Emerging targeted therapies in asthma: from upstream epithelial biology to novel biologic and small-molecule strategies

Biologic and targeted small-molecule therapies have transformed the management of severe asthma by enabling mechanism-based targeting of key inflammatory pathways and achieving substantial reductions in exacerbations, improved lung function, and decreased corticosteroid dependence. Despite these advances, a considerable proportion of patients continue to experience breakthrough exacerbations and incomplete disease control, suggesting residual inflammatory mechanisms beyond classical type-2 pathways. Current biologics targeting IgE, interleukin-5, interleukin-4 receptor alpha, and thymic stromal lymphopoietin demonstrate efficacy across biomarker defined populations, but their clinical benefits remain closely linked to baseline type-2 biomarkers and are often limited in patients with non-type-2 or mixed inflammatory phenotypes. Emerging transcriptomic and clinical evidence indicates that epithelial dysfunction, innate immune activation, and tissue repair pathways contribute to persistent disease instability despite targeted cytokine blockade. These findings have stimulated the development of novel therapeutic strategies, including biologics directed against upstream epithelial alarmins such as interleukin-33, oral small-molecule inhibitors such as Bruton tyrosine kinase inhibitors and lineage-directed eosinophil-suppressing agents, inhaled biologics, and nanobody-based therapies. In addition, long-acting and ultra-long-acting biologics aim to improve treatment durability and adherence, while bispecific antibodies are designed to integrate upstream and downstream inflammatory inhibition within a single molecular construct. These advances reflect a shift toward broader and more sustained pathway modulation. Future progress in asthma treatment will depend on integrating epithelial biology, refining biomarker guided patient selection, and developing multispecific and upstream targeting therapies to address persistent disease heterogeneity and improve long-term clinical outcomes.