European Regulators Move to Revoke Avacopan Authorization

A European Medicines Agency (EMA) committee recommended pulling the marketing authorization for avacopan (Tavneos) following a review over data integrity concerns in the vasculitis drug’s key supporting trial.

Due to breaches of good clinical practice, “the data from the pivotal trial on which the marketing authorization of Tavneos was based can no longer be relied upon to demonstrate the medicine’s efficacy,” the EMA Committee for Medicinal Products for Human Use (CHMP) concluded.

With no reliable randomized controlled trial data to confirm the drug’s efficacy, avacopan’s “benefits are no longer proven to outweigh its risks,” the committee stated. The drug has been associated with drug-induced liver injury (DILI), including fatal cases.

Its recommendation still needs to be confirmed by the European Commission before the authorization is revoked in the European Union.

The move marks the latest in the ongoing saga between regulators and drugmaker Amgen, which acquired the rights to avacopan from developer ChemoCentryx.

The oral complement 5a receptor inhibitor was approved based on data from ADVOCATE as an adjunctive treatment for adults with granulomatosis with polyangiitis and microscopic polyangiitis, two forms of severe anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis.

But the FDA has said that “manipulated” data submitted by ChemoCentryx supported the approval and has also called for the drug to be pulled from the market. Amgen has refused and recently recruited an independent firm to review the safety data in an effort to demonstrate that the drug still carries a positive risk-benefit profile.

ADVOCATE randomized patients to either avacopan or prednisone tapering with standard cyclophosphamide or rituximab therapy in each arm. The primary endpoint of sustained remission at week 52 was observed in 65.7% of the avacopan group and in 54.9% of the prednisone group, which was deemed significant for both noninferiority and superiority.

But the FDA said that after an initial analysis of the primary endpoint failed to achieve significance, unblinded ChemoCentryx personnel selected participants for readjudication and ultimately changed five patients treated with avacopan from “not in sustained remission” to “sustained remission,” resulting in a statistically significant superiority benefit over the control arm.

CHMP recommended that no new patients start on avacopan and said physicians should find alternatives for patients already taking the drug. The committee recommended liver function monitoring after discontinuation due to concerns about DILI, with different protocols depending on the duration of treatment.

Postmarketing data flagged by FDA earlier this year turned up dozens of serious DILI cases associated with avacopan, including fatal cases of vanishing bile duct syndrome (VBDS), a condition where the bile ducts are progressively destroyed before disappearing altogether.

Hepatotoxicity is listed as a potential serious adverse event in avacopan’s product labeling based on premarket trial data, but the FDA said the VBDS and DILI cases with fatal outcomes represented a new, more serious safety concern.