OP0227 Oral C5a Receptor Antagonist CCX168 Phase 2 Clinical TRIAL in Anca-Associated Renal Vasculitis:

Abstract

Background In ANCA vasculitis, the anaphylatoxin C5a amplifies neutrophil influx and activation through C5aR. CCX168, an oral specific C5aR antagonist, is in clinical development for ANCA-associated renal vasculitis (AARV). Objectives A Phase 2 clinical trial was conducted to investigate the potential of CCX168 to contribute to disease remission and permit glucocorticoid reduction or avoidance in patients with active AARV receiving cyclophosphamide (CYC). Methods This randomized, double-blind, placebo-controlled Phase 2 trial was performed in a stepwise manner. In Step 1 (N=12), CCX168+CYC+low dose prednisone (20 mg/day starting dose) was compared to standard-of-care (SOC) (CYC+high dose prednisone, 60 mg/day starting dose). In Step 2 (N=14), CCX168+CYC and no prednisone was compared to SOC. Eligible patients had GPA, MPA, or renal limited vasculitis, were PR3 or MPO-ANCA positive, and had active renal vasculitis with a GFR >30ml/min. The dose of CCX168 was 30 mg BID PO for 12 weeks and the dose of CYC was 15 mg/kg IV q2-3 wks. Results Baseline characteristics and efficacy results at Week 12 are shown in the table. The number of steroid rescue events was not higher in the CCX168 groups compared to SOC. The incidence of renal remission was higher in the CCX168 groups compared to the SOC control group. The percent decrease from baseline in BVAS, urinary ACR and urinary MCP-1/creatinine was higher in the CCX168 groups compared to SOC. Renal function, as measured by eGFR, increased in all 3 groups, with the largest increase (6.8 mL/min/1.73 m2) in the CCX168+low dose steroids group. CCX168 appeared to be well tolerated. No unexpected serious adverse reactions were observed with CCX168 use. There was one early withdrawal from study, in the control, SOC, group. Parameter CCX168+CYC+Low-Dose Steroids CCX168+CYC+No Steroids Standard of Care: CYC+High-Dose Steroids (N=8) (N=8) (N=9) Demographics and baseline characteristics Age, mean (SD); Male/Female (%) 55 (15); 50:50 58 (14); 50:50 55 (16); 70/30 Newly diagnosed/relapsing disease (%) 75/25 87.5/12.5 70/30 MPO/PR3+ ANCA (%) 62.5/37.5 50/37.5 40/60 BVAS version 3, mean (SD) 13 (8) 14 (8) 9 (4) eGFR, mL/min/1.73 m2, mean (SD) 52 (18) 57 (25) 57 (15) Efficacy results Steroid rescue events 0 1 (13%) 1 (11%) Renal remission* 6 (75%) 5 (63%) 4 (44%) U-ACR mean % change** −63% −59% −9% eGFR mean (SE) change (mL/min/1.73 m2) 6.8 (2.1) 0.6 (3.6) 2.2 (3.3) Urinary MCP-1/creatinine mean % change** −72% −52% −37% BVAS mean (SE) % change** −71 (9)% −65 (11)% −26 (25)% *Renal remission is defined as a reduction from baseline in urinary RBCs and improvement in renal function based on eGFR. **Based on ratio of geometric means of Wk12:Baseline. Conclusions CCX168 plus CYC appear to be at least as effective, if not more effective, as full dose steroids plus CYC in treatment of patients with an ANCA associated renal vasculitis flare. Disclosure of Interest D. Jayne Consultant for: ChemoCentryx, Inc., A. Bruchfeld Consultant for...

Update on the treatment of ANCA associated vasculitis

“…The preliminary results of a small phase II trial evaluating efficacy and safety indicate that CCX168 plus cyclophosphamide is at least as effective, if not more effective, as full dose steroids plus cyclophosphamide in patients with newly diagnosed renal AAV [69]. Since high-dose glucocorticoids are increasingly believed to be the major contributor to early toxicity and infectious adverse events, the possibility of a steroid-sparing agent, with the convenience of oral administration is an extremely exciting development.…”

Biologics in vasculitides: Where do we stand, where do we go from now?

“…CYC plus high-dose prednisone tapering. The results showed that CCX168 plus CYC appeared to be at least as effective, if not more effective, as full-dose GC plus CYC in improving renal parameters and inducing remission of renal vasculitis [85]. TCZ was successfully used in a case of a woman with MPO-ANCA pauci-immune glomerulonephritis with necrotizing and crescent formation associated with rheumatoid arthritis [86].…”

Patogeneza zapaleń naczyń związanych z przeciwciałami przeciwko cytoplazmie neutrofilów

“…Przeprowadzona została II faza badań klinicznych nad CCX168 (nazwa handlowa Avacopan) w AAV (https://clinicaltrials.gov, identyfikator badania: NCT01363388). Wstępne doniesienia wskazywały, że stosowanie CCX168 w połączeniu z cyklofosfamidem jest co najmniej równie skuteczne co cyklofosfamid w połączeniu z wysokimi dawkami sterydów u pacjentów z AAV [52]. Najnowsze doniesienia na tym etapie, zaprezentowane podczas kongresu ERA-EDTA w Wiedniu (53rd ERA-EDTA Congress, 2016), potwierdzają bezpieczeństwo i skuteczność CCX168 stosowanego w połączeniu z rytuksymabem lub cyklofosfamidem zamiast standardowo stosowanych wysokich dawek sterydów [53].…”