Journal Club Review of “Avacopan for the Treatment of ANCA‐Associated Vasculitis”

JOURNAL CLUB: Jayne DRW, Merkel PA, Schall TJ, Bekker P; ADVOCATE Study Group. Avacopan for the treatment of ANCA‐associated vasculitis. N Engl J Med 2021;384:599‐609. OBJECTIVE: The C5a receptor inhibitor avacopan is being studied for the treatment of antineutrophil cytoplasmic antibody (ANCA)‐associated vasculitis. METHODS: In this randomized, controlled trial, we assigned patients with ANCA‐associated vasculitis in a 1:1 ratio to receive oral avacopan at a dose of 30 mg twice daily or oral prednisone on a tapering schedule. All the patients received either cyclophosphamide (followed by azathioprine) or rituximab. The first primary endpoint was remission, defined as a Birmingham Vasculitis Activity Score (BVAS) of 0 (on a scale from 0 to 63, with higher scores indicating greater disease activity) at week 26 and no glucocorticoid use in the previous 4 weeks. The second primary endpoint was sustained remission, defined as remission at both weeks 26 and 52. Both endpoints were tested for noninferiority (by a margin of 20 percentage points) and for superiority. RESULTS: A total of 331 patients underwent randomization; 166 were assigned to receive avacopan, and 165 were assigned to receive prednisone. The mean BVAS at baseline was 16 in both groups. Remission at week 26 (the first primary endpoint) was observed in 120 of 166 patients (72.3%) receiving avacopan and in 115 of 164 patients (70.1%) receiving prednisone (estimated common difference, 3.4 percentage points; 95% confidence interval [CI], ‐6.0 to 12.8; P < 0.001 for noninferiority; P = 0.24 for superiority). Sustained remission at week 52 (the second primary endpoint) was observed in 109 of 166 patients (65.7%) receiving avacopan and in 90 of 164 patients (54.9%) receiving prednisone (estimated common difference, 12.5 percentage points; 95% CI, 2.6 to 22.3; P < 0.001 for noninferiority; P = 0.007 for superiority). Serious adverse events (excluding worsening vasculitis) occurred in 37.3% of the patients receiving avacopan and in 39.0% of those receiving prednisone. CONCLUSION: 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.