OP0046 Effect of a selective c5ar antagonist, avacopan (CCX168), on plasma complement levels in anca associated vasculitis (AAV)
Authors: D.O. Bunch, J. Deng, E.A. McInnis, P. Bekker, J.L. Hillson, T.J. Schall, C.J. Jennette, P. Nachman, J. Deng
Journal: Annals of the Rheumatic Diseases (2018)

Immunobiology of vasculitis <h3>Background</h3> The interaction between primed neutrophils and anti-neutrophil cytoplasmic autoantibodies (ANCA) releases factors that activate the alternative complement pathway, initiating an amplification loop that is thought to sustain necrotizing inflammation during flares of AAV.<sup>1</sup> Avacopan (CCX168), a selective, orally available, small molecule C5aR1 antagonist, was associated with rapid clinical benefit in the Phase 2 CLEAR trial in patients with AAV,<sup>2</sup> indicating that therapeutic intervention in this pathogenic process can be accomplished by inhibiting the C5aR1-dependent cellular response to C5a, without broad inhibition of upstream complement functions important to host defense. <h3>Objectives</h3> The present study was designed to<sup><sup>1</sup></sup> confirm the reported elevated levels of complement activation products in AAV,<sup><sup>2</sup></sup> demonstrate that inhibiting cellular (e.g. neutrophil) activation by C5a with avacopan is effective in AAV while preserving upstream functions of complement, and<sup><sup>3</sup></sup> compare effects of avacopan to those of high dose prednisone. <h3>Methods</h3> The CLEAR trial compared 3 regimens in 67 patients with AAV:<sup><sup>1</sup></sup> full dose prednisone (60 mg daily, tapered);<sup><sup>2</sup></sup> avacopan 30 mg twice daily plus low dose prednisone (20 mg, tapered);<sup><sup>3</sup></sup> avacopan 30 mg twice daily plus no prednisone. All also received either cyclophosphamide or rituximab. Bb, C3a, C5a, sC5b-9 and properdin were analysed by ELISA in plasma collected at baseline and at intervals in AAV patients, and in 20 healthy controls matched for age, gender and ethnic background. Paired t-test was used for within group comparison and unpaired t-test was used for between group comparisons using log transformed data. P-values were corrected for multiple comparisons. <h3>Results</h3> Before treatment, levels of C3a, C5a, sC5b-9 and properdin were significantly elevated in AAV patients compared to matched healthy controls (geomean [95%], C3a, 67.2 [57.5–78.7] vs 23.2 [16.9–31.9] ng/mL, p&lt;0.001; C5a, 7.55 [6.50–8.78] vs 5.19 [3.87–6.95] ng/mL, p&lt;0.05; sC5b-9, 241(222–262) vs 155(136–178) ng/mL, p&lt;0.001; Properdin, 18.4 [16.9–20.0] vs 13.1 [11.4–15.6] µg/mL, p&lt;0.001). In subjects treated with full dose prednisone, levels of Bb, C3a, and C5a decreased significantly on Day 8 and 29 rising again at day 85, coincident with tapering. Consistent with its mode of action (inhibition of C5aR1, the receptor at the terminus of the complement cascade), avacopan did not impact circulating complement levels. There were no changes from baseline in mean plasma sC5b-9 or properdin levels in any treatment group. <h3>Conclusions</h3> Avacopan was associated with rapid improvement in AAV disease activity without apparent impact on assembly of C5b-9 (the membrane attack complex) or upstream activities of the complement system important for host defense (e.g. bacterial infections) and tissue repair. In contrast, glucocorticoids were associated with dose-dependent reduction of circulating levels of upstream complement activation products. <h3>References</h3> [1] Xiao H, et al. Am J Pathol2007;170:52. [2] Jayne DRW, et al. <i>JASN</i>2017;28:2756. <h3>Disclosure of Interest</h3> D. Bunch: None declared, J. Deng Shareholder of: Shareholder of Chemocentryx, Employee of: Employee of Chemocentryx, E. McInnis: None declared, P. Bekker: None declared, J. Hillson: None declared, T. Schall: None declared, C. Jennette: None declared, P. Nachman: None declared, J. Deng: None declared