Denifanstat for the treatment of metabolic dysfunction-associated steatohepatitis: a multicentre, double-blind, randomised, placebo-controlled, phase 2b trial
作者：Rohit Loomba, Pierre Bédossa, Katharine Grimmer, George Kemble, Eduardo B. Martins, William McCulloch, Marie O’Farrell, Wen-Wei Tsai, Jose Cobiella, Eric Lawitz, Madhavi Rudraraju, Stephen A. Harrison · 发表于：The Lancet. Gastroenterology & hepatology · 年份：2024 · DOI：10.1016/s2468-1253(24)00246-2 · 被引用次数：98 · 研究领域：Liver Disease Diagnosis and Treatment、Fatty Acid Research and Health、Drug-Induced Hepatotoxicity and Protection
BACKGROUND: Denifanstat, an oral fatty acid synthase (FASN) inhibitor, blocks de-novo lipogenesis, a key pathway driving progressive lipotoxicity, inflammation, and fibrosis in metabolic dysfunction-associated steatohepatitis (MASH). This study aimed to examine the safety and efficacy of denifanstat for improving liver histology in individuals with MASH and moderate to advanced fibrosis. METHODS: This multicentre, double-blind, randomised, placebo-controlled, phase 2b trial was conducted at 100 clinical sites in the USA, Canada, and Poland. After a screening period of up to 90 days, participants aged 18 years and older with biopsy-confirmed MASH and stage F2 or F3 fibrosis were randomly assigned (2:1) to receive either 50 mg oral denifanstat or placebo once per day for 52 weeks. Participants were dynamically allocated to treatment groups via a centrally administered interactive web-based response system and stratified by type 2 diabetes, region, and fibrosis stage. Investigators, patients, and the sponsor were masked to group allocation until database lock. The primary efficacy endpoints were a 2-point or greater improvement in non-alcoholic fatty liver disease activity score (NAS) without a worsening of fibrosis or MASH resolution with a 2-point or greater improvement in NAS without a worsening of fibrosis at week 52, assessed by intention to treat. Safety was assessed in all participants who received at least one dose of study drug. This trial is registered with ClinicalTri...