What are the treatment options with biologics, such as omalizumab (anti-IgE), mepolizumab (anti-interleukin-5), and benralizumab (anti-interleukin-5 receptor alpha), for patients with severe, uncontrolled asthma?

Biologic Therapy for Severe Uncontrolled Asthma

For patients aged 12 years and older with severe persistent asthma inadequately controlled on high-dose inhaled corticosteroids plus long-acting beta-agonists, biologic therapy should be initiated, with the specific agent selected based on phenotype: omalizumab for allergic asthma with elevated IgE and positive aeroallergen testing, or anti-IL-5/IL-5R agents (mepolizumab, benralizumab) for eosinophilic asthma with elevated blood eosinophils. 1, 2

When to Initiate Biologics

Biologics are indicated at Step 5 or 6 of asthma management when patients remain uncontrolled despite optimized therapy with high-dose ICS-LABA for an adequate duration. 1, 2 The 2020 NAEPP guidelines specifically recommend considering biologic agents at these advanced treatment steps, though they note the systematic review did not include specific recommendations for individual biologics. 1

• Before initiating biologics, verify adherence to controller medications, proper inhaler technique, environmental trigger control, and management of comorbid conditions. 1
• Consultation with an asthma specialist is recommended when Step 4 or higher therapy is required. 1

Selecting the Appropriate Biologic Agent

For Allergic Asthma: Omalizumab (Anti-IgE)

Omalizumab is the first-line biologic choice for patients with documented allergic asthma, defined by positive skin testing or RAST to perennial aeroallergens and elevated serum IgE levels. 2, 3, 4

• Omalizumab binds to the Fc portion of IgE, preventing IgE binding to high-affinity receptors (FcεRI) on mast cells and basophils, thereby decreasing mediator release in response to allergen exposure. 3, 4
• Clinical efficacy is greatest in patients with elevated T2 biomarkers, even though the primary indication is allergic asthma. 5
• Omalizumab reduces exacerbations irrespective of blood eosinophil levels in severe allergic asthma. 6

Dosing: Administered subcutaneously every 2-4 weeks based on body weight and baseline IgE levels (consult dosing tables). 4

For Eosinophilic Asthma: Anti-IL-5/IL-5R Agents

For patients with severe eosinophilic asthma (elevated blood eosinophils) and recurrent exacerbations, anti-IL-5 or anti-IL-5R biologics are indicated, irrespective of allergic status. 6, 5

Mepolizumab (Anti-IL-5)

• Dosing: 100 mg subcutaneously every 4 weeks for patients aged 12 years and older. 7
• Mepolizumab has demonstrated efficacy in reducing exacerbations and oral corticosteroid requirements in severe eosinophilic asthma. 5, 8
• In real-world studies, 30% of mepolizumab-treated patients achieved complete disease remission after 12 months. 8
• Mepolizumab is also indicated for treatment-dependent allergic bronchopulmonary aspergillosis (ABPA) when biologics are considered. 1

Benralizumab (Anti-IL-5 Receptor Alpha)

• Benralizumab targets the IL-5 receptor (IL-5R-α) rather than IL-5 itself. 5
• It has demonstrated steroid-sparing efficacy and reduces exacerbation rates in patients with elevated blood eosinophil counts. 5
• Real-world data shows 40% of benralizumab-treated patients achieved complete disease remission after 12 months. 8

Critical Safety Requirements for Omalizumab

Omalizumab carries an FDA black-box warning for anaphylaxis (risk approximately 0.09%) and must be administered in a healthcare setting by providers trained in anaphylaxis recognition and treatment. 1, 2, 3, 4

• Patients must be observed for an appropriate period after each injection (typically 2 hours after the first three doses, then 30 minutes for subsequent doses). 1, 3
• All patients must be prescribed an epinephrine autoinjector and trained in its use. 9, 3
• Healthcare facilities administering omalizumab must be equipped to treat anaphylaxis immediately. 1, 2

Common pitfall: The initial concern about malignant neoplasms with omalizumab was subsequently deemed unrelated to the drug, with an expert oncology panel concluding only 3 of 25 reported neoplasms were even remotely related to omalizumab. 1

Algorithm for Biologic Selection

Step 1: Confirm severe persistent asthma uncontrolled on high-dose ICS-LABA (Step 5-6). 1, 2

Step 2: Phenotype the patient:

• Allergic phenotype: Positive skin testing or RAST to perennial aeroallergens + elevated IgE → Omalizumab 2, 3
• Eosinophilic phenotype: Elevated blood eosinophils (typically ≥300 cells/µL) + recurrent exacerbations → Mepolizumab or Benralizumab 6, 5
• Mixed allergic-eosinophilic phenotype: Both criteria met → Consider starting with anti-IL-5/IL-5R agents, as real-world evidence shows patients with severe eosinophilic allergic asthma uncontrolled on omalizumab respond well when switched to mepolizumab. 10

Step 3: Consider comorbidities that may favor specific biologics:

• Chronic rhinosinusitis with nasal polyps → Omalizumab (also approved for this indication) 4
• Treatment-dependent ABPA → Mepolizumab, benralizumab, or omalizumab 1

Switching Between Biologics

For patients with severe eosinophilic allergic asthma inadequately controlled on omalizumab, switching to mepolizumab without a washout period is an effective strategy. 10

• A multicenter Italian study of 41 patients switched from omalizumab to mepolizumab showed significant improvements: exacerbations decreased from 5.8±1.8 to 0.7±0.9 per year, ACT scores improved from 12±2.7 to 21.9±2.7, and oral corticosteroid dependence decreased from 46% to 5%. 10
• This suggests that in mixed phenotype patients, the eosinophilic component may be the dominant driver requiring targeted therapy. 10

Monitoring and Response Assessment

• Assess treatment response at 8-12 weeks using clinical improvement (≥50% symptom reduction), imaging findings, and ≥20% reduction in serum total IgE (for omalizumab). 1
• For anti-IL-5/IL-5R agents, monitor peripheral blood eosinophil levels, which should decrease significantly. 8
• All biologics have demonstrated excellent safety profiles in clinical trials and real-world use. 5

Important Considerations

Do not use biologics as monotherapy or before optimizing ICS-LABA therapy. 3 Biologics are add-on treatments to standard controller medications, not replacements. 1

• Patients should not discontinue systemic or inhaled corticosteroids except under direct physician supervision, as reduction may cause systemic withdrawal symptoms or unmask previously suppressed conditions. 7
• Higher adherence rates are observed with biologics requiring office administration (like omalizumab) compared to self-administered ICS-LABA, likely due to direct observation of therapy. 1