What are the treatment options for severe asthma using Interleukin (IL)-5 inhibitors, such as mepolizumab (mepolizumab), reslizumab (reslizumab), and benralizumab (benralizumab)?

IL-5 Inhibitors for Severe Asthma

Primary Indication and Patient Selection

IL-5 inhibitors (mepolizumab, reslizumab, and benralizumab) are indicated as add-on maintenance therapy for severe eosinophilic asthma in patients aged 12 years and older (18+ for reslizumab) who remain uncontrolled despite high-dose inhaled corticosteroids plus additional controllers. 1, 2, 1

Defining Severe Eosinophilic Asthma

Patients must meet ALL of the following criteria:

• Blood eosinophil count ≥150 cells/μL at screening (or ≥300 cells/μL within the past 12 months) 1
• History of ≥2 exacerbations in the previous year requiring systemic corticosteroids, hospitalization, or emergency department visits 1
• Currently on high-dose ICS plus long-acting β2-agonists with or without oral corticosteroids 3, 1
• Poor disease control despite optimized inhaled therapy 3

Available IL-5 Inhibitors and Dosing

Mepolizumab (Nucala)

• 100 mg subcutaneously every 4 weeks 1
• Targets IL-5 directly, preventing eosinophil maturation and survival 4, 5

Reslizumab (Cinqair)

• 3 mg/kg intravenously every 4 weeks over 20-50 minutes 2
• Must be administered by healthcare professional prepared to manage anaphylaxis 2
• Only approved for patients ≥18 years 2

Benralizumab (Fasenra)

• 30 mg subcutaneously: first 3 doses every 4 weeks, then every 8 weeks 6
• Targets IL-5 receptor alpha, causing complete eosinophil depletion within 24 hours in 100% of patients 3

Comparative Efficacy

Mepolizumab demonstrates superior efficacy compared to benralizumab and reslizumab in reducing exacerbations and improving asthma control across all eosinophil thresholds. 7

Exacerbation Reduction

• Mepolizumab reduces exacerbations by 47-53% versus placebo 1
• Mepolizumab reduces exacerbations by 34-45% versus benralizumab (rate ratio 0.55-0.66, p<0.05) and 45% versus reslizumab (rate ratio 0.55, p=0.007) in patients with ≥400 cells/μL 7
• All three agents reduce exacerbations by approximately 50% versus placebo 3, 8

Asthma Control and Quality of Life

• Mepolizumab significantly improves ACQ scores versus benralizumab across all eosinophil subgroups (p<0.05) 7
• All agents provide modest improvements in validated quality of life scores 3

Oral Corticosteroid Sparing

• Significant reduction in maintenance oral corticosteroid requirements with all three agents 3, 1
• Mean baseline OCS use of 12-13 mg reduced substantially over 24 weeks 1

Clinical Outcomes Data

Hospitalization and Emergency Visits

• Mepolizumab 100 mg reduces hospitalizations/ED visits by 61% (rate ratio 0.39,95% CI 0.18-0.83) 1
• Mepolizumab reduces hospitalizations alone by 60% (rate ratio 0.40,95% CI 0.19-0.81) 1

Lung Function

• Benralizumab significantly improves FEV1 versus reslizumab in patients with ≥400 cells/μL (p=0.025) 7
• Modest improvements in FEV1 observed with all agents 1, 9

Safety Profile

All three IL-5 inhibitors demonstrate favorable safety profiles with no significant differences in adverse events versus placebo. 10, 8

Common Adverse Events

• Mepolizumab: Headache, injection site reactions, back pain 1
• Reslizumab: Oropharyngeal pain (≥2%), anaphylaxis in 0.3% of patients 2
• Benralizumab: Worsening asthma, nasopharyngitis, injection site reactions 11

Critical Safety Considerations

• Reslizumab carries a boxed warning for anaphylaxis and must be administered in settings equipped to manage life-threatening reactions 2
• Do not discontinue corticosteroids abruptly; taper gradually if appropriate 2
• Treat pre-existing helminth infections before initiating therapy; discontinue if helminth infection occurs and doesn't respond to treatment 2

Treatment Algorithm

First-Line Selection

Choose mepolizumab or benralizumab as first-line agents for patients with blood eosinophils ≥300 cells/μL 3

• Mepolizumab preferred based on superior exacerbation reduction and asthma control versus other IL-5 inhibitors 7
• Benralizumab alternative if complete eosinophil depletion desired or less frequent dosing preferred (every 8 weeks after loading) 6, 3

When to Consider Reslizumab

• Patient preference for weight-based dosing
• Acceptance of IV administration and anaphylaxis risk
• Age ≥18 years required 2

Treatment Monitoring

• Continue optimized inhaled therapy; IL-5 inhibitors should never be used as monotherapy 3
• Monitor for treatment response at 4-6 months 3
• Consider non-eosinophilic causes if inadequate response 3
• Therapeutic drug monitoring recommended for benralizumab per European Respiratory Society 11, 6

Alternative Considerations

If anti-IL-5 therapy fails or is contraindicated, consider dupilumab (anti-IL-4 receptor alpha), which demonstrates superior exacerbation reduction in some studies for patients with eosinophils ≥300 cells/μL 3

Beyond Asthma: Other Approved Indications

Eosinophilic Granulomatosis with Polyangiitis (EGPA)

• Mepolizumab recommended for relapsing-refractory EGPA without organ/life-threatening manifestations, particularly requiring prednisone ≥7.5 mg daily for respiratory control 10
• Benralizumab approved for EGPA with refractory asthma/ENT disease despite high-dose glucocorticoids and optimized inhaled therapy 6
• For severe EGPA remission maintenance, traditional DMARDs preferred over mepolizumab 10

Chronic Rhinosinusitis with Nasal Polyps (CRSwNP)

• Mepolizumab 750 mg IV reduced need for revision surgery (30% vs 10%, p=0.006) and improved symptom scores in severe CRSwNP 10
• Dupilumab remains the only FDA-approved monoclonal antibody for CRSwNP 10

Eosinophilic Esophagitis (EoE)

• IL-5 inhibitors NOT recommended for EoE outside clinical trials 10
• 90% of patients failed histologic remission despite tissue eosinophil reduction 10
• No significant symptomatic improvement versus placebo 10

Hypereosinophilic Syndrome

• Benralizumab shows promise with 74% sustained response at 48 weeks 11, 6

Critical Pitfalls to Avoid

• Never use IL-5 inhibitors for acute bronchospasm or status asthmaticus 2
• Never discontinue background asthma therapy when initiating biologics 3, 1
• Never abruptly stop corticosteroids; taper gradually under supervision 2
• Ensure adequate trial of standard therapy before initiating biologics 3
• Recognize that eosinophil counts will rebound after treatment discontinuation 10