MO039SUCCESSFUL STEROID REPLACEMENT IN ANCA-ASSOCIATED VASCULITIS WITH C5A RECEPTOR INHIBITOR CCX168 IN PHASE 2 RANDOMISED TRIAL (CLEAR)

Abstract

Introduction and Aims: To investigate the potential of the orally administered complement 5a receptor inhibitor CCX168 to substantially or completely replace steroids while maintaining or improving efficacy in patients with active ANCA‐associated vasculitis (AAV) receiving cyclophosphamide (CYC) or rituximab (RTX). Methods: This randomised, double‐blind, placebo‐controlled Phase 2 trial (CLEAR) in 11 European countries included 3 groups: (1) High dose steroids standard of care (SOC) control: Placebo + CYC or RTX + 60 mg starting dose of prednisone, (2) CCX168 30 mg b.i.d. + CYC or RTX + 20 mg starting dose of prednisone, or (3) CCX168 30 mg b.i.d. + CYC or RTX + no prednisone. The CYC regimen was 15 mg/kg IV q2 to 4 weeks. The RTX regimen was 375 mg/m2 IV weekly for 4 weeks. The primary endpoint compared each CCX168 group to SOC control, based on Birmingham Vasculitis Activity Score (BVAS) response, defined as BVAS decrease from baseline of >50% and no worsening in any body system. Eligible patients had GPA, MPA, or renal limited vasculitis and PR3 or MPO‐ANCA positivity. Results: 67 patients were enrolled. The table shows baseline characteristics and efficacy results at Week 12. Groups were well balanced. The study met its primary endpoint: BVAS response at week 12 was numerically superior and statistically non‐inferior to SOC control (P = 0.002 and P = 0.01 for each CCX168 group vs. control). Three of 22 (14%) and 6 of 21 (29%) patients in the low and no steroids CCX168 groups, respectively, and 1 of 20 (5%) on SOC had BVAS remission at Week 4 and 12, showing a more rapid and sustained response with CCX168. The CCX168 treatment groups performed better than SOC for most of the secondary endpoints (see table). Health‐related quality of life measurements improved more with CCX168 vs. SOC. CCX168 was well tolerated. One serious adverse reaction of pneumonia (SOC), one of hepatic and pancreatic enzyme elevations in a patient with a history of alcohol abuse who also received CYC, cotrimoxazole, and pantoprazole (CCX168), and one of worsening renal function in a patient who had rapidly declining renal function prior to study entry (CCX168) were observed. Conclusions: CCX168 successfully replaced chronic steroids suggesting a new treatment paradigm for AAV, with the same or better efficacy compared to SOC. These results provide a clear path to Phase 3 and suggest that the well‐known serious side effects of chronic steroid treatment can likely be avoided in AAV treatment. (Table Presented).