A Study to Test Safety and Efficacy of BI456906 in Adults With Non-alcoholic Steatohepatitis (NASH) and Fibrosis (F1-F3)

Study Overview
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Brief Summary
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This study is open for men and women with a liver disease called nonalcoholic steatohepatitis (NASH) and liver fibrosis. The purpose of the study is to find out whether a medicine called BI 456906 helps patients with NASH and liver fibrosis. The study tests 3 different doses of BI 456906 to find the dose that helps best. Participants are put into 4 groups randomly, which means by chance. There are 3 groups that each receive a different dose of BI 456906 and there is 1 group that receives placebo. BI 456906 and placebo are given as an injection under the skin once per week. The placebo injection looks like the BI 456906 injection but does not contain any medicine. Participants are in the study for a little over 1 year (60 weeks). During this time, they visit the study site several times and have some video calls in addition. At the visits, the study doctors take different measurements. To see whether the treatment works, the doctors take a very small sample of liver tissue (biopsy) from each participant at the start and at the end of the study. They also examine the liver by ultrasound and MRI. The doctors also regularly check the general health of the participants.

Official Title
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Multicenter, Double-blind, Parallel-group, Randomized, 48 Weeks, Dose-ranging, Placebo-controlled Phase II Trial to Evaluate Efficacy, Safety and Tolerability of Multiple Subcutaneous (s.c.) Doses of BI 456906 in Patients With Non-alcoholic Steatohepatitis (NASH) and Fibrosis.

Conditions
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Non-alcoholic Steatohepatitis (NASH)

Intervention / Treatment
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* Drug: BI 456906
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients ≥ 18 years (or who are of legal age in countries where that is greater than 18 years) and ≤ 80 years of age at time of consent. Diagnosis of non-alcoholic steatohepatitis (NASH) (Non-alcoholic Fatty Liver Disease (NAFLD) Activity Score (NAS) ≥ 4, with at least 1 point in inflammation and ballooning each) and fibrosis stage F1-F3 proven by a biopsy conducted during the screening period or by a historical biopsy conducted within the last 6 months prior to randomization and stable body weight defined as less than 5% self-reported change in body weight between the historical biopsy and randomization, if a historical biopsy is used. Liver fat fraction ≥ 8% measured by Magnetic Resonance Imaging (MRI)-Proton Density Fat Fraction (PDFF) and liver stiffness > 6.0 kPa measured by FibroScan® at Visit 1 (if biopsy is scheduled during the screening period MRI-PDFF and FibroScan® assessments have to be performed prior to the biopsy). However, the diagnosis of NASH and fibrosis at liver biopsy (including historical biopsy) is the primary assessment to establish patient eligibility. Patients willing and able to undergo liver biopsies per protocol as judged by the Investigator. Signed and dated written informed consent in accordance with ICH-GCP and local legislation prior to admission to the trial. Women of childbearing potential (WOCBP)1 must be willing and able to use two forms of effective contraception where at least one form is highly effective methods of birth control per International Council on Harmonisation (ICH) M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and correctly. A list of contraception methods meeting these criteria is provided in the patient information. Further inclusion criteria apply. Exclusion Criteria: Current or history of significant alcohol consumption (defined as intake of > 210 g/ week in males and > 140 g/ week in females on average over a consecutive period of more than 3 months) or inability to reliably quantify alcohol consumption based on Investigator judgement within the last 5 years. Intake of medications historically associated with liver injury, hepatic steatosis or steatohepatitis within 12 weeks prior to Visit 1. Intake of restricted medications or any medications considered likely to interfere with the safe conduct of the trial. History of other forms of chronic liver disease (e.g., viral hepatitis, autoimmune liver disease, primary biliary sclerosis, primary sclerosing cholangitis, Wilson's disease, hemochromatosis, Alpha-1 Antitrypsin (A1At) deficiency, history of liver transplantation). Hepatitis B and C testing will be done at Visit 1. Patients with positive Hepatitis B surface antigen (HBsAg) should be excluded. Patients treated for hepatitis C must have a negative RNA test at screening and also be Hepatitis C Virus (HCV) RNA negative for at least 3 years prior to screening in order to be eligible for the trial. Suspicion, diagnosis, or history of hepatocellular carcinoma (HCC), or any documented active or suspected malignancy or history of malignancy within 5 years prior to screening, except appropriately treated basal cell carcinoma of the skin or in situ carcinoma of uterine cervix. Personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2, manifest hypo- or hyperthyroidism at Visit 1. History of chronic or acute pancreatitis or elevation of serum lipase/amylase > 2x ULN or fasting serum triglyceride levels of > 500 mg/dL (> 5.65 mmol/L) at screening. Known history of HIV (Human Immunodeficiency Virus) infection and/or tuberculosis and/or an acute COVID-19 infection at Visit 1 (confirmed by SARS CoV-2 RT-PCR test). Further exclusion criteria apply.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: BI 456906 low dose<br>low dose | Drug: BI 456906<br>* BI 456906<br>|
| Experimental: BI 456906 medium dose<br>medium dose | Drug: BI 456906<br>* BI 456906<br>|
| Experimental: BI 456906 high dose<br>high dose | Drug: BI 456906<br>* BI 456906<br>|
| Placebo Comparator: Placebo<br>Placebo | Drug: Placebo<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of patients with histological improvement of NASH (NAS reduction of 2 or more points) after 48 weeks of treatment | Non-alcoholic Fatty Liver Disease (NAFLD) Activity Score (NAS) represents the sum of scores for steatosis (0-3), lobular inflammation (0-3) and ballooning (0-2); the total score ranges from 0 to 8. Improvement in histological findings is defined as a composite of: Improvement in NASH is defined as a composite of: Decrease of at least 2 points in NAS with at least 1 point decrease in NAS subscore of either lobular inflammation or ballooning AND No worsening of fibrosis, defined as absence of any increase in the fibrosis stage. | Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improvement of liver fat content (yes/no) defined as at least 30 percent (%) relative reduction in liver fat content after 48 weeks of treatment compared to baseline | Assessment will be done by magnetic resonance imaging proton density fat fraction measurement (MRI-PDFF) | Week 48 | 
| Absolute and relative change of liver fat content from baseline after 48 weeks of treatment assessed by MRI-PDFF |  | Week 48 | 
| Improvement of fibrosis (yes/no) defined as at least one stage decrease in fibrosis stage after 48 weeks of treatment assessed by liver biopsy |  | Week 48 | 
| Absolute change from baseline in NAS after 48 weeks of treatment assessed by liver biopsy |  | Week 48 |