#3236 CHANGE IN ALBUMINURIA IN PATIENTS WITH ANCA-ASSOCIATED VASCULITIS TREATED WITH AVACOPAN

Abstract

Abstract Background and Aims Urinary albumin:creatinine ratio (UACR) is an important biomarker of active glomerulonephritis, a common complication of antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis. In most glomerular diseases, high UACR levels and low estimated glomerular filtration rates are associated with the long-term risk of end-stage kidney disease, cardiovascular disease, and death.[1] In the double-dummy, double-blind, controlled ADVOCATE Phase 3 trial, patients were randomized to receive avacopan, an oral C5a receptor (C5aR) antagonist that blocks C5a-mediated neutrophil activation and migration, or a prednisone taper. All patients received background immunosuppression with either cyclophosphamide followed by azathioprine, or rituximab. Primary endpoints were remission at week 26 and sustained remission at week 52. Prespecified secondary endpoints included the evaluation of kidney function.[2] The effect of avacopan on UACR in patients with ANCA-associated vasculitis is described. Method This post hoc analysis compared the time to achieve the maximum mean difference in percent change in UACR from baseline between the avacopan and prednisone taper groups using Kaplan-Meier survival analysis. Change in UACR from baseline was a prespecified secondary endpoint but was not adjusted for multiplicity. This analysis included patients from the ADVOCATE trial with kidney involvement (based on the Birmingham Vasculitis Activity Score) and a UACR of at least 10 mg/g at baseline. Results The baseline geometric mean UACR mg/g (range) in the avacopan group (n = 125) and the prednisone taper group (n = 128) was 433 (20 to 6461) and 312 (11 to 5367), respectively. A statistically significant UACR reduction (based on least-square means) in the avacopan group compared to the prednisone taper group occurred as early as week 2 (−25% vs. 6%, p = 0.0068, difference between groups: −29%, 95% confidence interval (CI) [−45%, −9%]). UACR continued to decrease at week 4 to the maximum difference between the two groups (−40% vs. 0%, p<0.0001, difference between groups: −40%, 95% CI [−53%, −22%]) (Figure 1). UACR was comparable between the two groups by week 13 (−55% vs. −49%, p = 0.3028, difference between groups: −12%, 95% CI [−32%, 13%]). During the 52-week treatment period, 84% (105/125) of patients in the avacopan group achieved a 40% UACR reduction from baseline within a median time of 29 days (95% CI [29, 88]), compared to 83% (106/128) of patients in the prednisone taper group within a median time of 92 days (95% CI [91, 180]) (logrank p = 0.0450) (Figure 2). At week 52, there was a greater overall mean improvement in estimated glomerular filtration rate (eGFR) of 7.6 mL/min/1.73 m2 in the avacopan group compared to 4.6 mL/min/1.73 m2 in the prednisone taper group (p = 0.0432). Conclusion In the ADVOCATE trial, UACR, an important early indicator of improving kidney function, improved three times faster in the avacopan group compared to the prednisone taper group. The rapid reduction in UACR seen in patients with ANCA-associated vasculitis receiving avacopan suggests more rapid control of glomerular inflammation which may have contributed to the observed subsequent greater improvement in eGFR.