Safety, Tolerability, and Efficacy of Selonsertib, Firsocostat, and Cilofexor in Adults With Nonalcoholic Steatohepatitis (NASH)

This is an interventional treatment trial for Nonalcoholic Steatohepatitis (NASH) Read More

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.