Background/Purpose:  Complement 5a (C5a) is involved in the pathogenesis of anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV). CCX168 is an orally administered, small molecule selective inhibitor of the C5a receptor (C5aR). It was shown to be effective and safe in a randomized clinical trial (CLEAR) in patients with AAV, and safely substituted for treatment with prednisone without a loss of efficacy. In the current trial (named CLASSIC), conducted in the USA and Canada, CCX168 was added to full-dose glucocorticoids plus either rituximab (RTX) or cyclophosphamide (CYC) to investigate the safety profile of CCX168 in addition to standard of care (SOC) treatment.

Methods:  Patients with new or relapsing AAV and PR3 or MPO ANCA were eligible. Patients were randomized into one of three groups: i. SOC+placebo (N=13), ii. SOC+10 mg CCX168 twice daily (N=13), or iii. SOC+30 mg CCX168 twice daily (N=16) and were treated for 12 weeks with CCX168/placebo. Two patients, one in each of the CCX168 groups, were excluded from the intention to treat analysis but included in the safety analysis: one did not receive any study drug and one received only 2 weeks of study drug and thus did not have any on-treatment disease activity assessment. All patients received either RTX (375 mg/m² IV weekly for 4 weeks) or CYC (15 mg/kg IV up to 1.2 g, on Days 1, 15, 29, 57, and 85) at investigators’ discretion. The starting dose of prednisone for all patients was 60 mg/day, tapered to 10 mg/day by week 12. Since CCX168 was added to full-dose glucocorticoid SOC treatment, the primary endpoint was safety measured by comparison of the incidence of adverse events (AEs) among the groups. Efficacy was mainly assessed based on clinical response, defined as a decrease of Birmingham Vasculitis Activity Score (BVAS) from baseline to week 12 of at least 50%, and no worsening in any body system; however, the study was not powered to detect differences among groups.

Results:  Forty-two patients with AAV were enrolled. Presenting features were typical of AAV and well balanced across groups. Mean±SD age: 58±13 years; female/male: 55%/45%; newly-diagnosed/relapsing AAV: 64%/36%; PR3/MPO-ANCA: 50%/50%; BVAS: 15.3±6.6, eGFR: 59±27 mL/min/1.73 m²; RTX/CYC use: 93%/7%. A total of 7 patients had serious adverse events, 2 of 13 patients in the SOC+placebo group, 2 of 13 in the SOC+10 mg CCX168 group, and 3 of 16 in the SOC+30 mg CCX168 group. These included 4 infection-related SAEs: toe gangrene (1), cellulitis and skin abscesses (1), and sepsis and urinary tract infection (1 each) in the three groups, respectively. Total AEs occurred in 13, 11, and 15 patients in the three groups, respectively. Response at week 12, based on BVAS, was achieved in 10, 11, and 12 patients, respectively, in each group. Early remission (BVAS = 0 at week 4) was achieved in 2, 1, and 5 patients, respectively. eGFR mean change from baseline to week 12 was 0.8, -0.8, and 3.1 mL/min/1.73 m², respectively, in each group.

Conclusion:  CCX168 was found to be safe when added to SOC high-dose glucocorticoids and either RTX or CYC. Based on these results and the prior CLEAR trial, 30 mg CCX168 twice daily appears to be an appropriate and safe dose for further study in patients with AAV.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-randomized-clinical-trial-of-ccx168-an-orally-administered-c5ar-inhibitor-for-treatment-of-patients-with-anca-associated-vasculitis/