Cited by 167Liver Disease Diagnosis and TreatmentDrug-Induced Hepatotoxicity and ProtectionCancer, Lipids, and Metabolism

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

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Alkhouri, Naim, Lawitz, Eric, Noureddin, Mazen, DeFronzo, Ralph, Shulman, Gerald I.·2020·Expert Opinion on Investigational Drugs

DOI 10.1080/13543784.2020.1668374PMC PMC7063378

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Abstract

Introduction: De novo lipogenesis (DNL) plays a major role in fatty acid metabolism and contributes significantly to triglyceride accumulation within the hepatocytes in patients with nonalcoholic steatohepatitis (NASH). Acetyl-CoA carboxylase (ACC) converts acetyl-CoA to malonyl CoA and is a rate-controlling step in DNL. Furthermore, malonyl-CoA is an important regulator of hepatic mitochondrial fat oxidation through its ability to inhibit carnitine palmitoyltransferase I. Therefore, inhibiting ACC pharmacologically represents an attractive approach to treating NASH.Areas covered: This article summarizes preclinical and clinical data on the efficacy and safety of the liver-targeted ACC inhibitor GS-0976 (Firsocostat) for the treatment of NASH. In a phase 2 trial that included 126 patients with NASH and fibrosis, GS-0976 20 mg daily for 12 weeks showed significant relative reduction in liver fat by 29%; however, treatment was associated with an increase in plasma triglycerides with 16 patients having levels >500 mg/dL.Expert opinion: Preclinical and preliminary clinical data support the development of GS-0976 as treatment for NASH. ACC-induced hypertriglyceridemia can be mitigated by fish oil or fibrates, but the long-term cardiovascular effects require further investigations.

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Authors: Alkhouri, N., Lawitz, E., Noureddin, M., DeFronzo, R., & Shulman, G. I.
Affiliations: The University of Texas at San Antonio Health Science Center (US)
Cedars-Sinai Medical Center (US)
Yale University (US)
Corresponding author: Alkhouri, Naim
ORCID: Alkhouri, Naim
Lawitz, Eric
Noureddin, Mazen
DeFronzo, Ralph
Shulman, Gerald I.
Venue: Expert Opinion on Investigational Drugs
Publisher: Informa UK Limited
Published: 2019-09-19
Volume: 29
Issue: 2
Pages: 135-141
ISSN: 1354-3784 (ISSN-L)
1744-7658
DOI: 10.1080/13543784.2020.1668374
PMC: PMC7063378
OpenAlex: W2973125925
Cited by: 162
References: 53
Citations by year: 2026: 16 · 2025: 23 · 2024: 29 · 2023: 24 · 2022: 24 · 2021: 26 · 2020: 19 · 2019: 1
FWCI: 14.08
Type: journal article
Language: en
Open access: green
europepmc.org
Locations: Expert Opinion on Investigational Drugs (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: National Institutes of Health (UL1TR001863)
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK119968, R01DK114793, R01DK116774, R01DK113984, P30DK034989, P30DK045735)
National Center for Advancing Translational Sciences
Topics: Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
Keywords: acetyl-CoA carboxylase inhibitors, nonalcoholic steatohepatitis, de novo lipogenesis, hepatic lipid accumulation, hypertriglyceridemia, liver fibrosis, fish oil, fibrates, cardiovascular safety, malonyl-CoA
MeSH terms: Acetyl-CoA Carboxylase, Animals, Enzyme Inhibitors, Fatty Acids, Humans, Oxazoles, Pyrimidines, Triglycerides, Drugs, Investigational, Lipogenesis, Isobutyrates, Non-alcoholic Fatty Liver Disease

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

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