TVB-2640 (FASN Inhibitor) for the Treatment of Nonalcoholic Steatohepatitis: FASCINATE-1, a Randomized, Placebo-Controlled Phase 2a Trial

Rohit Loomba*, Rizwana Mohseni, K. Jean Lucas, Julio A. Gutierrez, Robert G. Perry, James F. Trotter, Robert S. Rahimi, Stephen A. Harrison, Veeral Ajmera, Jeffrey D. Wayne, Marie O'Farrell, William McCulloch, Katharine Grimmer, Mary Rinella, Vincent Wai-Sun Wong, Vlad Ratziu, Gregory J. Gores, Brent A. Neuschwander-Tetri, George Kemble

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

95 Scopus citations

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. 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. 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. 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.

Original languageEnglish (US)
Pages (from-to)1475-1486
Number of pages12
JournalGastroenterology
Volume161
Issue number5
DOIs
StatePublished - Nov 2021

Keywords

  • PRO-C3
  • Palmitate

ASJC Scopus subject areas

  • Gastroenterology
  • Hepatology

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