Clinical Pearls & Morning Reports
Jayne et al. conducted a phase 3 randomized trial that compared avacopan with a tapering schedule of prednisone in patients with antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis concurrently treated with immunosuppressive drugs. Read the NEJM Original Article here.
Q: Are patients with ANCA-associated vasculitis at risk for life-threatening complications?
A: Patients with ANCA–associated vasculitis may have life-threatening complications, including impairment in kidney function caused by progressive focal necrotizing glomerulonephritis. ANCA-associated vasculitis can also result in deterioration of health-related quality of life because of organ damage, as well as toxic effects from medications used to treat the disorder, including from long-term use of glucocorticoids.
Q: How does avacopan work?
A: Activation of the alternative complement pathway, which results in terminal C5a production, is a component of the pathogenesis of ANCA-associated vasculitis. Avacopan is an orally administered small-molecule C5a receptor antagonist that selectively blocks the effects of C5a through the C5a receptor (C5aR, also called CD88), including blocking neutrophil chemoattraction and activation.
A: In the trial, patients were randomly assigned in a 1:1 ratio to receive 30 mg of avacopan twice daily orally plus prednisone-matching placebo or a tapering oral regimen of prednisone plus avacopan-matching placebo in a double-dummy design. Avacopan (30 mg twice daily) was given for 52 weeks, with 8 weeks of follow-up. Prednisone was given on a tapering schedule for 20 weeks (60 mg per day tapered to discontinuation by week 21). The two primary efficacy end points were clinical remission at week 26, defined as a Birmingham Vasculitis Activity Score (BVAS) of 0 (version 3, a composite of signs and symptoms in nine organ systems; total range, 0 to 63, with higher scores indicating more disease activity) and no receipt of glucocorticoids for 4 weeks before week 26, and sustained remission, defined as remission at week 26 and at week 52 and no receipt of glucocorticoids for 4 weeks before week 52. Remission at week 26 (the first primary end point) was observed in 120 of 166 patients (72.3%) in the avacopan group and in 115 of 164 patients (70.1%) in the prednisone group (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 end point) was observed in 109 of 166 patients (65.7%) in the avacopan group and in 90 of 164 patients (54.9%) in the prednisone group (estimated common difference, 12.5 percentage points; 95% CI, 2.6 to 22.3; P<0.001 for noninferiority; P=0.007 for superiority). Glucocorticoids were used by patients in the avacopan group, although the mean daily glucocorticoid dose in the avacopan group was one third of that in the prednisone group.
A: The effects of avacopan on eGFR and albuminuria in this trial were consistent with those in previous studies in mice and humans that showed a beneficial effect of avacopan on kidney function in the context of vasculitis. The number of serious adverse events (excluding events of worsening vasculitis) was 33% higher in the prednisone group than in the avacopan group, a finding consistent with a higher exposure to glucocorticoids in that group, and there were more deaths, life-threatening or serious adverse events, and infections in the prednisone group than in the avacopan group. Because avacopan does not block the formation of C5b and the membrane attack complex, as occurs with C5 blockers such as eculizumab, Neisseria meningitidis infections were an adverse event of special interest; no cases were observed.