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Abstract
BACKGROUND AND AIMS:
De novo lipogenesis is increased in livers of patients with nonalcoholic steatohepatitis (NASH). Acetyl-CoA carboxylase catalyzes the rate-limiting step in this process. We evaluated the safety and efficacy of GS-0976, an inhibitor of acetyl-CoA 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 ≥8%, based on the magnetic resonance imaging-estimated proton density fat fraction (MRI-PDFF), and liver stiffness ≥2.5 kPa, based on magnetic resonance elastography measurement, or historical biopsy consistent with NASH and F1-F3 fibrosis. Patients were randomly assigned (2:2:1) to groups given GS-0976 (20 mg), GS-0976 (5mg), 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 relationship between dose and efficacy.
RESULTS:
A ≥30% relative decrease from baseline in MRI-PDFF (PDFF response) occurred in 48% of patients given 20 mg GS-0976 (P=.004 vs placebo), 23% given 5 mg GS-0976 (P=.43 vs placebo), and 15% given placebo. Median relative decreases in MRI-PDFF were greater in patients given 20 mg GS-0976 (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 reduction in the fibrosis marker TIMP1 was observed in patients given 20 mg GS-0976. Plasma levels of acylcarnitine species also decreased in patients with a PDFF response given 20 mg GS-0976. 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 weeks administration of 20 mg GS-0976 to reduce hepatic steatosis, selected markers of fibrosis, and liver biochemistry. ClinicalTrials.gov no: NCT02856555.