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.
Declaration of interest
GI Shulman receives investigator-initiated support from Merck, AstraZeneca and Gilead Sciences (the maker of GS-0976) and he serves on Scientific Advisory Boards for Merck, AstraZeneca, Gilead Sciences, Aegerion Pharmaceuticals, Novo Nordisk, iMetabolic Biopharma and Janseen Research and Development. N Alkhouri, E Lawitz, M Noureddin, and R DeFronz receive research funding from, and serve on Scientific Advisory Board for Gilead Sciences (the maker of GS-0976). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Reviewer disclosures
One reviewer received study support and provided consultation services for Gilead Sciences. One reviewer has served as a consultant for Astra Zeneca, Pfizer, AMGEN, Sanofi, Camp4, Medacorp, foresite labs, Akcea, Ionis, and Celgene.
Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose.