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

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.

PRIMARY OBJECTIVE The primary objectives of the study will be the evaluation of the long-term effectiveness of mepolizumab in patients with newly diagnosed or relapsing and refractory EGPA treated with mepolizumab at the dosage of 300mg/4 weeks. Effectiveness will be assessed over a 60-month follow-up, considering the achievement of complete and partial response, variations in lung function, disease relapses and respiratory exacerbations.

SECONDARY OBJECTIVES

Key secondary objectives will include:

• The persistence on mepolizumab in patients with EGPA initiating the drug at the dosage of 300mg/4 weeks (timeframe: 60 months from mepolizumab beginning). Persistence will be evaluated in terms of dosage switches (from 300 to 100mg/4 weeks) and treatment discontinuation.
• The long-term safety of mepolizumab in patients with EGPA initiating the drug at the dosage of 300mg/4 weeks (timeframe: 60 months from mepolizumab beginning).
• The effectiveness of mepolizumab dosage-switching in patients with EGPA switching to a different mepolizumab dosage (from mepolizumab 300mg/4 weeks to 100mg/4 weeks or vice versa).

Effectiveness will be assessed in terms of achievement of complete or partial response and variations in lung function, separately for patients increasing or decreasing mepolizumab monthly dosage (timeframe: 3 months following dosage switch).

• The safety of mepolizumab dosage-switching in patients with EGPA switching to a different mepolizumab dosage (from Mepolizumab 300mg/4 weeks to 100mg/4 weeks or vice versa) (timeframe: 3 months following dosage switch).

PATIENTS AND METHODS STUDY DESIGN AND DATA COLLECTION A multicenter, retrospective study will be conducted. Demographic, clinical, biological and treatment-related data will be retrospectively collected from medical charts. For patients starting on mepolizumab 300mg/4 weeks, data will be collected at the time of mepolizumab starting (T0) and at 3, 6, 12, 24, 36, 48 and 60 months of follow-up (T3-T60). For patients changing mepolizumab dosage, data will be collected at time of dosage switch (TS0) and after 3 months (TS3).

STUDY POPULATION The study cohort will include a non-predefined number of adult EGPA patients who meet the 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology Classification Criteria for EGPA or the criteria proposed in the MIRRA trial and receiving mepolizumab 300mg/4 weeks (either as first mepolizumab dosage or after a dosage increase from mepolizumab 100mg/4 weeks) in any calendar period at any of the 116 EGPA referral centres across European countries (Austria, France, Germany, Greece, Ireland, Italy, Netherlands, Portugal, Russia, Serbia, Spain, Sweden, Switzerland, Turkey, United Kingdom, and Australia) participating to the European EGPA Study Group.

Written informed consent from all participants and approval from the local ethical committees will be obtained. The study will be conducted in accordance with the tenets of the Declaration of Helsinki.

Only patients who presented at least 3 months of available follow-up data after mepolizumab beginning (or after dosage switch), and with available data regarding BVAS and OCS at baseline and 3 months, will be included.

Finally, all patients with inadequate data or a follow-up shorter than 3 months after mepolizumab initiation or after dosage switch, and patients receiving mepolizumab within a clinical trial will be excluded.

DATA COLLECTION AND OUTCOME ANALYSIS:

1. Primary endpoints

   EFFECTIVENESS will be assessed in terms of:

   • ACHIEVEMENT OF COMPLETE AND PARTIAL RESPONSE: Complete response (CR) will be defined as no disease activity (Birmingham Vasculitis Activity Score, BVAS=0) and an oral corticosteroid dosage (OCS, prednisolone or prednisone dose or equivalent) ≤4.0 mg/day, as defined by the MIRRA trial and by previous studies. Partial response (PR) will be defined as no disease activity and a prednisolone or prednisone dose >4.0 mg/day.

   At each follow-up timepoint, analysis will be conducted including only patients with data for both BVAS and OCS dosage. CR and PR rates will be calculated considering the number of patients meeting the CR or PR criteria (as defined above), over the total number of patients with available data for both BVAS and OCS dosage at the given timepoint.

   • VARIATIONS IN LUNG FUNCTION: Lung function will be assessed in terms of pre-bronchodilator forced expiratory volume in 1 second (FEV1).

   At baseline and at each follow-up timepoint, the median FEV1 will be calculated for patients with available data for the given timepoint. Also, for each patient percentage variation in the FEV1 at a given follow-up timepoint (TFU) will be calculated as (FEV1TFU- FEV1T0)/T0×100.

   • DISEASE RELAPSES: Disease relapses will be assessed only for patients who have achieved a CR at the previous follow-up timepoint, and will be defined by at least one the following criteria: a) active vasculitis (defined as BVAS>0) and/or b) worsening asthma and/or ENT manifestations leading to an increase in the OCS dose to more than 4.0 mg/day, an initiation of a new immunosuppressive therapy, or hospitalization, as defined by the MIRRA trial and by previous studies.

   At each follow-up timepoint, disease relapse rates will be calculated considering the number of patients meeting the criteria for a disease relapse (as defined above), over the total number of patients with available data for the given timepoint and with CR at the previous follow-up timepoint.

