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Efficacy of Dupilumab in a Phase 2 Randomized Trial of Adults With Active Eosinophilic Esophagitis.

Dupilumab 在成人活动性嗜酸性粒细胞性食管炎 2 期随机试验中的疗效。

  • 影响因子:7.07
  • DOI:10.1053/j.gastro.2019.09.042
  • 作者列表:"Hirano I","Dellon ES","Hamilton JD","Collins MH","Peterson K","Chehade M","Schoepfer AM","Safroneeva E","Rothenberg ME","Falk GW","Assouline-Dayan Y","Zhao Q","Chen Z","Swanson BN","Pirozzi G","Mannent L","Graham NMH","Akinlade B","Stahl N","Yancopoulos GD","Radin A
  • 发表时间:2020-01-01
Abstract

BACKGROUND & AIMS:Eosinophilic esophagitis (EoE) is an allergen-mediated inflammatory disease with no approved treatment in the United States. Dupilumab, a VelocImmune-derived human monoclonal antibody against the interleukin (IL) 4 receptor, inhibits IL4 and IL13 signaling. Dupilumab is effective in the treatment of allergic, atopic, and type 2 diseases, so we assessed its efficacy and safety in patients with EoE. METHODS:We performed a phase 2 study of adults with active EoE (2 episodes of dysphagia/week with peak esophageal eosinophil density of 15 or more eosinophils per high-power field), from May 12, 2015, through November 9, 2016, at 14 sites. Participants were randomly assigned to groups that received weekly subcutaneous injections of dupilumab (300 mg, n = 23) or placebo (n = 24) for 12 weeks. The primary endpoint was change from baseline to week 10 in Straumann Dysphagia Instrument (SDI) patient-reported outcome (PRO) score. We also assessed histologic features of EoE (peak esophageal intraepithelial eosinophil count and EoE histologic scores), endoscopically visualized features (endoscopic reference score), esophageal distensibility, and safety. RESULTS:The mean SDI PRO score was 6.4 when the study began. In the dupilumab group, SDI PRO scores were reduced by a mean value of 3.0 at week 10 compared with a mean reduction of 1.3 in the placebo group (P = .0304). At week 12, dupilumab reduced the peak esophageal intraepithelial eosinophil count by a mean 86.8 eosinophils per high-power field (reduction of 107.1%; P < .0001 vs placebo), the EoE-histologic scoring system (HSS) severity score by 68.3% (P < .0001 vs placebo), and the endoscopic reference score by 1.6 (P = .0006 vs placebo). Dupilumab increased esophageal distensibility by 18% vs placebo (P < .0001). Higher proportions of patients in the dupilumab group developed injection-site erythema (35% vs 8% in the placebo group) and nasopharyngitis (17% vs 4% in the placebo group). CONCLUSIONS:In a phase 2 trial of patients with active EoE, dupilumab reduced dysphagia, histologic features of disease (including eosinophilic infiltration and a marker of type 2 inflammation), and abnormal endoscopic features compared with placebo. Dupilumab increased esophageal distensibility and was generally well tolerated. ClinicalTrials.gov, Number: NCT02379052.

摘要

背景与目的: 嗜酸性粒细胞性食管炎 (EoE) 是一种过敏原介导的炎症性疾病,在美国尚无批准的治疗方法。Dupilumab,一种 VelocImmune 衍生的抗白细胞介素 (IL) 4 受体的人单克隆抗体,抑制 IL4 和 IL13 信号。Dupilumab 治疗过敏性、特应性和 2 型疾病有效,因此我们评估了其在 EoE 患者中的疗效和安全性。 方法: 我们对患有活动性 EoE 的成年人进行了一项 2 期研究 (2 次吞咽困难/周,峰值食管嗜酸性粒细胞密度为 15 个或更多嗜酸性粒细胞/高倍视野),从 2015年5月12日,到 2016年11月9日,在 14 个地点。参与者被随机分配到接受 dupilumab (300 mg,n = 23) 或安慰剂 (n = 24) 每周皮下注射 12 周的组。主要终点是 Straumann 吞咽困难仪 (SDI) 患者报告结局 (PRO) 评分从基线到第 10 周的变化。我们还评估了 EoE 的组织学特征 (食管上皮内嗜酸性粒细胞峰值计数和 EoE 组织学评分) 、内镜下可视化特征 (内镜参考评分) 、食管扩张性和安全性。 结果: 研究开始时平均 SDI PRO 评分为 6.4。在 dupilumab 组,SDI PRO 评分在第 10 周时平均降低 3.0,而安慰剂组平均降低 1.3 (P = .0304)。12 周时,dupilumab 每高倍视野平均减少 86.8 个嗜酸性粒细胞 (减少 107.1%; P < .0001 vs 安慰剂),EoE-组织学评分系统 (HSS) 严重程度评分为 68.3% (P < .0001 vs 安慰剂),内镜参考评分为 1.6(P = .0006 vs 安慰剂)。Dupilumab 增加食管扩张性 18% vs 安慰剂 (P <.0001)。Dupilumab 组中较高比例的患者出现注射部位红斑 (安慰剂组为 35% vs 8%) 和鼻咽炎 (安慰剂组为 17% vs 4%)。 结论: 在一项针对活动性 EoE 患者的 2 期试验中,dupilumab 减少了吞咽困难、疾病的组织学特征 (包括嗜酸性粒细胞浸润和 2 型炎症标志物),与安慰剂相比,异常内镜特征。Dupilumab 增加了食管扩张性,一般耐受性良好。ClinicalTrials.gov,编号: nct02379052。

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