Review of Biologics in Children With Severe Asthma

Stanley J. Szefler, MD

Disclosures

December 21, 2018

Editorial Collaboration

Medscape &

Current and Future Biologics

Biologic therapies, in particular those targeting the "allergic" or T-helper 2 (Th2) pathway, are being considered for children with severe asthma. However, a great deal of variability exists in the extent to which these biologic therapies have been studied in children.

Omalizumab

Omalizumab is a humanized anti-immunoglobulin (Ig) E monoclonal antibody that binds circulating IgE, causing a decrease in IgE levels; inhibition of IgE binding with its receptors; and downregulation of IgE receptors on mast cells, basophils, and dendritic cells.[3] Omalizumab binds to free IgE, but not to IgE bound to mast cells, resulting in a decreased release of inflammatory mediators related to the allergic response.

Omalizumab use in both adults and children with asthma reduced exacerbations and hospitalizations and increased the likelihood of withdrawing ICS therapy.[3]

Omalizumab is approved by the US Food and Drug Administration for moderate to severe asthma in patients aged 6 years or older with environmental allergies. Studies are ongoing with omalizumab, including the Preventing Asthma in High Risk Kids (PARK) study, to determine whether 2 years of omalizumab in children aged 2-3 years will prevent progression to persistent asthma.

Mepolizumab, Reslizumab, and Benralizumab

IL5 is a cytokine that recruits eosinophils from the bone marrow and promotes both the activation and longevity of these cells.[3] Three anti-IL5 biologic therapies have been approved: mepolizumab, reslizumab, and benralizumab. Mepolizumab and reslizumab are humanized monoclonal antibodies against IL5, whereas benralizumab is a humanized monoclonal antibody against the IL5 receptor.

None of these therapies have been studied in children younger than 12 years. Mepolizumab and benralizumab are approved for severe eosinophilic asthma for patients aged 12 years and older, while reslizumab is only approved for those aged 18 years and older. The studies performed with these medications have been largely limited to eosinophilic asthma under the assumption that eosinophilia is predictive of response to these medications, although the criteria for inclusion of eosinophilia has varied slightly among the studies. Whereas some data are available in adults, less information is available with adolescents.

Dupilumab

The IL4 cytokine is an essential cytokine to Th2 cell polarization, whereas the IL13 cytokine is associated with periostin production in the bronchial epithelial cells, ultimately resulting in smooth-muscle contraction, mucus production, airway remodeling and hyperresponsiveness, and goblet cell hyperplasia.[3] IL13 also works with IL4 to result in IgE production.[3] The IL4 receptor (alpha subunit) is critical for both IL4 and IL13 signal transduction.[3]

Dupilumab is a human monoclonal antibody to the alpha subunit of the IL4 receptor, thereby blocking the activity of IL4 and IL13, and has been shown to not only reduce asthma exacerbations but also improve pulmonary function.

Dupilumab was recently approved for the treatment of moderate to severe asthma in patients aged 12 years or older with an eosinophilic phenotype or oral corticosteroid- dependent asthma. A study is ongoing with dupilumab in children aged 6 years to younger than 12 years with uncontrolled persistent asthma.

Fevipiprant

Currently in clinical trials, fevipiprant is a competitive antagonist to chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTh2).[3] CRTh2 is a prostaglandin D2 receptor that mediates inflammatory effects largely through its production by allergic cells, such as mast cells.[3] Results with fevipiprant have been inconsistent and limited to phase 2 studies.[4,5]

Tezepelumab

Tezepelumab is a human anti-thymic stromal lymphopoietin (TSLP) monoclonal immunoglobulin that prevents binding of TSLP with its receptor, preventing TSLP-initiated inflammatory responses through activation of dendritic cells and mast cells.[3]

Tezepelumab is still undergoing clinical trials. Although no studies have been conducted in the pediatric population, a phase 2 study of tezepelumab in adults with uncontrolled asthma despite medium to high ICS and long-acting beta-agonist therapy noted significant reductions in exacerbation rates.[6] The biomarker profile of patients most likely to respond also remains unknown.

What Still Lies Ahead

The Global Initiative for Asthma recently published a pocket guide that includes recommendations for the diagnosis and management of difficult-to-control asthma in adolescents and adults.[7] This resource should be useful in the consideration of biologic treatments for patients; however, little information is currently available to differentiate the comparative efficacy of the various biologics. Defining predictive and monitoring biomarkers to assess the likelihood of patients responding to these medications will be important. Until then, cost, convenience, available patient profiles, and family burden should be part of the decision-making process. Long-term studies will also be needed to determine whether these new treatments can prevent disease progression as well as further prevent or even reverse airway damage that has already occurred. New medications are being introduced that may significantly affect the disease, but the risk versus benefit must be carefully assessed, especially in children, to determine which patients are most likely to show a favorable response.

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