Avacopan as an add-on therapy for ANCA-associated vasculitis: a pharmacological overview

ANCA-associated vasculitis (AAV) is a rare, life-threatening disease which may result in serious pulmonary and kidney damage. Cyclophosphamide or rituximab and high-dose glucocorticoids significantly improved patient outcomes, but at the expense of severe complications. Moreover, many patients still relapse and bear a significant burden of both disease- and treatment-related complications. Alternative complement pathway and C5a receptor signaling were demonstrated to play an important role in AAV pathogenesis. Avacopan is selective C5a receptor inhibitor successfully tested in renal AAV as glucocorticoid-sparing agent. Pharmacokinetic/pharmacodynamic properties, clinical efficacy and safety of avacopan, available clinical trials and real-world experience with avacopan. In the phase 3 trial avacopan was shown to be non-inferior at six and superior at 12 months compared to high-dose glucocorticoids and either cyclophosphamide or rituximab in patients with active AAV. Treatment with avacopan was well tolerated and associated with improved quality of life. In patients with severe renal AAV, renal function improved more in avacopan-treated than in high-dose glucocorticoid-treated patients. Avacopan could thus replace high-dose glucocorticoids to avoid glucocorticoid-related toxicity and to improve long term renal outcome. As avacopan is CYP 3A4 inhibitor and substrate, drug-drug interactions must be considered during the treatment.

抗中性粒细胞胞浆抗体相关性血管炎（ANCA-associated vasculitis, AAV）是一种罕见的危及生命的疾病，可导致严重的肺脏与肾脏损伤。环磷酰胺（Cyclophosphamide）或利妥昔单抗（rituximab）联合大剂量糖皮质激素（glucocorticoids）可显著改善患者结局，但会以发生严重并发症为代价。此外，仍有诸多患者会出现疾病复发，且需承受疾病相关与治疗相关并发症的沉重负担。研究证实，补体旁路途径（alternative complement pathway）与C5a受体信号通路（C5a receptor signaling）在AAV的发病机制中发挥重要作用。阿伐可泮（avacopan）是一种选择性C5a受体抑制剂，作为糖皮质激素节约剂已在肾性AAV中完成成功的临床试验。本数据集涵盖阿伐可泮的药代动力学/药效动力学（Pharmacokinetic/Pharmacodynamic）特性、临床疗效与安全性、已开展的相关临床试验以及阿伐可泮的真实世界应用经验。在Ⅲ期临床试验（phase 3 trial）中，相较于大剂量糖皮质激素联合环磷酰胺或利妥昔单抗的治疗方案，阿伐可泮在活动性AAV患者中展现出6个月时的非劣效性，以及12个月时的优效性。阿伐可泮治疗的耐受性良好，且可改善患者的生活质量。在重症肾性AAV患者中，接受阿伐可泮治疗者的肾功能改善程度优于大剂量糖皮质激素治疗组。因此，阿伐可泮可替代大剂量糖皮质激素，以规避糖皮质激素相关毒性并改善长期肾脏结局。由于阿伐可泮是CYP3A4抑制剂与底物，治疗期间需考虑药物相互作用风险。