Background/Purpose: Eosinophilic inflammation is a key pathophysiological mechanism of eosinophilic granulomatosis with polyangiitis (EGPA). Oral glucocorticoids (OGCs) and immunosuppressants remain the basis for the standard of care (SoC),but their long-term use is associated withsignificantadverse effects, and relapses are frequently seen. The MANDARA trial compared the efficacy and safety of benralizumab (a monoclonal antibody against the IL-5 receptor) and mepolizumab (an anti-IL-5 agent, and the only approved drug for EGPA) in patients with EGPA receiving SoC.

Methods: MANDARA was a randomized, active-controlled, parallel-group, multicenter, 52-week double-blind with open-label extension, Phase III non-inferiority study (NCT04157348). Patients (≥18 years) with documented EGPA based on asthma and blood eosinophilia plus ≥2 additional features of EGPA, and a history of relapsing/refractory disease requiring stable OGCs (≥7.5 mg prednisone/prednisolone daily) ± stable immunosuppressive therapy for ≥4 weeks before randomization, were included. Benralizumab 1 x 30 mg or mepolizumab 3 x 100 mg were administered by subcutaneous injection every 4 weeks for 52 weeks, and OGC was tapered if disease was controlled. The primary endpoint was the proportion of patients achieving remission (defined as Birmingham Vasculitis Activity Score [BVAS] = 0 and OGC dose ≤4 mg/day) at both Weeks 36 and 48. Secondary endpoints included accrued and maintained remission, OGC use, other clinical benefits, time to first relapse, and safety.

Results: 140 patients were randomized (mean [standard deviation; SD] age 52.3 [14.1] years; 60.0% women) to benralizumab (n=70) or mepolizumab (n=70). The adjusted remission rate at both Weeks 36 and 48 was 59.2% for the benralizumab group and 56.5% for the mepolizumab group (difference: 2.71%; 95% confidence interval [CI]: –12.54, 17.96; p=0.7278), confirming non-inferiority of benralizumab to mepolizumab (using the predefined margin of –25%; Figure 1). Secondary efficacy endpoints are shown in Table 1. The proportion of patients who relapsed was the same for benralizumab vs mepolizumab (both 30.0%; Figure 2). The mean (SD) OGC dose was 11.02 (5.25) mg/day at baseline. At Weeks 48–52, 86.1% vs 73.9% in the benralizumab and mepolizumab groups, respectively, had a reduction in OGC dose of ≥50% from baseline, and 41.4% vs 25.8% were fully tapered off OGC. Adverse events (AEs) were reported in 90.0% of benralizumab and 95.7% of mepolizumab recipients, most commonly COVID-19 (21.4% vs 27.1%), headache (17.1% vs 15.7%), and arthralgia (17.1% vs 11.4%). Serious AEs were reported in 5.7% of benralizumab and 12.9% of mepolizumab recipients. No benralizumab and 2 mepolizumab recipients experienced AEs leading to discontinuation of treatment.

Conclusion: This study demonstrated non-inferiority of benralizumab vs mepolizumab over 52 weeks in patients with relapsing/refractory EGPA receiving SoC and provides evidence for the efficacy and utility of benralizumab, with more benralizumab-treated patients being fully tapered off OGC. Both study drugs were well tolerated with a similar proportion of patients reporting AEs.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/efficacy-and-safety-of-benralizumab-compared-with-mepolizumab-in-the-treatment-of-eosinophilic-granulomatosis-with-polyangiitis-in-patients-receiving-standard-of-care-therapy-phase-3-mandara-study/