Comparative Safety of Biologic Therapies in Chronic Obstructive Pulmonary Disease: A Systematic Review and Network Meta-Analysis

Abstract Background Biologic therapies targeting type 2 inflammatory pathways have emerged for eosinophilic chronic obstructive pulmonary disease (COPD), but comparative safety across different molecular targets remains unclear. This network meta-analysis evaluated and ranked the safety of biologic therapies in COPD. Methods We systematically searched PubMed, Cochrane CENTRAL, and ClinicalTrials.gov through September 2026 for randomized controlled trials comparing biologics with placebo in adult COPD. Network meta-analysis with SUCRA ranking, trial sequential analysis (TSA), and pre-specified subgroup analyses were performed. PROSPERO: CRD4202615024201. Results Ten RCTs (7,758 patients; 7 biologics, 6 targets) were included. Biologics did not increase serious adverse events (RR = 0.97, 95% CI 0.86–1.08), death (RR = 0.81, 0.50–1.32), or pneumonia (RR = 0.97, 0.78–1.21). Treatment-related adverse events were higher (RR = 1.41, 1.25–1.58), driven by injection-site reactions (RR = 2.32, 1.79-3.00). SUCRA ranking identified CNTO 6785 as safest and dupilumab as highest risk. Subgroup analysis revealed IL-5 pathway agents had no excess treatment-related AE risk, while IL-4Rα pathway agents showed significantly higher risk. TSA confirmed sufficient evidence for treatment-related AEs but not for mortality. Conclusions Biologics in COPD have acceptable serious-event safety. IL-5 pathway agents have the most favorable tolerability profile. These findings support preferential use of IL-5-targeted biologics when multiple options are available for eosinophilic COPD. Trial registration This is a systematic review and network metaanalysis no clinical trial registration is required. The protocol was prospectively registered on PROSPERO (CRD4202615024201).