Avacopan Added to Standard-of-care Therapy in ANCA-associated Vasculitis With Severe Kidney Involvement

ANCA-associated vasculitis (AAV) is a rare auto-immune disease, with high mortality in the absence of treatment. There is still an unmet need to define new treatment strategies to reduce drug side effects, as well as to reverse rare cases of refractory AAV and improve the kidney response to improve the long-term outcomes.

Severe forms of AAV-related necrotizing and crescentic rapidly progressive glomerulonephritis (RPGN) (i.e. estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m²) are associated with higher mortality, higher incidence of infections, and long-term consequences including chronic kidney disease (CKD) with subsequent complications (end-stage kidney disease (ESKD) requiring dialysis, cardiovascular diseases) and a burden of financial costs.

In patients with AAV and RPGN, recent guidelines recommend using a standard-of-care (SOC) immunosuppressive regimen including an induction regimen (rituximab or cyclophosphamide), plus glucocorticoids (GCs) (starting at 60 mg/day and tapering over 6-12 months) (+ or - plasma exchanges).

Since GCs also participate to the long-term control of AAV, new molecular pathophysiology-driven therapeutic approaches rapidly blocking and/or reversing AAV lesions are needed to go beyond the progressive control of AAV using GCs alone. Thus, an add-on approach including GCs-based immunosuppressive regimen plus a new targeted therapy may lead to both AAV control (systemic disease) and improvement of the kidney outcome (organ involvement).

Avacopan a selective inhibitor of the C5a receptor, recently emerged as a new therapeutic option in AAV. In a phase 3 comparative study (that included a small subset of patients with eGFR 15-29 mL/min/1.7m2), avacopan was superior to glucocorticoids taper with respect to sustained remission at week 52. In the avacopan arm, the cumulative dose of GCs was dramatically reduced and avacopan was thus proposed as an alternative to GCs rather to a synergic treatment. In the subgroup of patients with eGFR <30 mL/min/1.73m², avacopan was associated with a better eGFR gain at week 52 compared to prednisone, but data in this population at-risk of worse kidney outcomes are scarce, and did not include patients with eGFR < 15 mL/min/1.73m², those patients being excluded from the study.

In the REVERSE study, investigators put forward the hypothesis that avacopan added on GCs regimen may significantly improve the kidney outcome of severe AAV (synergic approach), and thus improve short- and long-term global outcomes (survival, cardiovascular status). REVERSE will thus compare GCs-based SOC + placebo to GCs-based SOC + avacopan.