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

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

Official Title
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A Proof of Concept, Open-Label Study Evaluating the Safety, Tolerability, and Efficacy of Monotherapy and Combination Regimens in Subjects With Nonalcoholic Steatohepatitis (NASH)

Conditions
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Nonalcoholic Steatohepatitis

Intervention / Treatment
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* Drug: Semaglutide
* Drug: Firsocostat
* Drug: Cilofexor


Participation Criteria
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Eligibility Criteria
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Key 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.

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Semaglutide<br>Semaglutide 0.24 mg - 2.4 mg (dose escalated over 16 weeks) for 24 weeks | Drug: Semaglutide<br>* Solution administered subcutaneously with pre-filled PDS290 pen-injector once weekly<br>|
| Experimental: Semaglutide + Firsocostat 20 mg<br>Semaglutide 0.24 mg - 2.4 mg (dose escalated over 16 weeks) + firsocostat 20 mg for 24 weeks | Drug: Semaglutide<br>* Solution administered subcutaneously with pre-filled PDS290 pen-injector once weekly<br>Drug: Firsocostat<br>* Tablets administered orally once daily<br>* Other names: GS-0976;|
| Experimental: Semaglutide + Cilofexor 30 mg<br>Semaglutide 0.24 mg - 2.4 mg (dose escalated over 16 weeks) + cilofexor 30 mg for 24 weeks | Drug: Semaglutide<br>* Solution administered subcutaneously with pre-filled PDS290 pen-injector once weekly<br>Drug: Cilofexor<br>* Tablets administered orally once daily<br>* Other names: GS-9674;|
| Experimental: Semaglutide + Cilofexor 100 mg<br>Semaglutide 0.24 mg - 2.4 mg (dose escalated over 16 weeks) + cilofexor 100 mg for 24 weeks | Drug: Semaglutide<br>* Solution administered subcutaneously with pre-filled PDS290 pen-injector once weekly<br>Drug: Cilofexor<br>* Tablets administered orally once daily<br>* Other names: GS-9674;|
| Experimental: Semaglutide + Firsocostat 20 mg + Cilofexor 30 mg<br>Semaglutide 0.24 mg - 2.4 mg (dose escalated over 16 weeks) + firsocostat 20 mg + cilofexor 30 mg for 24 weeks | Drug: Semaglutide<br>* Solution administered subcutaneously with pre-filled PDS290 pen-injector once weekly<br>Drug: Firsocostat<br>* Tablets administered orally once daily<br>* Other names: GS-0976;Drug: Cilofexor<br>* Tablets administered orally once daily<br>* Other names: GS-9674;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs) | 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. | First dose date up to Week 24 plus 30 days | 
| Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities | 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. | First dose date up to 24 weeks plus 30 days |