Investigational approaches for unmet need in severe asthma.

INTRODUCTION: Molecular antibodies (mAb) targeting inflammatory mediators are effective in T2-high asthma. The recent approval of Tezepelumab presents a novel mAb therapeutic option for those with T2-low asthma. AREAS COVERED: We discuss a number of clinical problems pertinent to severe asthma that are less responsive to current therapies, such as persistent airflow obstruction and airway hyperresponsiveness. We discuss selected investigational approaches, including a number of candidate therapies under investigation in two adaptive platform trials currently in progress, with particular reference to this unmet need, as well as their potential in phenotypes such as neutrophilic asthma and obese asthma, which may or may not overlap with a T2-high phenotype. EXPERT OPINION: The application of discrete targeting approaches to T2-low molecular phenotypes, including those phenotypes in which inflammation may not arise within the airway, has yielded variable results to date. Endotypes associated with T2-low asthma are likely to be diverse but await validation. Investigational therapeutic approaches must, likewise, be diverse if the goal of remission is to become attainable for all those living with asthma.

The use of biologics in personalized asthma care.

INTRODUCTION: The role of biologic treatments in severe asthma continues to expand, with five agents now approved. Selection of biologic treatment has become increasingly complex in the setting of overlapping indications and in the absence of head-to-head trials. Long-term safety data are still limited for more recently approved agents. AREAS COVERED: We review the evidence supporting the choice of biologic and predicting treatment response utilizing existing widely available biomarkers. In addition, we provide a digest of the long-term safety data currently available for agents approved since 2015. Data sources were identified by using PubMed in 2021. EXPERT OPINION: We generally favor omalizumab in the first instance for those severe asthma patients also eligible for other biologics, due to the greater long-term safety data available for this agent. Clinical characteristics predicting response, treatment priorities, and comorbidities must also be considered.

Autopsy and Imaging Studies of Mucus in Asthma. Lessons Learned about Disease Mechanisms and the Role of Mucus in Airflow Obstruction.

Autopsy studies in fatal asthma have clearly documented the central role of airway plugging with pathologic mucus in the pathophysiology of death from asthma, but the role of mucus plugs in chronic severe asthma has been less well understood. Recently, multidetector computerized tomography imaging of the lungs has emerged as a valuable method to visualize mucus plugs in asthma. These multidetector computerized tomography data have revealed mucus plugs as a common occurrence in severe forms of asthma. In addition, an image-based mucus plug scoring system shows that mucus plugs are strongly associated with measures of airflow obstruction and with biomarkers of type 2 cytokine and eosinophilic inflammation. These data provide a rationale for treating airflow obstruction in severe asthma with mucolytics, and they also raise the possibility that treatments that target type 2 inflammation may decrease mucus plugs in asthma.