Pharmacology Consult

New biologic drugs for asthma: What PCPs need to know

In recent years, we have made significant strides in our understanding of the pathogenesis of asthma. As a result, specific new pharmacotherapies and therapeutic treatment strategies are now available.

As IDC readers are aware, asthma pathophysiology involves airway hyper- responsiveness and inflammation. Recently published data have given us a clearer understanding of the inflammatory component of asthma. Clinically severe asthma is now described by type 2 (T2) high and T2 low subtypes. T2 high asthma is characterized by high levels of airway and peripheral eosinophils. Concentrations of various inflammatory mediators become elevated, such as interleukin (IL)-4, IL-5 and IL-13. Mast cell activity, including the activity of numerous chemical inflammatory mediators produced by mast cells, are also elevated. T2 low asthma is described as a lack of eosinophilia, yet a neutrophilic or paucigranulocytic inflammatory environment is prominent. Proinflammatory mediators responsible for T2 low inflammation are believed to include IL-6, IL-8, IL-12 and tumor necrosis factor-alpha, among others. Besides the role and activity of various specific inflammatory mediators, T2 high and T2 low asthma also differ clinically with respect to patients’ responsiveness to corticosteroid treatment and the presence of environmental allergies, among other characteristics. The pathophysiology and role of the numerous inflammatory cells and their chemical mediators in the pathogenesis of asthma are very complex, and it is only briefly discussed here for the purposes of introducing newly available pharmacotherapies. The interplay of these cells and mediators results in the clinical characteristics of asthma that health care practitioners are familiar with, including airway responsiveness, increased airway mucus, inflammation and remodeling.

Edward A. Bell

Because asthma occurs so frequently in the pediatric population and results in significant morbidity and mortality, several guidelines on its diagnosis and management have been published. The National Asthma Education and Prevention Program — coordinated by the NIH’s National Heart, Lung, and Blood Institute (NHLBI) — published an expert panel report (EPR) in 1991, with the latest update published in 2007 (EPR-3). The EPR-4 Working Group was organized in 2018, and summary results are likely to be published soon. Most recently, guidelines by the Global Initiative for Asthma (GINA) were published in 2019. GINA is a collaborative effort between the NHLBI and WHO.

Biologic agents for treating asthma

Five biologic agents are now available to treat moderate-to-severe asthma (see Table). Notice that all these biologic pharmacotherapies include “mab” as the trailing letters in the generic names, indicating “monoclonal antibody.” Xolair has been available for 17 years, and in 2016, it was relabeled for ages 6 to 12 years. Dupixent (Dupilumab, Regeneron Pharmaceuticals and Sanofi) is the most recently labeled biologic, for use in children aged 12 years and older with moderate-to- severe asthma. These biologics reduce the pathophysiologic consequences of increased activity of various inflammatory mediators involved in the pathogenesis of asthma, although they differ in the specific inflammatory cell types and mediators affected. Choosing the right biologic agent is difficult because its effectiveness will depend upon the specific genotype and phenotype of asthma that the patient is diagnosed with. Additional studies are needed to aid clinicians in this regard. Biologics reduce asthma exacerbations overall by approximately 50%, although this may vary among individual patients. Pediatric primary care providers are unlikely to prescribe biologics for asthma because pediatric pulmonologists or allergists will be consulted. However, it is important for primary care providers to be familiar with the role of biologic agents and the changing treatment strategies for pediatric asthma.

Upon reviewing the Table, differences among the biologic agents are readily apparent. These include mechanisms of action (ie, the specific inflammatory mediators affected), age labeling (only Cinqair [reslizumab, Teva Respiratory LLC] has no pediatric labeling), route of administration and dosing interval scheduling. Dupilumab may be given at home, whereas the other agents are administered in a health care setting. As one can imagine, all biologic agents are relatively expensive — approximately $1,000 and up to several thousand dollars per dose. From a pharmacoeconomic perspective, however, if the biologic agents can prevent asthma exacerbations (ie, ED visits or hospitalizations), their higher cost may be justified. Studies evaluating this premise are needed, however.

Changing asthma treatment strategies

Newly published studies and treatment guidelines recommend against using short-acting bronchodilator agents (SABAs) alone for mild asthma. Data indicate that as-needed use of a low-dose inhaled corticosteroid (ICS) combined with formoterol (a long-acting beta2 agonist) for symptom relief is more effective than SABA use alone in children aged 12 years and older and adults with mild asthma. Other studies suggest that as-needed low-dose ICS plus formoterol is as clinically effective as daily maintenance ICS therapy in adolescents and adults with mild asthma. Formoterol is available in combination with budesonide as Symbicort (AstraZeneca) and with mometasone as Dulera (Merck). Additional data indicate that intermittent use of an ICS during an upper respiratory tract infection can decrease asthma exacerbations in children aged younger than 5 years with recurrent wheezing.

Conclusions

Available and recommended pharmacotherapy options for the treatment of asthma in children and adolescents are rapidly changing. As-needed use of an ICS plus formoterol oral inhaler is clinically effective, and may be more likely to improve treatment adherence vs. daily maintenance therapy in older children with mild asthma. Five biologic agents are now available to target specific key inflammatory mediators that are important in the pathogenesis of asthma. Although these biologics are effective, individualizing therapy to maximize effectiveness for individual children and adolescents with moderate-to- severe asthma will be difficult until additional clinical data become available.

