinion of the investigator, there are features of metabolic syndrome and NAFLD is the most likely cause of liver disease. Metabolic syndrome may include type 2 diabetes mellitus (T2DM), obesity, dyslipidemia and hypertension. A liver biopsy at baseline showing NAFLD Activity Score (NAS) >=4 with at least 1 point each in steatosis, inflammation and ballooning and Fibrosis CRN score of 3. Able and willing to comply with all study assessments, including a liver biopsy at Week 52. Exclusion Criteria: Cirrhosis (based on screening biopsy or historical biopsy showing definitive cirrhosis). Current alcohol consumption ≥14 standard drinks (24 units, 196 g ethanol) per week for females or ≥21 standard drinks (37 units, 294g ethanol) per week for males. Weight reduction surgery (including gastric banding and intragastric balloon insertion) within 2 years of Screening 1. History of cancer within previous 2 years from Screening 1, except adequately resected non-melanoma skin cancer.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: High Dose GSK4532990<br> | Drug: GSK4532990<br>* GSK4532990 will be administered.<br>|
| Experimental: Low Dose GSK4532990<br> | Drug: GSK4532990<br>* GSK4532990 will be administered.<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Placebo will be administered.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving ≥ 1 Stage Improvement in Histological Fibrosis with no Worsening of NASH | Improvement in histological fibrosis is assessed with Clinical research network (CRN) Scoring. No worsening of NASH is defined as no increase in the NAFLD Activity Score (NAS) for steatosis, ballooning, or inflammation. | At Week 52 | 
| Percentage of Participants Achieving NASH Resolution with no Worsening of Fibrosis | NASH resolution is defined as a ballooning score of 0 and an inflammation score of 0-1. No worsening of fibrosis is defined as no increase in CRN fibrosis score. | At Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in Pro-peptide of type III collagen (Pro-C3 ) |  | Baseline (Day 1) and at Week 24 and 52 | 
| Change from baseline in liver fat using Magnetic resonance imaging-proton density fat fraction (MRI-PDFF) |  | Baseline (Day 1) and at Week 24 and 52 | 
| Change from baseline in Liver stiffness measurement (LSM) by Vibration-controlled transient elastography (VCTE) |  | Baseline (Day 1) and at Week 24 and 52 | 
| Change from baseline in Enhanced Liver Fibrosis (ELF) Score | The ELF score will be calculated using a published algorithm combining the values of a set of extracellular matrix markers, including tissue inhibitor of metalloproteinases-1 (TIMP-1), type III procollagen (PIIINP), and hyaluronic acid (HA). The ELF score is used as a prognostic marker for disease progression: ELF score < 9.8 : Low risk of progression, ELF score 9.8 to < 11.3 : Moderate risk of progression and ELF score > = 11.3 : High risk of progression. | Baseline (Day 1) and at Week 24 and 52 | 
| Percentage of Participants Achieving ≥30% relative reduction in liver fat from baseline using MRI-PDFF at Week 24 |  | At Week 24 | 
| Percentage of Participants Achieving ≥30% relative reduction in liver fat from baseline using MRI-PDFF at Week 52 |  | At Week 52 | 
| Change from Baseline in Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Gamma-glutamyl transferase (GGT) (Units Per Liter) |  | Baseline (Day 1) and at Week 24 and 52 | 
| Percentage of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) |  | Up to Week 66 | 
| Change from Baseline in Vital Signs - Blood Pressure (millimeters of Mercury) |  | Baseline (Day 1) and up to Week 52 | 
| Change from Baseline in Vital Signs - Temperature (Celsius) |  | Baseline (Day 1) and up to Week 52 | 
| Change from Baseline in Vital Signs - Heart Rate (Beats per minute) |  | Baseline (Day 1) and up to Week 52 | 
| Change from Baseline in Vital Signs - Respiratory Rate (Breaths per minute) |  | Baseline (Day 1) and up to Week 52 | 
| Change From Baseline in Clinical Chemistry Parameter: total bilirubin, direct Bilirubin and creatinine (Micromoles per Liter) |  | Baseline (Day 1) and up to Week 52 | 
| Area under the concentration-time curve from time zero (pre-dose) to the last quantifiable concentration (AUC0-t) of GSK4532990 |  | Pre-dose (Day 1), 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post dose | 
| Maximum observed concentration (Cmax) of GSK4532990 |  | Pre-dose (Day 1), 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post dose | 
| Percentage of Participants with Anti-drug Antibodies (ADA) to GSK4532990 |  | Up to Week 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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17β-Hydroxysteroid Dehydrogenase type 13 Minimization for the treatment of NASH (HORIZON), GSK4532990, Non-alcoholic steatohepatitis (NASH), Non-alcoholic fatty liver disease (NAFLD)