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Abstract Details
TVB-2640 (FASN inhibitor) for the treatment of nonalcoholic steatohepatitis: FASCINATE-1, a randomized, placebo-controlled Ph2a trial
Gastroenterology. 2021 Jul 20;S0016-5085(21)03276-5. doi: 10.1053/j.gastro.2021.07.025.Online ahead of print.
Rohit Loomba1, Rizwana Mohseni2, K Jean Lucas3, Julio A Gutierrez4, Robert G Perry5, James F Trotter6, Robert S Rahimi6, Stephen A Harrison7, Veeral Ajmera8, Jeffrey D Wayne9, Marie O'Farrell10, William McCulloch10, Katharine Grimmer10, Mary Rinella11, Vincent Wai-Sun Wong12, Vlad Ratziu13, Gregory J Gores14, Brent A Neuschwander-Tetri15, George Kemble10
Author information
1NAFLD Research Center, Division of Gastroenterology and Hepatology, Department of Medicine, University of California at San Diego, La Jolla, CA, USA. Electronic address: roloomba@ucsd.edu.
2Catalina Research Institute, Montclair, CA, USA.
3Lucas Research, Morehead City, NC, USA.
4Prosciento, Chula Vista, CA, USA.
5Panax Clinical Research, Miami Lakes, FL, USA.
6Baylor University Medical Center, Texas Digestive Disease Consultants, Dallas, TX, USA.
7Pinnacle Clinical Research, San Antonio, TX, USA.
8NAFLD Research Center, Division of Gastroenterology and Hepatology, Department of Medicine, University of California at San Diego, La Jolla, CA, USA.
9Clinical Trials Research, Lincoln, CA, USA.
10Sagimet Biosciences Inc., San Mateo, CA USA.
11Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
12Dept of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong.
13Sorbonne Université, Assistance Publique-Hôpitaux de Paris, Hôpital Pitié-Salpêtriére, Inst for Cardiometabolism and Nutrition, Paris, France.
14Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.
15Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine, St. Louis, MO, USA.
Abstract
Background and aims: Increased de novo lipogenesis creates excess intrahepatic fat and lipotoxins, propagating liver damage in nonalcoholic steatohepatitis (NASH). TVB-2640, a fatty acid synthase (FASN) 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 NASH patients in the United States.
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 MRI-proton density fat fraction (MRI-PDFF), and evidence of liver fibrosis by MR-elastography (MRE) ≥2·5kPa or liver biopsy were eligible. 99 patients were randomized to receive placebo or 25mg or 50mg of TVB-2640 (orally, once-daily for 12 weeks. The primary endpoints of this study were safety and relative change in liver fat following treatment.
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 25mg cohort (n=30; least squares mean [LSM]: -15·5%, 95% CI -31·3 - -0·23 P=0·053), and 28·1% in the 50mg cohort (n=28; LSM: -28·0%, 95% CI -44·5 - -11·6, P=0·001). 11% of patients in the placebo group achieved a ≥30% relative reduction of liver fat compared to 23% in the 25mg group, and 61% in the 50mg group (P<0·001). 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.
Conclusions: TVB-2640 significantly reduced liver fat and improved biochemical, inflammatory and fibrotic biomarkers after 12 weeks, in a dose-dependent manner in NASH patients. ClinicalTrials.gov (NCT03938246).