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

Diabetes Obes Metab. 2020 Dec 2. doi: 10.1111/dom.14272. Online ahead of print.

Abstract

Aims: Hepatic de novo lipogenesis (DNL) is an attractive therapeutic target for treating non-alcoholic fatty liver disease (NAFLD) but clinical data on the safety and efficacy of fatty acid synthase (FASN) inhibitors is limited. To Here we assess the therapeutic potential of fatty acid synthase (FASN) inhibition with FT-4101, a potent, selective, orally bioavailable, small-molecule for the treatment of NASH by 1) evaluating the dose-response of single FT-4101 doses (3, 6 and 9 mg) on hepatic DNL in healthy subjects (study 1) and 2) demonstrating the safety, tolerability and efficacy on hepatic steatosis after 12 weeks FT-4101 dosing in NALFD patients (study 2).

Materials and methods: In study 1, three sequential cohorts of healthy males (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, male and female NAFLD subjects (n=14) randomly received 12 weeks of intermittent once-daily dosing (4 cycles of 2 weeks on, 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 was 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: FASN inhibition with 3 mg FT-4101 safely reduces hepatic DNL and steatosis in NAFLD patients. This article is protected by copyright. All rights reserved.