From the Mount Sinai Center for Eosinophilic Disorders, Icahn School of Medicine at Mount Sinai, New York (M.C.), and Regeneron Pharmaceuticals, Tarrytown (R.L., E. Mortensen, A.S., E. McCann, M.A.K., M.P.K., J.D.H., C.S., W.K.L., M.F.W., A.F., G.D.Y., J.M.) - both in New York; the Center for Esophageal Diseases and Swallowing, Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, Chapel Hill (E.S.D.); the Division of Allergy and Immunology, Children's Hospital of Philadelphia, and the Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania - both in Philadelphia (J.M.S.); the Divisions of Pathology and Laboratory Medicine (M.H.C.) and Allergy and Immunology (M.E.R.), Department of Pediatrics, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati; the Section of Allergy and Immunology, Department of Pediatrics, University of Arkansas for Medical Sciences and Arkansas Children's Hospital, Little Rock (R.D.P.); the Kenneth Griffin Esophageal Center, Division of Gastroenterology and Hepatology, Northwestern University Feinberg School of Medicine, Chicago (I.H.); Sanofi, Bridgewater, NJ (E.L., L.G.); Sanofi, Prague, Czech Republic (R.M.); and Sanofi, Cambridge, MA (N.P.).
N Engl J Med. 2024 Jun 27;390(24):2239-2251. doi: 10.1056/NEJMoa2312282.
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. (Funded by Sanofi and Regeneron Pharmaceuticals; EoE KIDS ClinicalTrials.gov number, NCT04394351.).
背景：度普利尤单抗是一种人源化单克隆抗体，可阻断白细胞介素-4 和白细胞介素-13 通路，已在五种以 2 型炎症为特征的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。
方法：在这项 3 期试验中，我们按 2:2:1:1 的比例随机分配了 11 岁以下的活动性嗜酸性食管炎患儿，这些患儿对质子泵抑制剂无反应，接受高暴露或低暴露皮下度普利尤单抗方案或安慰剂（两组）（第 A 部分）。在第 A 部分结束时，每个度普利尤单抗组中的合格患者继续接受相同的方案，而安慰剂组中的患者被分配接受高暴露或低暴露度普利尤单抗治疗 36 周（第 B 部分）。在每个暴露水平下，根据基线体重，度普利尤单抗分为四个剂量级别中的一个进行给药。主要终点是第 16 周时组织学缓解（食管上皮内嗜酸性粒细胞计数峰值，≤6 个/高倍视野）。关键次要终点按层次进行测试。
结果：在第 A 部分中，高暴露组的 37 名患者中有 25 名（68%），低暴露组的 31 名患者中有 18 名（58%），安慰剂组的 34 名患者中有 1 名（3%）达到组织学缓解（高暴露组与安慰剂组之间的差异，65 个百分点[95%置信区间{CI}，48 至 81；P<0.001]；低暴露组与安慰剂组之间的差异，55 个百分点[95%CI，37 至 73；P<0.001]）。与安慰剂相比，高暴露度度普利尤单抗方案在组织学、内镜和转录组学方面均有显著改善。与第 A 部分中接受度普利尤单抗治疗的患者相比，所有患者从基线到第 52 周的组织学、内镜和转录组学指标的改善通常与从基线到第 16 周的改善相似。在第 A 部分中，接受度普利尤单抗（任一剂量）的患者中，新冠病毒病 2019 发生率、恶心、注射部位疼痛和头痛至少比接受安慰剂的患者高 10 个百分点。在第 A 部分期间，有 3 名接受度普利尤单抗的患者和第 B 部分期间共有 6 名患者报告了严重不良事件。
结论：度普利尤单抗治疗组患儿的组织学缓解率明显高于安慰剂组。与安慰剂相比，高暴露度度普利尤单抗方案也改善了关键次要终点的指标。（由赛诺菲和再生元制药公司资助；EoE KIDS ClinicalTrials.gov 编号，NCT04394351。）
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