Severe pediatric asthma is characterized by early onset and is often associated with high levels of total serum immunoglobulin E (IgE), sensitization to multiple aeroallergens, and increased blood eosinophils. Each clinical phenotype of severe asthma in youth has been linked to endotypes, 2 of which are highly prevalent and based on the type of airway inflammation: type 2 and nontype 2.

Type 2 asthma is characterized by eosinophilic airway inflammation and allergic sensitization and is primarily driven by IgE and key signature cytokines (interleukin [IL]-4, IL-5, and IL-13) released by cells in the innate and adaptive immune systems. Nontype 2 asthma is less common in youth and is characterized by either neutrophilic or paucigranulocytic airway inflammation driven by IL-8, IL-17, IL-22, other T cell-related cytokines, and epithelial cell-derived cytokines.

The researchers say that shifting from phenotype evaluation to endotype analysis in severe asthma has allowed for the identification and application of patient-specific treatment. With a better understanding of the inflammatory mediators involved in asthma, new monoclonal antibodies can be developed to effectively target type 2 asthma in youth.

Omalizumab is the first monoclonal anti-IgE available for children aged 6 years and older with severe allergic asthma. This therapy is recommended as an add-on when children have elevated serum IgE (>30 and <1500 IU/mL) and positive specific IgE to at least 1 aeroallergen. Omalizumab was deemed safe and effective after being tested in pediatric patients in several randomized controlled trials that eventually led to its final registration more than 10 years ago.

Omalizumab works by binding to free IgE to reduce cell-bound IgE, which helps down-regulate IgE receptors and prevents the release of proinflammatory mediators. This therapy is effective at reducing the rate of exacerbated asthma, the number of asthma-attack-related hospitalizations, and the need for oral corticosteroids in children with severe asthma. Children who use omalizumab are shown to experience better asthma control and improved quality of life. Furthermore, the use of omalizumab is shown to result in discontinuation of oral corticosteroids, a decrease in the dose of inhaled corticosteroids, and a minor improvement in lung function.

The researchers say that data are still lacking on clinical phenotypes and validated biomarkers predicting response to omalizumab, and that further investigation is still needed. At present, unmet needs include the limit on omalizumab use in children under the age of 6, in children with nonallergic asthma, and in children with total IgE greater than 1500 IU/mL.

Mepolizumab is a new IL-5-targeted agent that was recently approved by the US Food and Drug Administration and the European Union as an add-on to treat children older than age 12 years with severe eosinophilic asthma and a history of asthma exacerbations. At present, mepolizumab is available for subcutaneous use as a lyophilized powder in a single-dose glass vial. The recommended dose in the United Kingdom is 100 mg for children aged 12 years and older and 40 mg for children between the ages of 6 and 11 years, where mepolizumab has been approved for use in this population.

In 2 double-blind, randomized, placebo-controlled studies involving patients with asthma, mepolizumab was shown to significantly decrease the number of asthma exacerbations, especially in patients with a baseline blood eosinophil count of at least 500 cells/μL. Results from another study showed that use of mepolizumab led to a 50% median reduction in oral corticosteroid use and a significant improvement in lung function.

The researchers say that despite these positive findings, the efficacy and safety of mepolizumab in the pediatric population remains unknown because sufficient evidence is still needed. To date, only 28 youths between the ages of 12 and 17 years have been enrolled in mepolizumab phase 3 studies.

Reslizumab is another IL-5 targeted agent approved in 2016 as an add-on for patients aged 18 years and older with severe eosinophilic asthma. The researchers recommend reslizumab when asthma of this phenotype cannot be controlled despite maintenance with high-dose inhaled corticosteroids and another drug, and only when the following conditions are met: blood eosinophil count is at least 400 cells/μL, the patient has had at least 3 asthma exacerbations during the past year, and the company offers reslizumab at the agreed discount level in the patient access scheme.

Results from a phase 3 trial and 4 placebo-controlled efficacy and safety studies for reslizumab revealed that patients with uncontrolled eosinophilic asthma aged 12 years and older who used at least a medium dose of inhaled corticosteroids experienced significant improvements in symptoms, lung function, exacerbations, and asthma-related quality of life. Results from a single-blind, placebo-controlled trial showed that this therapy was effective at reducing local and systemic eosinophilia, and at improving asthma control and forced expiratory volume (FEV).

Reslizumab has not been found effective in patients between the ages of 12 and 17 years because the therapy was shown to decrease lung function and increase asthma exacerbation rates in this population. Reslizumab has not been tested in children aged 11 years and under for this reason. The researchers say further studies are needed to improve the safety of reslizumab and identify patients at high risk for adverse events before it can be used in the pediatric population.

Benralizumab is the last of 3 IL-5 targeted agents proven effective as an add-on for children aged 12 and older with severe asthma. This therapy induces depletion of eosinophils and regulates eosinophil-associated proteins and genes. Baseline clinical factors proposed to identify patients who may be most responsive to benralizumab include having a blood eosinophils count of at least 300 cells/mm3, having a positive history of nasal polyposis, experiencing frequent exacerbation, and using oral corticosteroids.

Results from 2 randomized, double-blind, parallel-group, placebo-controlled phase 3 trials revealed that patients with asthma aged 12 to 75 years who had at least 2 exacerbations while using inhaled corticosteroids and long-acting β2-agonists were able to experience a significant decrease in annual exacerbation rate when using benralizumab. These patients also experienced an improvement in asthma symptoms and prebronchodilator FEV. The researchers say the clinical response to benralizumab is greater in patients who have higher baseline serum eosinophil levels.

At present, there are several ongoing phase 3 trials evaluating the safety and efficacy of benralizumab for severe uncontrolled asthma in the pediatric population. Phase 3 trials are also being conducted to assess changes in lung function with benralizumab in patients who also have eosinophilic inflammation.

Dupilumab is a biologic agent targeted against the IL-4 receptor α-chain that was approved in the United States in 2018 for patients aged 12 years and older with moderate-to-severe asthma and eosinophilia (≥300 cells/μL). This therapy works by blocking the signal transduction network regulated by IL-4 and IL-13. Dupilumab is available as a subcutaneous injection using a prefilled syringe.

Dupilumab has been tested for safety and efficacy in patients with persistent asthma in 2 large, randomized, double-blind, placebo-controlled, parallel-group phase 3 studies. One trial showed that despite daily therapy with inhaled corticosteroids, patients with uncontrolled, moderate-to-severe asthma who received dupilumab experienced a significant reduction in the annual rate of severe exacerbations, especially those with higher baseline blood eosinophil count (>300 cells/mm3) and fractional exhaled nitric oxide greater than 25 ppb. Results from the other trial revealed that in patients with severe steroid-dependent asthma, dupilumab reduced use of oral corticosteroids while significantly reducing the rate of severe exacerbations and improving FEV.

There are ongoing trials testing dupilumab in children between the ages of 6 and 12 years to determine whether the therapy can effectively and safely treat uncontrolled asthma in this population.

Currently, researchers are focusing on limitations surrounding the efficacy and safety of available biologic therapies for severe asthma in the pediatric population. Up to this point, trials of the 5 newly approved therapies have included limited numbers of patients younger than age 18 years. Also, new biologic therapies that target upstream cytokines involved in both Type 2 high and low asthma endotypes are in various stages of clinical development. However, none of these therapies are being investigated in youth.

Reference

Licari A, Manti S, Castagnoli R, et al. Targeted therapy for severe asthma in children and adolescents: current and future perspectives. Pediatr Drugs. 2019;21(4):215–237.

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