OP0204 Characterization of the novel C5AR antagonist CCX168, a potential therapeutic for ANCA-vasculitis, rheumatoid arthritis, and other autoimmune disorders
Authors: J.P. Powers, P.J. Bekker, D.J. Dairaghi, J.C. Jennette, D.A. Johnson, M. Leleti, S. Miao, L.C. Seitz, Y. Wang, H. Xiao, T.J. Schall, J.C. Jaen
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> The C5a receptor (C5aR) is expressed by cells of the innate immune system and is thought to play a key role in numerous autoimmune diseases, such as anti-neutrophil cytoplasmic antibody (ANCA) vasculitis and rheumatoid arthritis (RA). CCX168 is an orally active antagonist of C5aR that has completed Phase 1 evaluation and is currently in a Phase 2 trial for induction of remission in patients with ANCA-associated renal vasculitis (AARV). <h3>Objectives</h3> To evaluate CCX168 in preclinical and clinical studies to determine safety, pharmacokinetic, and pharmacodynamics properties, and integrate these properties into a PK/PD relationship predictive of receptor coverage required for effective use in treating C5aR-mediated autoimmune diseases in humans. <h3>Methods</h3> The <i>in vitro</i> potency of CCX168 against C5aR was assessed by [<sup>125</sup>I]-C5a binding and chemotaxis assays. Inhibition of C5a-induced leukopenia by CCX168 was determined in multiple species. In the Phase 1 program, <i>ex vivo</i> analysis of C5aR coverage on blood neutrophils was performed based on C5a-induced chemotaxis and CD11b expression. A similar PD assay was performed on blood samples from human C5aR knock-in mice dosed orally with CCX168. PK/PD requirements were defined for inhibition of C5aR-mediated neutrophil activation and prevention of anti-MPO IgG induced glomerulonephritis by CCX168 in these mice. <h3>Results</h3> CCX168 potently blocks [<sup>125</sup>I]-C5a binding to human C5aR with an IC<sub>50</sub> of 0.62 nM, C5a-mediated chemotaxis with an IC<sub>50</sub> of 0.25 nM (U937 cells), and C5a-mediated Ca<sup>2+</sup> mobilization with an IC<sub>50</sub> of 0.2 nM in human neutrophils. In human whole blood, CCX168 blocks C5a-mediated chemotaxis of neutrophils (IC<sub>50</sub> 1.7 nM) and CD11b upregulation (IC<sub>50</sub> 4 nM), and also blocks the granulocyte chemotactic activity displayed by human synovial fluid samples (IC<sub>50</sub> ∼5 nM). In human C5aR knock-in mice, CCX168 inhibited C5a-induced leukopenia with an ED<sub>50</sub> of ∼0.03 mg/kg, and oral dosing to these mice markedly suppressed the induction of glomerulonephritis by anti-MPO IgG. The lowest dose that produced near-maximal therapeutic benefit in this model was 4 mg/kg bid. CCX168 was well tolerated with excellent oral bioavailability and dose-proportional exposure in a Phase 1 study in healthy volunteers, and plasma levels of CCX168 of 197 ng/mL (∼400 nM) were reached after a 100 mg dose, far exceeding the levels required in the anti-MPO mouse model for near-maximal prevention of glomerulonephritis. Twelve hours following a 100 mg single dose of CCX168, there was a 94% reduction in C5a-induced CD11b upregulation on blood neutrophils (<i>ex vivo</i> PD assay). The combined clinical and preclinical PK/PD results indicate a 30 mg bid dosing regimen in humans should result in &gt;90% receptor coverage on human blood leukocytes at all times. <h3>Conclusions</h3> CCX168 is a highly potent, orally active, antagonist of C5aR which was well tolerated in Phase 1. The PK/PD data from preclinical and human Phase 1 studies indicate that 30 mg CCX168 bid in humans should result in &gt;90% coverage of C5aR in blood at all times, considered optimal for C5aR antagonism in patients with autoimmune diseases such as vasculitis and RA. A Phase 2 trial of CCX168 in patients with AARV is currently underway. <h3>Disclosure of Interest</h3> J. Powers Employee of: ChemoCentryx, P. Bekker Employee of: ChemoCentryx, D. Dairaghi Employee of: ChemoCentryx, J. Jennette: None Declared, D. Johnson Employee of: ChemoCentryx, M. Leleti Employee of: ChemoCentryx, S. Miao Employee of: ChemoCentryx, L. Seitz Employee of: ChemoCentryx, Y. Wang Employee of: ChemoCentryx, H. Xiao: None Declared, T. Schall Employee of: ChemoCentryx, J. Jaen Employee of: ChemoCentryx