From the Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, Birmingham (S.P.B.); LungenClinic Grosshansdorf (member of the German Center for Lung Research [DZL]), Airway Research Center North (ARCN), Grosshansdorf (K.F.R.), Christian-Albrechts University, DZL, ARCN, Kiel (K.F.R.), and the Department of Medicine, Pulmonary and Critical Care Medicine, University of Marburg, DZL, Marburg (C.F.V.) - all in Germany; the Section on Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston (N.A.H.); King's Centre for Lung Health, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London (M.B.), and the Medicines Evaluation Unit, Manchester University NHS Foundation Trust, University of Manchester, Manchester (D.S.) - both in the United Kingdom; the Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, University of California, San Francisco, San Francisco (S.A.C.); the Respiratory Medicine Unit, University of Ferrara, S. Anna University Hospital, Ferrara, Italy (A.P.); Sanofi, Bridgewater, NJ (E.L., X.L., D.B.); Sanofi, Cambridge, MA (N.P., R.M.A., L.B.R.); and Regeneron Pharmaceuticals, Tarrytown, NY (G.D.Y., B.A., J.M., A.B.).
N Engl J Med. 2024 Jun 27;390(24):2274-2283. doi: 10.1056/NEJMoa2401304. Epub 2024 May 20.
BACKGROUND: Dupilumab, a fully human monoclonal antibody that blocks the shared receptor component for interleukin-4 and interleukin-13, key and central drivers of type 2 inflammation, has shown efficacy and safety in a phase 3 trial involving patients with chronic obstructive pulmonary disease (COPD) and type 2 inflammation and an elevated risk of exacerbation. Whether the findings would be confirmed in a second phase 3 trial was unclear. METHODS: In a phase 3, double-blind, randomized trial, we assigned patients with COPD who had a blood eosinophil count of 300 cells per microliter or higher to receive subcutaneous dupilumab (300 mg) or placebo every 2 weeks. The primary end point was the annualized rate of moderate or severe exacerbations. Key secondary end points, analyzed in a hierarchical manner to adjust for multiplicity, included the changes from baseline in the prebronchodilator forced expiratory volume in 1 second (FEV) at weeks 12 and 52 and in the St. George's Respiratory Questionnaire (SGRQ; scores range from 0 to 100, with lower scores indicating better quality of life) total score at week 52. RESULTS: A total of 935 patients underwent randomization: 470 were assigned to the dupilumab group and 465 to the placebo group. As prespecified, the primary analysis was performed after a positive interim analysis and included all available data for the 935 participants, 721 of whom were included in the analysis at week 52. The annualized rate of moderate or severe exacerbations was 0.86 (95% confidence interval [CI], 0.70 to 1.06) with dupilumab and 1.30 (95% CI, 1.05 to 1.60) with placebo; the rate ratio as compared with placebo was 0.66 (95% CI, 0.54 to 0.82; P<0.001). The prebronchodilator FEV increased from baseline to week 12 with dupilumab (least-squares mean change, 139 ml [95% CI, 105 to 173]) as compared with placebo (least-squares mean change, 57 ml [95% CI, 23 to 91]), with a significant least-squares mean difference at week 12 of 82 ml (P<0.001) and at week 52 of 62 ml (P = 0.02). No significant between-group difference was observed in the change in SGRQ scores from baseline to 52 weeks. The incidence of adverse events was similar in the two groups and consistent with the established profile of dupilumab. CONCLUSIONS: In patients with COPD and type 2 inflammation as indicated by elevated blood eosinophil counts, dupilumab was associated with fewer exacerbations and better lung function than placebo. (Funded by Sanofi and Regeneron Pharmaceuticals; NOTUS ClinicalTrials.gov number, NCT04456673.).
背景：Dupilumab 是一种完全人源化的单克隆抗体，可阻断白细胞介素-4 和白细胞介素-13 的共享受体成分，这两种细胞因子是 2 型炎症的关键和核心驱动因素。在一项涉及慢性阻塞性肺疾病（COPD）和 2 型炎症以及加重风险较高的患者的 3 期试验中，Dupilumab 显示出疗效和安全性。是否在第二次 3 期试验中得到证实尚不清楚。
方法：在一项 3 期、双盲、随机试验中，我们将血嗜酸性粒细胞计数为每微升 300 个或更高的 COPD 患者随机分配接受皮下注射 Dupilumab（300mg）或安慰剂，每 2 周一次。主要终点是中度或重度加重的年发生率。主要次要终点按层次分析进行分析，以调整多重性，包括从基线到第 12 周和第 52 周的支气管扩张前用力呼气量（FEV）的变化，以及第 52 周的圣乔治呼吸问卷（SGRQ；评分范围为 0 至 100，得分越低表示生活质量越好）总分的变化。
结果：共有 935 名患者接受了随机分组：470 名患者分配到 Dupilumab 组，465 名患者分配到安慰剂组。按照预先规定，主要分析在中期阳性分析后进行，包括 935 名参与者的所有可用数据，其中 721 名参与者在第 52 周进行了分析。Dupilumab 组中度或重度加重的年发生率为 0.86（95%置信区间[CI]，0.70 至 1.06），安慰剂组为 1.30（95%CI，1.05 至 1.60）；与安慰剂相比，其比率为 0.66（95%CI，0.54 至 0.82；P<0.001）。与安慰剂相比，Dupilumab 组从基线到第 12 周时支气管扩张前 FEV 增加（最小二乘均值变化为 139ml[95%CI，105 至 173]），而安慰剂组最小二乘均值变化为 57ml[95%CI，23 至 91]），第 12 周的最小二乘均值差异为 82ml（P<0.001），第 52 周的最小二乘均值差异为 62ml（P = 0.02）。从基线到 52 周，SGRQ 评分的变化在两组之间无显著差异。两组的不良事件发生率相似，与 Dupilumab 的既定特征一致。
结论：在血嗜酸性粒细胞计数升高提示存在 2 型炎症的 COPD 患者中，Dupilumab 与安慰剂相比，加重次数更少，肺功能改善更好。（由 Sanofi 和 Regeneron Pharmaceuticals 资助；NOTUS ClinicalTrials.gov 编号，NCT04456673。）
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