EU regulators cite data manipulation in Tavneos market withdrawal

European regulators have laid out in greater detail the concerns underpinning their decision to strip the rare disease drug Tavneos of its marketing authorization in the European Union, alleging serious breaches of clinical trial protocol that they say fundamentally undermine the evidence base supporting the complement inhibitor.

The European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) published documents Thursday setting out its rationale for the withdrawal recommendation it issued in June, which the European Commission formally adopted last week. CSL Vifor, which held Tavneos' EU marketing rights, confirmed the Commission's decision, saying it was "disappointed" but would respect and implement the outcome in full.

Tavneos, approved in Europe in 2022 to treat the two most common forms of ANCA-associated vasculitis — granulomatosis with polyangiitis and microscopic polyangiitis — was originally developed by ChemoCentryx, which Amgen (AMGN) acquired for $3.7bn that same year. In Europe the drug was commercialized by CSL Vifor, an arm of CSL (CSLLY).

At the center of the regulatory dispute is the phase 3 Advocate study that secured Tavneos' original approvals on both sides of the Atlantic. The CHMP alleged that an ongoing review of the trial this year uncovered "serious breaches to good clinical practice principles in the handling of primary endpoint data." Specifically, regulators contend that study sponsor personnel gained access to unblinded efficacy data following an initial database lock, at which point they became aware that superiority over the comparator had not been demonstrated at the trial's key 52-week assessment.

Armed with that knowledge, the CHMP alleges, personnel re-adjudicated nine patients "based on knowledge of treatment outcomes," after which the primary analysis was rerun — converting a non-significant result into a statistically significant finding for superiority at week 52. Regulators noted that the original analysis and the post-unblinding data modifications were never disclosed. "On the contrary," the CHMP wrote, "the clinical study report specifically stated that the unblinding process outlined in the protocol has been followed."

The committee said it did not accept the sponsor's justification for the re-adjudication, and separately flagged safety concerns including fatal cases of drug-induced liver injury and vanishing bile duct syndrome reported in patients receiving Tavneos since its initial EU authorization — events that had prompted multiple updates to the drug's product information. "On balance," the CHMP concluded, "considering that the pivotal study supporting the marketing authorization is considered as not reliable due to the serious GCP breach, it is concluded that there is no longer demonstration of benefit outweighing the risks of Tavneos, in particular the serious hepatic risks."

Amgen has pushed back forcefully. In an emailed statement, the company said it disagreed with the EMA's decision and was "deeply concerned about the impact this decision may have on rare disease patients," arguing that the agency's interpretation "fails to appropriately recognize the totality of evidence supporting the effectiveness and favorable benefit-risk profile of Tavneos." The company pointed to a body of real-world studies and secondary endpoint data it believes supports the drug's value to patients living with ANCA-associated vasculitis, a rare and potentially life-threatening condition capable of causing irreversible organ damage.

The EU withdrawal does not directly affect Tavneos' US status, but Amgen is fighting a parallel regulatory battle with the FDA, which earlier this year issued a market withdrawal request of its own, citing safety and data concerns broadly consistent with those raised by the EMA. Amgen initially resisted that request and late last month submitted a data and analysis package to the agency in support of a formal hearing, including a third-party re-evaluation of the Advocate study conducted by the Duke Clinical Research Institute, supplemented by real-world evidence and testimonials from patients and healthcare professionals.