美国麻省总医院Lacey B. Robinson团队分析了度匹鲁单抗用于COPD伴血嗜酸性粒细胞2型炎症的证据。这一研究成果于2024年5月20日发表在《新英格兰医学杂志》上。

度匹鲁单抗是一种全人源单克隆抗体，可阻断白细胞介素-4和白细胞介素-13的共享受体成分，这两种成分是2型炎症的关键和中心驱动因素。在一项涉及慢性阻塞性肺病（COPD）和2型炎症患者以及加重风险升高的3期临床试验中，度匹鲁单抗显示出了有效性和安全性。这些发现是否会在第二阶段3期试验中得到证实尚不清楚。

在一项3期双盲随机试验中，研究组将血液嗜酸性粒细胞计数为每微升300个或更高的COPD患者分为每2周接受一次皮下度匹鲁单抗（300mg）或安慰剂治疗。主要终点是中度或重度恶化的年化率。以分层方式进行分析以校正多重性的关键次要终点，包括第12周和第52周的支气管扩张前1秒用力呼气量（FEV1）和第52周圣乔治呼吸问卷（SGRQ；得分范围从0到100，得分越低表示生活质量越好）总分与基线的变化。

共有935名患者接受了随机分组：470名患者被分配到度匹鲁单抗组，465名患者被分到安慰剂组。如前所述，主要分析是在阳性中期分析后进行的，包括935名参与者的所有可用数据，其中721人在第52周被纳入分析。中度或重度急性加重的年化率在度匹鲁单抗组为0.86（95%可信区间[CI]，0.70至1.06），在安慰剂组为1.30（95%置信区间，1.05至1.60）；与安慰剂组相比的比率为0.66（95%CI为0.54至0.82；P＜0.001）。与安慰剂（最小平方均值变化，57 ml[95%CI，23至91]）相比，使用度匹鲁单抗的支气管扩张前FEV1从基线到第12周增加（最小平方均值变化，139 ml[95%置信区间，105至173]），第12周的82 ml（P<0.001）和第52周的62 ml（P=0.02）具有显著的最小平方均值差异。从基线到52周，SGRQ评分的变化在组间没有显著差异。两组的不良事件发生率相似，与度匹鲁单抗的既定情况一致。

研究结果表明，在COPD和2型炎症患者中，如血液嗜酸性粒细胞计数升高所示，与安慰剂相比，度匹鲁单抗与更少的恶化和更好的肺功能相关。

附：英文原文

Title: Dupilumab for COPD with Blood Eosinophil Evidence of Type 2 Inflammation

Author: Surya P. Bhatt, Klaus F. Rabe, Nicola A. Hanania, Claus F. Vogelmeier, Mona Bafadhel, Stephanie A. Christenson, Alberto Papi, Dave Singh, Elizabeth Laws, Naimish Patel, George D. Yancopoulos, Bolanle Akinlade, Jennifer Maloney, Xin Lu, Deborah Bauer, Ashish Bansal, Raolat M. Abdulai, Lacey B. Robinson

Issue&Volume: 2024-05-20

Abstract:

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 (FEV1) 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 prebronchiodilator FEV1 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.

DOI: 10.1056/NEJMoa2401304

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2401304