Safety, Tolerability, and Efficacy of Selonsertib, Firsocostat, and Cilofexor in Adults 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 selonsertib, firsocostat, cilofexor, fenofibrate and/or Vascepa® in adults with nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH).

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

Conditions
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Nonalcoholic Steatohepatitis (NASH), Nonalcoholic Fatty Liver Disease (NAFLD)

Intervention / Treatment
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* Drug: SEL
* Drug: FIR
* Drug: CILO
* Drug: FENO
* Drug: VAS


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Males and females between 18-75 years of age (Cohorts 1-9: 18-75 years and Cohorts 10-13: ≥ 18 years); inclusive based on the date of the screening visit Willing and able to provide informed consent prior to any study specific procedures being performed For Cohorts 1 through 6 and 9, individuals must meet the following conditions: Clinical diagnosis of nonalcoholic fatty liver disease (NAFLD) Screening FibroTest® < 0.75, unless a historical liver biopsy within 12 months of Screening does not reveal cirrhosis. In individuals with Gilbert's syndrome or hemolysis, FibroTest® will be calculated using direct bilirubin instead of total bilirubin, Screening magnetic resonance imaging - proton density fat fraction (MRI-PDFF) with ≥ 10% steatosis, Screening magnetic resonance elastography (MRE) with liver stiffness ≥ 2.88 kPa, OR A historical liver biopsy within 12 months of Screening consistent with NASH (defined as the presence of steatosis, inflammation, and ballooning) with stage 2-3 fibrosis according to the NASH Clinical Research Network (CRN) classification (or equivalent), AND No documented weight loss > 5% between the date of the liver biopsy and Screening; For Cohorts 7 and 8, individuals must have a clinical diagnosis of NAFLD and have at least one of the following criteria: Screening MRE with liver stiffness ≥ 4.67 kPa, A historical FibroScan® ≥ 14 kPa within 6 months of Screening, Screening FibroTest® ≥ 0.75, A historical liver biopsy consistent with stage 4 fibrosis according to the NASH CRN classification (or equivalent); For Cohorts 10 and 11, individuals must have a clinical diagnosis of NAFLD and meet at least two criteria for metabolic syndrome modified from the NCEP ATP III Guidelines and one of the following criteria at Screening: A historical liver biopsy within 6 months of Screening consistent with NASH and bridging fibrosis (F3) or within 12 months of Screening consistent with NASH and compensated cirrhosis (F4) in the opinion of the investigator, Screening liver stiffness by MRE ≥ 3.64 kPa; Screening liver stiffness by FibroScan® ≥ 9.9 kPa; For Cohorts 12 and 13, individuals must have a clinical diagnosis of NAFLD/NASH and at least two criteria for metabolic syndrome as modified from the NCEPT ATP III Guidelines, OR one of the following criteria: A historical liver biopsy within 6 months of Screening consistent with NASH for individuals without compensated cirrhosis (F4); or within 12 months of Screening consistent with NASH for individuals with compensated cirrhosis (F4) in the opinion of the investigator, A historical MRE with liver stiffness ≥ 2.88 kPa within 6 months of Screening, A historical FibroScan® with liver stiffness ≥ 9.9 kPa within 6 months of Screening, AND No documented weight loss > 5% between the date of the historical liver biopsy, historical MRE, or historical FibroScan® and Screening; Platelet count ≥ 100,000/µL; Serum creatinine < 2 mg/dL (Cohorts 1-9) at Screening; Estimated glomerular filtration rate (eGFR) ≥ 80 mL/min (Cohorts 10-11) or ≥ 60 mL/min (Cohorts 12-13), as calculated by the Cockcroft-Gault equation at Screening; For Cohorts 10-13, serum triglyceride level ≥ 150 mg/dL at Screening. Key Exclusion Criteria: Pregnant or lactating females Other causes of liver disease including autoimmune, viral, and alcoholic liver disease Any history of decompensated liver disease, including ascites, hepatic encephalopathy or variceal bleeding For Cohorts 7-8, 10-13, Child-Pugh-Turcotte (CPT) score > 6 History of liver transplantation History of hepatocellular carcinoma; Weight reduction surgery in the past 2 years or planned during the study; Documented weight loss > 5% between the date of the historical liver biopsy and Screening, if applicable; Body Mass Index (BMI) < 18 kg/m2; ALT > 5 x ULN at Screening; For Cohorts 10-13, HbA1c ≥ 9.5% (or serum fructosamine ≥ 381 µmol if HbA1c is unable to be resulted) at Screening; For Cohorts 10-13, hemoglobin ≤ 10.6 g/dL at Screening; INR > 1.2 (Cohorts 1-9) or INR > 1.4 (Cohorts 10-13) at Screening, unless on anticoagulation therapy; Total bilirubin > 1x ULN (Cohorts 1 through 6 and 9), >1.5 x ULN (Cohorts 7 and 8), or >1.3 x ULN (Cohorts 10-13) except in confirmed cases of Gilbert's syndrome; Triglycerides ≥ 500 mg/dL (Cohorts 5-8 and 10-13) or ≥ 250 mg/dL (Cohort 9) at Screening; Model for End-Stage Liver Disease (MELD) score > 12 at Screening (Cohorts 10 -13), unless due to an alternate etiology such as therapeutic anticoagulation; Chronic hepatitis B (HBsAg positive); Chronic hepatitis C (HCV RNA positive). individuals cured of HCV infection less than 2 years prior to the Screening visit are not eligible (Cohorts 10-13); HIV Ab positive; Presence of gallstones within 6 months of Screening (Cohorts 10-13); Alcohol consumption greater than 21 oz/week for males or 14 oz/week for females (1oz/30 mL of alcohol is present in 1 12oz/360 mL beer, 1 4oz/120 mL glass of wine, and a 1 oz/30 mL measure of 40% proof alcohol); Positive urine screen for amphetamines, cocaine or opiates (i.e., heroin, morphine) at Screening. Individuals on stable methadone or buprenorphine maintenance treatment for at least 6 months prior to Screening may be included in the study. Individuals with a positive urine drug screen due to prescription opioid-based medication are eligible if the prescription and diagnosis are reviewed and approved by the investigator; Unstable cardiovascular disease; History of intestinal resection of the extent that would result in malabsorption; Use of any prohibited concomitant medications as described in the protocol; History of a malignancy within 5 years of Screening with the following exceptions: Adequately treated carcinoma in situ of the cervix, Adequately treated basal or squamous cell cancer or other localized non-melanoma skin cancer. Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 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: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Cohorts 1-6 and 9 will be enrolled sequentially while Cohorts 7 and 8 will be randomized in parallel. Cohorts 10 and 11 will be randomized in parallel. Cohorts 12 and 13 will be randomized in parallel.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: SEL 18 mg (Non-cirrhotic)<br>Non-cirrhotic participants will receive selonsertib (SEL) 18 mg tablet orally once daily for 12 weeks. | Drug: SEL<br>* Administered orally once daily<br>* Other names: GS-4997;|
| Experimental: Cohort 2: FIR 20 mg (Non-cirrhotic)<br>Non-cirrhotic participants will receive firsocostat (FIR) 20 mg tablet orally once daily for 12 weeks. | Drug: FIR<br>* Administered orally once daily<br>* Other names: GS-0976;|
| Experimental: Cohort 3: CILO 30 mg (Non-cirrhotic)<br>Non-cirrhotic participants will receive cilofexor (CILO) 30 mg tablet once daily for 12 weeks. | Drug: CILO<br>* Administered orally once daily<br>* Other names: GS-9674;|
| Experimental: Cohort 4: SEL 18 mg + CILO 30 mg (Non-cirrhotic)<br>Non-cirrhotic participants will receive SEL 18 mg tablet + CILO 30 mg tablet once daily for 12 weeks. | Drug: SEL<br>* Administered orally once daily<br>* Other names: GS-4997;Drug: CILO<br>* Administered orally once daily<br>* Other names: GS-9674;|
| Experimental: Cohort 5: SEL 18 mg + FIR 20 mg (Non-cirrhotic)<br>Non-cirrhotic participants will receive SEL 18 mg tablet + FIR 20 mg tablet once daily for 12 weeks. | Drug: SEL<br>* Administered orally once daily<br>* Other names: GS-4997;Drug: FIR<br>* Administered orally once daily<br>* Other names: GS-0976;|
| Experimental: Cohort 6: CILO 30 mg + FIR 20 mg (Non-cirrhotic)<br>Non-cirrhotic participants will receive CILO 30 mg tablet + FIR 20 mg tablet once daily for 12 weeks. | Drug: FIR<br>* Administered orally once daily<br>* Other names: GS-0976;Drug: CILO<br>* Administered orally once daily<br>* Other names: GS-9674;|
| Experimental: Cohort 7: CILO 20 mg (Cirrhotic)<br>Participants with Child-Pugh-Turcotte Class A cirrhosis will receive FIR 20 mg tablet once daily for 12 weeks. | Drug: FIR<br>* Administered orally once daily<br>* Other names: GS-0976;|
| Experimental: Cohort 8: CILO 30 mg (Cirrhotic)<br>Participants with Child-Pugh-Turcotte Class A cirrhosis will receive CILO 30 mg tablet once daily for 12 weeks. | Drug: CILO<br>* Administered orally once daily<br>* Other names: GS-9674;|
| Experimental: Cohort 9: SEL 18 mg + FIR 20 mg + CILO 30 mg (Non-cirrhotic)<br>Non-cirrhotic participants will receive SEL 18 mg tablet + FIR 20 mg tablet + CILO 30 mg tablet once daily for 12 weeks. | Drug: SEL<br>* Administered orally once daily<br>* Other names: GS-4997;Drug: FIR<br>* Administered orally once daily<br>* Other names: GS-0976;Drug: CILO<br>* Administered orally once daily<br>* Other names: GS-9674;|
