Emerging Targeted Therapies in Asthma: From Upstream Epithelial Biology to Novel Biologic and Small-Molecule Strategies.

Biologic and targeted small-molecule therapies have revolutionized the management of severe asthma by specifically targeting key inflammatory pathways. These advances have led to significant reductions in exacerbations, improved lung function, and decreased dependence on corticosteroids. However, a substantial number of patients still experience breakthrough exacerbations and inadequate disease control, indicating that there are residual inflammatory mechanisms beyond the classical type-2 pathways. Current biologics that target immunoglobulin E, interleukin-5, interleukin-4 receptor alpha, and thymic stromal lymphopoietin show efficacy in biomarker-defined populations. Yet, their clinical benefits are closely tied to baseline type-2 biomarkers, and they often fall short for patients with non-type-2 or mixed inflammatory phenotypes. Emerging evidence from transcriptomic and clinical studies suggests that factors such as epithelial dysfunction, innate immune activation, and tissue repair pathways contribute to ongoing disease instability, even with targeted cytokine blockade. These insights have spurred the development of new therapeutic strategies, including biologics aimed at upstream epithelial alarmins like interleukin-33, oral small-molecule inhibitors such as Bruton tyrosine kinase inhibitors, lineage-directed eosinophil-suppressing agents, inhaled biologics, and nanobody-based therapies. Additionally, long-acting and ultra- long-acting biologics are designed to enhance treatment durability and adherence, while bispecific antibodies integrate both upstream and downstream inflammatory inhibition into a single molecular construct. These advancements signify a shift towards broader and more sustained modulation of inflammatory pathways. Future progress in asthma treatment will hinge on integrating insights from 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.