美国纽约西奈山伊坎医学院Mirna Chehade团队研究了度匹鲁单抗治疗1 - 11岁嗜酸性食管炎患者的疗效与安全性。2024年6月27日出版的《新英格兰医学杂志》发表了这项最新研究成果。

度匹鲁单抗是一种阻断白介素-4和白介素-13途径的人类单克隆抗体，在五种以2型炎症为标志的不同特应性疾病中显示出疗效，包括成人和青少年的嗜酸性食管炎。

在这项3期临床试验中，研究组以2:2:1:1的比例，将对质子泵抑制剂无反应的1至11岁活动性嗜酸性食管炎患者随机分配至16周的高暴露或低暴露皮下度匹鲁单抗方案或安慰剂（两组）（A部分）。在A部分结束时，每个度匹鲁单抗组中符合条件的患者继续相同的方案，安慰剂组中的患者被分配到较高暴露量或较低暴露量的度匹鲁单抗，持续36周（B部分）。在每个暴露水平上，根据基线体重分配四个剂量中的一个给药。主要终点是第16周的组织学缓解（食管上皮内嗜酸性粒细胞计数峰值，每高倍视野≤6）。对关键次要终点进行了分层测试。

在A部分中，高暴露组37名患者中有25名（68%）、低暴露组31名患者中有18名（58%）和安慰剂组34名患者中有1名（3%）出现组织学缓解（高暴露方案和安慰剂之间的差异为65个百分点[95%置信区间{CI}，48-81；P<0.001]；低暴露方案和安慰剂之间的差异为55个百分点[95%CI，37-73；P<0.001]）。与安慰剂相比，更高暴露量的度匹鲁单抗方案在组织学、内镜和转录组学测量方面有显著改善。在基线至第52周期间，所有患者的组织学、内镜和转录组学指标的改善与A部分中接受度匹鲁单抗治疗患者的基线至第16周期间的改善大致相似。在A部分中，接受度匹鲁单抗（任一剂量）治疗的患者新冠病毒感染、恶心、注射部位疼痛和头痛的发生率至少比接受安慰剂治疗的患者高10个百分点。在A部分期间接受度匹鲁单抗治疗的3名患者和在B部分期间的6名患者报告了严重不良事件。

研究结果表明，度匹鲁单抗导致嗜酸性食管炎患儿的组织学缓解率明显高于安慰剂组。与安慰剂相比，更高暴露量的度匹鲁单抗方案也改善了关键次要终点的测量。

附：英文原文

Title: Dupilumab for Eosinophilic Esophagitis in Patients 1 to 11 Years of Age

Author: Mirna Chehade, Evan S. Dellon, Jonathan M. Spergel, Margaret H. Collins, Marc E. Rothenberg, Robert D. Pesek, Ikuo Hirano, Ruiqi Liu, Elizabeth Laws, Eric Mortensen, Renata Martincova, Arsalan Shabbir, Eilish McCann, Mohamed A. Kamal, Matthew P. Kosloski, Jennifer D. Hamilton, Carin Samuely, Wei Keat Lim, Matthew F. Wipperman, Annamaria Farrell, Naimish Patel, George D. Yancopoulos, Lila Glotfelty, Jennifer Maloney

Issue&Volume: 2024-06-27

Abstract:

BACKGROUND

Dupilumab is a human monoclonal antibody that blocks interleukin-4 and interleukin-13 pathways and has shown efficacy in five different atopic diseases marked by type 2 inflammation, including eosinophilic esophagitis in adults and adolescents.

METHODS

In this phase 3 trial, we randomly assigned, in a 2:2:1:1 ratio, patients 1 to 11 years of age with active eosinophilic esophagitis who had had no response to proton-pump inhibitors to 16 weeks of a higher-exposure or lower-exposure subcutaneous dupilumab regimen or to placebo (two groups) (Part A). At the end of Part A, eligible patients in each dupilumab group continued the same regimen and those in the placebo groups were assigned to higher-exposure or lower-exposure dupilumab for 36 weeks (Part B). At each level of exposure, dupilumab was administered in one of four doses tiered according to baseline body weight. The primary end point was histologic remission (peak esophageal intraepithelial eosinophil count, ≤6 per high-power field) at week 16. Key secondary end points were tested hierarchically.

RESULTS

In Part A, histologic remission occurred in 25 of the 37 patients (68%) in the higher-exposure group, in 18 of the 31 patients (58%) in the lower-exposure group, and in 1 of the 34 patients (3%) in the placebo group (difference between the higher-exposure regimen and placebo, 65 percentage points [95% confidence interval {CI}, 48 to 81; P<0.001]; difference between the lower-exposure regimen and placebo, 55 percentage points [95% CI, 37 to 73; P<0.001]). The higher-exposure dupilumab regimen led to significant improvements in histologic, endoscopic, and transcriptomic measures as compared with placebo. The improvements in histologic, endoscopic, and transcriptomic measures between baseline and week 52 in all the patients were generally similar to the improvements between baseline and week 16 in the patients who received dupilumab in Part A. In Part A, the incidence of coronavirus disease 2019, nausea, injection-site pain, and headache was at least 10 percentage points higher among the patients who received dupilumab (at either dose) than among those who received placebo. Serious adverse events were reported in 3 patients who received dupilumab during Part A and in 6 patients overall during Part B.

CONCLUSIONS

Dupilumab resulted in histologic remission in a significantly higher percentage of children with eosinophilic esophagitis than placebo. The higher-exposure dupilumab regimen also led to improvements in measures of key secondary end points as compared with placebo.

DOI: NJ202406273902408

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2312282