With all eyes on Tavneos’ seemingly precarious approval status in the U.S., Amgen is advancing plans to defend the ANCA-associated vasculitis (AAV) drug it inherited in its $3.7 billion buyout of ChemoCentryx.
The California pharma on Thursday submitted data and analyses to the FDA to help secure a hearing in hopes of keeping Tavneos on the U.S. market. The package includes a third-party re-evaluation of the med’s controversial pivotal trial, real-world evidence and patient and HCP testimonials.
The rare disease med has faced mounting regulatory scrutiny at home and abroad this year, driven by safety flags and concerns around the ChemoCentryx-run study that helped secure Tavneos its vasculitis approvals in places like the U.S. and the European Union earlier in the decade.
Amgen resisted a request by the FDA to voluntarily pull its complement inhibitor from the U.S. market near the start of the year and, after the FDA turned up the heat, initiated the process to request a hearing instead. Meanwhile, the European Medicines Agency’s Committee for Medicinal Products for Human Use recommended in late June that the drug’s marketing authorization be rescinded in the EU.
“Amgen strongly disagrees with the FDA's proposal to withdraw Tavneos from the U.S. market,” the company reiterated in a press statement announcing its July 23 data submission. The company espoused continued confidence in the medicine’s benefit-risk profile, especially in light of the evidence handed over, and suggested that it remains a vital treatment option for “appropriate patients” given the “seriousness of AAV.”
In mounting its Tavneos defense, Amgen said earlier this year that it had brought on the Duke Clinical Research Institute (DCRI) to review data from the phase 3 Advocate study supporting Tavneos’ initial green lights. The FDA has suggested that the results from the ChemoCentryx study were “manipulated” to pave the way for an approval.
The issue was further complicated this summer when the New England Journal of Medicine retracted those phase 3 results, first published in 2021, late last month. In a retraction notice, the Journal explained that an FDA investigation had concluded that “the primary end-point assessments in nine patients were readjudicated after database lock and trial unblinding,” which it said was “inconsistent with proper research conduct.”
Now, that DCRI re-examination is at the heart of the package (PDF) Amgen has submitted for its hearing, which Amgen says “confirmed noninferiority of Tavneos versus a prednisone taper for remission at Week 26 … and sustained remission at Week 52.”
Amgen did caveat that superiority wasn’t demonstrated at 52 weeks in the Tavneos arm versus the prednisone taper cohort, as was the case in the original study analysis, but the company suggested that the “overall findings remained similar to the original ADVOCATE results with a treatment effect that directionally favored Tavneos for sustained remission.”
Alongside those data, Amgen also submitted real-world evidence in the form of a comparative effectiveness study and a meta analysis, plus a post-marketing evaluation on safety homing in on liver-related adverse events.
Leveraging its global safety database, Amgen says it determined that “serious hepatic adverse events were reported at a rate of approximately 31 events per 1,000 patient-years,” noting that most reported events were “reversible laboratory abnormalities.”
That said, the company did acknowledge cases of serious liver injury and vanishing bile duct syndrome (VBDS) too, including some that resulted in death, predominantly in Japanese patients over the age of 65.
Hepatotoxicity concerns were identified during Tavneos’ development and paved the way for liver monitoring recommendations included in its U.S. prescribing info since its 2021 approval. Updated hepatotoxicity warning and monitoring recommendations became official in the medicine’s U.S. label in late May, Amgen pointed out.
In March, after flagging concerns with the pivotal ChemoCentryx trial, the FDA linked Tavneos to 76 cases of drug-induced liver injury with “reasonable evidence” of a causal association with the drug from its FDA Adverse Event Reporting System, noting that nearly all cases had a serious outcome, including 54 hospitalizations and deaths in eight.
Data considerations aside, Amgen is also appealing to the FDA on the grounds that its drug remains a vital resource for AAV patients, with some of those patient perspectives reflected on the Federal Register.
Continued access to treatments is important, Amgen argues, given that patients with severe active granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA)—the two main forms of AAV for which Tavneos is approved—face “difficult treatment tradeoffs” and have few other approved options available to them.
Amgen also suggested that other treatment regimens patients might be forced to return to, like prolonged steroid use, come with substantial burdens of their own.