GS-0976 Reduces Hepatic Steatosis and Fibrosis Markers in Patients With Nonalcoholic Fatty Liver Disease
| Autor: | B. Mccolgan, Michael J. Bennett, Stephen A. Harrison, Mazen Noureddin, Adrian S. Ray, G. Mani Subramanian, Chuhan Chung, L. Wang, Michelle Lai, Rohit Loomba, Eliza Harting, Michael Charlton, Michael S. Middleton, Peter Ruane, Robert P. Myers, Zeid Kayali, Jacqueline M. Tarrant, Eric Lawitz |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Liver Cirrhosis Male Effects Coenzymes Gastroenterology Oral and gastrointestinal Hepatitis 0302 clinical medicine Isobutyrates Fibrosis Non-alcoholic Fatty Liver Disease Nonalcoholic fatty liver disease Oxazoles medicine.diagnostic_test Liver Disease Middle Aged De Novo Lipogenesis Magnetic Resonance Imaging 6.1 Pharmaceuticals Lipogenesis Elasticity Imaging Techniques Biomedical Imaging 030211 gastroenterology & hepatology Female Magnetic Resonance Elastography medicine.medical_specialty Chronic Liver Disease and Cirrhosis Clinical Trials and Supportive Activities Clinical Sciences Placebo Article Paediatrics and Reproductive Medicine 03 medical and health sciences Double-Blind Method Clinical Research Internal medicine Carnitine Biopsy medicine Humans Hepatology Gastroenterology & Hepatology business.industry Neurosciences Evaluation of treatments and therapeutic interventions Magnetic resonance imaging Tissue inhibitor of metalloproteinase medicine.disease Fatty Liver Kinetics 030104 developmental biology Pyrimidines Tissue Inhibitor of Metalloproteinase 1 Steatosis business Digestive Diseases Biomarkers Acetyl-CoA Carboxylase |
| Zdroj: | Gastroenterology, vol 155, iss 5 |
| Popis: | Background & aimsDe 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.MethodsWe 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.ResultsA 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 20mg. 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% and13% in serum levels of triglycerides were observed in patients given GS-0976.ConclusionsIn 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. |
| Databáze: | OpenAIRE |
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