Avacopan delivers real-world remission gains amid ongoing scrutiny

Clinical takeaway: In patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA), avacopan added to standard immunosuppressive therapy was associated with high remission rates, substantial glucocorticoid sparing, and improved kidney function through one year in this small real-world cohort. Given ongoing regulatory concerns, clinicians should closely monitor liver function and weigh potential benefits against known and evolving safety risks.

Avacopan, an oral C5a receptor antagonist approved in 2021 for severe active ANCA-associated vasculitis (AAV), has come under scrutiny after the publication of its pivotal ADVOCATE trial was retracted over concerns about data integrity. In March, FDA warned of serious liver injury, including fatal cases , and in April its Center for Drug Evaluation and Research proposed withdrawing approval because new information indicated a lack of substantial evidence of effectiveness. Independent real-world data may help clarify the role of complement inhibition in AAV, where long-term glucocorticoid exposure remains a major treatment challenge.

In this prospective observational study, 46 patients started avacopan at 18 Italian centers between 2022 and 2024. Most had relapsing disease (61%), 70% had kidney involvement, and 43% had rapidly progressive glomerulonephritis.

Clinical remission was achieved by 78% of patients at week 12 and 88% at week 26, and by 97% (31 of 32) of those reaching week 52. Glucocorticoid-free remission rose from 20% at week 12 to 53% at week 52, including 75% of newly diagnosed patients versus 40% of those with relapsing disease. Mean glucocorticoid doses fell nearly 80%, from 23 mg/day at baseline to 5 mg/day by week 12.

Among patients with kidney involvement, median eGFR rose from 30.5 to 53.5 mL/min/1.73 m² over 52 weeks, with proteinuria, serum creatinine, and hematuria also improving. Quality-of-life scores improved by week 12 and held through one year, with continued gains in physical function.

Relapses occurred in three patients, all with relapsing disease at baseline. Nine patients (20%) discontinued avacopan, including four because of infections, and infections accounted for 40% of adverse events. Two infection-related deaths occurred in patients older than 70 with long-standing relapsing disease.

Only two patients had mild liver enzyme elevations, but the authors noted the small sample cannot exclude rare events. In a US registry of 238 patients, two (0.8%) had confirmed avacopan-associated liver injury, including one severe case. Both recovered after discontinuation. Separately, FDA’s review of postmarketing data through October 2024 identified 76 cases of drug-induced liver injury considered reasonably linked to avacopan, including eight deaths.

“Further independent comparative studies will be important to better define the role of complement-targeted therapies in the management of AAV, particularly in light of the evolving therapeutic and regulatory landscape,” Quartuccio and colleagues wrote.

Source: Quartuccio L, et al. (2026 Oct 11) ACR Open Rheumatol. Real-World Use of Avacopan in Antineutrophil Cytoplasmic Antibody–Associated Vasculitis: Early and Long-Term Clinical, Renal, and Patient-Reported Outcomes in an Italian Rheumatology–Nephrology Network