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

NCT02781584 | Completed Phase 2 Results DMC FDA Drug

• 1 other identifier: GS-US-384-3914
• Study Type: interventional
• Target: 220
• Locations: 2 countries
• Sites: 13

Brief 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).

Conditions

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

Outcome Measures

Primary Outcomes (3)

• 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.

Study Arms (13)

Cohort 1: SEL 18 mg (Non-cirrhotic)

EXPERIMENTAL

Non-cirrhotic participants will receive selonsertib (SEL) 18 mg tablet orally once daily for 12 weeks.

Drug: SEL

Cohort 2: FIR 20 mg (Non-cirrhotic)

EXPERIMENTAL

Non-cirrhotic participants will receive firsocostat (FIR) 20 mg tablet orally once daily for 12 weeks.

Drug: FIR

Cohort 3: CILO 30 mg (Non-cirrhotic)

EXPERIMENTAL

Non-cirrhotic participants will receive cilofexor (CILO) 30 mg tablet once daily for 12 weeks.

Drug: CILO

Cohort 4: SEL 18 mg + CILO 30 mg (Non-cirrhotic)

EXPERIMENTAL

Non-cirrhotic participants will receive SEL 18 mg tablet + CILO 30 mg tablet once daily for 12 weeks.

Drug: SEL; Drug: CILO

Cohort 5: SEL 18 mg + FIR 20 mg (Non-cirrhotic)

EXPERIMENTAL

Non-cirrhotic participants will receive SEL 18 mg tablet + FIR 20 mg tablet once daily for 12 weeks.

Drug: SEL; Drug: FIR

Cohort 6: CILO 30 mg + FIR 20 mg (Non-cirrhotic)

EXPERIMENTAL

Non-cirrhotic participants will receive CILO 30 mg tablet + FIR 20 mg tablet once daily for 12 weeks.

Drug: FIR; Drug: CILO

Cohort 7: CILO 20 mg (Cirrhotic)

EXPERIMENTAL

Participants with Child-Pugh-Turcotte Class A cirrhosis will receive FIR 20 mg tablet once daily for 12 weeks.

Drug: FIR

Cohort 8: CILO 30 mg (Cirrhotic)

EXPERIMENTAL

Participants with Child-Pugh-Turcotte Class A cirrhosis will receive CILO 30 mg tablet once daily for 12 weeks.

Drug: CILO

Cohort 9: SEL 18 mg + FIR 20 mg + CILO 30 mg (Non-cirrhotic)

EXPERIMENTAL

Non-cirrhotic participants will receive SEL 18 mg tablet + FIR 20 mg tablet + CILO 30 mg tablet once daily for 12 weeks.

Drug: SEL; Drug: FIR; Drug: CILO

Cohort 10: FIR 20 mg + FENO 48 mg

EXPERIMENTAL

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; Drug: FENO

Cohort 11: FIR 20 mg + FENO 145 mg

EXPERIMENTAL

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; Drug: FENO

Cohort 12: FIR 20 mg + CILO 30 mg + VAS 2g

EXPERIMENTAL

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; Drug: CILO; Drug: VAS

Cohort 13: FIR 20 mg + CILO 30 mg + FENO 145 mg

EXPERIMENTAL

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; Drug: CILO; Drug: FENO

Interventions

SEL DRUG

Administered orally once daily

Also known as: GS-4997

Cohort 1: SEL 18 mg (Non-cirrhotic); Cohort 4: SEL 18 mg + CILO 30 mg (Non-cirrhotic); Cohort 5: SEL 18 mg + FIR 20 mg (Non-cirrhotic); Cohort 9: SEL 18 mg + FIR 20 mg + CILO 30 mg (Non-cirrhotic)

