Matera Maria Gabriella, Calzetta Luigino, Rogliani Paola, Cazzola Mario
Unit of Pharmacology, Department of Experimental Medicine, University of Campania 'Luigi Vanvitelli', Naples, Italy.
Department of Medicine and Surgery, Respiratory Disease and Lung Function Unit, University of Parma, Parma, Italy.
Int J Chron Obstruct Pulmon Dis. 2025 Sep 10;20:3163-3173. doi: 10.2147/COPD.S550144. eCollection 2025.
Chronic obstructive pulmonary disease (COPD) is a heterogeneous condition with limited response to standard anti-inflammatory therapies. Biologics targeting specific inflammatory pathways have emerged as potential treatments, but their efficacy remains variable across distinct COPD endotypes.
To systematically evaluate the efficacy and trial quality of biologics tested in COPD patients using a multicriteria decision analysis (MCDA) approach, with attention to type 2 (T2) and non-T2 inflammatory targets.
We assessed 20 trials encompassing 12 biologics and 9294 patients with COPD. Each trial was scored (0-3 per domain, total 12 points) across four domains: exacerbation reduction, lung function improvement, biomarker stratification, and trial design quality.
Dupilumab (anti-IL-4Rα) demonstrated the most robust efficacy in eosinophilic COPD, with consistent reductions in exacerbation rates and improvements in FEV, supported by high trial quality. Mepolizumab and benralizumab (anti-IL-5/IL-5R) showed moderate efficacy in biomarker-enriched populations. Anti-alarmins, specifically tozorakimab (anti-IL-33), itepekimab (anti-IL-33/IL-1RL1), astegolimab (anti-ST2), and tezepelumab (anti-TSLP), showed mixed results, with modest lung function gains but largely non-significant effects on exacerbation rates. Agents targeting non-T2 pathways, including infliximab (anti-TNF-α), canakinumab (anti-IL-1β), MEDI8968 (anti-IL-1R1), CNTO6785 (anti-IL-17A), and ABX-IL8 (anti-IL-8), consistently failed to demonstrate clinical efficacy, often due to small sample sizes, early-phase design, and lack of biomarker stratification.
Biologics targeting T2 inflammation offer therapeutic promise in eosinophilic COPD when guided by biomarkers. Conversely, current biologics directed at non-T2 and alarmin pathways yield limited or inconsistent benefits, emphasizing the need for improved phenotyping and targeted intervention strategies in non-eosinophilic COPD.
慢性阻塞性肺疾病（COPD）是一种异质性疾病，对标准抗炎治疗的反应有限。针对特定炎症途径的生物制剂已成为潜在的治疗方法，但其疗效在不同的COPD内型中仍存在差异。
采用多标准决策分析（MCDA）方法系统评价在COPD患者中测试的生物制剂的疗效和试验质量，重点关注2型（T2）和非T2炎症靶点。
我们评估了20项试验，涉及12种生物制剂和9294例COPD患者。每项试验在四个领域进行评分（每个领域0-3分，总分12分）：减少急性加重、改善肺功能、生物标志物分层和试验设计质量。
度普利尤单抗（抗IL-4Rα）在嗜酸性粒细胞性COPD中显示出最强的疗效，急性加重率持续降低，第一秒用力呼气容积（FEV）改善，试验质量高。美泊利单抗和贝那利珠单抗（抗IL-5/IL-5R）在生物标志物富集人群中显示出中等疗效。抗警报素，特别是托珠单抗（抗IL-33）、伊特佩单抗（抗IL-33/IL-1RL1）、阿斯特利单抗（抗ST2）和替泽佩单抗（抗TSLP），结果不一，肺功能有适度改善，但对急性加重率的影响大多不显著。针对非T2途径的药物，包括英夫利昔单抗（抗TNF-α）、卡那单抗（抗IL-1β）、MEDI8968（抗IL-1R1）、CNTO6785（抗IL-17A）和ABX-IL8（抗IL-8），始终未能显示出临床疗效，这通常是由于样本量小、早期设计以及缺乏生物标志物分层。
在生物标志物的指导下，针对T2炎症的生物制剂在嗜酸性粒细胞性COPD中具有治疗前景。相反，目前针对非T2和警报素途径的生物制剂产生的益处有限或不一致，这强调了在非嗜酸性粒细胞性COPD中改进表型分析和靶向干预策略的必要性。
