Background/Purpose: Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) are life-threatening rare autoimmune diseases to anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Standard of care (SOC) treatment includes glucocorticoids (GCs) in combination with cyclophosphamide (CYC) or rituximab (RTX). SOC is still associated with incomplete treatment response, disease relapses, and long-term side effects. Complement component 5a (C5a) is known to prime and activate neutrophils, which is a major contributor to the pathogenesis of AAV. IFX-1, a monoclonal antibody, specifically binds to C5a inhibiting C5a-induced biological effects. Observations in previous clinical studies of sepsis, hidradenitis suppurativa, and cardiac surgery indicate that IFX-1 is safe and well-tolerated. These data suggest that IFX-1 might be a safe, tolerable, and efficacious agent for the treatment of AAV.

Methods: We describe the design of an ongoing clinical trial evaluating the safety of two different doses of IFX-1 or placebo as add-on therapy to SOC in subjects with moderate to severe GPA or MPA.

Results: This randomized, placebo-controlled, multicenter trial is evaluating the safety of two different doses of IFX-1 in combination with SOC, including a standard tapering schedule for GCs (ClinicalTrials.gov NCT03712345). The trial will be performed in about 40 sites in the USA and Canada and will include a total of 36 subjects, 12 per arm. A pharmacokinetic (PK) substudy is planned to enroll 15 subjects. Participation could last for up to 26 weeks, including a 16-week treatment and an 8-week follow-up period.

Major eligibility criteria are a diagnosis of new or relapsing GPA or MPA that requires treatment with CYC or RTX plus GCs, positive test for ANCA, and ≥ 1 major item or ≥ 3 minor items or ≥ 2 renal items on the Birmingham Vasculitis Assessment Score version 3 (BVASv3). Intravenous IFX-1 or placebo will be given on days 1, 4, 8, 15 and then every other week until Week 16. Primary outcome is the number and percentage of subjects who experience at least one treatment‑emergent adverse event (TEAE) per treatment group. Key secondary endpoints are IFX-1-related serious AEs and TEAEs, AEs of special interest, proportion of subjects achieving clinical response (reduction in BVAS of ≥50% at Week 16 and no worsening in any body system), proportion of subjects with clinical remission (BVAS = 0) at Week 16, and PK and pharmacodynamic (PD) parameters. The safety of subjects will be monitored continuously by an unblinded Independent Data Monitoring Committee.

Study enrollment in this trial began in October 2018.

Conclusion: This prospective Phase 2 trial of subjects with AAV is intended to demonstrate the safety, tolerability, and efficacy of IFX‑1, a C5a blocking therapy, in two different dose regimens in comparison with placebo.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/design-of-a-phase-2-multicenter-randomized-double-blind-placebo-controlled-trial-of-2-different-dose-regimens-of-ifx-1-a-c5a-inhibitor-as-an-add-on-therapy-for-granulomatosis-with-polyangiitis-o/