Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn's disease: unexpected results of a randomised, double-blind placebo-controlled trial

作者：Wolfgang Hueber, Bruce E. Sands, Steve Lewitzky, Marc Vandemeulebroecke, Walter Reinisch, Peter Higgins, Jan Wehkamp, Brian G. Feagan, Michael Yao, Marek Karczewski, Jacek Karczewski, Nicole Pezous, Stephan Bek, Gerard Bruin, Bjoern Mellgard, C Berger, Marco Londei, Arthur P. Bertolino, Gervais Tougas, Simon Travis, for the Secukinumab in Crohn's Disease Study Group · 发表于：Gut · 年份：2012 · DOI：10.1136/gutjnl-2011-301668 · 被引用次数：1522 · 研究领域：Inflammatory Bowel Disease、Psoriasis: Treatment and Pathogenesis、Autoimmune and Inflammatory Disorders

OBJECTIVE: The authors tested whether the anti-interleukin (IL)-17A monoclonal antibody secukinumab was safe and effective for the treatment of active Crohn's disease. DESIGN: In a double-blind, randomised, placebo-controlled proof-of-concept study, 59 patients with moderate to severe Crohn's disease (Crohn's Disease Activity Index (CDAI) ≥220 to ≤450) were assigned in a 2:1 ratio to 2×10 mg/kg intravenous secukinumab or placebo. The primary end point, addressed by bayesian statistics augmented with historical placebo information, was the probability that secukinumab reduces the CDAI by ≥50 points more than placebo at week 6. Ancillary analyses explored associations of 35 candidate genetic polymorphisms and faecal calprotectin response. RESULTS: 59 patients (39 secukinumab, 20 placebo, mean baseline CDAI 307 and 301, respectively) were recruited. 18/59 (31%) patients discontinued prematurely (12/39 (31%) secukinumab, 6/20 (30%) placebo), 10/59 (17%) due to insufficient therapeutic effect (8/39 (21%) secukinumab, 2/20 (10%) placebo). Fourteen serious adverse events occurred in 10 patients (seven secukinumab, three placebo); 20 infections, including four local fungal infections, were seen on secukinumab versus none on placebo. Primary end point analysis estimated <0.1% probability (CDAI (SD) =33.9 (19.7), 95% credible interval -4.9 to 72.9) that secukinumab reduces CDAI by ≥50 points more than placebo. Secondary area under the curve analysis (weeks 4-10) showed a significant di...