Hepatotoxicity of Avacopan: Real-World Incidence and Confirmed Cases of Severe Drug-Induced Liver Injury in a US National Rheumatology Registry.

Abstract

Avacopan, an oral C5a receptor inhibitor, approved for ANCA-associated vasculitis (AAV) in 2021. Following FDA reports of 76 worldwide drug induced liver injury (DILI) cases (66 in Japan, 5 in the US), the agency requested market withdrawal, which the manufacturer declined. US risk has not been quantified using real-world data. This study estimated the incidence of hepatic enzyme elevations among US avacopan users and characterized confirmed DILI cases. Data came from the Rheumatology Informatics System for Effectiveness Registry. We identified AAV patients with ≥1 avacopan prescription (October 2021-March 2025). Hepatic enzyme elevations were defined per FDA guidance (AST/ALT >3×ULN, alkaline phosphatase >2×ULN, total bilirubin >2 mg/dL). Person-time at risk was estimated from prescribing information. Patients meeting elevated laboratory thresholds underwent Roussel Uclaf Causality Assessment Method (RUCAM) evaluation. Among 238 AAV patients treated with avacopan, liver enzyme elevations during treatment were uncommon: 5 patients had elevated AST, 3 ALT, 4 Alk Phos, and 2 T.bili, with incidence rates of 4.24 (1.77, 10.19), 2.67 (0.86, 8.27), 3.56 (1.34, 9.49), and 1.80 (0.45, 7.19) per 100 person-years, respectively. Median time to first hepatic enzyme screening was 32 days, with testing intervals averaging 125 days. Two DILI cases (0.8%) were identified, both with RUCAM scores of 9 (highly probable causality), including one with histologically-confirmed severe hepatocellular injury. Hepatic enzyme elevations during avacopan therapy were infrequent in this US cohort, yet severe DILI occurred. Findings support vigilant early monitoring and informed discussions of potential risks during ongoing regulatory reassessment.