Avacopan: Investigators Retract Suspect ADVOCATE Data, EMA Seeks to Revoke Authorization

The New England Journal of Medicine retracted the pivotal ADVOCATE trial on June 29, 2026, the same week the European Medicines Agency (EMA) recommended revoking avacopan's (Tavneos; Amgen) marketing authorization in the European Union — a convergence of regulatory and scientific actions that has placed the oral C5a receptor inhibitor's future in both markets in serious doubt.^1-4

The retraction notice, published by NEJM editor Eric Rubin, MD, was requested by 2 of the trial's academic authors, David Jayne, MD, and Peter Merkel, MD, MPH. According to the notice, an ongoing FDA investigation found that primary endpoint assessments in 9 of the trial's 331 patients were readjudicated after database lock and after trial unblinding — without the knowledge of the academic authors and without disclosure in the published article. The NEJM editors concluded this conduct was inconsistent with proper research conduct and retracted the article.³

The ADVOCATE trial, originally published in 2021, was the sole pivotal evidence base supporting avacopan's regulatory approvals in both the US and EU. In the trial, a 52-week course of avacopan was compared with placebo alongside a 20-week corticosteroid course, both added to standard induction therapy with either rituximab or cyclophosphamide followed by azathioprine, in patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA). The published results reported avacopan was noninferior to prednisone taper in inducing remission at week 26 and superior at week 52 — the 52-week superiority finding that has since been identified as dependent on the contested endpoint readjudications.³

Regulatory timeline

The FDA requested voluntary withdrawal of avacopan in January 2026, citing concerns about endpoint re-adjudication in the ADVOCATE trial. Amgen declined. The FDA formally proposed withdrawal on April 27, 2026, on 2 grounds: lack of substantial evidence of effectiveness in light of the data manipulation, and the application containing untrue statements of material fact.⁵ Amgen has commissioned the Duke Clinical Research Institute to conduct an independent, blinded re-adjudication of ADVOCATE's primary endpoints and is preparing to present findings at an FDA hearing scheduled for July 2026.¹

The EMA initiated its review of avacopan in January 2026 following the same data integrity concerns. On June 26, the EMA's Committee for Medicinal Products for Human Use (CHMP) concluded the ADVOCATE study was conducted in breach of good clinical practice (GCP) principles, that the study data provided at the time of the marketing authorization application were incorrect and misleading, and that supportive post-marketing data and post-hoc analyses were insufficient to demonstrate the medicine's benefits independently.² The CHMP recommended revocation of avacopan's EU marketing authorization. A final legally binding decision by the European Commission is pending.

Safety concerns compound data integrity issues

Separate from the efficacy questions, both agencies have identified serious postmarketing hepatotoxicity signals. The FDA's March 31, 2026, drug safety communication identified 76 cases of DILI with reasonable evidence of a causal association with avacopan, including 74 serious outcomes, 54 hospitalizations, and 8 deaths.⁶ Seven cases involved biopsy-confirmed vanishing bile duct syndrome (VBDS), a serious and previously unexpected adverse event characterized by progressive destruction of intrahepatic bile ducts; 3 of those 7 cases were fatal. Median time from avacopan initiation to DILI onset was 46 days (range, 22–140 days). The majority of cases showed a cholestatic or mixed pattern of injury, with substantial elevations in alkaline phosphatase and total bilirubin.⁶ A disproportionate number of serious hepatic cases were reported from Japan.

The CHMP has recommended that no new patients be started on avacopan and that existing patients be switched to alternative treatments. For patients who have received avacopan for less than 3 months, the EMA recommends liver function monitoring at least every 2 weeks until 3 months from treatment initiation; for those treated for more than 3 months, monitoring every 4 weeks for up to 6 months, then as clinically indicated.² If VBDS is suspected, immediate discontinuation is required.² Avacopan remains on the US market pending the outcome of Amgen's hearing before the FDA.

References

1. Clinical Trials Arena. Medical journal retracts Tavneos pivotal paper amid wider regulatory clampdown. July 1, 2026. https://www.clinicaltrialsarena.com/news/amgen-tavneos-nejm-pivotal-paper-retraction/

2. European Medicines Agency. EMA recommends revoking marketing authorisation for Tavneos. June 26, 2026. https://www.ema.europa.eu/en/news/ema-recommends-revoking-marketing-authorisation-tavneos

3. Rubin EJ. Retraction: Jayne DRW et al. Avacopan for the treatment of ANCA-associated vasculitis, N Engl J Med 2021;384:599-609. N Engl J Med. Published online June 29, 2026. doi:10.1056/NEJMe2608684

4. Jayne DRW, Merkel PA, Schall TJ, Bekker P. Avacopan for the treatment of ANCA-associated vasculitis. N Engl J Med. 2021;384:599-609. doi:10.1056/NEJMoa2023386 [Retracted]

5. US Food and Drug Administration, Center for Drug Evaluation and Research. CDER proposes to withdraw approval of Tavneos. April 27, 2026. https://www.fda.gov/drugs/drug-alerts-and-statements/cder-proposes-withdraw-approval-tavneos

6. US Food and Drug Administration. FDA identifies cases of serious liver injury in patients taking Tavneos (avacopan) for severe active ANCA-associated vasculitis. March 31, 2026. https://www.fda.gov/drugs/drug-safety-communications/fda-identifies-cases-serious-liver-injury-patients-taking-tavneos-avacopan-severe-active-anti