   • RESPIRATORY EXACERBATIONS: Respiratory exacerbations will be defined as any of the following events: asthma attack needing an increase in OCS dosage >30%, emergency department admission related to asthma, and/or use of acute OCS, antibiotics, or short-acting beta-agonists (SABA).

   At each follow-up timepoint, respiratory exacerbations rates will be calculated considering the number of patients meeting the criteria for a respiratory exacerbation (as defined above), over the total number of patients with available data for the given timepoint.

2. Secondary endpoints

   • SAFETY: All adverse events (AEs) occurring during treatment and recorded in the medical charts will be retrieved and reported, irrespectively of the causality association with treatment. Serious adverse events (SAEs) will be assessed according to the World Health Organization criteria (European Medicines Agency. ICH Topic E 2 A - Clinical Safety Data Management: Definitions and Standards for Expedited Reporting. CPMP/ICH/377/95.).

   At each follow-up timepoint, AE and SAE rates will be calculated considering the number of patients with at least one AE or SAE, over the total number of patients with available data for the given timepoint.

   Individual ICSRs will not be generated from retrospective review of medical charts, and safety data will only be summarised as aggregated data in the study reports.

   • PERSISTENCE: Persistence will be assessed in terms of variations in Mepolizumab monthly dosage or treatment discontinuation.

   At each follow-up timepoint, dosage switch and discontinuation rates will be calculated considering the number of patients switching dosage or discontinuing treatment, over the total number of patients with available data for the given timepoint.

3. Additional Endpoints

Additional endpoints monitored at T0 and at all follow-up timepoints will include:

• CHANGES IN ORGAN MANIFESTATIONS (assessed separately from BVAS items): for each disease manifestation, the proportion of patients with active symptoms will be calculated over the total number of patients with available data for the given timepoint.
• OCS-SPARING EFFECT: at baseline and at each follow-up timepoint, the median daily OCS dosage will be calculated, for all patients with available data for the given timepoint. Also, the proportion of patients achieving a daily OCS dosage of 0 will be calculated over the total number of patients with available data for the given timepoint.
• DMARD-SPARING EFFECT: at each timepoint, the proportion of patients discontinuing a DMARD treatment (which was ongoing or was newly started at T0) will be calculated over the total number of patients with available data for the given timepoint.
• VARIATION IN THE PROPORTION OF ANCA-POSITIVE PATIENTS: at each timepoint, the proportion of ANCA positive patients will be calculated over the total number of patients with available results of ANCA testing for the given timepoint. ANCA-negativization rates will be assessed for patients with positive ANCA testing at T0, as the proportion of patients with a negative ANCA test at a given follow-up timepoint, over the total number of patients with available results of ANCA testing for the given timepoint and with positive ANCA at T0.
• VARIATION IN EOSINOPHIL COUNT: at baseline and at each follow-up timepoint, the median eosinophil count will be calculated for patients with available data for the given timepoint.

STATISTICAL PLAN AND DATA ANALYSIS Data will be presented as median value and interquartile range (IQR) for continuous variables, and as absolute number and percentage for qualitative variables. All analyses will include only patients with available data at the given timepoint; for each variable and timepoint, the total number of available observations will be reported.

For primary and secondary endpoints, rates will be reported as relative frequency (%), and 95% binomial exact confidence intervals (CIs) will be estimated.

Three continuous variables (OCS dose, FEV1 and eosinophil count), chosen based on their clinical relevance, will be formally compared across the different follow-up timepoints (T0-T60), using the MMRM models comparing follow-up timepoints (months 3, 6, … 60) with the baseline (month 0).

Only patients with available data at all timepoints will be included in these analyses. The corresponding parametric tests will be used in the case the distribution of the data will follow a normal distribution.

Statistical analyses will be performed using Stata (version 14) and Graphpad Prism (version 9).

SAMPLE SIZE JUSTIFICATION No formal sample size calculation is performed. Indeed, the study cohort will include a non-predefined number of EGPA patients receiving Mepolizumab 300mg/4 weeks in any calendar period at any of the 116 EGPA referral centres participating to the European EGPA Study Group, according to the inclusion and exclusion criteria defined above.

Based on a feasibility assessment performed during the 8th EESG Meeting (26th Sept 2024, Florence, Italy) with partners from these centres, it is expected that 300-350 patients will be included in the study. Moreover, based on the feasibility assessment coming from the same meeting, the investigators expect to collect data from approximately:

300-350 patients at 3 months 280-300 at 6 months 200-230 at 12 months 150-170 at 24 months 80-100 at 36 months, at T36 months and T48 months 50 at 60 months These estimates reflect expected lost in follow-up over time, which is common in retrospective real-world observational studies.

Based on previous data, the investigators anticipate that CR at 24 months will be 58% in patients on Mepolizumab 300mg/months (expected n=170), and 33% in patients on Mepolizumab 100mg/month (expected n=130). Considering a type I error of 5%, the expected power of the study is 99%.