Study of Semaglutide, and the Fixed-Dose Combination of Cilofexor and Firsocostat, Alone and in Combination, in Adults With Cirrhosis Due to Nonalcoholic Steatohepatitis (NASH)

Study Overview
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Brief Summary
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The goals of this clinical study are to learn more about the study drugs, semaglutide (SEMA) with the fixed-dose combination (FDC) of cilofexor/firsocostat (CILO/FIR), and understand whether they cause fibrosis improvement and Nonalcoholic Steatohepatitis (NASH) resolution in participants with cirrhosis due to NASH.

Official Title
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A Phase 2, Randomized, Double-Blind, Double-Dummy, Placebo-Controlled Study Evaluating the Safety and Efficacy of Semaglutide, and the Fixed-Dose Combination of Cilofexor and Firsocostat, Alone and in Combination, in Subjects With Compensated Cirrhosis (F4) Due to Nonalcoholic Steatohepatitis (NASH)

Conditions
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Nonalcoholic Steatohepatitis

Intervention / Treatment
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* Drug: Semaglutide (SEMA)
* Drug: Cilofexor (CILO)/Firsocostat (FIR)
* Drug: PTM SEMA
* Drug: PTM CILO/FIR


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Liver biopsy consistent with cirrhosis (F4) due to NASH in the opinion of the central reader. In participants who have never had a liver biopsy, a screening liver biopsy may be performed Screening laboratory parameters as determined by the study central laboratory: Estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73m^2, as calculated by the Modification of Diet in Renal Disease (MDRD) equation HbA1c ≤ 10% INR ≤ 1.4, unless due to therapeutic anticoagulation Platelet count ≥ 125,000/uL Alanine Aminotransferase (ALT) < 5 x ULN Serum albumin ≥ 3.5 g/dL Serum Alkaline Phosphatase (ALP) ≤ 2 x ULN BMI ≥ 23 kg/m^2 at screening Key Exclusion Criteria: Prior history of decompensated liver disease, including ascites, hepatic encephalopathy (HE), or variceal bleeding Child-Pugh (CP) score > 6 at screening, unless due to an alternative etiology such as Gilbert's syndrome or therapeutic anticoagulation Model for End-stage Liver Disease (MELD) score > 12 at screening, unless due to an alternative etiology such as therapeutic anticoagulation Other causes of liver disease based on medical history and/or central reader review of liver histology, including but not limited to: alcoholic liver disease, autoimmune disorders (eg, primary biliary cholangitis, primary sclerosing cholangitis, autoimmune hepatitis), drug-induced hepatotoxicity, Wilson disease, clinically significant iron overload, or alpha-1-antitrypsin deficiency Chronic HBV infection (HBsAg positive), or Chronic HCV infection (HCV antibody and HCV RNA positive). Participants cured of HCV infection less than 2 years prior to the screening visit are not eligible History of liver transplantation Current or prior history of hepatocellular carcinoma (HCC) Men who habitually drink greater than 21 units/week of alcohol or women who habitually drink greater than 14 units/week of alcohol (one unit is equivalent to 12 oz/360 mL of beer, a 4 oz/120 mL glass of wine, or 1 oz/30 mL of hard liquor). For individuals on vitamin E regimen ≥ 800 IU/day, or pioglitazone, dose must be stable, in the opinion of the investigator for at least 180 days prior to the historical or screening liver biopsy For individuals on medications for diabetes, dose must be stable, in the opinion of the investigator, for at least 90 days prior to the historical or screening liver biopsy History of type 1 diabetes Treatment with a glucagon-like peptide-1 receptor agonist (GLP-1 RA) in the period from 90 days prior to the screening visit and for individuals with a qualifying historical liver biopsy, for 90 days prior to the date of the historical liver biopsy For participants who have not completed a series of an authorized COVID-19 vaccination regimen prior to screening, a positive result for COVID-19 on SARS-CoV-2 RT-PCR test Note: Other protocol defined Inclusion/Exclusion criteria may 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SEMA + CILO/FIR FDC<br>Participants will receive semaglutide (SEMA) 0.24-2.4 mg once weekly (dose escalation every 4 weeks) and fixed-dose combination (FDC) of cilofexor and firsocostat (CILO/FIR 30 mg/20 mg) once daily for 72 weeks | Drug: Semaglutide (SEMA)<br>* Administered as subcutaneous (SC) injection<br>Drug: Cilofexor (CILO)/Firsocostat (FIR)<br>* Tablets administered orally<br>* Other names: GS-9674/GS-0976;|
| Experimental: SEMA + Placebo-To-Match (PTM) CILO/FIR<br>Participants will receive SEMA 0.24-2.4 mg once weekly (dose escalation every 4 weeks) and PTM CILO/FIR administered once daily for 72 weeks | Drug: Semaglutide (SEMA)<br>* Administered as subcutaneous (SC) injection<br>Drug: PTM CILO/FIR<br>* Tablets administered orally<br>|
| Experimental: PTM SEMA + CILO/FIR FDC<br>PTM Semaglutide once weekly and CILO/FIR 30 mg/20 mg FDC administered once daily for 72 weeks | Drug: Cilofexor (CILO)/Firsocostat (FIR)<br>* Tablets administered orally<br>* Other names: GS-9674/GS-0976;Drug: PTM SEMA<br>* Administered as SC injection<br>|
| Placebo Comparator: PTM SEMA + PTM CILO/FIR<br>PTM Semaglutide once weekly and PTM CILO/FIR once daily for 72 weeks | Drug: PTM SEMA<br>* Administered as SC injection<br>Drug: PTM CILO/FIR<br>* Tablets administered orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Achieve ≥ 1-Stage Improvement in Fibrosis According to the NASH Clinical Research Network (CRN) Classification Without Worsening of NASH in Participants Treated With SEMA + CILO/FIR Versus Placebo | Worsening of NASH is defined as a ≥ 1-point increase in hepatocellular ballooning or lobular inflammation. | Week 72 | 
| Percentage of Participants With NASH Resolution in Participants Treated with SEMA+CILO/FIR Versus Placebo | NASH resolution is defined as lobular inflammation of 0 or 1 and hepatocellular ballooning of 0. | Week 72 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With NASH Resolution In Participants Treated With SEMA+CILO/FIR Versus CILO/FIR Alone |  | Week 72 | 
| Percentage of Participants Who Achieve ≥1-Stage Improvement in Fibrosis (According to the NASH CRN Classification) Without Worsening of NASH in Participants Treated With SEMA+CILO/FIR Versus SEMA Alone | Worsening of NASH is defined as a ≥ 1-point increase in hepatocellular ballooning or lobular inflammation. | Week 72 |