Евросоюз отозвал разрешение на продажу препарата Tavneos из-за нарушений в клинических испытаниях

With the European Union formally reversing its marketing authorization for the rare disease med Tavneos last week, regulators from the bloc are laying out their concerns about the data backing the complement inhibitor in greater detail. Tavneos, which is used in the two most common forms of the autoimmune disorder ANCA-associated vasculitis, was originally developed by ChemoCentryx, which itself was acquired by Amgen for $3.7 billion in 2022. Stateside, Amgen is fighting to keep Tavneos on the market after an FDA market withdrawal request earlier this year kicked off a regulatory back-and-forth over safety and data concerns tied to a ChemoCentryx-run study. In Europe, meanwhile, Tavneos’ marketing rights fell under the purview of CSL Vifor. CSL Vifor confirmed late last week that the European Commission had given the final word on Tavneos’ marketing status in the EU, adopting a June recommendation from the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) to revoke the drug’s commercial clearance. Tavneos had boasted a 2022 go-ahead in Europe to treat the two forms of ANCA-associated vasculitis known as active granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), as part of a combination with either Roche’s Rituxan (rituximab) or the chemotherapy cyclophosphamide. The phase 3 Advocate study that helped Tavneos clinch its original green lights in Europe and the U.S. has since come back to haunt the drug and the companies that have inherited it from ChemoCentryx. In regulatory documents published (PDF) Thursday, the CHMP delved deeper into its recent market withdrawal recommendation, noting up top that an ongoing review of the trial this year flagged “serious breaches to [good clinical practice] principles in the handling of primary endpoint data in the pivotal clinical study.” Specifically, CHMP suggested that study sponsor personnel were able to look at unblinded efficacy data after an initial database lock, alerting them to the fact that superiority had not been demonstrated at the study’s key 52-week juncture. With this new knowledge, CHMP alleges, the study personnel were able to re-adjudicate nine patients “based on knowledge of treatment outcomes, after which the primary analysis was rerun resulting in a change from a non-significant to a statistically significant result for superiority at week 52.” The sponsors didn’t share this original analysis and the post-unblinding data modifications, according to the CHMP, which noted that “[o]n the contrary, the clinical study report specifically stated that the unblinding process outlined in the protocol has been followed.” CHMP added that it wasn’t buying the study sponsor’s explanation for why the re-adjudication was necessary and also flagged safety concerns on several fatal cases of drug-induced liver injury or vanishing bile duct syndrome reported among patients taking Tavneos since the medicine’s marketing authorization in the EU. Those safety flags had resulted in multiple product information updates since initial authorization, the regulator added. “On balance,” the CHMP wrote, “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.” Tavneos’ EU marketing operator CSL Vifor wrote last week that it was “disappointed” in the European Commission’s decision but that it nonetheless respected the outcome and was “committed to implementing it in full.” For its part, Amgen said in an emailed statement that “[w]e disagree with the European Medicines Agency’s (EMA's) decision to withdraw Tavneos from the European market and are deeply concerned about the impact this decision may have on rare disease patients.” A company spokesperson argued that the EMA’s interpretation of the data “fails to appropriately recognize the totality of evidence supporting the effectiveness and favorable benefit-risk profile of Tavneos,” pointing to a bulk of real-world studies and secondary endpoint findings that the company believes make a strong case for the drug’s worth to ANCA-associated vasculitis patients. “People living with ANCA-associated vasculitis (AAV) face a rare, serious and potentially life-threatening disease that can cause irreversible organ damage,” Amgen’s statement concluded. “Achieving and sustaining remission while reducing exposure to steroids and their serious toxicities remains a key treatment goal and removing Tavneos from the market further limits treatment options for this community.” Late last month, Amgen submitted a data and analysis package to the FDA to help secure a hearing in defense of Tavneo’s U.S. market position. Crucially, the package contains a third-party re-evaluation of the controversial Advocate study, bolstered by real-world evidence and patient and HCP testimonials backing the drug. Amgen’s request for a hearing with the FDA over Tavneos came after the company initially resisted a request by the agency in January to pull the drug from the market voluntarily. Amgen has vehemently defended Tavneos' risk-benefit profile, bringing on the Duke Clinical Research Institute to review the phase 3 data that won the med its initial green lights and sparked much of the present controversy. The FDA, meanwhile, has sounded off on safety and data manipulation concerns that are largely in line with those of its counterparts at the EMA.