The New England Journal of Medicine has retracted the 2021 ADVOCATE trial of avacopan (Tavneos, Amgen) after US regulators found data discrepancies in nine patients.

Two academic authors of the trial requested the retraction, which followed a Food and Drug Administration investigation into the drug for ANCA-associated vasculitis (AAV).

According to the retraction notice [link here], primary endpoint assessments were readjudicated after database lock and trial unblinding, without the knowledge of the two authors. The notice said this was not disclosed in the original article and was inconsistent with proper research conduct.

An editorial in The Lancet Rheumatology described the retraction as the latest instalment in an ongoing controversy surrounding avacopan that could spell the end for the drug [link here].

FDA flagged liver injury risk earlier this year

It comes after the FDA earlier this year issued a drug safety communication [link here] about the drug, reporting 76 cases of liver injury, including hospitalisations and deaths in patients on avacopan. The agency said this was “reasonable evidence of a causal association with avacopan use”.

The FDA recommended doctors prescribing avacopan:

• Conduct liver panel testing every two weeks in the first month, then monthly for the next five months, then as clinically indicated
• Discontinue treatment if ALT or AST exceeded three times the upper limit of normal, ALP exceeded twice the upper limit of normal, or there was evidence of symptomatic cholestasis such as jaundice or pruritus
• Refer patients to hepatologists if liver abnormalities or symptoms did not improve

The agency followed this with public advice stating that unblinded study personnel had manipulated the results of the pivotal trial, making the drug appear effective when the original analysis did not support that conclusion.

The FDA proposed withdrawing the drug from the market and recommended doctors discuss avacopan and alternative treatments with patients while a final decision was pending.

Amgen stands by the drug; Europe has already acted

Amgen, which has not withdrawn avacopan from the market, said it remained confident in the drug’s overall benefit-risk profile [link here].

According to the Lancet Rheumatology editorial, regulators in Japan, the UK and Europe had all launched reviews of avacopan. The European Medicines Agency concluded the ADVOCATE trial breached good clinical practice principles and was advising patients currently taking the drug to discuss other options with their doctor.

The editorial’s authors wrote that questions about the integrity and reliability of the data were deeply concerning.

They wrote: “Avacopan’s fate in Europe has been decided. We await the outcome of the FDA hearing.”

“With the retraction of the ADVOCATE trial, the end for avacopan seems inevitable—and patients with ANCA-associated vasculitis seem set to lose access to an effective drug because of the nefarious actions of a few unscrupulous individuals.”