What is the role of biologics in treating severe, uncontrolled asthma?

Role of Biologics in Severe, Uncontrolled Asthma

Biologics are indicated for patients aged 6 years and older with severe asthma that remains uncontrolled despite high-dose inhaled corticosteroid plus long-acting beta-agonist (ICS-LABA) therapy, particularly those with eosinophilic or allergic phenotypes. 1

When to Consider Biologics

Biologics should be initiated when patients meet the following criteria:

• Severe persistent asthma uncontrolled on high-dose ICS-LABA combination therapy despite optimal adherence and inhaler technique 1
• Two or more exacerbations requiring systemic corticosteroids in the past 12 months 2
• Need for maintenance oral corticosteroids or frequent bursts to maintain control 1
• Significantly impaired quality of life with persistent symptoms despite maximal conventional therapy 1
• Step 5 or Step 6 therapy level according to asthma management guidelines 3

Phenotype-Directed Biologic Selection

The choice of biologic must be guided by specific phenotypic and biomarker characteristics:

For Allergic Asthma

• Omalizumab (anti-IgE) is the first-line choice for patients with elevated total IgE levels (30-700 IU/mL for adults, up to 1300 IU/mL for children) and documented allergic sensitization to perennial aeroallergens via skin testing or specific IgE 1, 3
• Omalizumab is the only biologic with extensive pediatric data in ages 6-11 years and is preferred for females planning pregnancy 1

For Eosinophilic Asthma

• Mepolizumab (anti-IL-5) is FDA-approved for ages 6 years and older, demonstrating steroid-sparing efficacy and exacerbation reduction 1, 4
• Benralizumab (anti-IL-5Rα) causes rapid eosinophil depletion within 24 hours and is FDA-approved for ages 6 years and older 1, 2
• Both require blood eosinophil count ≥150 cells/μL, though counts ≥300 cells/μL predict better response 1, 2

For Type 2 Inflammation

• Dupilumab (anti-IL-4Rα) is recommended for patients with elevated eosinophils (≥150 cells/μL) and/or elevated FeNO (≥25 ppb), particularly when nasal polyposis or atopic dermatitis coexist 1
• Dupilumab blocks both IL-4 and IL-13 pathways, providing broader Type 2 inflammation control 1

For Non-Type 2 Asthma

• Tezepelumab (anti-TSLP) is the only biologic effective in non-Type 2 asthma after excluding other chronic obstructive airway diseases 1, 3
• Tezepelumab demonstrated consistent exacerbation reduction across all eosinophil subgroups, including those with BEC <300 cells/μL 5

Critical Biomarkers for Patient Selection

Before initiating biologics, obtain the following:

• Blood eosinophil count: Threshold ≥150 cells/μL for anti-IL-5/IL-5R therapies, with higher counts (≥300 cells/μL) predicting better response 1, 2
• Fractional exhaled nitric oxide (FeNO): Useful for dupilumab selection and general Type 2 inflammation assessment; ≥25 ppb suggests Type 2 inflammation 1
• Total IgE and specific IgE to perennial aeroallergens: Required for omalizumab eligibility 1
• Nasal endoscopy and CT sinuses: When chronic rhinosinusitis with nasal polyps is suspected as a comorbidity 1

Dosing Regimens

Benralizumab

• 30 mg subcutaneously every 4 weeks for the first 3 doses, then every 8 weeks thereafter 2

Mepolizumab

• 100 mg subcutaneously every 4 weeks for severe asthma in patients aged 6 years and older 4

Monitoring and Response Assessment

Assess clinical response at 8-12 weeks using the following parameters 1:

• Reduction in asthma exacerbations
• Improvement in symptom control (ACQ-6 or ACT scores)
• Lung function improvement (FEV1)
• Reduction in oral corticosteroid requirements

Continue monitoring every 3-6 months with clinical review, biomarker reassessment, and spirometry 1

Real-world evidence demonstrates that biologics provide significant long-term improvements: at 24 months, patients initiating biologics showed a 0.13 L greater improvement in FEV1 compared to those not receiving biologics (P = 0.004), along with reduced exacerbations and improved asthma control 6

When to Refer to Specialist

Specialist consultation is strongly recommended for 1, 3:

• Patients requiring Step 4 or higher therapy
• Those being considered for biologic therapy
• Patients with more than 2 oral corticosteroid bursts per year
• Recent exacerbation requiring hospitalization
• Prior life-threatening asthma episode or intubation

Common Pitfalls to Avoid

• Do not use LABAs as monotherapy—they carry an FDA black-box warning and must always be combined with ICS 3
• Do not assume all biologics work equally across eosinophil ranges: tezepelumab is the only biologic demonstrating efficacy in patients with BEC <300 cells/μL 5
• Do not overlook adherence and inhaler technique before escalating to biologics—up to one-third of patients may have corticosteroid insensitivity, but many have treatable barriers to control 3
• Omalizumab requires anaphylaxis preparedness: there is a 0.09% risk of anaphylaxis, necessitating observation after each injection and patient education 3

The evidence strongly supports that biologics reduce exacerbations, improve lung function, and enable oral corticosteroid reduction in appropriately selected patients with severe asthma 2, 4, 6. The key to success lies in accurate phenotyping and biomarker-guided selection rather than empiric trial-and-error approaches 3, 1.