Immune response modifiers in the treatment of asthma: A PRACTALL document of the American Academy of Allergy, Asthma & Immunology and the European Academy of Allergy and Clinical Immunology

Five percent to 10% of patients with asthma have severe disease that is not responsive to mainstream controller medications. Only approximately 13% of this group meet the criteria for treatment with omalizumab, the only available FDA-approved IRM approved for asthma. Clearly, as discussed above, asthma is a complex variable heterogeneous disease. Lotvall et al8 describe their approach in dividing asthma into distinct entities based not only on clinical presentations but also specific mechanisms, such as asthma endotypes. Although the use of IRMs in the treatment of asthma and atopic disorders has not been as successful as anticipated by many or compared with their use in patients with rheumatic diseases, there have been some advances in our understanding of how to use these IRMs in disease endotypes. Although many of the studies with a variety of IRMs have shown little clinical efficacy, subset analysis of patient groups who exhibit certain characteristics, such as sputum eosinophilia, show improved priary end points and clinical efficacy that have led to new studies with a more defined patient population. A good example is the study of anti-IL-5 (mepolizumab). Recent studies of patients with eosinophilic refractory asthma44 and in patients with prednisonedependent asthma with sputum eosinophils41 have been encouraging on the use of anti-IL-5 in certain asthma endotypes. At the same time, we must continue to be vigilant for adverse events and safety while studying these IRMs, as experienced by Wenzel et al131 in a recent study of golimumab, an anti-TNF mAb that had an unfavorable safety profile. Advances in the bioengineering of mAbs, fusion proteins, and small molecules that can be taken orally will be important steps in improving outcomes. For example, mAbs, perhaps bispecific antibodies, fusion proteins, or combination biologics that target more than 1 cytokine receptor or cytokine, such as pitrakinra,26 will be more successful. The biggest issue is identifying asthma endotypes to tailor the correct IRM and to evaluate carefully the best primary outcome for defined patient subpopulations. The development of useful biomarkers is critical to identify patient-specific therapies and achieve these therapeutic goals. A case in point is the study of an anti-IL-13 mAb (lebrikizumab) using blood eosinophil counts and serum periostin levels as biomarkers to identify potential asthma endotypes that would respond to this treatment approach.29 As these clinical trials point out, elucidating the pathobiology and immunology of these patient subpopulations is a critical strategy for success. The development of new biomarkers will be critical in identifying these patient endotypes for more appropriate use of specific IRMs. Novel therapies must be directed at specific asthma endotypes if these new treatment modalities are going to be clinically efficacious and brought from the bench to the bedside.