LB003A RANDOMIZED, DOUBLE-BLIND, ACTIVE CONTROLLED STUDY OF AVACOPAN IN ANTI-NEUTROPHIL CYTOPLASMIC ANTIBODY-ASSOCIATED VASCULITIS

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Abstract Background and Aims Complement fragment C5a is strongly linked to the pathogenesis of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). The C5a receptor (C5aR), is a G protein-coupled receptor present on neutrophils. Avacopan (previously CCX168) is an orally-administered selective antagonist of C5aR which blocks C5a-induced cell activation. Two previous Phase 2 clinical trials provided evidence of effectiveness of avacopan in AAV. This Phase 3 study evaluated the efficacy and safety of avacopan for the treatment of AAV as well as the potential of avacopan to eliminate extensive use of glucocorticoids (GC) and GC-related toxicities. Method Eligible subjects were randomized 1:1 to receive either prednisone or avacopan in combination with either a) cyclophosphamide (oral or IV) followed by azathioprine or b) rituximab (four IV infusions). Randomization was stratified by the treatment regimen (rituximab, IV cyclophosphamide, or oral cyclophosphamide), ANCA serotype, and newly-diagnosed or relapsing disease. Treatment period was 52 weeks; primary efficacy endpoints were the proportion of subjects achieving disease remission at Week 26, and sustained disease remission at Week 52. Remission was defined as a Birmingham Vasculitis Activity Score (BVAS) of zero and not taking glucocorticoids for AAV within 4 weeks prior to Week 26. Sustained remission was defined as being in remission at Week 26 and sustained through Week 52 without relapse. Change in estimated glomerular filtration rate (eGFR) from baseline to week 52 was a pre-specified secondary endpoint. Results 330 subjects were randomized and dosed: 166 in the avacopan and 164 in the prednisone groups. At Week 26, 72.3% subjects achieved remission in the avacopan compared to 70.1% in the prednisone group (p<0.0001 for non-inferiority). At Week 52, 65.7% subjects achieved sustained remission in the avacopan compared to 54.9% in the prednisone group achieving both non-inferiority and superiority to prednisone group (p=0.0066 for superiority of avacopan). The avacopan arm had a significant reduction in glucocorticoid-related toxicity compared to the prednisone arm as measured by the Glucocorticoid Toxicity Index of Cumulative Worsening Score (p=0.0002) and Aggregate Improvement Score (p=0.0082). In subjects with renal disease at baseline, the avacopan group (n=134) showed a mean increase in eGFR of 7.3 mL/min/1.73 m2 from baseline to week 52 as compared to 4.1 mL/min/1.73 m2 increase in the prednisone group (n=132) (p=0.029). A pre-specified sub-group analysis showed a greater difference in the avacopan sub-group with a baseline eGFR <30 (13.7 mL/min/1.73 m2 vs. 8.2 mL/min/1.73 m2; p<.005). Conclusion Treatment with avacopan resulted in remission in patients with AAV receiving rituximab or cyclophosphamide/azathioprine at a rate that was non-inferior to the active comparator prednisone at Week 26 and superior to prednisone in sustained remission at Week 52. A significant reduction in glucocorticoid-related toxicity was observed in the avacopan vs. prednisone arms. The increase in eGFR seen with avacopan was marked among subjects with more severe renal disease. The safety profile of avacopan was acceptable for use in patients with AAV. The ADVOCATE trial demonstrated avacopan is an effective treatment for patients with AAV.