Promises and challenges of biologics for severe asthma.

Patients with severe asthma that remain uncontrolled incur significant medical burden and healthcare costs. Severe asthma is a heterogeneous airway disorder with complex pathophysiological mechanisms which can be broadly divided into type 2 (T2)-high and T2-low inflammatory pathways. Recent advances in asthma therapeutics with the advent of biologics have heralded an era of promising targeted therapy in this group of patients. The current available biologics, including anti-IgE mAb, anti-IL-5/IL-5R mAb and anti-IL-4Rα mAb, mainly target patients with an asthma endotype characterised by T2-high inflammation. While they have delivered positive outcomes in terms of reduction in exacerbations, improving lung function and quality of life, as well as reducing the dependence on oral corticosteroids, they have not functioned as the "panacea" as a significant proportion of patients do not respond completely to these targeted therapies. In addition, there is a lack of markers that can predict treatment response and clinicians are guided only by subjective asthma symptom scores. Suboptimal treatment response is common for individual patients. There has also been a dearth of effective targeted therapy for patients with T2-low asthma and treatment options remain limited for these patients. There is a pipeline of newer biologics targeting cytokines that operate at the interface between innate and adaptive immunity (e.g. IL-17A, thymic stromal lymphopoietin (TSLP), IL-25, IL-33, IL-32 and IL-36γ) with potential of modifying and reducing the severity of asthma. This commentary provides an overview of treatment with the current biologics and highlights the limitations, challenges and unmet needs in clinical management. We also summarise up-and-coming potential targets and therapeutic biologics for severe asthma.