What is Mepolizumab (anti-interleukin-5 antibody) used for in patients with severe asthma, hypereosinophilic syndrome (HES), or eosinophilic granulomatosis with polyangiitis (EGPA)?

What is Mepolizumab?

Mepolizumab is a humanized monoclonal antibody that targets interleukin-5 (IL-5), approved for treating severe eosinophilic asthma, eosinophilic granulomatosis with polyangiitis (EGPA), hypereosinophilic syndrome (HES), and chronic rhinosinusitis with nasal polyps (CRSwNP). 1

Mechanism of Action

• Mepolizumab binds to IL-5 with high affinity (dissociation constant of 100 pM), blocking its binding to the IL-5 receptor on eosinophils. 1
• IL-5 is the major cytokine responsible for eosinophil growth, differentiation, recruitment, activation, and survival. 1
• By inhibiting IL-5 signaling, mepolizumab reduces eosinophil production and survival, achieving an 83-85% reduction in blood eosinophil counts within 4 weeks of treatment. 1

Clinical Indications and Dosing

For EGPA (Eosinophilic Granulomatosis with Polyangiitis)

For active, non-severe EGPA, mepolizumab 300 mg subcutaneously every 4 weeks combined with glucocorticoids is the preferred first-line treatment over traditional immunosuppressants (methotrexate, azathioprine, mycophenolate mofetil). 2

• For active, severe EGPA with organ- or life-threatening manifestations, cyclophosphamide or rituximab combined with high-dose glucocorticoids is recommended over mepolizumab, as patients with severe disease were excluded from the pivotal mepolizumab trial. 2
• For relapsing-refractory EGPA without organ-threatening manifestations, mepolizumab is recommended for both remission induction and maintenance therapy. 2
• The FDA-approved dose for EGPA is 300 mg every 4 weeks, though real-world evidence suggests 100 mg every 4 weeks may be effective for respiratory-predominant disease, with dose escalation to 300 mg if response is inadequate. 2, 3

For Severe Eosinophilic Asthma

• Mepolizumab 100 mg subcutaneously every 4 weeks is approved for patients aged 12 years and older with severe eosinophilic asthma. 1
• For children aged 6-11 years, the dose is 40 mg subcutaneously every 4 weeks. 1

For Hypereosinophilic Syndrome (HES)

• Mepolizumab is indicated for HES in patients aged 12 years and older. 1

For Chronic Rhinosinusitis with Nasal Polyps (CRSwNP)

• Mepolizumab 100 mg subcutaneously every 4 weeks is approved for adults with CRSwNP. 1

Clinical Effectiveness in EGPA

In the MIRRA trial, mepolizumab 300 mg every 4 weeks demonstrated efficacy in inducing and maintaining remission in patients with relapsing-refractory EGPA, while improving lung function and enabling glucocorticoid sparing. 2

• Real-world European multicenter data showed that both 100 mg and 300 mg doses achieved comparable complete response rates (35.7% at 24 months), with significant reductions in disease activity scores, prednisone doses, and eosinophil counts. 3
• In real-world studies, 76-81% of patients achieved complete response (defined as no disease activity with prednisone ≤7.5 mg/day) by 12 months on low-dose mepolizumab (100 mg). 4, 5
• Mepolizumab is particularly effective for controlling respiratory manifestations (asthma and ENT disease) in EGPA, reducing asthma exacerbations by approximately 50-86%. 4, 6, 5

Role in Treatment Algorithm

EGPA Treatment Strategy

For non-severe EGPA with predominantly asthma, sinus disease, and non-severe vasculitis:

• First-line: Glucocorticoids + mepolizumab 300 mg every 4 weeks 2
• Alternative: Glucocorticoids + methotrexate, azathioprine, or mycophenolate mofetil if mepolizumab is not suitable 2

For severe EGPA with organ-threatening manifestations (glomerulonephritis, cardiomyopathy, severe neuropathy):

• First-line: High-dose glucocorticoids + cyclophosphamide or rituximab 2
• Mepolizumab is NOT recommended for initial treatment of severe disease 2

For maintenance therapy:

• Mepolizumab can be used for remission maintenance, particularly in patients requiring prednisone ≥7.5 mg/day for respiratory control 2
• Rituximab is preferred for maintenance in patients with severe disease who achieved remission on rituximab 2

For refractory respiratory manifestations (asthma/ENT) without systemic vasculitis:

• Add mepolizumab after optimizing inhaled therapies 2

Pharmacodynamics and Onset

• Blood eosinophil reduction occurs within 48 hours (Day 3) of the first dose, with maximal reduction (83-90%) achieved by 4 weeks and maintained throughout treatment. 1
• Clinical benefits in asthma control, exacerbation reduction, and glucocorticoid sparing typically manifest within the first 3-6 months of treatment. 3, 4

Safety Profile

• Mepolizumab has a favorable safety profile in real-world studies, with most adverse events being non-serious. 3
• In the European multicenter study of 203 EGPA patients, 21.7% experienced adverse events, with only 6 serious adverse events reported. 3
• Common adverse events include injection site reactions, headache, and infections, though these are generally mild. 7

Important Clinical Considerations

Mepolizumab should NOT be used as rescue therapy for acute bronchospasm or acute EGPA exacerbations. 1

Optimize inhaled therapies (high-dose inhaled glucocorticoids and long-acting β2-agonists) concurrently with mepolizumab for asthma control in EGPA patients. 2

Multidisciplinary collaboration with pulmonologists and otolaryngologists is essential for managing respiratory manifestations in EGPA patients on mepolizumab. 2, 8

For patients with inadequate response to mepolizumab, consider alternative IL-5 pathway inhibitors (benralizumab, reslizumab) or switching to different immunosuppressive strategies based on disease manifestations. 2

No dose adjustment is required for elderly patients, though greater sensitivity cannot be ruled out. 1