Making Use of Avacopan in Clinical Practice

Abstract Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a severe multisystem autoimmune disease in which renal involvement is common and often progresses to end-stage kidney disease without timely intervention. Standard remission induction therapy combines high-dose glucocorticoids (GCs) with cyclophosphamide or rituximab. While effective, cumulative GC exposure drives substantial treatment-related morbidity, including infection, diabetes, osteoporosis, and cardiovascular complications, highlighting the urgent need for GC-sparing strategies. Avacopan, an oral selective C5a receptor antagonist, represents a novel therapeutic approach targeting the alternative complement pathway, a key mediator of neutrophil activation and vascular injury in AAV. The pivotal phase 3 ADVOCATE trial demonstrated that avacopan achieved non-inferior remission at 26 weeks and superior sustained remission at 52 weeks compared with a standard GC taper, while reducing GC-related toxicity and improving renal recovery, particularly in patients with advanced kidney impairment. Since approval in 2021, real-world studies and case series have given further confidence in avacopan’s efficacy across diverse patient subgroups, including those with severe renal disease, diffuse alveolar haemorrhage, and refractory manifestations. However, real-world data also highlight variability in GC tapering practices and safety signals, particularly hepatotoxicity in Japanese cohorts. Several unanswered questions remain, including the long-term safety, clinical benefit of treatment beyond one year, and optimal GC concomitant use or even the feasibility of complete GC avoidance. Ongoing large-scale studies and international real-world evidence will be essential to define avacopan’s optimal role in clinical practice, ensuring equitable access for patients with AAV.