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

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. 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. 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. 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.

Loomba R ，Kayali Z ，Noureddin M ，Ruane P ，Lawitz EJ ，Bennett M ，Wang L ，Harting E ，Tarrant JM ，McColgan BJ ，Chung C ，Ray AS ，Subramanian GM ，Myers RP ，Middleton MS ，Lai M ，Charlton M ，Harrison SA ... -  《-》

Acetyl-CoA Carboxylase Inhibitor GS-0976 for 12 Weeks Reduces Hepatic De Novo Lipogenesis and Steatosis in Patients With Nonalcoholic Steatohepatitis.

Increased de novo lipogenesis (DNL) contributes to the pathogenesis of nonalcoholic steatohepatitis (NASH). Acetyl-CoA carboxylase catalyzes the rate-limiting step in DNL. We evaluated the safety and efficacy of GS-0976, a small molecule inhibitor of acetyl-CoA carboxylase, in patients with NASH. In an open-label prospective study, patients with NASH (n = 10) received GS-0976 20 mg orally once daily for 12 weeks. NASH was diagnosed based on a proton density fat fraction estimated by magnetic resonance imaging (MRI-PDFF) ≥10% and liver stiffness by magnetic resonance elastography (MRE) ≥2.88 kPa. The contribution from hepatic DNL to plasma palmitate was measured by 14 days of heavy water labeling before and at the end of treatment. We performed the same labelling protocol in an analysis of healthy volunteers who were not given DNL (controls, n = 10). MRI-PDFF and MRE at baseline, and at weeks 4 and 12 of GS-0976 administration, were measured. We analyzed markers of liver injury and serum markers of fibrosis. The contribution of hepatic DNL to plasma palmitate was significantly greater in patients with NASH compared with controls (43% vs 18%) (P = .003). After 12 weeks administration of GS-0976, the median hepatic DNL was reduced 22% from baseline in patients with NASH (P = .004). Compared with baseline, reductions in MRI-PDFF at week 12 (15.7% vs 9.1% at baseline; P = .006), liver stiffness by MRE (3.4 kPa vs 3.1 kPa at baseline; P = .049), TIMP metallopeptidase inhibitor 1 (275 ng/mL vs 244 ng/mL at baseline; P = .049), and serum level of alanine aminotransferase (101 U/L vs 57 U/L at baseline; P = .23) were consistent with decreased hepatic lipid content and liver injury. At week 12, 7 patients (70%) had a ≥30% decrease in MRI-PDFF. In an open-label study, patients with NASH given GS-0976 for 12 weeks had reduced hepatic DNL, steatosis, and markers of liver injury. ClinicalTrials.gov no: NCT02856555.

Lawitz EJ ，Coste A ，Poordad F ，Alkhouri N ，Loo N ，McColgan BJ ，Tarrant JM ，Nguyen T ，Han L ，Chung C ，Ray AS ，McHutchison JG ，Subramanian GM ，Myers RP ，Middleton MS ，Sirlin C ，Loomba R ，Nyangau E ，Fitch M ，Li K ，Hellerstein M ... -  《-》

Acetyl-CoA carboxylase 1 and 2 inhibition ameliorates steatosis and hepatic fibrosis in a MC4R knockout murine model of nonalcoholic steatohepatitis.

Matsumoto M ，Yashiro H ，Ogino H ，Aoyama K ，Nambu T ，Nakamura S ，Nishida M ，Wang X ，Erion DM ，Kaneko M ... -  《PLoS One》

GS-0976 (Firsocostat): an investigational liver-directed acetyl-CoA carboxylase (ACC) inhibitor for the treatment of non-alcoholic steatohepatitis (NASH).

Alkhouri N ，Lawitz E ，Noureddin M ，DeFronzo R ，Shulman GI ... -  《-》

Cilofexor, a Nonsteroidal FXR Agonist, in Patients With Noncirrhotic NASH: A Phase 2 Randomized Controlled Trial.

We evaluated the safety and efficacy of cilofexor (formerly GS-9674), a small-molecule nonsteroidal agonist of farnesoid X receptor, in patients with nonalcoholic steatohepatitis (NASH). In this double-blind, placebo-controlled, phase 2 trial, 140 patients with noncirrhotic NASH, diagnosed by magnetic resonance imaging-proton density fat fraction (MRI-PDFF) ≥8% and liver stiffness ≥2.5 kPa by magnetic resonance elastography (MRE) or historical liver biopsy, were randomized to receive cilofexor 100 mg (n = 56), 30 mg (n = 56), or placebo (n = 28) orally once daily for 24 weeks. MRI-PDFF, liver stiffness by MRE and transient elastography, and serum markers of fibrosis were measured at baseline and week 24. At baseline, median MRI-PDFF was 16.3% and MRE-stiffness was 3.27 kPa. At week 24, patients receiving cilofexor 100 mg had a median relative decrease in MRI-PDFF of -22.7%, compared with an increase of 1.9% in those receiving placebo (P = 0.003); the 30-mg group had a relative decrease of -1.8% (P = 0.17 vs. placebo). Declines in MRI-PDFF of ≥30% were experienced by 39% of patients receiving cilofexor 100 mg (P = 0.011 vs. placebo), 14% of those receiving cilofexor 30 mg (P = 0.87 vs. placebo), and 13% of those receiving placebo. Serum gamma-glutamyltransferase, C4, and primary bile acids decreased significantly at week 24 in both cilofexor treatment groups, whereas significant changes in Enhanced Liver Fibrosis scores and liver stiffness were not observed. Cilofexor was generally well-tolerated. Moderate to severe pruritus was more common in patients receiving cilofexor 100 mg (14%) than in those receiving cilofexor 30 mg (4%) and placebo (4%). Cilofexor for 24 weeks was well-tolerated and provided significant reductions in hepatic steatosis, liver biochemistry, and serum bile acids in patients with NASH. ClinicalTrials.gov No. NCT02854605.

Patel K ，Harrison SA ，Elkhashab M ，Trotter JF ，Herring R ，Rojter SE ，Kayali Z ，Wong VW ，Greenbloom S ，Jayakumar S ，Shiffman ML ，Freilich B ，Lawitz EJ ，Gane EJ ，Harting E ，Xu J ，Billin AN ，Chung C ，Djedjos CS ，Subramanian GM ，Myers RP ，Middleton MS ，Rinella M ，Noureddin M ... -  《-》