TY - JOUR
T1 - TVB-2640 (FASN Inhibitor) for the Treatment of Nonalcoholic Steatohepatitis
T2 - FASCINATE-1, a Randomized, Placebo-Controlled Phase 2a Trial
AU - Loomba, Rohit
AU - Mohseni, Rizwana
AU - Lucas, K. Jean
AU - Gutierrez, Julio A.
AU - Perry, Robert G.
AU - Trotter, James F.
AU - Rahimi, Robert S.
AU - Harrison, Stephen A.
AU - Ajmera, Veeral
AU - Wayne, Jeffrey D.
AU - O'Farrell, Marie
AU - McCulloch, William
AU - Grimmer, Katharine
AU - Rinella, Mary
AU - Wai-Sun Wong, Vincent
AU - Ratziu, Vlad
AU - Gores, Gregory J.
AU - Neuschwander-Tetri, Brent A.
AU - Kemble, George
N1 - Publisher Copyright:
© 2021 The Authors
PY - 2021/11
Y1 - 2021/11
N2 - 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.
AB - 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.
KW - PRO-C3
KW - Palmitate
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U2 - 10.1053/j.gastro.2021.07.025
DO - 10.1053/j.gastro.2021.07.025
M3 - Article
C2 - 34310978
AN - SCOPUS:85115162308
SN - 0016-5085
VL - 161
SP - 1475
EP - 1486
JO - Gastroenterology
JF - Gastroenterology
IS - 5
ER -