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John R. Ellis Distinguished Chair of Pharmacy Practice
Professor of Clinical Sciences
Director, Drake Drug Information Center
Drake University College of Pharmacy and Health Sciences
Internal Medicine Clinical Pharmacist
Iowa Methodist Medical Center
Des Moines, Iowa
Geoffrey C. Wall, PharmD, FCCP, BCPS, has disclosed that he has received consulting fees from Janssen.
Asthma is a chronic airway disease that involves bronchospasm, often in response to an atopic reaction. Symptoms include wheezing, shortness of breath, and cough and chest tightness and can range from mild to life threatening. Although asthma affects patients of all ages, it is a major disease of the young—and in this age group asthma can be a significant cause of morbidity and even mortality. The economic costs of asthma are considerable. The average cost of an exacerbation is approximately $2,333, and patients with asthma are frequent users of emergency medical services, including emergency department visits. Combined, asthma costs in the United States were $81.9 billion in 2013.
Type 2 Inflammation and Severe Asthma
Similar to chronic obstructive pulmonary disease, an inflammatory disease causing airflow blockage and problems related to breathing, asthma has several distinct pathophysiologic phenotypes. Allergens and atopic reactions play a major role in type 2 asthma. Type 2 “high” asthma is orchestrated by Th2 cytokines such as interleukin (IL)-4, IL-5, and IL-13, and patients with “ultra-high” type 2 asthma have a more severe form of the disease. Type 2 “low” asthma is more complex and characterized by neutrophilic instead of eosinophilic inflammation and the proinflammatory cytokine IL-6 (a lymphocyte chemoattractant) as a possible biomarker. Given the numerous biologic drugs approved and in development for asthma, finding biomarkers to define the type of asthma a patient has may help with appropriate drug selection.
Using Clinical Practice Guidelines for Proper Treatment Selection
The US guidelines for treating patients with asthma were updated with the publication of the Expert Panel Report 4 “2020 Focused Updates to the Asthma Management Guidelines: A Report from the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group” and the annually updated Global Initiative for Asthma (GINA) evidence-based guidelines. Understanding these guidelines is crucial for evidence-based treatment of patients with asthma.
Single Maintenance and Reliever Therapy (SMART Therapy)
One relatively new treatment concept that both guidelines highlight is SMART therapy. With this therapy, patients use 1 inhaler for both maintenance and as-needed quick relief. Formoterol-containing agents can be used in this manner due to their rapid onset of β-2 agonism and effects. The rationale for SMART therapy concerns the use of inhaled corticosteroids (ICSs). When patients use a rapid-acting drug for their symptoms, they still have inflammation of the airways that is not being addressed. Formoterol rapidly treats the bronchospasm-related symptoms, and the extra dose of the ICS treats inflammation. Studies have suggested the SMART approach is easier for patients and may result in reducing exacerbations requiring formal healthcare. There is no evidence that this approach lessens the effect of maintenance ICS use. However, for the pharmacist, this may mean that an inhaler intended to last 30 days often will not, making insurance coverage challenging.
Both guidelines acknowledge the role of biologic drugs for severe asthma refractory to standard therapy and/or requiring oral corticosteroids for control. Several agents are approved by the FDA for this indication, including omalizumab (an anti–immunoglobulin E [IgE] antibody), mepolizumab and reslizumab (both anti–IL-5 antibodies), benralizumab (an IL-5 receptor antagonist), dupilumab (an IL-4 receptor antagonist), and tezepelumab-ekko (an antithymic stromal lymphopoietin antibody). Selection of these agents is dependent on age, type of asthma, biomarker information, and insurance coverage. The GINA guidelines suggest starting with anti-IgE therapy if the patient is older than 6 years of age and has severe allergic asthma, a positive sensitization on skin prick testing or specific IgE, an elevated IgE level, and exacerbations in the past year. Anti–IL-5 therapy is suggested if age appropriate for the individual drug and the patient has severe eosinophilic asthma (blood eosinophils ≥300 cells/µL) and exacerbations in the past year. Finally, GINA suggests anti–IL-4 therapy if the patient is older than 12 years of age and has severe eosinophilic asthma or the need for maintenance oral steroids, exacerbations in the past year, and either blood eosinophils ≥150 cells/µL or fractional exhaled nitric oxide ≥25 ppb. Although an in-depth review of these agents is beyond the scope of this commentary, all biologic agents have been shown to be safe and effective in patients with severe asthma, with significant improvement in symptoms and a decrease in both exacerbations and the need for oral steroids in many patients who use them. This benefit often has been seen weeks after starting these drugs in clinical trials. The exact role of tezepelumab-ekko in the treatment algorithm remains to be elucidated, and it is worth noting that no specific biomarkers associated with its use have been recommended to date.
These medications have been shown to be safe, with nonspecific symptoms such as injection-site reactions and headache listed as adverse events. Conjunctivitis is listed as an adverse event for dupilumab, and clinicians should monitor patients receiving this drug for its development.
As might be expected, biologics are expensive. As payers decide on drug selection and coverage, it is worth noting that there are few pharmacoeconomic studies examining the cost effectiveness of these drugs in severe asthma. The studies published to date largely have found that the cost of most biologics per quality-adjusted life-year was below the traditional willingness-to-pay threshold of $100,000.
In your practice, how confident are you in understanding when to consider add-on biologic therapy for severe asthma? Which tools do you use to inform your decision on the best therapy for patients with severe asthma? Answer the polling question and join the conversation by posting a comment in the discussion section.