A new study published in The Lancet has found that two years of treatment with anti–interleukin-5/receptor (IL-5/R) therapy leads to durable remission, reduced oral glucocorticoid (OGC) use, low relapse rates, and sustained depletion of blood eosinophils (bEOS) in patients with eosinophilic granulomatosis with polyangiitis (EGPA).
Interleukin-5 inhibitors, including benralizumab and mepolizumab, have emerged as important advances in the management of EGPA, a rare eosinophilic vasculitis. Benralizumab is a humanized IgG1κ monoclonal antibody designed to bind selectively to the isoleucine-61 residue in domain 1 of the IL-5 receptor alpha chain (IL-5Rα). By attaching to an extracellular epitope near the IL-5 binding site, it prevents IL-5 from engaging the receptor and blocks downstream signaling pathways. Mepolizumab, another key therapy, directly targets circulating IL-5, reducing eosinophil maturation and survival. Notably, genome-wide association studies have identified the IL5 genomic region as a major locus associated with EGPA susceptibility.
The MANDARA trial evaluated these therapies over an extended period. After 52 weeks of randomized treatment, all participants entered an open-label extension in which they received benralizumab. Of the 128 patients who joined the extension, 66 continued benralizumab while 62 transitioned from mepolizumab. By week 104, remission was achieved in 62.1% of patients who continued benralizumab and 67.7% of those who switched from mepolizumab. Relapse-free status during the first extension year was reported in 77.3% of the benralizumab/benralizumab group and 67.7% of the mepolizumab/benralizumab group.
OGC withdrawal increased over time, rising from 40.9% to 43.9% in the benralizumab continuation group and from 25.8% to 43.5% among patients who switched therapies. Median cumulative OGC doses during the extension year were 950 mg and 791 mg, respectively. Eosinophil depletion remained robust in both arms. Median bEOS levels in the benralizumab/benralizumab group held steady at 20 cells/µL at weeks 52 and 100. Patients who transitioned from mepolizumab to benralizumab experienced a rapid decline from 70 cells/µL to 20 cells/µL within four weeks of switching. Adverse events were common but consistent with expectations for long-term biologic therapy.
The study provides compelling evidence that long-term IL-5–targeted therapy, particularly benralizumab, offers sustained clinical benefits for individuals with EGPA. The treatment not only maintains remission and minimizes relapse but also significantly reduces glucocorticoid dependence, a major goal in EGPA management. The findings further highlight benralizumab’s capacity for deep eosinophil depletion, including in patients previously treated with mepolizumab. As biologic options continue to expand, these results strengthen the role of IL-5–directed therapies as a cornerstone of long-term EGPA care.
References
- Merkel PA, Nair PK, Khalidi N, Terrier B, Hellmich B, Bourdin A, Jayne DRW, Jackson DJ, Roufosse F, Pagnoux C, Specks U, Börjesson Sjö L, Ho CN, Jison M, McCrae C, Necander S, Rodríguez-Suárez E, Shavit A, Walton C, Wechsler ME; MANDARA Study Group. Two-year efficacy and safety of anti-interleukin-5/receptor therapy for eosinophilic granulomatosis with polyangiitis. Ann Rheum Dis. 2025 Nov;84(11):1888-1899.
- Pelaia C, Calabrese C, Vatrella A, Busceti MT, Garofalo E, Lombardo N, Terracciano R, Pelaia G. Benralizumab: From the Basic Mechanism of Action to the Potential Use in the Biological Therapy of Severe Eosinophilic Asthma. Biomed Res Int. 2018 May 10;2018:4839230.
- Bettiol A, Urban ML, Dagna L, Cottin V, Franceschini F, Del Giacco S; European EGPA Study Group. Mepolizumab for Eosinophilic Granulomatosis With Polyangiitis: A European Multicenter Observational Study. Arthritis Rheumatol. 2022 Feb;74(2):295-306.