FDA Advisory Committee Narrowly Supports Approval of Avacopan
A committee of the U.S. Food and Drug Administration (FDA) — which provides the agency with non-binding recommendations from independent medical experts — has narrowly supported the approval of avacopan for the treatment of ANCA-associated vasculitis (AAV).
In the final segment of a public meeting, the committee voted a 9–9 split on whether the efficacy data support approval of avacopan and 10–8 that the therapy’s safety profile adequately supported approval. In a third question, the committee voted 10–8 on whether the benefit-risk profile supported the approval at the proposed dose of 30 mg twice daily.
However, according to a briefing document released by the agency a few days earlier, “complexities of the study design … raise questions about the interpretability of the data to define a clinically meaningful benefit of avacopan and its role in the management of AAV.”
While the FDA considers the committee’s recommendations, it will make the final decision whether to approve avacopan following its review process. A final decision is expected by July 7.
“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 Schall, PhD, president and CEO of ChemoCentryx, which is developing the therapy, said in a press release.
Avacopan is an orally administered therapy designed to block the receptor for the C5a protein, one of the most potent pro-inflammatory proteins of the complement system.
According to ChemoCentryx, C5a plays a key role in activating immune cells called neutrophils, which cause damage to small blood vessels in people with AAV. Avacopan is designed to stop these neutrophils from erroneously attacking the blood vessels, preventing vascular damage and swelling, which are hallmarks of the condition.
ChemoCentryx’s application seeking FDA approval was based on the ADVOCATE Phase 3 trial (NCT02994927), which evaluated avacopan in 331 patients with granulomatosis with polyangiitis and microscopic polyangiitis, the two most common AAV subtypes.
Participants were assigned randomly to receive avacopan or the glucocorticoid prednisone for 52 weeks (about one year). In both treatment arms, patients also received either rituximab or cyclophosphamide, followed by azathioprine.
The ADVOCATE study met both of its primary outcome goals, demonstrating that avacopan was similar to prednisone (non-inferior) at inducing clinical remission at week 26, and superior to the glucocorticoid at sustaining that remission at week 52.
The committee’s concerns focused on non-inferiority being insufficient to show that avacopan can replace glucocorticoids, especially because 86% of participants received glucocorticoids at the investigator’s discretion outside the study design.
Furthermore, avacopan can increase exposure to systemic glucocorticoids, which raised further uncertainties about the actual difference in glucocorticoid exposures and its impact on comparisons between the two groups at week 26.
Finally, there were differences between subgroups that received rituximab or cyclophosphamide treatment, as well as in the outcome assessments performed by investigators and the overseeing committee.
“Although primary efficacy comparisons were statistically significant, the review team has identified several areas of concern, raising uncertainties about the interpretability of these data and the clinical meaningfulness of these results,” the FDA wrote.
Before the May 6 meeting, the committee convened a public forum to discuss the therapy’s potential approval, in which “discussion from patients and clinicians … underscored the need for new treatment options,” said Schall.
Avacopan is under review by the European Medicines Agency, which is expected to respond by the second half of this year.
“We hope that the FDA will take into account the dire situation faced by patients living with this debilitating disease,” said Joyce Kullman, Vasculitis Foundation executive director. “ANCA vasculitis flares can lead to kidney failure and death; current therapy all too often causes serious, even fatal, side effects; and patients suffer a lower quality of life due to the disease and to the way it is treated.”