Randomized Trial of C5a Receptor Inhibitor Avacopan in ANCA-Associated Vasculitis

Abstract

Alternative C activation is involved in the pathogenesis of ANCA-associated vasculitis. However, glucocorticoids used as treatment contribute to the morbidity and mortality of vasculitis. We determined whether avacopan (CCX168), an orally administered, selective C5a receptor inhibitor, could replace oral glucocorticoids without compromising efficacy. In this randomized, placebo-controlled trial, adults with newly diagnosed or relapsing vasculitis received placebo plus prednisone starting at 60 mg daily (control group), avacopan (30 mg, twice daily) plus reduced-dose prednisone (20 mg daily), or avacopan (30 mg, twice daily) without prednisone. All patients received cyclophosphamide or rituximab. The primary efficacy measure was the proportion of patients achieving a ≥50% reduction in Birmingham Vasculitis Activity Score by week 12 and no worsening in any body system. We enrolled 67 patients, 23 in the control and 22 in each of the avacopan groups. Clinical response at week 12 was achieved in 14 of 20 (70.0%) control patients, 19 of 22 (86.4%) patients in the avacopan plus reduced-dose prednisone group (difference from control 16.4%; two-sided 90% confidence limit, -4.3% to 37.1%; =0.002 for noninferiority), and 17 of 21 (81.0%) patients in the avacopan without prednisone group (difference from control 11.0%; two-sided 90% confidence limit, -11.0% to 32.9%;=0.01 for noninferiority). Adverse events occurred in 21 of 23 (91%) control patients, 19 of 22 (86%) patients in the avacopan plus reduced-dose prednisone group, and 21 of 22 (96%) patients in the avacopan without prednisone group. In conclusion, C5a receptor inhibition with avacopan was effective in replacing high-dose glucocorticoids in treating vasculitis.

Evidence for Alternative Complement Cascade Activation in Primary CNS Vasculitis

“…Our finding of elevated levels of C5 is of particular significance given the recent success of a clinical trial using CCX168 (Avacopan) to treat ANCA-associated vasculitis 9,21 .…”

“…More specifically, we observe significant alteration of several regulatory components of the alternative pathway, and elevated levels of the terminal cascade including complement C5 (C5), complement C8 (C8) and complement C9 (C9). In previous studies C5 has been shown to be a therapeutically relevant target for systemic Anti-Neutrophil Cytoplasmic Antibody (ANCA) vasculitis, and recent clinical trials of C5 inhibitors further support this notion 9 . Our results suggest a rationale for investigating whether C5 inhibitors could serve as a novel therapy for PACNS.…”

Treatment of Rapidly Progressive Glomerulonephritis in the Elderly

“…Avacopan, previously called CCX168, is an orally administered small-molecule C5aR antagonist that blocks the effects of C5a and prevented the development of GN induced by anti-myeloperoxidase antibodies in a murine model of ANCA associated vasculitis (AAV) [37]. Jayne et al [38] recently studied the drug as a potential steroid-sparing agent in the treatment of this disease. Sixty-seven patients (mean age 58, GFR at baseline 50 mL/min; patients with severe systemic involvement like pulmonary hemorrhage or cerebral vasculitis were excluded) were randomized into 3 arms.…”

“…Adverse effects were lower in the experimental arms. Better quality of life scores and less new onset or worsening diabetes was seen as well with avacopan [38]. The ongoing ADVOCATE study (NCT 02994927) will look at using this drug to completely replace glucocorticoids in patients with more severe renal ANCA disease.…”

Calcineurin inhibitor-induced endothelial cell injury – A role for complement

“…(El Karoui et al, 2012) In anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis, C5a and C5a receptor (C5aR/CD88) play a key pathogenetic role. (Furuta and Jayne, 2013;Halbwachs and Lesavre, 2012;Jayne et al, 2017;Kettritz, 2014) C5a, acting on the C5aR is a potent neutrophil chemoattractant. (Hammerschmidt et al, 1981) In the presence of ANCA, C5a can lead to a decrease in neutrophil deformability, which in turn slows their ability to migrate across small blood vessels.…”