FDA panel narrowly endorses avacopan for ANCA-associated vasculitis amid efficacy concerns
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The FDA Arthritis Advisory Committee recently voted 10-8 that the safety and risk-benefit profiles for 30 mg dose of avacopan were sufficient to support its approval for the treatment of adult patients with ANCA-associated vasculitis.
However, the committee was divided — in a 9-9 split vote — on whether the provided efficacy data supported approval of avacopan (CCX168, ChemoCentryx) for this indication.
The FDA committee based its decision on results from the ADVOCATE trial, a phase 3, randomized, double-blind, active-controlled study of avacopan among adult patients with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) (n=331). Investigators randomly assigned patients to receive either avacopan or prednisone for 52 weeks, with patients treated concomitantly with rituximab (Rituxan; Genentech, Biogen) or cyclophosphamide/azathioprine.
The ADVOCATE study met both of its primary endpoints, with avacopan demonstrating noninferiority to prednisone for inducing clinical remission at week 26, and demonstrating superiority to prednisone in sustaining remission at week 52. However, the FDA maintained concerns related to how this efficacy data could be interpreted.
“The complicated study design will make the results difficult to interpret,” Suzette Peng, MD, a practicing adult rheumatologist and a clinical reviewer in the FDA’s Division of Rheumatology and Transplant Medicine, said. “We noted that there were multiple variables such as removing [standard of care] glucocorticoids and replacing it with avacopan and then comparison of a prednisone taper over 20 to 26 weeks to avacopan treatment for 52 weeks which would make it difficult to determine the treatment effect of avacopan.”
Peng noted that, in previous communications with ChemoCentryx, the FDA had stated that “a noninferiority comparison would not be sufficient to show that avacopan can replace glucocorticoids as it would be difficult to establish whether avacopan is effective or whether [rituximab] or [cyclophosphamide] was the primary driver of efficacy in both treatment arms.”
The FDA committee also voiced concerns that the noninferiority data was insufficient to demonstrate that avacopan could replace glucocorticoids, considering the majority of patients received glucocorticoids beyond the study design.
“The agency has determined that the applicant did not provide adequate justification for the selected noninferiority margin,” Rachel Glaser, MD, clinical team leader in the FDA’s Division of Rheumatology and Transplant Medicine, said. “In addition, glucocorticoids were used by 86% of patients in the avacopan arm through Week 26, and therefore, the noninferiority assessment is not the intended comparison of avacopan vs. prednisone, but instead a comparison of avacopan plus lower dose glucocorticoids vs. higher dose glucocorticoids.”
She added that “based on the study design which specified the use of glucocorticoids in the prednisone arm, it cannot be concluded that differences in doses of glucocorticoids used were due to a treatment effect of avacopan, rather than the design of the study.”
Although the FDA is not required to follow the recommendations of the advisory committees, it usually does, with a final decision expected by July 7. Additionally, the European Medicines Agency is currently reviewing avacopan and is expected to weigh in during the second half of 2021.
“We are grateful to the committee for their careful deliberations and look forward to working with the FDA as its review of our application continues,” Thomas J. Schall, PhD, president and CEO of ChemoCentryx, said in a press release. “Discussion from patients and clinicians during the public forum portion of the meeting underscored the need for new treatment options.”
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