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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.

SUBMITTER: Loomba R

PROVIDER: S-EPMC6318218 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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

Loomba Rohit R Kayali Zeid Z Noureddin Mazen M Ruane Peter P Lawitz Eric J EJ Bennett Michael M Wang Lulu L Harting Eliza E Tarrant Jacqueline M JM McColgan Bryan J BJ Chung Chuhan C Ray Adrian S AS Subramanian G Mani GM Myers Robert P RP Middleton Michael S MS Lai Michelle M Charlton Michael M Harrison Stephen A SA

Gastroenterology 20180727 5

<h4>Background & aims</h4>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.<h4>Methods</h4>We analyzed data from 126 patients with hepatic steatosis of at least 8%, based on the magnetic resonance i ...[more]

PMID: 30059671

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Project description:Abstract Background Overweight/obesity are associated with relative growth hormone (GH) deficiency, and GH deficiency has been implicated in the development of nonalcoholic fatty liver disease (NAFLD). NAFLD and its progressive form, nonalcoholic steatohepatitis (NASH), are associated with significant morbidity and mortality, and no approved therapies currently exist. We hypothesized that GH administration would reduce hepatic steatosis, inflammation and fibrosis in individuals with overweight/obesity and NAFLD. Methods A randomized, double-blind, placebo-controlled trial of GH administration in adults with overweight/obesity and NAFLD was conducted (NCT02217345). Fifty-three adults ages 18-70 years with BMI ≥25 kg/m2 and NAFLD were randomly assigned to receive daily subcutaneous GH or placebo for 6 months. Target IGF-1 was upper quartile of normal. Primary endpoints included intrahepatic lipid content (IHL) by proton magnetic resonance spectroscopy (1H-MRS) and radiographic inflammation and fibrosis by LiverMultiScan corrected T1 score (cT1). Secondary endpoints included alanine transaminase (ALT), visceral adipose tissue (VAT) by dual-energy x-ray absorptiometry (DEXA), hsCRP and HOMA-IR. Data are reported as mean ± SD. Results Forty-one subjects completed the 6-month study. Mean age (45±12 years), BMI (33±5 kg/m2), sex distribution (50% female) and baseline IHL (21.4±14.5%) did not differ between the GH and placebo groups. Over the 6-month study period, there was no difference in change in weight between the groups (GH -0.7±3.8% and placebo -0.6±4.0%, p=0.7). Change in absolute percent IHL was significantly greater in the GH vs placebo group (-5.1±10.5% vs 3.8±6.9%, p=0.003), resulting in a net treatment effect of an 8.9% reduction in IHL (95% CI 3.3-14.6%). Improvements in serum ALT (-10±13 IU/L vs -2±12 IU/L, p=0.009) and cT1 score (-11±63 ms vs 27±57 ms, p=0.037) were greater in the GH vs placebo group. There were also significant reductions in DEXA VAT area (-10±9 cm2 vs 0±20 cm2, p=0.050) and hsCRP (-0.8±0.9 mg/dL vs -0.3±1.7 mg/dL, p=0.017) in the GH vs placebo group. In multivariable models controlling for age, sex, change in weight and change in HOMA-IR, significant effects of GH vs placebo were observed on IHL (p=0.012) and ALT (p=0.015) with a trend towards improvement in cT1 score (p=0.088). In a secondary analysis excluding all subjects with >3% weight loss, which has been shown to independently impact NAFLD outcomes, there were significant improvements in IHL (p=0.001), ALT (p=0.040) and cT1 score (p=0.050) in the GH vs placebo group. No subjects were discontinued due to hyperglycemia (fasting glucose ≥126 mg/dL or HbA1c ≥6.5%). Mild edema was the only treatment-emergent side effect that had a significantly greater incidence in the GH vs placebo group (19% vs 0%, p=0.048). Conclusion GH administration reduces hepatic steatosis and markers of hepatic inflammation and fibrosis in adults with overweight/obesity and NAFLD. The GH/IGF-1 axis may offer targetable therapeutic options for NAFLD/NASH. Presentation: Tuesday, June 14, 2022 10:00 a.m. - 10:15 a.m.

