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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
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)...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Blackwell Publishing Ltd
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898808/ https://www.ncbi.nlm.nih.gov/pubmed/33289350 http://dx.doi.org/10.1111/dom.14272 |
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author | Beysen, Carine Schroeder, Patricia Wu, Eric Brevard, Julie Ribadeneira, Maria Lu, Wei Dole, Kiran O'Reilly, Terry Morrow, Linda Hompesch, Marcus Hellerstein, Marc K. Li, Kelvin Johansson, Lars Kelly, Patrick F. |
author_facet | Beysen, Carine Schroeder, Patricia Wu, Eric Brevard, Julie Ribadeneira, Maria Lu, Wei Dole, Kiran O'Reilly, Terry Morrow, Linda Hompesch, Marcus Hellerstein, Marc K. Li, Kelvin Johansson, Lars Kelly, Patrick F. |
author_sort | Beysen, Carine |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7898808 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Blackwell Publishing Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-78988082021-03-03 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 Beysen, Carine Schroeder, Patricia Wu, Eric Brevard, Julie Ribadeneira, Maria Lu, Wei Dole, Kiran O'Reilly, Terry Morrow, Linda Hompesch, Marcus Hellerstein, Marc K. Li, Kelvin Johansson, Lars Kelly, Patrick F. Diabetes Obes Metab Original Articles 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. Blackwell Publishing Ltd 2020-12-21 2021-03 /pmc/articles/PMC7898808/ /pubmed/33289350 http://dx.doi.org/10.1111/dom.14272 Text en © 2020 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Original Articles Beysen, Carine Schroeder, Patricia Wu, Eric Brevard, Julie Ribadeneira, Maria Lu, Wei Dole, Kiran O'Reilly, Terry Morrow, Linda Hompesch, Marcus Hellerstein, Marc K. Li, Kelvin Johansson, Lars Kelly, Patrick F. 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 |
title | 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 |
title_full | 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 |
title_fullStr | 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 |
title_full_unstemmed | 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 |
title_short | 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 |
title_sort | 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 |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898808/ https://www.ncbi.nlm.nih.gov/pubmed/33289350 http://dx.doi.org/10.1111/dom.14272 |
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