FC 032THE EFFECT OF AVACOPAN, A COMPLEMENT C5A RECEPTOR INHIBITOR, ON KIDNEY FUNCTION IN PATIENTS WITH ANCA-ASSOCIATED VASCULITIS WITH RENAL DISEASE
Authors: Jayne David , Merkel Peter , Bekker Pirow , McMahon Jeffrey , Schall Thomas J , The ADVOCATE Clinical Trial Investigators On behalf of 
Published: May 2021

Abstract

Background and Aims
Anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis is a life- or organ-threatening condition in which patients experience severe inflammation of small arteries. Renal involvement is common in ANCA-associated vasculitis and is correlated with high morbidity and mortality. Current treatment regimens have limited efficacy for renal disease in patients presenting with organ- or life-threatening ANCA-associated vasculitis.
Avacopan, a novel orally-administered antagonist of the complement fragment C5a receptor (C5aR), was evaluated through a Phase 3 trial in patients with ANCA vasculitis. Efficacy and safety results have been previously reported; this abstract provides details of the effects on renal function in patients with renal involvement.

Method
The ADVOCATE trial was a randomized, double-blind, active controlled, double-dummy, 52-week treatment Phase 3 trial of 331 patients with ANCA-associated vasculitis. Patients were randomized 1:1 and received either a standard daily prednisone dosing with taper (i.e., starting at 60 mg / day tapered to 0 mg by Week 21), or daily avacopan. Background therapy included either: a) cyclophosphamide (oral or IV) followed by azathioprine, or, b) rituximab (four IV infusions). Patients with active glomerulonephritis at baseline were included in this analysis. Kidney function was analyzed based on the following parameters, which were assessed at pre-specified time-points: changes in the urine albumin-to-creatinine ratio (UACR), estimated glomerular filtration rate (eGFR), and Urinary Monocyte Chemoattractant Protein-1 (MCP-1):Creatinine ratio.

Results
At the baseline visit, 265 patients had renal disease. eGFR improved more in the avacopan group (n=131) compared to the prednisone group (n=134). At Week 26, eGFR increased 5.8 mL/min/1.73 m2 (from a baseline of 44.6 mL/min/1.73 m2), compared to 2.9 mL/min/1.73 m2 in the prednisone group (from a baseline of 45.6 mL/min/m2), P=0.046. At Week 52, the increases in eGFR were 7.3 mL/min/1.73 m2 and 4.1 mL/min/1.73 m2, respectively, P=0.029. The improvement was most prominent in subjects with Stage 4 kidney disease at baseline (eGFR &lt; 30 mL/min/1.73 m2), in whom eGFR improved 13.7 mL/min/1.73 m2 at Week 52 in the avacopan group (from a baseline of 21.1 mL/min/1.73 m2) compared to 8.2 mL/min/1.73 m2 in the prednisone group (from a baseline of 21.6 mL/min/1.73 m2), P=0.005. In addition to the differences in eGFR, a more rapid decrease in UACR was observed with avacopan; by Week 3 this difference was statistically significant, and at Week 4, a 40% decrease from baseline occurred in the avacopan group vs no change from baseline in the prednisone group (P&lt;0.0001). By Week 52, both groups showed a similar decrease in UACR from baseline. The urinary MCP-1:creatinine ratio decreased 59% in the avacopan group by Week 13 vs 52% in the prednisone group, P=0.03, but there was a similar decrease in the two treatment groups by Week 52.

Conclusion
Treatment with avacopan in patients with ANCA-associated vasculitis with renal disease led to greater recovery in eGFR when compared to standard prednisone therapy, especially in patients with Stage 4 kidney disease (eGFR &lt;30 mL/min/1.73 m2). Avacopan also led to more rapid improvement in the UACR and urinary MCP-1:creatinine ratio than prednisone. Since albuminuria is an independent risk factor for progression of renal disease (in addition to eGFR decline), the more rapid improvement in albuminuria with avacopan may also provide long-term benefit. These findings have important implications for the health of patients with ANCA-associated vasculitis.