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 ¹³ C-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.

Keywords: drug development; drug mechanism; fatty liver disease; pharmacodynamics; phase I−II study; randomized trial.

FIGURE 1

Plasma concentration−time profiles and pharmacokinetic characteristics of FT‐4101 following A, single oral doses and B, before and after intermittent repeat dosing for 11 weeks. Data (n = 9) for Study 2 were collected after the first dose of FT‐4101 at baseline (Cycle 1, Day 1) and after the last dose at week 11 (Cycle 4, Day 14). *Data based on n = 2. Data are mean ± SEM in the figures and mean ± SD in the accompanying tables. AUC, area under the concentration−time curve; C_max, maximum observed plasma concentration; T_max, time to reach C_max

FIGURE 2

Time‐course of fructose stimulated de novo lipogenesis (DNL) following single oral doses of A, 3 mg FT‐4101, B, 6 mg FT‐4101, C, 9 mg FT‐4101 or placebo. Fructose stimulated DNL represents the fraction of newly synthesized palmitate in plasma triglycerides, corrected for pre‐fructose DNL values and measured during short‐term 1‐¹³C₁ acetate labelling. D, Percent DNL inhibition was calculated using the fructose stimulated area under the concentration−time curve (AUC)_0‐12h. Data are mean ± SEM (A‐C) and mean ± SD (D)

FIGURE 3

Repeat dosing of 3 mg FT‐4101 inhibits hepatic de novo lipogenesis (DNL) and steatosis in subjects with non‐alcoholic fatty liver disease. Hepatic DNL represents the steady‐state fraction of newly synthesized palmitate in fasting plasma triglycerides measured after 2 weeks deuterated water labelling. Individual hepatic DNL measured at baseline and in responses to 11 weeks of A, 3 mg FT‐4101 or B, placebo intermittent treatment. Individual magnetic resonance imaging (MRI)‐proton density fat fraction (PDFF) measured at baseline and in responses to 6 and 12 weeks of D, 3 mg FT‐4101 or E, placebo intermittent treatment. Percent change from baseline in hepatic DNL (C) and MRI‐PDFF (F) after repeat intermittent dosing with placebo or 3 mg FT‐4101. G, Relationship between percent changes in steady‐state hepatic DNL and hepatic steatosis (MRI‐PDFF) after 11 to 12 weeks of placebo and FT‐4101 treatment. The box plots provide medians with 25% and 75% quartiles and minimum and maximum values as whiskers. Linear regression was used to evaluate the relationship between DNL and MRI‐PDFF. Round symbols are individual values and values in panels A‐D are means. *P = 0.05 versus baseline (week 0)

FIGURE 4

Effect of intermittent repeat dosing of A, placebo and B, 3 mg FT‐4101 on sebum sapienate content of individuals with non‐alcoholic fatty liver disease and C, percent change from baseline in sebum sapienate content with FT‐4101 compared to placebo. *P = 0.098 versus baseline (week 0). The box plots provide medians with 25% and 75% quartiles and minimum and maximum values as whiskers. Values in panels A‐B are means

FIGURE 5

Effect of intermittent repeat dosing of A, placebo and B, 3 mg FT‐4101 on fasting plasma triglycerides (TG) of individuals with non‐alcoholic fatty liver disease and C, percent change from baseline in fasting plasma TG with FT‐4101 compared to placebo. The box plots provide medians with 25% and 75% quartiles and minimum and maximum values as whiskers