Long-Term Safety and Effectiveness of Mepolizumab 300 mg in Europe (Mepo LTF Study)

BACKGROUND Eosinophilic granulomatosis with polyangiitis (EGPA, formerly Churg-Strauss syndrome) is an anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) characterized by asthma, ear- nose-throat (ENT) involvement, blood and tissue eosinophilia and systemic vasculitic manifestations. The treatment mainly relies on systemic glucocorticoids and inhaled therapies for respiratory symptoms. Its course is usually chronic-relapsing, thus patients are at risk for permanent tissue or organ damage, also due to glucocorticoid-related toxicity. For this reason, immunosuppressive treatments are often required, to reduce disease activity, and also to spare glucocorticoids.

Among novel targeted therapies, Mepolizumab is a monoclonal antibody against interleukin (IL)-5, a cytokine involved in eosinophil maturation, differentiation and survival. Increased serum levels of IL-5 are observed in eosinophilic disorders, including EGPA, and a genome-wide association study identified the IL5 region as one of the main EGPA-associated loci. Mepolizumab is approved at the dosage of 100mg/4 weeks subcutaneously for the treatment of severe eosinophilic asthma, and at the dosage of 300mg/4 weeks for hypereosinophilic syndrome (HES) and for EGPA, following the positive results of the MIRRA trial.

In the last years, a growing number of large observational cohort studies reported on the successful use of drugs targeting the IL-5 axis (including mepolizumab and the anti-IL5Ra benralizumab) for EGPA in the real-life clinical setting, also at the dosages approved for eosinophilic asthma (i.e., 100mg/4 weeks for mepolizumab; 300 mg/4 weeks for 3 administrations, then every 8 weeks for benralizumab).

However, real-life effectiveness and safety data for these drugs are mostly limited to the first 12 months of treatment, with few longer-term data (not exceeding 24 months from treatment beginning). Also, large observational cohorts mainly included patients on mepolizumab at the dosage approved for eosinophilic asthma (100mg/4 weeks), as it was the most frequently used (off-label) for EGPA across Europe, and real-life data on mepolizumab 300mg/4weeks are limited to smaller subgroups of patients.

Moreover, the effect of dose variation (escalation from 100 to 300mg/4 weeks or reduction from 300 to 100mg/4 weeks) in patients with inappropriate response or suboptimal tolerance to mepolizumab has never been assessed.

AIMS OF THE STUDY This study will fill an important gap, allowing to better understand the role and clinical positioning of anti-IL5 treatments for the long-term management of respiratory and systemic disease manifestations in EGPA patients initiating mepolizumab at the dosage of 300mg/4 weeks. Also, it will shed light on the effectiveness and safety of dosage switching (from 300 to 100mg/4 weeks or vice versa) in patients with inappropriate response or suboptimal tolerance to mepolizumab.