Summary

This integrated analysis combines safety data from three pivotal clinical trials—two phase 2 (CLEAR and CLASSIC) and one phase 3 (ADVOCATE)—evaluating avacopan, an oral selective complement C5a receptor antagonist, in patients with antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV), specifically granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). A total of 439 patients (239 avacopan-treated, 200 controls) were assessed for adverse events (AEs), serious adverse events (SAEs), and adverse events of special interest, including infections, white blood cell (WBC) count reductions, hepatic abnormalities, and hypersensitivity reactions.

Key Findings:

Safety Profile: Avacopan demonstrated a favorable safety profile with significantly lower exposure-adjusted rates of overall AEs (1,099.8 vs 1,251.7 per 100 patient-years), SAEs (70.7 vs 91.5), infections (142.2 vs 166.6), and WBC count reductions (22.6 vs 34.2) compared to non-avacopan regimens.

Hepatic Abnormalities: SAEs related to hepatic function were slightly higher in the avacopan group (4.4% vs 2.8%), though no cases met criteria for severe drug-induced liver injury. Hepatic events resolved upon treatment interruption/discontinuation.

Infections: Infection-related SAEs were fewer in the avacopan cohort (13.3% vs 15.2%), with pneumonia being the most common. No Neisseria meningitidis infections were reported. Importantly, reductions in glucocorticoid exposure with avacopan likely contributed to lower infection rates.

WBC Count and Hypersensitivity: Avacopan was associated with fewer serious neutropenia and lymphopenia events. Hypersensitivity AEs were comparable between groups, with two angioedema cases reported only in the avacopan group.

Hospitalizations and Mortality: Rates of hospitalization due to SAEs were similar, with slightly shorter hospital stays in the avacopan group. Seven deaths occurred in the phase 3 trial, with causes including infections and worsening GPA, distributed across both treatment arms.

Clinical relevance:

Avacopan offers a significant advancement in treating GPA and MPA by improving remission rates and kidney function while substantially reducing glucocorticoid exposure and its associated toxicity. The reduced incidence of infections and WBC count abnormalities underscores its safety advantage over traditional glucocorticoid-based regimens. However, careful monitoring for hepatic function is warranted. These findings support current EULAR (2022) and KDIGO (2024) guidelines recommending avacopan to minimize glucocorticoid use in AAV. Ongoing and future studies will further elucidate long-term safety and optimize clinical use.

References

Merkel P et al. ACR Open Rheumatology 2025

Composed by

PD Dr. med. Thomas Neumann, Stv. Chefarzt, Kantonsspital St. Gallen