Back to Search
Start Over
TVB-2640 (FASN Inhibitor) for the Treatment of Nonalcoholic Steatohepatitis: FASCINATE-1, a Randomized, Placebo-Controlled Phase 2a Trial.
- Source :
-
Gastroenterology [Gastroenterology] 2021 Nov; Vol. 161 (5), pp. 1475-1486. Date of Electronic Publication: 2021 Jul 23. - Publication Year :
- 2021
-
Abstract
- Background & Aims: Increased de novo lipogenesis creates excess intrahepatic fat and lipotoxins, propagating liver damage in nonalcoholic steatohepatitis. TVB-2640, a fatty acid synthase inhibitor, was designed to reduce excess liver fat and directly inhibit inflammatory and fibrogenic pathways. We assessed the safety and efficacy of TVB-2640 in patients with nonalcoholic steatohepatitis in the United States.<br />Methods: 3V2640-CLIN-005 (FASCINATE-1) was a randomized, placebo-controlled, single-blind study at 10 US sites. Adults with ≥8% liver fat, assessed by magnetic resonance imaging proton density fat fraction, and evidence of liver fibrosis by magnetic resonance elastography ≥2.5 kPa or liver biopsy were eligible. Ninety-nine patients were randomized to receive placebo or 25 mg or 50 mg of TVB-2640 (orally, once-daily for 12 weeks). The primary end points of this study were safety and relative change in liver fat after treatment.<br />Results: Liver fat increased in the placebo cohort by 4.5% relative to baseline; in contrast TVB-2640 reduced liver fat by 9.6% in the 25-mg cohort (n = 30; least squares mean: -15.5%; 95% confidence interval, -31.3 to -0.23; P = .053), and 28.1% in the 50-mg cohort (n = 28; least squares mean: -28.0%; 95% confidence interval, -44.5 to -11.6; P = .001). Eleven percent of patients in the placebo group achieved a ≥30% relative reduction of liver fat compared to 23% in the 25-mg group, and 61% in the 50-mg group (P < .001). Secondary analyses showed improvements of metabolic, pro-inflammatory and fibrotic markers. TVB-2640 was well tolerated; adverse events were mostly mild and balanced among the groups.<br />Conclusions: TVB-2640 significantly reduced liver fat and improved biochemical, inflammatory, and fibrotic biomarkers after 12 weeks, in a dose-dependent manner in patients with nonalcoholic steatohepatitis. ClinicalTrials.gov, Number NCT03938246.<br /> (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Adult
Biomarkers blood
Enzyme Inhibitors adverse effects
Fatty Acid Synthase, Type I metabolism
Female
Humans
Lipids blood
Liver diagnostic imaging
Liver enzymology
Liver Cirrhosis diagnostic imaging
Liver Cirrhosis enzymology
Male
Middle Aged
Nitriles adverse effects
Non-alcoholic Fatty Liver Disease diagnostic imaging
Non-alcoholic Fatty Liver Disease enzymology
Piperidines adverse effects
Single-Blind Method
Time Factors
Treatment Outcome
Triazoles adverse effects
United States
Enzyme Inhibitors therapeutic use
Fatty Acid Synthase, Type I antagonists & inhibitors
Lipogenesis drug effects
Liver drug effects
Liver Cirrhosis drug therapy
Nitriles therapeutic use
Non-alcoholic Fatty Liver Disease drug therapy
Piperidines therapeutic use
Triazoles therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 1528-0012
- Volume :
- 161
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Gastroenterology
- Publication Type :
- Academic Journal
- Accession number :
- 34310978
- Full Text :
- https://doi.org/10.1053/j.gastro.2021.07.025