Study to Evaluate the Safety and Efficacy of Selonsertib, Firsocostat, Cilofexor, and Combinations in Participants With Bridging Fibrosis or Compensated Cirrhosis Due to Nonalcoholic Steatohepatitis (NASH)

• SEL (Drug): 18 mg tablet administered orally once daily without regard to food
• FIR (Drug), also known as GS-0976: 20 mg tablet administered orally once daily without regard to food
• CILO (Drug), also known as GS-9674: 30 mg tablet administered orally once daily without regard to food
• Placebo to match FIR (Drug): Tablet administered orally once daily without regard to food
• Placebo to match CILO (Drug): Tablet administered orally once daily without regard to food
• Placebo to match SEL (Drug): Tablet administered orally once daily without regard to food

Primary outcomes

• Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs) [First dose date up to 48 weeks plus 30 days]
• Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities [First dose date up to 48 weeks plus 30 days]: Treatment-emergent laboratory abnormalities were defined as values that increase at least one toxicity grade from baseline. Participants with any laboratory abnormality were reported.
• Percentage of Participants Who Achieved a ≥ 1-Stage Improvement in Fibrosis Without Worsening of NASH at Week 48 [Week 48]: Fibrosis improvement was defined as ≥ 1-stage decrease from baseline in fibrosis according to the NASH clinical research network classification (CRN) classification. Worsening of NASH was defined as ≥ 1-point increase from baseline in hepatocellular ballooning or lobular inflammation. The 95% CI was based on the Clopper-Pearson method.

Sex: All, ages: 18 Years to 80 Years

Key Inclusion Criteria:

* Liver biopsy consistent with NASH and F3 or F4 in the opinion of the central reader
* In participants who have never had a liver biopsy, liver stiffness by FibroScan® ≥ 14.0 kPa and Enhanced Liver Fibrosis (ELF™) Test score ≥ 9.8 at Screening
* Screening laboratory parameters, as determined by the central laboratory:

  * Estimated glomerular filtration rate (eGFR) ≥ 60 mL/min, as calculated by the Cockcroft-Gault equation
  * Hemoglobin A1c (HbA1c) ≤ 9.5%
  * Alanine aminotransferase (ALT) < 5 x Upper Limits of Normal (ULN)
  * Platelet count ≥ 125,000/μL

Key Exclusion Criteria:

* Prior history of decompensated liver disease including ascites, hepatic encephalopathy, or variceal bleeding
* Child-Pugh (CP) score > 6 at Screening, unless due to an alternative etiology such as Gilbert's syndrome or therapeutic anticoagulation
* Model for End-Stage Liver Disease (MELD) score > 12 at Screening, unless due to an alternate etiology such as therapeutic anticoagulation
* Other causes of liver disease based on medical history and/or centralized review of liver histology, including but not limited to: alcoholic liver disease, hepatitis B, hepatitis C, autoimmune disorders (eg, primary biliary cholangitis, primary sclerosing cholangitis, autoimmune hepatitis), drug-induced hepatotoxicity, Wilson disease, clinically significant iron overload, or alpha-1-antitrypsin deficiency requiring treatment
* History of liver transplantation
* Current or prior history of hepatocellular carcinoma

Note: Other protocol defined Inclusion/ Exclusion criteria may apply

Participant flow

Outcome results

• Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs) (Primary), Number, percentage of participants: Selonsertib 84.6; Firsocostat 85.0; Cilofexor 92.5; SEL + FIR 88.6; SEL + CILO 96.1; FIR + CILO 91.0; Placebo 79.5
• Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities (Primary), Number, percentage of participants: Selonsertib 94.9; Firsocostat 100.0; Cilofexor 97.5; SEL + FIR 98.7; SEL + CILO 96.1; FIR + CILO 100.0; Placebo 94.9
• Percentage of Participants Who Achieved a ≥ 1-Stage Improvement in Fibrosis Without Worsening of NASH at Week 48 (Primary), Number, percentage of participants: Selonsertib 28.6 (3.7 to 71.0); Firsocostat 12.1 (3.4 to 28.2); Cilofexor 11.8 (3.3 to 27.5); SEL + FIR 15.5 (8.0 to 26.0); SEL + CILO 19.1 (10.6 to 30.5); FIR + CILO 20.9 (11.9 to 32.6); Placebo 10.5 (2.9 to 24.8) (p 0.9449)

Adverse events

Time frame: First dose date up to 48 weeks plus 30 days

Serious adverse events by term

Other adverse events by term

1 more sites not listed.

• Results publication: Loomba R, et al. Safety and efficacy of combination therapies including cilofexor/firsocostat in patients with bridging fibrosis and cirrhosis due to NASH: Results of the Phase 2b ATLAS trial [accepted for oral presentation]. European Association for the Study of the Liver (EASL); 2020; Virtual.
• Results publication: Loomba R, Alkhouri N, Strasser S, Wong VWS, Schall RA, McColgan B, et al. Clinical utility and application of non-invasive tests of fibrosis in the selection of patients with advanced fibrosis due to NASH in the Phase 2 ATLAS trial (Poster SAT-315). EASL; 2019; Vienna, Austria.
• Results publication: Loomba R, Alkhouri N, Patel K, Zhang J, McColgan BJ, Djedjos S, et al. Validation of Cutoffs for Controlled Attenuation Parameter with MRI-Proton Density Fat Fraction (PDFF) as a Reference Standard in Subjects with Nonalcoholic Steatohepatitis (NASH) Across Multiple Randomized, Controlled Trials (Poster 1727). American Association for the Study of Liver Diseases (AASLD); 2019; Boston, MA, USA.
• Results publication: Loomba R, Alkhouri N, Noureddin M, Zhang J, McColgan BJ, Djedjos S, et al. Validation of the Diagnostic Accuracy of Magnetic Resonance Elastography (MRE) for the Detection of Advanced Fibrosis Due to Nash Across Multiple Phase 2 and 3 Clinical Trials (Poster 1728). AASLD; 2019; Boston, MA, USA.
• Results publication: Alkhouri N, Strasser SI, Wong VWS, Aguilar R, Chuang J, Huss R, et al. Alcohol use is Underreported in Clinical Trials of NASH: Baseline Alcohol Biomarkers from a Phase 2 Clinical Trial (Poster 1765). AASLD; 2019; Boston, MA, USA.
• Results publication: Loomba R, Noureddin M, Kowdley KV, Kohli A, Sheikh A, Neff G, Bhandari BR, Gunn N, Caldwell SH, Goodman Z, Wapinski I, Resnick M, Beck AH, Ding D, Jia C, Chuang JC, Huss RS, Chung C, Subramanian GM, Myers RP, Patel K, Borg BB, Ghalib R, Kabler H, Poulos J, Younes Z, Elkhashab M, Hassanein T, Iyer R, Ruane P, Shiffman ML, Strasser S, Wong VW, Alkhouri N; for the ATLAS Investigators. Combination Therapies Including Cilofexor and Firsocostat for Bridging Fibrosis and Cirrhosis Attributable to NASH. Hepatology. 2021 Feb;73(2):625-643. doi: 10.1002/hep.31622. PMID 33169409

• Study Protocol (PDF, 2019-04-25)
• Statistical Analysis Plan (PDF, 2019-05-22)

• Gilead Study Director, Study director, Gilead Sciences