Abstract
BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: Dupilumab (anti-IL-4Rα) demonstrated the most robust efficacy in eosinophilic COPD, with consistent reductions in exacerbation rates and improvements in FEV(1), 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. CONCLUSION: 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.