The FDA released a briefing document that expressed concerns over ChemoCentryx’s avacopan. Company shares plummeted 46.5% at the news.
Only two days after a briefing document resulted in ChemoCentryx’s stock to plunge, the U.S. Food and Drug Administration (FDA)’s Arthritis Advisory Committee held an almost evenly split vote on the company’s avacopan for the treatment of Antineutrophil Cytoplasmic Autoantibody (ANCA)-associated vasculitis (AAV).
On May 5, the FDA released a briefing document that expressed concerns over the company’s avacopan. Company shares plummeted 46.5% at the news. The agency is reviewing the company’s submission based on data from one Phase III trial and two Phase II trials.
ANCA-associated vasculitis is a systemic illness where the complement pathway, part of the immune system, is over-activated, which further activates neutrophils that causes inflammation and destruction of small blood vessels. This can cause organ damage, and failure typically focused on the kidney. It can be fatal if it goes untreated.
Avacopan is a first-in-class, oral small molecule with a highly targeted mode of action. It precisely blocks the C5aR receptor for the pro-inflammatory complement system fragment, C5aq, on inflammatory cells such as neutrophils. Current treatments for ANCA-associated vasculitis include broad immunosuppression with steroids.
The adcom voted on three questions.
The first question was if the efficacy data supported approval of the drug for adults with AAV (granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA)). The committee split down the middle 9-9.
The second question was if the drug’s safety profile was enough to support approval of the treatment for the cited indications. They voted 10-8 that it was.
The third question was if the benefit-risk profile was adequate to support approval at the proposed dose of 30 mg twice a day for those indications. The committee voted 10-8 that it was.
“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,” said Thomas J. Schall, president and chief executive officer of ChemoCentryx. “Discussion from patients and clinicians during the public forum portion of the meeting underscored the need for new treatment options.”
A note to investors on May 4 by Michelle Gilson, an analyst with Canaccord Genuity, said the briefing documents “missed the big picture.”
John Sperati, a part of the adcom from the nephrology division at Johns Hopkins University School of Medicine, said “the data suggest avacopan may mildly reduce steroid exposure,” but it was “rather unclear the extent to which avacopan is providing the benefit” compared to low-dose steroids. “In the end, given the charge to us from the FDA for a single study submitted for approval, I did not believe the data were sufficiently very persuasive, from a statistical perspective.”
On the other hand, Susanne May, a professor of biostatistics at the clinical trials center at the University of Washington in Seattle, who voted yes, said the data “maybe just barely” met the criteria of substantial evidence of efficacy.
The FDA has granted Avacopan orphan drug status. The target action date for the agency is July 7. They are not required to take the advisory committee’s recommendation, which with an almost 50/50 split doesn’t provide much to build on anyway.
The study that seems to be causing the problem enrolled 331 patients with ANCA vasculitis in 20 countries. They either received avacopan plus either Roche/Biogen’s Rituxan (rituximab) or cyclophosphamide (followed by azathioprine/mycophenolate) or prednisone plus either Rituxan or cyclophoasamide (followed by azathioprine/mycophenolate).
The study lasted for 52 weeks. It also hit both primary endpoints, showing disease remission at 26 weeks (noninferior to standard of care) and sustained remission at 52 weeks (superior to standard of care). The adcom’s issued was with different BVAS (Birmingham Vasculitis Activity Score) numbers from investigators versus the adjudication committee.
Suzette Peng from the FDA, ahead of the advisory committee meeting, said that, “in presubmission communications, [FDA] 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 Rituxan or cyclophosphamide was the primary driver of efficacy in both treatment arms.”
“We hope that the FDA will take into account the dire situation faced by patients living with this debilitating disease,” said Joyce Kullman, executive director, Vasculitis Foundation.
