Efficacy and Safety of Biologic Therapies Targeting Type 2 and Epithelial-Alarmin Pathways in Chronic Obstructive Pulmonary Disease: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials.

People with chronic obstructive pulmonary disease (COPD) who have type 2/eosinophilic inflammation may remain at high exacerbation risk despite optimized triple inhaled therapy. Seven monoclonal antibodies targeting four pathways, namely, interleukin (IL)-4/13, IL-5/IL-5 receptor α (IL-5Rα), IL-33/suppression of tumorigenicity 2 (ST2), and thymic stromal lymphopoietin (TSLP), have now been tested in COPD, and previous COPD-biologics network meta-analyses provided cross-agent rankings and certainty assessments but predated the 2025-26 pivotal and alarmin-trial wave and did not include the complete seven-agent, three-pathway evidence set. We aimed to compare and rank biologics targeting type 2 and epithelial-alarmin pathways for moderate/severe COPD exacerbations. We conducted a systematic review and random-effects network meta-analysis of placebo-controlled randomized controlled trials (RCTs) of eligible biologics in adults with COPD, prospectively registered in the International Prospective Register of Systematic Reviews (PROSPERO; CRD420261448694) and reported according to the PRISMA 2020 statement and its extension for network meta-analysis (PRISMA-NMA). MEDLINE via PubMed, CENTRAL, Europe PMC, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (WHO ICTRP), and Google Scholar were searched to 12 July 2026. Two independent reviewers screened records, with disagreements resolved by adjudication and quality control. Risk of bias was assessed using Cochrane Risk of Bias 2 (RoB 2). The primary outcome was the annualized rate of moderate/severe exacerbations, expressed as a rate ratio (RR) with 95% confidence interval (CI) versus placebo and analysed with frequentist netmeta (placebo-anchored, star network), with Bayesian sensitivity analyses and P-score ranking; certainty was assessed using Grading of Recommendations Assessment, Development and Evaluation (GRADE) via Confidence in Network Meta-Analysis (CINeMA). Of 2,719 records identified and 2,321 screened, 15 trial nodes were included; the primary maintenance exacerbation network comprised nine RCTs (placebo plus four agents: dupilumab, mepolizumab, benralizumab, astegolimab). All four agents reduced moderate/severe exacerbations versus placebo, three significantly. Dupilumab had the largest estimated relative reduction and highest P-score (RR: 0.68, 95% CI: 0.59-0.79; P-score: 0.9947), followed by astegolimab (RR: 0.85, 95% CI: 0.75-0.96; P-score: 0.5766), mepolizumab (RR: 0.88, 95% CI: 0.79-0.97; P-score: 0.4708) and benralizumab (RR: 0.88, 95% CI: 0.77-1.01; P-score: 0.4471). Heterogeneity was low (I² = 9.68%). Dupilumab was favored over each other agent in indirect comparisons via the common placebo; the astegolimab/mepolizumab/benralizumab cluster did not differ significantly. Dupilumab remained first across all sensitivity analyses and all three analytic engines, but the complete ranking was not stable. GRADE-CINeMA certainty was moderate for dupilumab and low for the other three agents. Across completed COPD biologic RCTs, dupilumab (in an eosinophil-enriched population) is the most effective agent for reducing moderate/severe exacerbations; astegolimab, mepolizumab, and benralizumab produce smaller, similar reductions of uncertain relative order. The evidence is limited by a star-shaped network (no head-to-head trials; transitivity untestable) and by mixing of eosinophil populations across trials.