Disclosure: Bell reports no relevant financial disclosures.

In recent years, we have made significant strides in our understanding of the pathogenesis of asthma. As a result, specific new pharmacotherapies and therapeutic treatment strategies are now available.

As IDC readers are aware, asthma pathophysiology involves airway hyper- responsiveness and inflammation. Recently published data have given us a clearer understanding of the inflammatory component of asthma. Clinically severe asthma is now described by type 2 (T2) high and T2 low subtypes. T2 high asthma is characterized by high levels of airway and peripheral eosinophils. Concentrations of various inflammatory mediators become elevated, such as interleukin (IL)-4, IL-5 and IL-13. Mast cell activity, including the activity of numerous chemical inflammatory mediators produced by mast cells, are also elevated. T2 low asthma is described as a lack of eosinophilia, yet a neutrophilic or paucigranulocytic inflammatory environment is prominent. Proinflammatory mediators responsible for T2 low inflammation are believed to include IL-6, IL-8, IL-12 and tumor necrosis factor-alpha, among others. Besides the role and activity of various specific inflammatory mediators, T2 high and T2 low asthma also differ clinically with respect to patients’ responsiveness to corticosteroid treatment and the presence of environmental allergies, among other characteristics. The pathophysiology and role of the numerous inflammatory cells and their chemical mediators in the pathogenesis of asthma are very complex, and it is only briefly discussed here for the purposes of introducing newly available pharmacotherapies. The interplay of these cells and mediators results in the clinical characteristics of asthma that health care practitioners are familiar with, including airway responsiveness, increased airway mucus, inflammation and remodeling.

Edward A. Bell

Because asthma occurs so frequently in the pediatric population and results in significant morbidity and mortality, several guidelines on its diagnosis and management have been published. The National Asthma Education and Prevention Program — coordinated by the NIH’s National Heart, Lung, and Blood Institute (NHLBI) — published an expert panel report (EPR) in 1991, with the latest update published in 2007 (EPR-3). The EPR-4 Working Group was organized in 2018, and summary results are likely to be published soon. Most recently, guidelines by the Global Initiative for Asthma (GINA) were published in 2019. GINA is a collaborative effort between the NHLBI and WHO.

Biologic agents for treating asthma

Five biologic agents are now available to treat moderate-to-severe asthma (see Table). Notice that all these biologic pharmacotherapies include “mab” as the trailing letters in the generic names, indicating “monoclonal antibody.” Xolair has been available for 17 years, and in 2016, it was relabeled for ages 6 to 12 years. Dupixent (Dupilumab, Regeneron Pharmaceuticals and Sanofi) is the most recently labeled biologic, for use in children aged 12 years and older with moderate-to- severe asthma. These biologics reduce the pathophysiologic consequences of increased activity of various inflammatory mediators involved in the pathogenesis of asthma, although they differ in the specific inflammatory cell types and mediators affected. Choosing the right biologic agent is difficult because its effectiveness will depend upon the specific genotype and phenotype of asthma that the patient is diagnosed with. Additional studies are needed to aid clinicians in this regard. Biologics reduce asthma exacerbations overall by approximately 50%, although this may vary among individual patients. Pediatric primary care providers are unlikely to prescribe biologics for asthma because pediatric pulmonologists or allergists will be consulted. However, it is important for primary care providers to be familiar with the role of biologic agents and the changing treatment strategies for pediatric asthma.

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Upon reviewing the Table, differences among the biologic agents are readily apparent. These include mechanisms of action (ie, the specific inflammatory mediators affected), age labeling (only Cinqair [reslizumab, Teva Respiratory LLC] has no pediatric labeling), route of administration and dosing interval scheduling. Dupilumab may be given at home, whereas the other agents are administered in a health care setting. As one can imagine, all biologic agents are relatively expensive — approximately $1,000 and up to several thousand dollars per dose. From a pharmacoeconomic perspective, however, if the biologic agents can prevent asthma exacerbations (ie, ED visits or hospitalizations), their higher cost may be justified. Studies evaluating this premise are needed, however.

Changing asthma treatment strategies

Newly published studies and treatment guidelines recommend against using short-acting bronchodilator agents (SABAs) alone for mild asthma. Data indicate that as-needed use of a low-dose inhaled corticosteroid (ICS) combined with formoterol (a long-acting beta2 agonist) for symptom relief is more effective than SABA use alone in children aged 12 years and older and adults with mild asthma. Other studies suggest that as-needed low-dose ICS plus formoterol is as clinically effective as daily maintenance ICS therapy in adolescents and adults with mild asthma. Formoterol is available in combination with budesonide as Symbicort (AstraZeneca) and with mometasone as Dulera (Merck). Additional data indicate that intermittent use of an ICS during an upper respiratory tract infection can decrease asthma exacerbations in children aged younger than 5 years with recurrent wheezing.

Conclusions

Available and recommended pharmacotherapy options for the treatment of asthma in children and adolescents are rapidly changing. As-needed use of an ICS plus formoterol oral inhaler is clinically effective, and may be more likely to improve treatment adherence vs. daily maintenance therapy in older children with mild asthma. Five biologic agents are now available to target specific key inflammatory mediators that are important in the pathogenesis of asthma. Although these biologics are effective, individualizing therapy to maximize effectiveness for individual children and adolescents with moderate-to- severe asthma will be difficult until additional clinical data become available.

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Disclosure: Bell reports no relevant financial disclosures.