美国阿拉巴马大学伯明翰分校Surya P. Bhatt团队研究了度匹鲁单抗治疗嗜酸性粒细胞计数升高的2型慢性阻塞性肺炎的疗效。这一研究成果发表在2023年5月21日出版的《新英格兰医学杂志》上。

在一些慢性阻塞性肺病（COPD）患者中，2型炎症可能会增加病情恶化的风险，并可能表现为血液嗜酸性粒细胞计数升高。度匹鲁单抗是一种全人类单克隆抗体，阻断白细胞介素-4和白细胞介素-13的共享受体成分，这是2型炎症的关键驱动因素。

在这项临床3期、双盲、随机试验中，研究组将血液嗜酸性粒细胞计数至少为每微升300且尽管使用了标准三联疗法但病情恶化风险升高的COPD患者分为每2周皮下接受一次度匹鲁单抗（300 mg）或安慰剂治疗。主要终点是COPD中度或重度加重的年化率。校正多重性的关键次要终点和其他终点是支气管扩张前1秒用力呼气量（FEV1）的变化和圣乔治呼吸系统问卷（SGRQ；范围为0-100，分数越低表示生活质量越好）以及评估COPD呼吸系统症状（E-RS–COPD；范围为0-40，分数越小表示症状越轻）。

共有939名患者接受了随机分组：度匹鲁单抗组468名，安慰剂组471名。度匹鲁单抗组的中度或重度急性发作的年化率为0.78，安慰剂组的年化发病率为1.10（比率比为0.70；P<0.001）。从基线到第12周，度匹鲁单抗组和安慰剂组的支气管扩张前FEV1分别增加了160毫升和77毫升的最小二乘（LS）平均值（LS平均值差异，83毫升；P<0.001），这种差异一直持续到第52周。在第52周，度匹鲁单抗组的SGRQ评分LS平均值提高了−9.7，安慰剂的LS平均值提高了−6.4（95%可信区间，−8.0至−4.8）（LS平均差异为−3.4；P=0.002）。在第52周时，E-RS–COPD评分在度匹鲁单抗组和安慰剂组LS平均值分别提高了−2.7和−1.6（LS平均差异，−1.1；P=0.001），导致死亡的不良事件在两组中是平衡的。

研究结果表明，在患有2型炎症（如血液嗜酸性粒细胞计数升高）的COPD患者中，与服用安慰剂的患者相比，服用度匹鲁单抗的患者病情恶化更少，肺功能和生活质量更好，呼吸系统症状也不那么严重。

Title: Dupilumab for COPD with Type 2 Inflammation Indicated by Eosinophil Counts | NEJM

Author: Surya P. Bhatt, M.D., M.S.P.H.,, Klaus F. Rabe, M.D., Ph.D.,, Nicola A. Hanania, M.D.,, Claus F. Vogelmeier, M.D.,, Jeremy Cole, M.D.,, Mona Bafadhel, M.D., Ph.D.,, Stephanie A. Christenson, M.D.,, Alberto Papi, M.D.,, Dave Singh, M.D.,, Elizabeth Laws, Ph.D.,, Leda P. Mannent, M.D.,, Naimish Patel, M.D.,, Heribert W. Staudinger, M.D., Ph.D.,, George D. Yancopoulos, M.D., Ph.D.,, Eric R. Mortensen, M.D., Ph.D.,, Bolanle Akinlade, M.D.,, Jennifer Maloney, M.D.,, Xin Lu, Ph.D.,, Deborah Bauer, M.S.,, Ashish Bansal, M.D.,, Lacey B. Robinson, M.D., M.P.H.,, and Raolat M. Abdulai, M.D., M.M.Sc.

Issue&Volume: 2023-05-21

Abstract:

Background

In some patients with chronic obstructive pulmonary disease (COPD), type 2 inflammation may increase exacerbation risk and may be indicated by elevated blood eosinophil counts. Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin-4 and interleukin-13, key drivers of type 2 inflammation.

Methods

In a phase 3, double-blind, randomized trial, we assigned patients with COPD who had a blood eosinophil count of at least 300 per microliter and an elevated exacerbation risk despite the use of standard triple therapy to receive dupilumab (300 mg) or placebo subcutaneously once every 2 weeks. The primary end point was the annualized rate of moderate or severe exacerbations of COPD. Key secondary and other end points that were corrected for multiplicity were the change in the prebronchodilator forced expiratory volume in 1 second (FEV1) and in the scores on the St. George’s Respiratory Questionnaire (SGRQ; range, 0 to 100, with lower scores indicating a better quality of life) and the Evaluating Respiratory Symptoms in COPD (E-RS–COPD; range, 0 to 40, with lower scores indicating less severe symptoms).

Results

A total of 939 patients underwent randomization: 468 to the dupilumab group and 471 to the placebo group. The annualized rate of moderate or severe exacerbations was 0.78 (95% confidence interval [CI], 0.64 to 0.93) with dupilumab and 1.10 (95% CI, 0.93 to 1.30) with placebo (rate ratio, 0.70; 95% CI, 0.58 to 0.86; P<0.001). The prebronchodilator FEV1 increased from baseline to week 12 by a least-squares (LS) mean of 160 ml (95% CI, 126 to 195) with dupilumab and 77 ml (95% CI, 42 to 112) with placebo (LS mean difference, 83 ml; 95% CI, 42 to 125; P<0.001), a difference that was sustained through week 52. At week 52, the SGRQ score had improved by an LS mean of 9.7 (95% CI, 11.3 to 8.1) with dupilumab and 6.4 (95% CI, 8.0 to 4.8) with placebo (LS mean difference, 3.4; 95% CI, 5.5 to 1.3; P=0.002). The E-RS–COPD score at week 52 had improved by an LS mean of 2.7 (95% CI, 3.2 to 2.2) with dupilumab and 1.6 (95% CI, 2.1 to 1.1) with placebo (LS mean difference, 1.1; 95% CI, 1.8 to 0.4; P=0.001). The numbers of patients with adverse events that led to discontinuation of dupilumab or placebo, serious adverse events, and adverse events that led to death were balanced in the two groups.

Conclusions

Among patients with COPD who had type 2 inflammation as indicated by elevated blood eosinophil counts, those who received dupilumab had fewer exacerbations, better lung function and quality of life, and less severe respiratory symptoms than those who received placebo.

DOI: 10.1056/NEJMoa2303951

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2303951