Amgen has submitted a third-party review of avacopan's (Tavneos) pivotal trial data and other analyses to the FDA in a bid to keep the embattled drug for severe anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis on the market.
The FDA has proposed revoking approval of the oral complement 5a receptor inhibitor over claims of "manipulated" data in the pivotal study. (Amgen acquired the drug from ChemoCentryx after its 2021 approval.)
Avacopan has come under increasing scrutiny from regulators in the U.S. and abroad over concerns about the pivotal trial data and hepatic safety. On Thursday, Amgen sent the new data and analyses to support its request for a hearing to persuade the FDA not to withdraw its approval.
In a statement announcing the submission, Amgen said it "strongly disagrees" with the agency's proposal to withdraw approval of avacopan, which is indicated as an adjunctive treatment for adults with granulomatosis with polyangiitis and microscopic polyangiitis, two forms of severe ANCA-associated vasculitis that can cause irreversible organ damage.
"Our submission includes extensive scientific analyses demonstrating that Tavneos meets the statutory standard for substantial evidence of effectiveness," the company said. "Based on the totality of the evidence, we continue to believe Tavneos has a favorable benefit-risk profile and remains an important treatment option for appropriate patients."
Amgen had the Duke Clinical Research Institute perform a fully blinded re-adjudication of the primary endpoint analysis of ADVOCATE, a phase III trial that compared avacopan versus a prednisone tapering strategy in patients on cyclophosphamide or rituximab therapy.
In the independent review, noninferiority was demonstrated for avacopan in remission rates at 26 weeks (68.1% vs 67.1% with the prednisone taper) and sustained remission rates at 52 weeks (61.4% vs 52.4%, respectively), according to the company. But the difference between arms at 52 weeks no longer met criteria for superiority as it had in the original analysis.
According to an FDA investigation into avacopan's approval, ChemoCentryx personnel selected participants for re-adjudication after database lock and unblinding and changed five patients treated with avacopan from "not in sustained remission" to "sustained remission," resulting in a statistically significant superiority benefit.
Those data integrity concerns led the New England Journal of Medicine to retract the publication of the pivotal study and a key European Medicines Agency committee to recommend pulling the marketing authorization for the drug in Europe.
Amgen said that retaining an option that reduces long-term steroid use is an important benefit for patients and their physicians. Glucocorticoid exposure was reduced by 56% on average in the avacopan arm compared with the control arm, according to the Duke analysis.
Beyond quality-of-life implications, "long-term steroid use is also associated with serious cumulative side effects, including an increased risk of serious infections, osteoporosis, diabetes, cardiovascular disease, weight gain, and other complications," the company said.
The submitted data package also included a meta-analysis of avacopan's real-world effectiveness and safety, patient testimonials, and a post-marketing study that looked at liver safety.
The FDA earlier this year flagged fatal cases of drug-induced liver injury (DILI) associated with avacopan, along with fatal cases of vanishing bile duct syndrome (VBDS), a condition where the bile ducts are progressively destroyed.
Hepatotoxicity is listed as a potential serious adverse event in the product labeling for the drug, but the FDA said the VBDS and DILI cases with fatal outcomes represented new, more serious safety concerns.