GS-0976 Reduces Hepatic Steatosis and Fibrosis Markers in Patients With Nonalcoholic Fatty Liver Disease

Rohit Loomba, Zeid Kayali, Mazen Noureddin, Peter Ruane, Eric J. Lawitz, Michael Bennett, Lulu Wang, Eliza Harting, Jacqueline M. Tarrant, Bryan J. McColgan, Chuhan Chung, Adrian S. Ray, G. Mani Subramanian, Robert P. Myers, Michael S. Middleton, Michelle Lai, Michael Charlton, Stephen A. Harrison

Research output: Contribution to journalArticle

63 Scopus citations

Abstract

Background & Aims: De novo lipogenesis is increased in livers of patients with nonalcoholic steatohepatitis (NASH). Acetyl-coenzyme carboxylase catalyzes the rate-limiting step in this process. We evaluated the safety and efficacy of GS-0976, an inhibitor of acetyl-coenzyme A carboxylase in liver, in a phase 2 randomized placebo-controlled trial of patients with NASH. Methods: We analyzed data from 126 patients with hepatic steatosis of at least 8%, based on the magnetic resonance imaging-estimated proton density fat fraction (MRI-PDFF), and liver stiffness of at least 2.5 kPa, based on magnetic resonance elastography measurement or historical biopsy result consistent with NASH and F1–F3 fibrosis. Patients were randomly assigned (2:2:1) to groups given GS-0976 20 mg, GS-0976 5 mg, or placebo daily for 12 weeks, from August 8, 2016 through July 18, 2017. Measures of hepatic steatosis, stiffness, serum markers of fibrosis, and plasma metabolomics were evaluated. The primary aims were to confirm previous findings and evaluate the relation between dose and efficacy. Results: A relative decrease of at least 30% from baseline in MRI-PDFF (PDFF response) occurred in 48% of patients given GS-0976 20 mg (P =.004 vs placebo), 23% given GS-0976 5 mg (P =.43 vs placebo), and 15% given placebo. Median relative decreases in MRI-PDFF were greater in patients given GS-0976 20 mg (decrease of 29%) than those given placebo (decrease of 8%; P =.002). Changes in magnetic resonance elastography-measured stiffness did not differ among groups, but a dose-dependent decrease in the fibrosis marker tissue inhibitor of metalloproteinase 1 was observed in patients given GS-0976 20 mg. Plasma levels of acylcarnitine species also decreased in patients with a PDFF response given GS-0976 20 mg. GS-0976 was safe, but median relative increases of 11% and 13% in serum levels of triglycerides were observed in patients given GS-0976. Conclusions: In a randomized placebo-controlled trial of patients with NASH, we found 12-week administration of GS-0976 20 mg decreased hepatic steatosis, selected markers of fibrosis, and liver biochemistry. ClinicalTrials.gov ID NCT02856555.

Original languageEnglish (US)
Pages (from-to)1463-1473.e6
JournalGastroenterology
Volume155
Issue number5
DOIs
StatePublished - Nov 2018

Keywords

  • De Novo Lipogenesis
  • Effects
  • Magnetic Resonance Elastography
  • Tissue Inhibitor of Metalloproteinase 1

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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    Loomba, R., Kayali, Z., Noureddin, M., Ruane, P., Lawitz, E. J., Bennett, M., Wang, L., Harting, E., Tarrant, J. M., McColgan, B. J., Chung, C., Ray, A. S., Subramanian, G. M., Myers, R. P., Middleton, M. S., Lai, M., Charlton, M., & Harrison, S. A. (2018). GS-0976 Reduces Hepatic Steatosis and Fibrosis Markers in Patients With Nonalcoholic Fatty Liver Disease. Gastroenterology, 155(5), 1463-1473.e6. https://doi.org/10.1053/j.gastro.2018.07.027