Pos0862 the Efficacy of Eosinophil-Targeting Therapies According to Anca Status in Patients With Eosinophilic Granulomatosis With Polyangiitis: A Post-Hoc Analysis of the Phase 3 Mandara Study

Background: Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare inflammatory disorder, characterised by asthma, eosinophilia, and small-to-medium size vessel vasculitis. Clinical manifestations of EGPA differ based on the presence or absence of anti-neutrophil cytoplasmic antibodies (ANCA). ANCA-positive patients tend to present with more "vasculitic" manifestations, such as glomerulonephritis, while ANCA-negative patients have fewer of these "vasculitis" features but may have more of other manifestations, such as cardiomyopathy. Some clinical manifestations of EGPA result from the combination of eosinophilic infiltration and vasculitis. Thus, both ANCA-positive and ANCA-negative patients with EGPA can exhibit any disease manifestations. In the MANDARA trial of patients with EGPA, treatment with benralizumab was non-inferior to mepolizumab in terms of attaining remission. Objectives: To examine the efficacy of eosinophil-targeting therapies (benralizumab and mepolizumab) based on ANCA status in patients with EGPA in the MANDARA study. Methods: MANDARA was a Phase 3, randomised, double-blind, 52-week, non-inferiority, head-to-head study (NCT04157348) comparing benralizumab with mepolizumab in adults with non-severe relapsing/refractory EGPA who were maintained on ≥7.5 mg/day OGC (prednisolone/prednisone) ± stable immunosuppressive therapy during the screening period. 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 remission duration, OGC use, clinical benefits, and relapse. This post-hoc analysis pooled data from both treatment groups in the MANDARA study to evaluate these endpoints according to patients' ANCA status. In this analysis, ANCA-positive patients were defined as those who were positive for myeloperoxidase (MPO)-ANCA and/or proteinase 3 (PR3)-ANCA at study screening or had a historical record of ANCA-positivity. Results: Of the 140 patients randomised in the study; 40 (29%) were ANCA-positive (mean standard deviation; SD age 55.3 13.67 years; 42.5% women) and 100 (71%) were ANCA-negative (mean SD age 51.1 14.15 years; 67.0% women). BVAS and Vasculitis Damage Index (VDI) scores were similar between the ANCA-positive and -negative groups at baseline, whereas the proportion of patients who had ACQ-6 score ≥1.5 was higher, and the time since diagnosis was shorter, in the ANCA-positive vs -negative group (Table 1). The adjusted rate of remission at both Weeks 36 and 48 was similar regardless of ANCA status (ANCA-positive: 59.3%, ANCA-negative: 57.3%; difference: 2.05; 95% confidence interval CI: –15.04, 19.14, p=0.8139). The proportion of patients who relapsed was similar between the ANCA-positive (25.0%) and ANCA-negative (32.0%) groups, as was the time to first relapse (hazard ratio: 0.79 95% CI: 0.37, 1.57, p=0.4067). During Weeks 48 through 52, 78.4% and 80.7% in the ANCA-positive and -negative groups, respectively, had a reduction in OGC dose of ≥50% from baseline, and 34.3% versus 33.3%, respectively, were fully tapered off OGCs. Other secondary endpoints of remission duration/maintenance, clinical benefit, and complete response also did not differ based on ANCA status (Table 2). Conclusion: This analysis demonstrated that, irrespective of ANCA status, treatment of patients with non-severe EGPA with eosinophil-reducing therapies (benralizumab or mepolizumab) is associated with clinical benefits, with almost 60% of patients achieving or maintaining remission and one-third of patients fully tapering off OGCs. REFERENCES: NIL. Acknowledgements: Tanya Jandu and Anna Mett of inScience Communications, Springer Healthcare Ltd, UK, provided medical writing support, which was funded by AstraZeneca in accordance with Good Publication Practice 2022 guidelines. Disclosure of Interests: Benjamin Terrier AstraZeneca, GlaxoSmithKline, and Vifor Pharma, David R. W. Jayne Amgen, AstraZeneca, Bristol Myers Squibb, Boehringer, Chemocentryx, Chugai, GlaxoSmithKline, Novartis, Roche, Takeda, and Vifor Pharma, Amgen, AstraZeneca, Bristol Myers Squibb, Boehringer, Chemocentryx, Chugai, GlaxoSmithKline, Novartis, Roche, Takeda, and Vifor Pharma, Bernhard Hellmich AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Chugai, GlaxoSmithKline, InflaRx, Janssen, MSD, Pfizer, Novartis, Phadia, and Roche, AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Chugai, GlaxoSmithKline, InflaRx, Janssen, MSD, Pfizer, Novartis, Phadia, and Roche, Peter A Merkel Kyverna, Q32, and Sparrow, AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, GlaxoSmithKline, InflaRx, and Takeda. ArGenx, Cabaletta, CSL Behring, Dynacure, HiBio, Janssen, Novartis, NS Pharma, Regeneron Pharmaceuticals, and Vistera. Kyverna, Q32, and Sparrow. royalties from UpToDate, AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, GlaxoSmithKline, InflaRx, and Takeda. Eicos, Electra, Forbius, Genentech/Roche, Genzyme/Sanofi, and Neutrolis, Nancy Agmon-Levin Amgen, AstraZeneca, Bristol Myers Squibb, Boehringer, Chemocentryx, Chugai, GlaxoSmithKline, Novartis, Roche, Takeda, and Vifor Pharma, Amgen, AstraZeneca, Bristol Myers Squibb, Boehringer, Chemocentryx, Chugai, GlaxoSmithKline, Novartis, Roche, Takeda, and Vifor Pharma, Parameswaran Nair honoraria from Arrowhead, AstraZeneca, CSL Behring, GlaxoSmithKline, and Sanofi, institution received grant support from AstraZeneca, Cyclomedica, Equillium, Foresee, Genentech, Sanofi, and Teva, Ying Fan may own stock/stock options in AstraZeneca, AstraZeneca, Emmanuelle Maho may own stock/stock options in AstraZeneca, AstraZeneca, Sofia Necander may own stock/stock options in AstraZeneca, AstraZeneca, Anat Shavit may own stock/stock options in AstraZeneca, AstraZeneca.