Abstract
In this installment of the How I Do It series on severe asthma, we tackle the clinical conundrum of choosing the right biologic for the right patient with severe asthma. With six biologics now approved for use in this area comprising four different targeting strategies (anti-Ig E: omalizumab; anti-IL-5 and anti-IL-5-receptor: mepolizumab, reslizumab, and benralizumab; anti-IL-4-receptor: dupilumab; anti-thymic stromal lymphopoietin: tezepelumab), this question is increasingly complex. Recognizing that no head-to-head trial has compared biologics, we based our review on the expected effects of inhibiting different aspects of type 2 airway inflammation, supported whenever possible by clinical trial and real-world data. We use four variations of a case of severe uncontrolled asthma to develop concepts and considerations introduced in the previous installment (“Workup of Severe Asthma”) and discuss pregnancy-related, biomarker-related, comorbidity-related, and corticosteroid dependency-related considerations when choosing a biologic. The related questions of deciding when, why, and how to switch from one biologic to another also are discussed. Overall, we consider that the choice of biologics should be based on the available clinical trial data for the desired efficacy outcomes, the biomarker profile of the patient, safety profiles (eg, when pregnancy is considered), and opportunities to target two comorbidities with one biologic. Using systemic and airway biomarkers (blood eosinophils and exhaled nitric oxide [Feno]) and other phenotypic characteristics, we suggest a framework to facilitate therapeutic decision-making. Post hoc studies and new comparative studies are needed urgently to test this framework and to determine whether it allows us to make other clinically useful predictions.
Key Points
- Evolving Role of Biologic Therapy in Severe Asthma: Historically, corticosteroids were the mainstay of treatment for severe asthma, but their side effects led to the development of targeted monoclonal antibodies. Biologic therapies now provide precision medicine approaches based on underlying inflammation patterns.
- Biologic Selection Based on Phenotype and Endotype: Choosing a biologic requires assessing biomarkers such as blood eosinophil counts, exhaled nitric oxide fraction (FeNO), and IgE levels. Patients with eosinophilic inflammation benefit from anti-IL-5/IL-5R agents, whereas FeNO elevation suggests a response to anti-IL-4R or anti-TSLP therapies.
- Clinical Considerations for Biologic Use: Factors influencing biologic selection include exacerbation history, oral corticosteroid dependence, lung function parameters (e.g., FEV1), and asthma phenotype (allergic, eosinophilic, non-type 2). The presence of comorbidities such as nasal polyposis or chronic rhinosinusitis may favor specific agents like dupilumab.
- Comparison of Biologic Efficacy: While no direct head-to-head trials exist, indirect comparisons suggest that dupilumab and tezepelumab have the broadest efficacy across asthma phenotypes. Anti-IL-5 agents are particularly effective in patients with high blood eosinophils but do not lower FeNO.
- Biologic Use in Special Populations: Pregnant women with severe asthma may be prescribed biologics with the best safety profiles, such as omalizumab and mepolizumab. However, limited data exist on the long-term effects of biologic therapy during pregnancy.
- Switching Biologic Therapy: Patients who experience loss of efficacy with one biologic may require switching to another targeting a different inflammatory pathway. For example, a patient failing mepolizumab due to persistent FeNO elevation may benefit from dupilumab.
- Challenges in Biologic Decision-Making: Despite advancements, challenges remain in identifying the best biologic for each patient due to overlapping inflammatory pathways, regional prescription criteria, and reimbursement policies.
- Oral Corticosteroid-Sparing Effects of Biologics: Mepolizumab, benralizumab, and dupilumab have demonstrated the most robust ability to reduce oral corticosteroid use in severe asthma, while omalizumab and tezepelumab show less pronounced effects in this regard.
- Future Directions in Severe Asthma Treatment: Ongoing research focuses on refining predictive biomarkers, developing combination biologics, and exploring new inflammatory pathways to further optimize asthma management.
- Personalized Medicine in Asthma Care: A patient-centered approach incorporating biomarker-driven algorithms and shared decision-making is essential for optimizing biologic therapy in severe asthma.