FIR DRUG

Administered orally once daily

Also known as: GS-0976

Cohort 10: FIR 20 mg + FENO 48 mg; Cohort 11: FIR 20 mg + FENO 145 mg; Cohort 12: FIR 20 mg + CILO 30 mg + VAS 2g; Cohort 13: FIR 20 mg + CILO 30 mg + FENO 145 mg; Cohort 2: FIR 20 mg (Non-cirrhotic); Cohort 5: SEL 18 mg + FIR 20 mg (Non-cirrhotic); Cohort 6: CILO 30 mg + FIR 20 mg (Non-cirrhotic); Cohort 7: CILO 20 mg (Cirrhotic); Cohort 9: SEL 18 mg + FIR 20 mg + CILO 30 mg (Non-cirrhotic)

CILO DRUG

Administered orally once daily

Also known as: GS-9674

Cohort 12: FIR 20 mg + CILO 30 mg + VAS 2g; Cohort 13: FIR 20 mg + CILO 30 mg + FENO 145 mg; Cohort 3: CILO 30 mg (Non-cirrhotic); Cohort 4: SEL 18 mg + CILO 30 mg (Non-cirrhotic); Cohort 6: CILO 30 mg + FIR 20 mg (Non-cirrhotic); Cohort 8: CILO 30 mg (Cirrhotic); Cohort 9: SEL 18 mg + FIR 20 mg + CILO 30 mg (Non-cirrhotic)

FENO DRUG

Administered orally once daily

Cohort 10: FIR 20 mg + FENO 48 mg; Cohort 11: FIR 20 mg + FENO 145 mg; Cohort 13: FIR 20 mg + CILO 30 mg + FENO 145 mg

VAS DRUG

Administered orally two times daily

Cohort 12: FIR 20 mg + CILO 30 mg + VAS 2g

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:

You may not qualify if:

• 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;

Sponsors & Collaborators

• Gilead Sciences: lead

Study Sites (13)

Arizona Liver Health

Chandler, Arizona, 85224, United States

Location

Altman Clinical and Translational Research Clinic

La Jolla, California, 92093, United States

Location

Ruane Clinical Research Group Inc.

Los Angeles, California, 90036, United States

Location

Cedars-Sinai Medical Center

Los Angeles, California, 90048, United States

Location

Stanford Hospital and Clinics (SHC)

Stanford, California, 94305, United States

Location

Florida Research Institute

Lakewood Rch, Florida, 34211, United States

Location

Delta Research Partners, LLC

Bastrop, Louisiana, 71220, United States

Location

Gastro One

Germantown, Tennessee, 38138, United States

Location

Quality Medical Research

Nashville, Tennessee, 37211, United States

Location

Pinnacle Clinical Research, PLLC

Live Oak, Texas, 78233, United States

Location

American Research Corporation at the Texas Liver Institute

San Antonio, Texas, 78215, United States

Location

Pinnacle Clinical Research, PLLC

San Antonio, Texas, 78229, United States

Location

Auckland Clinical Studies Ltd

Auckland, 1010, New Zealand

Location

Related Publications (7)

• 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.

  BACKGROUND

• 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.

  PMID: 29705265 BACKGROUND

• 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.

  BACKGROUND

• 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.

  BACKGROUND

• 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.

  BACKGROUND

• 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.

  RESULT

• 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. 2023 Jan;21(1):143-152.e3. doi: 10.1016/j.cgh.2021.12.044. Epub 2022 Jan 6.

  PMID: 34999207 DERIVED

MeSH Terms

Conditions

Non-alcoholic Fatty Liver Disease

Interventions

firsocostat

Condition Hierarchy (Ancestors)

Fatty Liver; Liver Diseases; Digestive System Diseases

Results Point of Contact

• Title: Gilead Clinical Study Information Center
• Organization: Gilead Sciences

GileadClinicalTrials@gilead.com

1-833-445-3230 (GILEAD-0)

Study Officials

• Gilead Study Director

  Gilead Sciences

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: May 20, 2016
• First Posted: May 24, 2016
• Study Start: June 13, 2016
• Primary Completion: December 17, 2020
• Study Completion: December 17, 2020
• Last Updated: March 16, 2022
• Results First Posted: February 2, 2022

Record last verified: 2022-03

Data Sharing

• IPD Sharing: Will not share

Locations

NZ (1); US (12)