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

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

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).

Study Overview

• Status: Completed
• Conditions: Nonalcoholic Steatohepatitis (NASH); Nonalcoholic Fatty Liver Disease (NAFLD)
• Intervention / Treatment: Drug: SEL; Drug: FIR; Drug: CILO; Drug: FENO; Drug: VAS

• Study Type: Interventional
• Enrollment (Actual): 220
• Phase: Phase 2

Contacts and Locations

Study Locations

• New Zealand
  • Auckland, New Zealand, 1010
    • Auckland Clinical Studies Ltd
• United States
  • Arizona
    • Chandler, Arizona, United States, 85224
      • Arizona Liver Health
  • California
    • La Jolla, California, United States, 92093
      • Altman Clinical and Translational Research Clinic
    • Los Angeles, California, United States, 90048
      • Cedars-Sinai Medical Center
    • Los Angeles, California, United States, 90036
      • Ruane Clinical Research Group Inc.
    • Stanford, California, United States, 94305
      • Stanford Hospital and Clinics (SHC)
  • Florida
    • Lakewood Ranch, Florida, United States, 34211
      • Florida Research Institute
  • Louisiana
    • Bastrop, Louisiana, United States, 71220
      • Delta Research Partners, LLC
  • Tennessee
    • Germantown, Tennessee, United States, 38138
      • Gastro One
    • Nashville, Tennessee, United States, 37211
      • Quality Medical Research
  • Texas
    • Live Oak, Texas, United States, 78233
      • Pinnacle Clinical Research, PLLC
    • San Antonio, Texas, United States, 78215
      • American Research Corporation at the Texas Liver Institute
    • San Antonio, Texas, United States, 78229
      • Pinnacle Clinical Research, PLLC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

13

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1: SEL 18 mg (Non-cirrhotic); Non-cirrhotic participants will receive selonsertib (SEL) 18 mg tablet orally once daily for 12 weeks.	Drug: SEL; Administered orally once daily; Other Names: GS-4997
Experimental: Cohort 2: FIR 20 mg (Non-cirrhotic); Non-cirrhotic participants will receive firsocostat (FIR) 20 mg tablet orally once daily for 12 weeks.	Drug: FIR; Administered orally once daily; Other Names: GS-0976
Experimental: Cohort 3: CILO 30 mg (Non-cirrhotic); Non-cirrhotic participants will receive cilofexor (CILO) 30 mg tablet once daily for 12 weeks.	Drug: CILO; Administered orally once daily; Other Names: GS-9674
Experimental: Cohort 4: SEL 18 mg + CILO 30 mg (Non-cirrhotic); Non-cirrhotic participants will receive SEL 18 mg tablet + CILO 30 mg tablet once daily for 12 weeks.	Drug: SEL; Administered orally once daily; Other Names: GS-4997; Drug: CILO; Administered orally once daily; Other Names: GS-9674
Experimental: Cohort 5: SEL 18 mg + FIR 20 mg (Non-cirrhotic); Non-cirrhotic participants will receive SEL 18 mg tablet + FIR 20 mg tablet once daily for 12 weeks.	Drug: SEL; Administered orally once daily; Other Names: GS-4997; Drug: FIR; Administered orally once daily; Other Names: GS-0976
Experimental: Cohort 6: CILO 30 mg + FIR 20 mg (Non-cirrhotic); Non-cirrhotic participants will receive CILO 30 mg tablet + FIR 20 mg tablet once daily for 12 weeks.	Drug: FIR; Administered orally once daily; Other Names: GS-0976; Drug: CILO; Administered orally once daily; Other Names: GS-9674
Experimental: Cohort 7: CILO 20 mg (Cirrhotic); Participants with Child-Pugh-Turcotte Class A cirrhosis will receive FIR 20 mg tablet once daily for 12 weeks.	Drug: FIR; Administered orally once daily; Other Names: GS-0976
Experimental: Cohort 8: CILO 30 mg (Cirrhotic); Participants with Child-Pugh-Turcotte Class A cirrhosis will receive CILO 30 mg tablet once daily for 12 weeks.	Drug: CILO; Administered orally once daily; Other Names: GS-9674
Experimental: Cohort 9: SEL 18 mg + FIR 20 mg + CILO 30 mg (Non-cirrhotic); Non-cirrhotic participants will receive SEL 18 mg tablet + FIR 20 mg tablet + CILO 30 mg tablet once daily for 12 weeks.	Drug: SEL; Administered orally once daily; Other Names: GS-4997; Drug: FIR; Administered orally once daily; Other Names: GS-0976; Drug: CILO; Administered orally once daily; Other Names: GS-9674
Experimental: Cohort 10: FIR 20 mg + FENO 48 mg; 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; Administered orally once daily; Other Names: GS-0976; Drug: FENO; Administered orally once daily
Experimental: Cohort 11: FIR 20 mg + FENO 145 mg; 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; Administered orally once daily; Other Names: GS-0976; Drug: FENO; Administered orally once daily
Experimental: Cohort 12: FIR 20 mg + CILO 30 mg + VAS 2g; 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; Administered orally once daily; Other Names: GS-0976; Drug: CILO; Administered orally once daily; Other Names: GS-9674; Drug: VAS; Administered orally two times daily
Experimental: Cohort 13: FIR 20 mg + CILO 30 mg + FENO 145 mg; 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; Administered orally once daily; Other Names: GS-0976; Drug: CILO; Administered orally once daily; Other Names: GS-9674; Drug: FENO; Administered orally once daily

What is the study measuring?

