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

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.

Keywords: De Novo Lipogenesis; Effects; Magnetic Resonance Elastography; Tissue Inhibitor of Metalloproteinase 1.

Conflict of interest statement

Conflicts of Interest:

Rohit Loomba has served on advisory committees or review panels for Galmed Inc, Tobira Inc, Arrowhead Research Inc, has served as a consultant for Gilead Inc, Corgenix Inc, Janssen and Janssen Inc, Zafgen Inc, Celgene Inc, Alnylam Inc, Inanta Inc, Deutrx Inc, and has received grant/research support from Daiichi Sankyo Inc, AGA, Merck Inc, Promedior Inc, Kinemed Inc, Immuron Inc, and Adheron Inc.

Zeid Kayali discloses no conflicts of interest.

Mazen Noureddin has served on advisory committees or review panels for EchoSense, OWL, Abbott, Intercept, has received grant/research support from Genfit, Galectin, Shire, Conatus, Galmed, Zydus, Gilead, has served as a speaker for Echosense, and holds stock in Anaeots.

Peter Ruane discloses no conflicts of interest.

Eric J. Lawitz has served on advisory committees or review panels for AbbVie, Achillion Pharmaceuticals, Regulus, Theravance, Enanta, Idenix Pharmaceuticals, Janssen, Merck & Co, Novartis, Gilead, has received grant/research support from AbbVie, Achillion Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Idenix Pharmaceuticals, Intercept Pharmaceuticals, Janssen, Merck & Co, Novartis, Nitto Denko, Theravance, Salix, Enanta, has served as a speaker for Gilead, Janssen, AbbVie, Bristol Meyers Squibb, Merck, Intercept.

Michael Bennett discloses no conflicts of interest.

Lulu Wang, Eliza Harting, Jacqueline Tarrant, Bryan J. McColgan, Chuhan Chung, Adrian S. Ray, G. Mani Subramanian, and Robert P. Myers, are employees of and hold stock in Gilead Sciences, Inc.

Michael S. Middleton has served as a consultant for Bracco, Merge, has received grant/research support from Merck, Janssen, Alexion, AstraZeneca, Bristol-Myers Squibb, Galmed, General Electric, Guerbet, NuSirt, Sanofi, Shire, Celgene, Genentech, Intercept, Zydus, Gilead, Isis, Genzyme, Pfizer, Siemens, Bayer, Synageva, has served as an independent contractor for Takeda, and holds stock in Pfizer, General Electric.

Michelle Lai discloses no conflicts of interest.

Michael Charlton has served as a consultant for Novartis, Gilead, Intercept, NGM Bio, and has received grant/research support from Novartis, Gilead, Intercept, Genfit, Bristol Myers Squibb

Stephen A. Harrison has served on advisory committees or review panels for Fibrogen, Allergan, Intercept, has served as a consultant for NGM Bio, Madrigal, Octeta, Pfizer, Perspectum, Chronic Liver Disease Foundation, Genfit, has received grant/research Support from Galectin, Conatus, and has served as a speaker for Echosens.

Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1.. Flow Diagram of Study Participants.

Figure 2.. Reduction in MRI-PDFF with GS-0976.

(A) Relative changes in hepatic steatosis by MRI-PDFF between baseline and week 12 according to treatment group. Data are median (IQR). (B) Proportion of patients that achieved a ≥30% relative reduction in hepatic steatosis by MRI-PDFF between baseline and week 12.

Figure 3.. Liver stiffness measured by MRE and Transient Elastography.

(A) Relative changes in MRE-stiffness between baseline and week 12 according to treatment group. Data are median (IQR). (B)Proportion of patients that achieved a ≥15% relative reduction in MRE-stiffness between baseline and week 12. (C)Relative changes in liver stiffness by transient elastography between baseline and week 12 according to treatment group. Data are median (IQR).

Figure 4.. Liver biochemistry and serum markers of fibrosis are decreased with GS-0976 treatment.

(A) Changes in liver biochemistry and serum markers of fibrosis between baseline and week 12 according to treatment group. Data are median (IQR). (B) Changes in liver biochemistry and serum markers of fibrosis between baseline and week 12 according to PDFF response. Data are median (IQR).

Figure 5.

Relative changes of plasma acylcarnitine species between baseline and week 12 in patients treated with GS-0976 according to PDFF response.