Journal Club Review of "Avacopan for the Treatment of ANCA-Associated Vasculitis".

In this trial involving patients with ANCA-associated vasculitis, avacopan was noninferior but not superior to prednisone taper with respect to remission at week 26 and was superior to prednisone taper with respect to sustained remission at week 52. All the patients received cyclophosphamide or rituximab. The safety and clinical effects of avacopan beyond 52 weeks were not addressed in the trial. (Funded by ChemoCentryx; ADVOCATE ClinicalTrials.gov number, NCT02994927.).   https://pubmed.ncbi.nlm.nih.gov/33596356/   ANCA-associated vasculitis (AAV) is a chronic autoimmune disease characterized by progressive pauci-immune glomerulonephritis and inflammation of the respiratory tract traditionally requiring treatment with corticosteroids. The ADVOCATE trial was a phase III randomized double-blind placebo-controlled clinical trial to investigate whether avacopan, a C5a receptor inhibitor involved in blocking complement activation, could replace steroids in induction therapy for AAV in addition to standard-of-care therapy via a noninferiority trial design. The ADVOCATE trial met its primary endpoint of clinical remission at week 26 (3.4% difference between treatment and placebo; 95% CI: -6.0 to 12.8%; P < 0.001 for noninferiority) and at week 52 (12.5% difference; 95% CI: 2.6% to 22.3%; P = 0.007 for superiority). Strengths of this study include its international and multicenter involvement, rigorous study design and analysis, and minimal loss to follow-up. Potential weaknesses of this study include the lack of rituximab maintenance as part of standard-of-care treatment beyond week 4 of induction therapy and complete wean off prednisone by week 21, much faster than steroid weans in prior trials (including PEXIVAS), which may somewhat limit our interpretation of the noninferiority of avacopan to prednisone. Overall, the ADVOCATE trial yielded thought-provoking clinical implications that may revolutionize AAV treatment moving forward, including less reliance on corticosteroids to achieve clinical remission in AAV.