Real-world data sharpen concerns about avacopan

Clinical takeaway: Monitor liver function closely, particularly during the first months of avacopan therapy, and counsel patients about symptoms of liver injury. Although serious hepatotoxicity appears uncommon, this study confirms that severe drug-induced liver injury (DILI) can occur in real-world practice.

Avacopan (Tavneos) was approved in 2021 as a steroid-sparing adjunct for ANCA-associated vasculitis, but its safety profile has come under intense scrutiny in 2026. Earlier this year, FDA reported dozens of postmarketing DILI cases, including fatalities, and requested market withdrawal. More recently, the New England Journal of Medicine retracted publication of the pivotal ADVOCATE trial after concerns emerged regarding post-unblinding data changes.

In this real-world analysis from the Rheumatology Informatics System for Effectiveness (RISE) Registry, investigators evaluated 238 patients with ANCA-associated vasculitis treated with avacopan between October 2021 and March 2025. The primary objective was to quantify the incidence of hepatic laboratory abnormalities and identify confirmed cases of DILI.

Overall, clinically significant liver enzyme elevations were uncommon. Five patients developed elevated AST, three had elevated ALT, four had elevated alkaline phosphatase levels, and two developed elevated bilirubin during treatment. The first liver function assessment occurred a median of 32 days after treatment initiation, although monitoring intervals subsequently averaged more than 4 months.

Fourteen significant liver test abnormalities were identified, prompting detailed causality assessment. Two patients, representing approximately 0.8% of the cohort, met criteria for avacopan-associated DILI and received Roussel Uclaf Causality Assessment Method scores indicating a highly probable relationship to the drug. One case involved biopsy-confirmed severe hepatocellular injury. Both patients recovered within roughly 2 months after discontinuing avacopan, and neither developed vanishing bile duct syndrome.

The findings provide some reassurance that severe liver toxicity is not common among US patients receiving avacopan, but they also offer direct confirmation that serious DILI can occur in routine practice. The results arrive amid ongoing regulatory reassessment of the drug's benefit-risk profile in the US and internationally.

“Hepatic enzyme elevations during avacopan therapy were infrequent in this US cohort, yet severe DILI occurred,” the authors wrote, adding that the findings support “vigilant early monitoring and informed discussions of potential risks during ongoing regulatory reassessment.”

Source: Roberts ET, et al. (2026 Aug 24) Arthritis Rheumatol. Hepatotoxicity of Avacopan: Real-World Incidence and Confirmed Cases of Severe Drug-Induced Liver Injury in a US National Rheumatology Registry