Project description:Background Advanced confounder-corrected chemical shift-encoded MRI-derived proton density fat fraction (PDFF) is a leading parameter for fat fraction quantification in nonalcoholic fatty liver disease (NAFLD). Because of the limited availability of this MRI technique, there is a need to develop and validate alternative parameters to assess liver fat. Purpose To assess relationship of quantitative US parameters to MRI PDFF and to develop multivariable quantitative US models to detect hepatic steatosis and quantify hepatic fat. Materials and Methods Adults with known NAFLD or who were suspected of having NAFLD were prospectively recruited between August 2015 and February 2019. Participants underwent quantitative US and chemical shift-encoded MRI liver examinations. Liver biopsies were performed if clinically indicated. The correlation between seven quantitative US parameters and MRI PDFF was evaluated. By using leave-one-out cross validation, two quantitative US multivariable models were evaluated: a classifier to differentiate participants with NAFLD versus participants without NAFLD and a fat fraction estimator. Classifier performance was summarized by area under the receiver operating characteristic curve and area under the precision-recall curve. Fat fraction estimator performance was evaluated by correlation, linearity, and bias. Results Included were 102 participants (mean age, 52 years ± 13 [standard deviation]; 53 women), 78 with NAFLD (MRI PDFF ≥ 5%). A two-variable classifier yielded a cross-validated area under the receiver operating characteristic curve of 0.89 (95% confidence interval: 0.82, 0.96) and an area under the precision-recall curve of 0.96 (95% confidence interval: 0.93, 0.99). The cross-validated fat fraction predicted by a two-variable fat fraction estimator was correlated with MRI PDFF (Spearman ρ = 0.82 [P < .001]; Pearson r = 0.76 [P < .001]). The mean bias was 0.02% (P = .97), and 95% limits of agreement were ±12.0%. The predicted fat fraction was linear with MRI PDFF (R 2 = 0.63; slope, 0.69; intercept, 4.3%) for MRI PDFF of 34% or less. Conclusion A multivariable quantitative US approach yielded excellent correlation with MRI proton density fat fraction for hepatic steatosis assessment in nonalcoholic fatty liver disease. © RSNA, 2020 Online supplemental material is available for this article.

Project description:BACKGROUND:Nonalcoholic fatty liver disease (NAFLD) and resulting nonalcoholic steatohepatitis (NASH) are reaching global epidemic proportions. Lack of non-invasive diagnostic tools and effective therapies constitute two of the major hurdles for a bona fide treatment and a reversal of NASH progression and/or regression of the disease. Nitro-oleic acid (OA-NO2) has been proven effective in multiple experimental models of inflammation and fibrosis. Thus, the potential benefit of in vivo administration of OA-NO2 to treat advanced NAFLD was tested herein in a model of long-term NASH diet-induced liver damage. METHODS:Non-invasive imaging (e.g. photoacustic-ultrasound (PA-US)) was pursued to establish advanced experimental model of NASH in mice in which both steatosis and fibrosis were diagnosed prior experimental therapy with OA-NO2. Experimental controls included equimolar amounts of the non-nitrated oleic acid (OA). CLAMS and NMR-based analysis was used for energy metabolism. FINDINGS:CLAMS and NMR-based analysis demonstrates that OA-NO2 improves body composition and energy metabolism and inhibits hepatic triglyceride (TG) accumulation. Photoacoustic-ultrasound imaging revealed a robust inhibition of liver steatosis and fibrosis by OA-NO2. RNA-sequencing analysis uncovered inflammation and fibrosis as major pathways suppressed by OA-NO2 administration, as well as regulation of lipogenesis and lipolysis pathways, with a robust inhibition of SREBP1 proteolytic activation and subsequent lipogenesis gene expression by OA-NO2. These results were further supported by histological analysis and quantification of lipid accumulation, lobular inflammation (F4/80 staining) and fibrosis (collagen deposition, ?SMA staining) as well as established parameters of liver damage (ALT). In vitro studies indicate that OA-NO2 inhibits TG biosynthesis and accumulation in hepatocytes and inhibits fibrogenesis in human stellate cells. INTERPRETATION:OA-NO2 improve steatohepatitis and fibrosis and may constitute an effective therapeutic approach against advanced NAFLD that warrants further clinical evaluation.

Dataset Information

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

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

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