From the Respiratory Medicine Unit and Oxford Respiratory Biomedical Research Centre, Nuffield Department of Medicine, University of Oxford, Oxford (I.D.P.), and Clinical Statistics, GlaxoSmithKline, Uxbridge (B.M.) - both in the United Kingdom; the Department of Respiratory Medicine and CIC Nord, Aix-Marseille University, Marseille, France (P.C.); the Department of Thoracic Medicine and Surgery, Lewis Katz School of Medicine at Temple University, Philadelphia (G.J.C.); the Department of Pulmonary Medicine and Tuberculosis, University of Groningen and University Medical Center Groningen, Groningen, the Netherlands (H.A.M.K.); the Pulmonary Department, Mainz University Hospital, Mainz, Germany (S.K.); the Division of Pulmonary, Allergy, and Critical Care Medicine, Duke University, Durham (N.L.), and the Respiratory Medical Franchise (F.C.A.) and the Respiratory Therapeutic Area (E.S.B., S.S.H., D.B.R., S.W.Y.), GlaxoSmithKline, Research Triangle Park - all in North Carolina; the Department of Pneumology, Centre Hospitalier Universitaire-Université Catholique de Louvain, Namur, Namur, Belgium (J.-B.M.); the Division of Allergology and Respiratory Medicine, Showa University School of Medicine, Tokyo (H.S.); and the Department of Medicine, University of Pittsburgh, Pittsburgh (F.C.S.).
N Engl J Med. 2017 Oct 26;377(17):1613-1629. doi: 10.1056/NEJMoa1708208. Epub 2017 Sep 11.
Patients with chronic obstructive pulmonary disease (COPD) with an eosinophilic phenotype may benefit from treatment with mepolizumab, a monoclonal antibody directed against interleukin-5.
We performed two phase 3, randomized, placebo-controlled, double-blind, parallel-group trials comparing mepolizumab (100 mg in METREX, 100 or 300 mg in METREO) with placebo, given as a subcutaneous injection every 4 weeks for 52 weeks in patients with COPD who had a history of moderate or severe exacerbations while taking inhaled glucocorticoid-based triple maintenance therapy. In METREX, unselected patients in the modified intention-to-treat population with an eosinophilic phenotype were stratified according to blood eosinophil count (≥150 per cubic millimeter at screening or ≥300 per cubic millimeter during the previous year). In METREO, all patients had a blood eosinophil count of at least 150 per cubic millimeter at screening or at least 300 per cubic millimeter during the previous year. The primary end point was the annual rate of moderate or severe exacerbations. Safety was also assessed.
In METREX, the mean annual rate of moderate or severe exacerbations in the modified intention-to-treat population with an eosinophilic phenotype (462 patients) was 1.40 per year in the mepolizumab group versus 1.71 per year in the placebo group (rate ratio, 0.82; 95% confidence interval [CI], 0.68 to 0.98; adjusted P=0.04); no significant between-group differences were found in the overall modified intention-to-treat population (836 patients) (rate ratio, 0.98; 95% CI, 0.85 to 1.12; adjusted P>0.99). In METREO, the mean annual rate of moderate or severe exacerbations was 1.19 per year in the 100-mg mepolizumab group, 1.27 per year in the 300-mg mepolizumab group, and 1.49 per year in the placebo group. The rate ratios for exacerbations in the 100-mg and 300-mg mepolizumab groups versus the placebo group were 0.80 (95% CI, 0.65 to 0.98; adjusted P=0.07) and 0.86 (95% CI, 0.70 to 1.05; adjusted P=0.14), respectively. A greater effect of mepolizumab, as compared with placebo, on the annual rate of moderate or severe exacerbations was found among patients with higher blood eosinophil counts at screening. The safety profile of mepolizumab was similar to that of placebo.
Mepolizumab at a dose of 100 mg was associated with a lower annual rate of moderate or severe exacerbations than placebo among patients with COPD and an eosinophilic phenotype. This finding suggests that eosinophilic airway inflammation contributes to COPD exacerbations. (Funded by GlaxoSmithKline; METREX and METREO ClinicalTrials.gov numbers, NCT02105948 and NCT02105961 .).
嗜酸性表型的慢性阻塞性肺疾病（COPD）患者可能受益于美泊利珠单抗（一种针对白细胞介素-5 的单克隆抗体）的治疗。
我们进行了两项 3 期、随机、安慰剂对照、双盲、平行组试验，比较了美泊利珠单抗（METREX 中为 100mg，METREO 中为 100 或 300mg）与安慰剂，在接受吸入糖皮质激素三联维持治疗的 COPD 患者中，每 4 周皮下注射一次，共 52 周。在 METREX 中，根据筛选时血嗜酸性粒细胞计数（≥150 个/立方毫米或前一年中≥300 个/立方毫米），将未选择的、具有嗜酸性表型的改良意向治疗人群分层。在 METREO 中，所有患者筛选时的血嗜酸性粒细胞计数至少为 150 个/立方毫米或前一年中至少为 300 个/立方毫米。主要终点是中度或重度加重的年发生率。还评估了安全性。
在 METREX 中，具有嗜酸性表型的改良意向治疗人群（462 例患者）的平均年中度或重度加重发生率为美泊利珠单抗组每年 1.40 次，安慰剂组为每年 1.71 次（发生率比，0.82；95%置信区间[CI]，0.68 至 0.98；调整后的 P=0.04）；在总体改良意向治疗人群（836 例患者）中未发现组间有显著差异（发生率比，0.98；95%CI，0.85 至 1.12；调整后的 P>0.99）。在 METREO 中，100mg 美泊利珠单抗组、300mg 美泊利珠单抗组和安慰剂组的中度或重度加重的年发生率分别为 1.19 次、1.27 次和 1.49 次。与安慰剂相比，100mg 和 300mg 美泊利珠单抗组的恶化发生率分别为 0.80（95%CI，0.65 至 0.98；调整后的 P=0.07）和 0.86（95%CI，0.70 至 1.05；调整后的 P=0.14）。在筛选时血嗜酸性粒细胞计数较高的患者中，美泊利珠单抗与安慰剂相比，对中度或重度加重的年发生率的影响更大。美泊利珠单抗的安全性与安慰剂相似。
与安慰剂相比，美泊利珠单抗 100mg 剂量可降低 COPD 伴嗜酸性表型患者的中度或重度加重年发生率。这一发现表明嗜酸性气道炎症有助于 COPD 加重。（由葛兰素史克公司资助；METREX 和 METREO 临床试验.gov 编号，NCT02105948 和 NCT02105961 ）。