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.

Collaborators and Investigators

• Sponsor: Gilead Sciences

Publications and helpful links

General Publications

• Lawitz E, Neff G, Ruane P, Ziad Y, Jia C, Chuang J, et al. Fenofibrate Mitigates Increases in Serum Triglycerides Due to the ACC Inhibitor Firsocostat in Patients with Advanced Fibrosis Due to NASH. Poster presented at: The American Association for the Study of Liver Diseases (AASLD): The Liver Meeting; November 8-12, 2019; Boston, MA.
• Lawitz EJ, Coste A, Poordad F, Alkhouri N, Loo N, McColgan BJ, Tarrant JM, Nguyen T, Han L, Chung C, Ray AS, McHutchison JG, Subramanian GM, Myers RP, Middleton MS, Sirlin C, Loomba R, Nyangau E, Fitch M, Li K, Hellerstein M. Acetyl-CoA Carboxylase Inhibitor GS-0976 for 12 Weeks Reduces Hepatic De Novo Lipogenesis and Steatosis in Patients With Nonalcoholic Steatohepatitis. Clin Gastroenterol Hepatol. 2018 Dec;16(12):1983-1991.e3. doi: 10.1016/j.cgh.2018.04.042. Epub 2018 Apr 26.
• Lawitz E, Herring R, Younes ZH, Gane E, Ruane P, Schall RA, et al. Proof of Concept Study of an Apoptosis-Signal Regulating Kinase (ASK1) Inhibitor (Selonsertib) in Combination With An Acetyl-CoA Carboxylase Inhibitor (GS-0976) or a Farnesoid X Receptor Agonist (GS-9674) in Nash [Abstract PS-105]. European Association for the Study of the Liver (EASL); 2018 11-15 April; Paris, France.
• Lawitz E, Li K, Tarrant JM, Vimal M, Xu R, Song Q, et al. Hepatic de Novo Lipogenesis is Elevated in Patients with NASH Independent of Disease Severity [Abstract 2217]. American Association for the Study of Liver Diseases (AASLD); 2017 20-24 October Washington, DC.
• Lawitz EJ, Poordad F, Coste A, Loo N, Djedjos CS, McColgan B, et al. Acetyl-CoA carboxylase (ACC) inhibitor GS-0976 leads to suppression of hepatic de novo lipogenesis and significant improvements in MRI-PDFF, MRE, and markers of fibrosis after 12 weeks of therapy in patients with NASH [Abstract GS-009]. The International Liver Congress™ 2017: European Association for the Study of the Liver (EASL); 2017 19-23 April; Amsterdam, the Netherlands.
• Lawitz E, Bhandari BR, Ruane P, Kohli A, Harting E, Jia C, et al. Fenofibrate is Safe and Mitigates Increases in Serum Triglycerides in NASH Patients Treated with the Combination of the ACC Inhibitor Firsocostat and the FXR Agonist Cilofexor: A Randomized Trial. Poster presented at: The European Association for the Study of the Liver (EASL): International Liver Congress; June 23-26, 2021; Virtual Meeting.
• Lawitz EJ, Bhandari BR, Ruane PJ, Kohli A, Harting E, Ding D, Chuang JC, Huss RS, Chung C, Myers RP, Loomba R. Fenofibrate Mitigates Hypertriglyceridemia in Nonalcoholic Steatohepatitis Patients Treated With Cilofexor/Firsocostat. Clin Gastroenterol Hepatol. 2022 Jan 6:S1542-3565(22)00002-7. doi: 10.1016/j.cgh.2021.12.044. Online ahead of print.

Study record dates

Study Major Dates

• Study Start (Actual): June 13, 2016
• Primary Completion (Actual): December 17, 2020
• Study Completion (Actual): December 17, 2020

Study Registration Dates

• First Submitted: May 20, 2016
• First Submitted That Met QC Criteria: May 20, 2016
• First Posted (Estimate): May 24, 2016

Study Record Updates

• Last Update Posted (Actual): March 16, 2022
• Last Update Submitted That Met QC Criteria: March 7, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Firsocostat
• Other Study ID Numbers: GS-US-384-3914

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No