Background 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).
Objectives 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.
Methods The in vitro potency of CCX168 against C5aR was assessed by [125I]-C5a binding and chemotaxis assays. Inhibition of C5a-induced leukopenia by CCX168 was determined in multiple species. In the Phase 1 program, ex vivo 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.
Results CCX168 potently blocks [125I]-C5a binding to human C5aR with an IC50 of 0.62 nM, C5a-mediated chemotaxis with an IC50 of 0.25 nM (U937 cells), and C5a-mediated Ca2+ mobilization with an IC50 of 0.2 nM in human neutrophils. In human whole blood, CCX168 blocks C5a-mediated chemotaxis of neutrophils (IC50 1.7 nM) and CD11b upregulation (IC50 4 nM), and also blocks the granulocyte chemotactic activity displayed by human synovial fluid samples (IC50 ∼5 nM). In human C5aR knock-in mice, CCX168 inhibited C5a-induced leukopenia with an ED50 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 (ex vivo PD assay). The combined clinical and preclinical PK/PD results indicate a 30 mg bid dosing regimen in humans should result in >90% receptor coverage on human blood leukocytes at all times.
Conclusions 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 >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.
Disclosure of Interest 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
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