| Experimental: Cohort 10: FIR 20 mg + FENO 48 mg<br>Participants will receive fenofibrate (FENO) 48 mg tablet orally once daily for 2 weeks in the pretreatment phase, then FIR 20 mg tablet + FENO 48 mg tablet orally once daily for 24 weeks in the treatment phase. Participants with compensated cirrhosis due to NASH will be accepted to participate in this cohort. | Drug: FIR<br>* Administered orally once daily<br>* Other names: GS-0976;Drug: FENO<br>* Administered orally once daily<br>|
| Experimental: Cohort 11: FIR 20 mg + FENO 145 mg<br>Participants will receive FENO 145 mg tablet orally once daily for 2 weeks in the pretreatment phase, then FIR 20 mg tablet + FENO 145 mg tablet orally once daily for 24 weeks in the treatment phase. Participants with compensated cirrhosis due to NASH will be accepted to participate in this cohort. | Drug: FIR<br>* Administered orally once daily<br>* Other names: GS-0976;Drug: FENO<br>* Administered orally once daily<br>|
| Experimental: Cohort 12: FIR 20 mg + CILO 30 mg + VAS 2g<br>Participants will receive Vascepa® (VAS) 2 g capsule orally twice daily for 2 weeks in the pretreatment phase, then FIR 20 mg tablet once daily + CILO 30 mg tablet once daily + VAS 2 g capsule twice daily for 6 weeks in the treatment phase. Participants with compensated cirrhosis due to NASH will be accepted to participate in this cohort. | Drug: FIR<br>* Administered orally once daily<br>* Other names: GS-0976;Drug: CILO<br>* Administered orally once daily<br>* Other names: GS-9674;Drug: VAS<br>* Administered orally two times daily<br>|
| Experimental: Cohort 13: FIR 20 mg + CILO 30 mg + FENO 145 mg<br>Participants will receive FENO 145 mg tablet orally once daily for 2 weeks in the pretreatment phase, then FIR 20 mg tablet once daily + CILO 30 mg tablet once daily + FENO 145 mg tablet orally once daily for 6 weeks in the treatment phase. Participants with compensated cirrhosis due to NASH will be accepted to participate in this cohort. | Drug: FIR<br>* Administered orally once daily<br>* Other names: GS-0976;Drug: CILO<br>* Administered orally once daily<br>* Other names: GS-9674;Drug: FENO<br>* Administered orally once daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Experienced Treatment-Emergent Adverse Events | Treatment-emergent AEs were defined as events that met 1 or both of the following criteria: Any AEs with onset dates on or after the study drug start date and no later than 30 days after permanent discontinuation of study drug Any AEs leading to premature discontinuation of study drug | Cohorts 1-9: First dose date up to 12 weeks plus 30 days; Cohorts 10-11: First dose date up to 26 weeks plus 30 days; Cohorts 12-13: First dose date up to 8 weeks plus 30 days. For Cohorts 10-13, the first dose date included the Pre-treatment Phase. | 
| Percentage of Participants Who Experienced Treatment Emergent Serious Adverse Events | A treatment emergent serious adverse event (SAE) was defined as an event that, at any dose, results in the following: Death Life-threatening In-patient hospitalization or prolongation of existing hospitalization Persistent or significant disability/incapacity A congenital anomaly/birth defect A medically important event or reaction | Cohorts 1-9: First dose date up to 12 weeks plus 30 days; Cohorts 10-11: First dose date up to 26 weeks plus 30 days; Cohorts 12-13: First dose date up to 8 weeks plus 30 days. For Cohorts 10-13, the first dose date included the Pre-treatment Phase. | 
| Percentage of Participants Who Experienced Grade 3 or Higher Laboratory Abnormalities | Treatment-emergent laboratory abnormalities were defined as values that increased at least 1 toxicity grade from baseline at any postbaseline time point, up to and including the date of last dose of study drug plus 30 days for subjects who permanently discontinued study drug. If baseline laboratory data were missing, then any abnormality of at least Grade 1 was considered treatment emergent. Graded laboratory abnormalities were defined using the grading scheme in the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 for Cohorts 1-9 and CTCAE Version 5.0 for Cohorts 10-13. | Cohorts 1-9: First dose date up to 12 weeks plus 30 days; Cohorts 10-11: First dose date up to 26 weeks plus 30 days; Cohorts 12-13: First dose date up to 8 weeks plus 30 days. For Cohorts 10-13, the first dose date included the Pre-treatment Phase. |