safety, tolerability, and efficacy of selonsertib, firsocostat, and cilofexor in adults with nonalcoholic steatohepatitis (nash)

Conditions: Nonalcoholic Steatohepatitis (NASH); Nonalcoholic Fatty Liver Disease (NAFLD)

Summary: 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).


Eligibility criteria:
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.