Biologic Therapies in COPD: The Development Pipeline and the Unresolved Problem of Patient Selection

Biologic therapies are expanding treatment options for chronic obstructive pulmonary disease (COPD), but their development raises unresolved questions about patient selection and the assessment of treatment benefit. This narrative review critically discusses clinical evidence, selected emerging programmes and challenges in translating targeted therapies into practice. Mepolizumab and dupilumab have demonstrated reductions in exacerbations in eosinophil-selected populations. Trials of interleukin-33 (IL-33) or ST2 inhibition enrolled patients without a blood eosinophil threshold, and reduced exacerbations in some but not all of these trials: tozorakimab met its primary endpoint in both OBERON and TITANIA, astegolimab in ALIENTO but not in ARNASA, and itepekimab in AERIFY-1 but not in AERIFY-2. Within these programmes the point estimates were numerically larger at higher blood eosinophil counts, so the absence of an enrolment threshold broadens the populations in which efficacy has been demonstrated but does not establish that eosinophils lack predictive value. Two of the three IL-33 programmes also enriched for former smokers, replacing a biomarker criterion in part with a behavioural one. Blood eosinophil variability, discordance between circulating and airway inflammation, and the distinction between prognostic and predictive biomarkers further complicate treatment selection. Emerging strategies include inhibition of multiple inflammatory pathways, earlier biologic initiation and reassessment of background inhaled therapy. Exacerbation prevention remains a central therapeutic objective, although exacerbation rates alone cannot establish modification of the underlying disease course, and no trial has prespecified a responder definition, a reassessment interval or a stopping rule. Prospective evaluation of disease stability and complementary functional and imaging measures may provide a broader understanding of treatment effects. Future research should prioritise validated predictors of response, applicability to routine clinical populations, long-term safety and harmonised, clinically meaningful outcomes to support effective and sustainable use of biologic therapies in COPD.