Biologics in asthma management – Are we out of breath yet?

Abstract

The biologics authorized for the add-on therapy of severe asthma are monoclonal antibodies (mAbs). Before they are considered for therapy intensification, the patient’s asthma endotype is determined on the basis of phenotypic characteristics. So far, 5 biologics are available that target the signaling pathways of the “T H 2-high” asthma endotype, in which cytokines of the inflammation cascade mediated by type 2 T-helper cells are upregulated. The corresponding phenotype of this inflammatory endotype is severe eosinophilic asthma, with elevated eosinophils, immunoglobulin E, and fractional exhaled nitric oxide (FeNO). In contrast, the heterogeneous “T H 2-low” endotype is not yet sufficiently understood. Frequently described in this variant is an increase of sputum neutrophils and an increased expression of the T H 17-mediated interleukin-17 signaling pathway. There are numerous biologics currently in clinical trials, the thymic stromal lymphopoietin (TSLP) mAbs in particular have shown promising results independent of the asthma phenotype.

Eosinophilic Asthma, Phenotypes-Endotypes and Current Biomarkers of Choice

“…In the airways, ILC2s generate Th2 inflammatory responses by producing IL-5 and IL-13. IL-5, IL-3, IL-4, IL-9, and IL-13 are the most important eosinophilic cytokines, and their function is to stimulate eosinophilic production, bone marrow extrusion, proliferation, and differentiation factors [ 11 , 19 , 29 , 30 , 31 ].…”

“…The underlying mechanisms in this asthma subtype are under investigation. Research suggests the existence of several modulators, such as age and metabolic or epigenetic factors, while the role of different pathways including IL-17, neutrophil intrinsic abnormalities, and the inflammasome pathway remains obscure [ 29 , 30 ]. Until now, there have not been useful biomarkers in clinical practice to predict T2-low asthma.…”

“…Omalizumab binds to the third constant region of IgE, preventing its binding to the FcεRI receptor, which is expressed primarily on basophils and mast cells. The eligibility criteria for this biologic include poor asthma control on conventional therapy, sensitization to inhaled allergen(s) on skin prick testing or specific IgE, increased total serum IgE, a body weight within the local dosing range, and more than a specified number of exacerbations within the past year [ 19 , 27 , 30 , 105 ]. The results from numerous randomized clinical trials (RCTs) and real-life studies have demonstrated that omalizumab has a good safety profile, improves asthma control, lung function, and quality of life, and reduces exacerbations, emergency visits, hospitalizations, and the use of oral corticosteroids [ 19 , 27 , 30 , 105 , 113 ].…”

“…The eligibility criteria for this biologic include poor asthma control on conventional therapy, sensitization to inhaled allergen(s) on skin prick testing or specific IgE, increased total serum IgE, a body weight within the local dosing range, and more than a specified number of exacerbations within the past year [ 19 , 27 , 30 , 105 ]. The results from numerous randomized clinical trials (RCTs) and real-life studies have demonstrated that omalizumab has a good safety profile, improves asthma control, lung function, and quality of life, and reduces exacerbations, emergency visits, hospitalizations, and the use of oral corticosteroids [ 19 , 27 , 30 , 105 , 113 ]. In addition, the evidence also suggests that omalizumab is more effective in patients with higher levels of Th2 inflammation biomarkers, such as peripheral eosinophil levels [ 113 ].…”

“…Benralizumab has found to deplete peripheral blood basophils [ 114 ]. Oral corticosteroid use was also reduced with mepolizumab or benralizumab in comparison with placebo [ 19 , 27 , 30 , 105 , 113 , 114 , 115 , 116 , 117 ]. Despite their comparable effects, anti-IL-5 and anti-IL-5Rs have different mechanisms of action, and their effects vary depending on specific asthma endotypes.…”