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Clinical Trial
. 2021 Feb;73(2):625-643.
doi: 10.1002/hep.31622.

Combination Therapies Including Cilofexor and Firsocostat for Bridging Fibrosis and Cirrhosis Attributable to NASH

Rohit Loomba  1 , Mazen Noureddin  2 , Kris V Kowdley  3 , Anita Kohli  4 , Aasim Sheikh  5 , Guy Neff  6 , Bal Raj Bhandari  7 , Nadege Gunn  8 , Stephen H Caldwell  9 , Zachary Goodman  10 , Ilan Wapinski  11 , Murray Resnick  11 , Andrew H Beck  11 , Dora Ding  12 , Catherine Jia  12 , Jen-Chieh Chuang  12 , Ryan S Huss  12 , Chuhan Chung  12 , G Mani Subramanian  12 , Robert P Myers  12 , Keyur Patel  13 , Brian B Borg  14 , Reem Ghalib  15 , Heidi Kabler  16 , John Poulos  17 , Ziad Younes  18 , Magdy Elkhashab  19 , Tarek Hassanein  20 , Rajalakshmi Iyer  21 , Peter Ruane  22 , Mitchell L Shiffman  23 , Simone Strasser  24 , Vincent Wai-Sun Wong  25 , Naim Alkhouri  26 ; for the ATLAS Investigators
Affiliations
Clinical Trial

Combination Therapies Including Cilofexor and Firsocostat for Bridging Fibrosis and Cirrhosis Attributable to NASH

Rohit Loomba et al. Hepatology. 2021 Feb.

Abstract

Background and aims: Advanced fibrosis attributable to NASH is a leading cause of end-stage liver disease.

Approach and results: In this phase 2b trial, 392 patients with bridging fibrosis or compensated cirrhosis (F3-F4) were randomized to receive placebo, selonsertib 18 mg, cilofexor 30 mg, or firsocostat 20 mg, alone or in two-drug combinations, once-daily for 48 weeks. The primary endpoint was a ≥1-stage improvement in fibrosis without worsening of NASH between baseline and 48 weeks based on central pathologist review. Exploratory endpoints included changes in NAFLD Activity Score (NAS), liver histology assessed using a machine learning (ML) approach, liver biochemistry, and noninvasive markers. The majority had cirrhosis (56%) and NAS ≥5 (83%). The primary endpoint was achieved in 11% of placebo-treated patients versus cilofexor/firsocostat (21%; P = 0.17), cilofexor/selonsertib (19%; P = 0.26), firsocostat/selonsertib (15%; P = 0.62), firsocostat (12%; P = 0.94), and cilofexor (12%; P = 0.96). Changes in hepatic collagen by morphometry were not significant, but cilofexor/firsocostat led to a significant decrease in ML NASH CRN fibrosis score (P = 0.040) and a shift in biopsy area from F3-F4 to ≤F2 fibrosis patterns. Compared to placebo, significantly higher proportions of cilofexor/firsocostat patients had a ≥2-point NAS reduction; reductions in steatosis, lobular inflammation, and ballooning; and significant improvements in alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, bile acids, cytokeratin-18, insulin, estimated glomerular filtration rate, ELF score, and liver stiffness by transient elastography (all P ≤ 0.05). Pruritus occurred in 20%-29% of cilofexor versus 15% of placebo-treated patients.

Conclusions: In patients with bridging fibrosis and cirrhosis, 48 weeks of cilofexor/firsocostat was well tolerated, led to improvements in NASH activity, and may have an antifibrotic effect. This combination offers potential for fibrosis regression with longer-term therapy in patients with advanced fibrosis attributable to NASH.

Trial registration: ClinicalTrials.gov NCT03449446.

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References

    1. Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease‐meta‐analytic assessment of prevalence, incidence, and outcomes. Hepatology 2016;64:73‐84.
    1. Loomba R, Chalasani N. The hierarchical model of NAFLD: prognostic significance of histologic features in NASH. Gastroenterology 2015;149:278‐281.
    1. Angulo P, Kleiner DE, Dam‐Larsen S, Adams LA, Bjornsson ES, Charatcharoenwitthaya P, et al. Liver fibrosis, but no other histologic features, is associated with long‐term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology 2015;149:389‐397.e10.
    1. Sanyal AJ, Harrison SA, Ratziu V, Abdelmalek MF, Diehl AM, Caldwell S, et al. The natural history of advanced fibrosis due to nonalcoholic steatohepatitis: data from the simtuzumab trials. Hepatology 2019;70:1913‐1927.
    1. Rotman Y, Sanyal AJ. Current and upcoming pharmacotherapy for non‐alcoholic fatty liver disease. Gut 2017;66:180‐190.

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