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

Publication ,  Journal Article
Loomba, R; Noureddin, M; Kowdley, KV; Kohli, A; Sheikh, A; Neff, G; Bhandari, BR; Gunn, N; Caldwell, SH; Goodman, Z; Wapinski, I; Resnick, M ...
Published in: Hepatology
February 2021

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.

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Published In

Hepatology

DOI

EISSN

1527-3350

Publication Date

February 2021

Volume

73

Issue

2

Start / End Page

625 / 643

Location

United States

Related Subject Headings

  • Treatment Outcome
  • Severity of Illness Index
  • Pyrimidines
  • Pyridines
  • Oxazoles
  • Non-alcoholic Fatty Liver Disease
  • Middle Aged
  • Male
  • Liver Function Tests
  • Liver Cirrhosis
 

Citation

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Loomba, R., Noureddin, M., Kowdley, K. V., Kohli, A., Sheikh, A., Neff, G., … for the ATLAS Investigators, . (2021). Combination Therapies Including Cilofexor and Firsocostat for Bridging Fibrosis and Cirrhosis Attributable to NASH. Hepatology, 73(2), 625–643. https://doi.org/10.1002/hep.31622
Loomba, Rohit, Mazen Noureddin, Kris V. Kowdley, Anita Kohli, Aasim Sheikh, Guy Neff, Bal Raj Bhandari, et al. “Combination Therapies Including Cilofexor and Firsocostat for Bridging Fibrosis and Cirrhosis Attributable to NASH.Hepatology 73, no. 2 (February 2021): 625–43. https://doi.org/10.1002/hep.31622.
Loomba R, Noureddin M, Kowdley KV, Kohli A, Sheikh A, Neff G, et al. Combination Therapies Including Cilofexor and Firsocostat for Bridging Fibrosis and Cirrhosis Attributable to NASH. Hepatology. 2021 Feb;73(2):625–43.
Loomba, Rohit, et al. “Combination Therapies Including Cilofexor and Firsocostat for Bridging Fibrosis and Cirrhosis Attributable to NASH.Hepatology, vol. 73, no. 2, Feb. 2021, pp. 625–43. Pubmed, doi:10.1002/hep.31622.
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 J-C, 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-S, 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.
Journal cover image

Published In

Hepatology

DOI

EISSN

1527-3350

Publication Date

February 2021

Volume

73

Issue

2

Start / End Page

625 / 643

Location

United States

Related Subject Headings

  • Treatment Outcome
  • Severity of Illness Index
  • Pyrimidines
  • Pyridines
  • Oxazoles
  • Non-alcoholic Fatty Liver Disease
  • Middle Aged
  • Male
  • Liver Function Tests
  • Liver Cirrhosis