Inhibition of fatty acid synthase with FT‐4101 safely reduces hepatic de novo lipogenesis and steatosis in obese subjects with non‐alcoholic fatty liver disease: Results from two early‐phase randomized trials

Abstract

Aims To assess the therapeutic potential of fatty acid synthase (FASN) inhibition with FT‐4101, a potent, selective, orally bioavailable, small‐molecule by (a) evaluating the dose−response of single FT‐4101 doses (3, 6 and 9 mg) on hepatic de novo lipogenesis (DNL) in healthy participants (Study 1) and (b) demonstrating the safety, tolerability and efficacy on hepatic steatosis after 12 weeks of FT‐4101 dosing in patients with non‐alcoholic fatty liver disease (NAFLD; Study 2). Materials and Methods In Study 1, three sequential cohorts of healthy men (n = 10/cohort) were randomized to receive a single dose of FT‐4101 (n = 5/cohort) or placebo (n = 5/cohort) followed by crossover dosing after 7 days. Hepatic DNL was assessed during fructose stimulation from 13C‐acetate incorporation. In Study 2, men and women with NAFLD (n = 14) randomly received 12 weeks of intermittent once‐daily dosing (four cycles of 2 weeks on‐treatment, followed by 1 week off‐treatment) of 3 mg FT‐4101 (n = 9) or placebo (n = 5). Steady‐state DNL based on deuterated water labelling, hepatic steatosis using magnetic resonance imaging‐proton density fat fraction and sebum lipids and circulating biomarkers were assessed. Results Single and repeat dosing of FT‐4101 were safe and well tolerated. Single FT‐4101 doses inhibited hepatic DNL dose‐dependently. Twelve weeks of 3 mg FT‐4101 treatment improved hepatic steatosis and inhibited hepatic DNL. Decreases in sebum sapienate content with FT‐4101 at week 11 were not significant compared to placebo and rebounded at week 12. Biomarkers of liver function, glucose and lipid metabolism were unchanged. Conclusions Inhibition of FASN with 3 mg FT‐4101 safely reduces hepatic DNL and steatosis in NAFLD patients.

Methyl Brevifolincarboxylate Attenuates Free Fatty Acid-Induced Lipid Metabolism and Inflammation in Hepatocytes through AMPK/NF-κB Signaling Pathway

“…For example, a recent clinical trial of NAFLD/NASH reports that the ACC1 inhibitor, GS-0976 decreases liver steatosis [ 22 ]. The FASN inhibitor, FT-4101 reduces hepatic de novo lipogenesis and has entered into clinical trials of NAFLD [ 23 ]. Additionally, it is acknowledged that various natural FASN and ACC1 inhibitors including luteolin, curcumin and resveratrol attenuate NAFLD in various in vitro and in vivo models [ 8 , 14 ].…”

Rho-Kinase as a Therapeutic Target for Nonalcoholic Fatty Liver Diseases

“…Table 2 provides an overview of selected hepatic DNL studies in human subjects with NAFLD. In summary, hepatic DNL contributes about 5% to 10% of hepatic triglyceride appearance in healthy post-absorptive humans, whereas this rate is significantly elevated to 15% to 25% for patients with NAFLD [ 11 , 81 , 84 , 86 - 88 ]. Elevated DNL activity is tightly associated with increased hepatic lipid levels.…”

Hypoxia-Inducible Factors as Key Players in the Pathogenesis of Non-alcoholic Fatty Liver Disease and Non-alcoholic Steatohepatitis

“…Increased lipogenesis is an important feature of NAFLD in human patients (42)(43)(44). Again, studies support a potential HIFmediated upregulation of this process in the context of NAFLD, although the current evidence for this role of HIF is conflicting.…”