Safety, Tolerability, and Efficacy of Monotherapy and Combination Regimens in Participants With Nonalcoholic Steatohepatitis (NASH)

Phase 2

Completed

Brief Summary: The primary objective of this study is to evaluate the safety and tolerability of study drug(s) in participants with nonalcoholic steatohepatitis (NASH).

Recruitment & Eligibility

Inclusion Criteria

Historical liver biopsy consistent with NASH with stage 2-3 fibrosis according to NASH Clinical Research Network (CRN) classification OR clinical diagnosis of nonalcoholic fatty liver disease and screening FibroTest, magnetic resonance imaging - proton density fat fraction (MRI-PDFF), and FibroScan
Screening laboratory parameters, as determined by central laboratory:
- Alanine aminotransferase (ALT) ≤ 5 x upper limit of the normal range (ULN)
- Estimated glomerular filtration rate (eGFR) ≥ 30 milliliter/minute (mL/min), as calculated by the Modification of Diet in Renal Disease (MDRD) study equation
- HbA1c ≤ 9.5%
- International normalized ratio (INR) ≤ 1.2, unless due to therapeutic anti-coagulation therapy
- Platelet count ≥ 100,000/μL
- Total bilirubin < 1.3 x ULN unless alternate etiology such as Gilbert's syndrome present
- Calcitonin ≤ 100 ng/L
Body Mass Index (BMI) > 23 kg/m^2 and body weight of > 60 kg

Key

Exclusion Criteria

Any historical liver biopsy consistent with cirrhosis
Any history of decompensated liver disease, including ascites, hepatic encephalopathy, or variceal bleeding
Other causes of liver disease, including but not limited to: alcoholic liver disease, hepatitis B, hepatitis C, autoimmune disorders (eg, primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), autoimmune hepatitis), drug-induced hepatotoxicity, Wilson disease, clinically significant iron overload, or alpha-1-antitrypsin deficiency requiring treatment
History of liver transplantation
History of hepatocellular carcinoma
History of pancreatitis (acute or chronic)
Personal or first degree relative(s) history of multiple endocrine neoplasia type 2 or medullary thyroid carcinoma
Treatment with glucagon-like peptide-1 receptor agonists (GLP-1 RA) in the period from 90 days prior to the date of the Screening Visit
Individuals on antidiabetic medications must be on a stable dose for at least 90 days prior to the date of the Screening Visit and in the period between the date of the Screening Visit and Enrollment (Day -14)

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Arm && Interventions

Group	Intervention	Description
Semaglutide + Firsocostat 20 mg + Cilofexor 30 mg	Cilofexor	Semaglutide 0.24 mg - 2.4 mg (dose escalated over 16 weeks) + firsocostat 20 mg + cilofexor 30 mg for 24 weeks
Semaglutide	Semaglutide	Semaglutide 0.24 mg - 2.4 mg (dose escalated over 16 weeks) for 24 weeks
Semaglutide + Firsocostat 20 mg	Firsocostat	Semaglutide 0.24 mg - 2.4 mg (dose escalated over 16 weeks) + firsocostat 20 mg for 24 weeks
Semaglutide + Firsocostat 20 mg	Semaglutide	Semaglutide 0.24 mg - 2.4 mg (dose escalated over 16 weeks) + firsocostat 20 mg for 24 weeks
Semaglutide + Cilofexor 30 mg	Cilofexor	Semaglutide 0.24 mg - 2.4 mg (dose escalated over 16 weeks) + cilofexor 30 mg for 24 weeks
Semaglutide + Cilofexor 30 mg	Semaglutide	Semaglutide 0.24 mg - 2.4 mg (dose escalated over 16 weeks) + cilofexor 30 mg for 24 weeks
Semaglutide + Cilofexor 100 mg	Semaglutide	Semaglutide 0.24 mg - 2.4 mg (dose escalated over 16 weeks) + cilofexor 100 mg for 24 weeks
Semaglutide + Cilofexor 100 mg	Cilofexor	Semaglutide 0.24 mg - 2.4 mg (dose escalated over 16 weeks) + cilofexor 100 mg for 24 weeks
Semaglutide + Firsocostat 20 mg + Cilofexor 30 mg	Semaglutide	Semaglutide 0.24 mg - 2.4 mg (dose escalated over 16 weeks) + firsocostat 20 mg + cilofexor 30 mg for 24 weeks
Semaglutide + Firsocostat 20 mg + Cilofexor 30 mg	Firsocostat	Semaglutide 0.24 mg - 2.4 mg (dose escalated over 16 weeks) + firsocostat 20 mg + cilofexor 30 mg for 24 weeks

Primary Outcome Measures

Name	Time	Method
Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs)	First dose date up to Week 24 plus 30 days	Treatment-emergent adverse events (TEAEs) were defined as, any AEs with an onset date on or after the study drug start date and no later than 30 days after permanent discontinuation of study drug or any AEs leading to premature discontinuation of study drug. Participants were assessed for AEs according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities	First dose date up to 24 weeks plus 30 days	Treatment-emergent laboratory abnormalities, defined as values that increase at least one toxicity grade from baseline at any time post-baseline up to and including the date of last dose of study drug plus 30 days, were summarized by treatment group. Graded laboratory abnormalities were defined using the grading scheme in the CTCAE 5.0.

Secondary Outcome Measures

Name	Time	Method

Locations (17): Cedars Sinai Medical Center
🇺🇸
Los Angeles, California, United States
Institute for Liver Health - Arizona Liver Health
🇺🇸
Chandler, Arizona, United States
Quality Medical Research, PLLC
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Nashville, Tennessee, United States
University of California San Diego (UCSD)
🇺🇸
La Jolla, California, United States
Northwell Health
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Manhasset, New York, United States
Texas Clinical Research Institute
🇺🇸
Arlington, Texas, United States
American Research Corporation
🇺🇸
San Antonio, Texas, United States
The Liver Institute at Methodist Dallas Medical Center
🇺🇸
Dallas, Texas, United States
Inland Empire Clinical Trials, LLC
🇺🇸
Rialto, California, United States
Gastro One
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Germantown, Tennessee, United States
Ruane Clinical Research Group, Inc
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Los Angeles, California, United States
Medical Associates Research Group
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San Diego, California, United States
Beth Israel Deaconess Medical Center
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Boston, Massachusetts, United States
Jubilee Clinical Research, Inc.
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Las Vegas, Nevada, United States
Gastrointestinal Specialists of Georgia
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Marietta, Georgia, United States
Southern California Research Centers
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Coronado, California, United States
University Gastroenterology
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Providence, Rhode Island, United States