Background
Phase 3, multicenter, double-blind, placebo-controlled RCT. 85 patients with idiopathic hypereosinophilic syndrome (HES) requiring prednisone ≥10 mg/day to control symptoms and maintain AEC. Patients had stable eosinophilia (AEC ≥1,000/µL) despite ongoing corticosteroid therapy. Excluded: patients with FIP1L1-PDGFRA rearrangement (imatinib-eligible). This was the pivotal trial for IL-5–targeted therapy in HES.
Interventions and follow up
Arm A: Mepolizumab 750 mg IV every 4 weeks for 3 doses (then transition to open-label)
Arm B: Placebo IV every 4 weeks for 3 dose
Primary endpoint: Proportion achieving prednisone dose reduction to ≤10 mg/day for ≥8 consecutive weeks during the 9-week stable-steroid phase
mFollow up: 9 weeks (double-blind phase)
Arm B: Placebo IV every 4 weeks for 3 dose
Primary endpoint: Proportion achieving prednisone dose reduction to ≤10 mg/day for ≥8 consecutive weeks during the 9-week stable-steroid phase
mFollow up: 9 weeks (double-blind phase)
Results
Primary endpoint (steroid reduction achieved): 84% vs 43%, OR 7.18 (95% CI 2.49–20.73), P<.001
AEC normalization (<600/µL): 95% vs 45% at end of treatment, P<.001
Clinical response (symptom control on reduced prednisone): 85% vs 45%
Median prednisone dose reduction: From 20 mg to 0 mg (mepolizumab) vs 20 mg to 12 mg (placebo)
AEC normalization (<600/µL): 95% vs 45% at end of treatment, P<.001
Clinical response (symptom control on reduced prednisone): 85% vs 45%
Median prednisone dose reduction: From 20 mg to 0 mg (mepolizumab) vs 20 mg to 12 mg (placebo)
Adverse events
Main adverse events: Mepolizumab well-tolerated. Headache, arthralgia, fatigue reported but similar between arms. No anaphylaxis. Infections similar. Eosinophil rebound with discontinuation expected. No significant increase in parasitic infections in the short double-blind phase.
Conclusions
Mepolizumab significantly reduced peripheral eosinophil counts and enabled major steroid dose reduction in patients with HES, establishing anti-IL-5 therapy as effective in eosinophilia-driven systemic disease.
Key Limitations
Key Limitations: Short double-blind phase (9 weeks) limits assessment of long-term durability and organ protection. Small sample size (n=85). Excluded FIP1L1-PDGFRA–positive patients (imatinib-responsive subtype), meaning this trial addresses only idiopathic HES. The dose used (750 mg IV) is much higher than the approved asthma dose (100 mg SC), reflecting earlier uncertainty about dosing; clinical practice now uses lower SC doses. Organ-specific endpoints (cardiac, neurologic) were not powered.
Clinical Context
Mepolizumab (Nucala) is FDA approved for FIP1L1-PDGFRA–negative HES in patients ≥12 years (300 mg SC q4wk). Imatinib remains first-line for FIP1L1-PDGFRA–positive HES, where it achieves molecular remission. For idiopathic HES and PDGFRA-negative disease, mepolizumab enables corticosteroid sparing and is now standard of care. Benralizumab (anti-IL-5Rα) has emerging data in HES. This trial also provided mechanistic proof-of-concept for eosinophil-targeted therapy across eosinophilic diseases.
References