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

Nonalcoholic Steatohepatitis (NASH) Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02781584
• Other study ID #: GS-US-384-3914
• Status: Completed
• Phase: Phase 2
• Start date: June 13, 2016
• Est. completion date: December 17, 2020

Study information

• Verified date: March 2022
• Source: Gilead Sciences
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 220
• Est. completion date: December 17, 2020
• Est. primary completion date: December 17, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Fatty Liver
• Liver Diseases
• Non-alcoholic Fatty Liver Disease
• Nonalcoholic Fatty Liver Disease (NAFLD)
• Nonalcoholic Steatohepatitis (NASH)

Intervention

Drug:
• SEL
Administered orally once daily
• FIR
Administered orally once daily
• CILO
Administered orally once daily
• FENO
Administered orally once daily
• VAS
Administered orally two times daily

Locations

Country	Name	City	State
New Zealand	Auckland Clinical Studies Ltd	Auckland
United States	Delta Research Partners, LLC	Bastrop	Louisiana
United States	Arizona Liver Health	Chandler	Arizona
United States	Gastro One	Germantown	Tennessee
United States	Altman Clinical and Translational Research Clinic	La Jolla	California
United States	Florida Research Institute	Lakewood Ranch	Florida
United States	Pinnacle Clinical Research, PLLC	Live Oak	Texas
United States	Cedars-Sinai Medical Center	Los Angeles	California
United States	Ruane Clinical Research Group Inc.	Los Angeles	California
United States	Quality Medical Research	Nashville	Tennessee
United States	American Research Corporation at the Texas Liver Institute	San Antonio	Texas
United States	Pinnacle Clinical Research, PLLC	San Antonio	Texas
United States	Stanford Hospital and Clinics (SHC)	Stanford	California

Sponsors (1)

Lead Sponsor	Collaborator
Gilead Sciences

Countries where clinical trial is conducted

United States,  New Zealand, 

References & Publications (6)

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

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 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. — View Citation

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.

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.
Primary	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.
Primary	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.