Effectiveness and Safety of Avacopan in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis

Importance: Avacopan is a small-molecule C5aR1 antagonist used as adjunctive treatment for granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). Evidence of real-world clinical effectiveness and safety is limited. Objective: Compare effectiveness and describe safety outcomes of avacopan plus SoC versus SoC alone. Design: Retrospective U.S. cohort study with prevalent new-user design emulating sequential nested trials with up to 12-month follow-up. Index dates: first avacopan prescription (avacopan arm); first rituximab or cyclophosphamide claim (SoC arm) during trial window. Setting: Optum Market Clarity administrative claims (October 2015 - June 2025). Participants: Adults receiving rituximab or cyclophosphamide after newly diagnosed or relapsing GPA/MPA. Comparative effectiveness cohort: patients meeting baseline eligibility. Safety cohort: adults with an avacopan prescription, regardless of other eligibility. Interventions: Avacopan plus SoC vs SoC alone. Main Outcomes and Measures: Relapse, prednisone-equivalent daily dose (PEDD) [≤]7.5 mg, and serious hepatic event hospitalization were prespecified, whereas cumulative oral glucocorticoid exposure was analyzed post-hoc. A strict hepatic-event screen required [1] acute/subacute hepatic failure, central hemorrhagic liver necrosis, or toxic liver disease and [2] [≥]1 code indicative of severe acute liver injury on the same claim; a relaxed hepatic-event screen required either criterion. Standardized mortality ratio and censoring weights accounted for baseline covariates and informative censoring. Treatment effects in the avacopan-treated population were estimated. Results: The effectiveness analysis included 183 avacopan and 4096 SoC index dates. The safety cohort had 828 avacopan users. There were 38 events of relapse in the avacopan arm and 956 in the SoC arm (weighted hazard ratio [95% CI]: 0.81 [0.59, 1.13]). PEDD [≤]7.5 mg was numerically more common with avacopan plus SoC at most timepoints. Cumulative glucocorticoid exposure was lower with avacopan plus SoC; between-arm differences exceeded 500 mg from months 5 through 12. No avacopan-exposed patients met the strict hepatic event screen definition. Relaxed hepatic event screen events occurred in 2 (1.1%), 5 (0.6%), and 10 (0.5%) patients in the avacopan effectiveness, avacopan safety, and SoC cohorts, respectively. Conclusions and Relevance: Early evidence from claims data suggests avacopan plus SoC may reduce relapse risk and enable faster glucocorticoid tapering vs SoC alone. Serious hepatic events appear rare.