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The FDA the oral complement 5a receptor inhibitor avacopan (Tavneos) for the treatment of severe, active antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, drugmaker ChemoCentryx announced on Friday.

The drug will be recommended for adjunctive use in combination with standard therapies for the two main types of ANCA-associated vasculitis, granulomatosis with polyangiitis and microscopic polyangiitis. These vasculitidies are characterized by excessive activation of the complement system and neutrophil upregulation, which can result in inflammation and destruction of small vessels. Organ damage, particularly to the kidney, can ensue, and if inadequately managed, the outcome can be fatal.

"This is an important step forward in the treatment of this disease," said co-primary investigator Peter A. Merkel, MD, of the Perelman School of Medicine at the University of Pennsylvania and director of the international Vasculitis Clinical Research Consortium. "Patients will now have access to a new class of medication that provides beneficial effects for the treatment of ANCA-associated vasculitis," Merkel said in a press release.

The approval of avacopan was based on a pivotal clinical trial known as ADVOCATE, which was published in the in February.

ADVOCATE enrolled 331 patients with ANCA-associated vasculitis, who were randomized to avacopan 30 mg twice daily or oral prednisone on a tapered schedule. All patients also received cyclophosphamide followed by azathioprine or rituximab (Rituxan), plus glucocorticoids as needed.

Remission at week 26 was seen in 72.3% of patients in the avacopan group and in 70.1% of the prednisone group, which was an estimated common difference of 3.4 percentage points (95% CI -6 to 12.8). This difference was significant for noninferiority (P<0.001), but not for superiority (P=0.24). Sustained remission at week 52 was observed in 65.7% of the avacopan group and 54.9% of the prednisone group, which was significant for both noninferiority (P<0.001) and superiority (P=0.007).

"The ADVOCATE trial heralds a change in the treatment of ANCA-associated vasculitis that was previously unthinkable -- the possibility of inducing disease remission without glucocorticoids," wrote Kenneth Warrington, MD, of the Mayo Clinic in Rochester, Minnesota, in that accompanied the study.

However, when the FDA's Arthritis Advisory Committee met in May to evaluate the application for approval, opinions were sharply divided. The panel's split vote was 9 (yes) to 9 (no) for efficacy and 10 to 8 for safety. As to whether the benefit-risk profile supported approval, the vote again was 10 in favor and 8 against. Safety issues included cases of serious hepatic injury and angioedema.

The panel's concerns focused primarily on the study's noninferiority design and the reliance on a single pivotal study; the FDA usually requires two pivotal trials for approval. In addition, the permitted off-protocol use of prednisone could lead to difficulty in data interpretation.

"I have concerns about the study design and the use of non-study protocol steroids. It's a single study and not very persuasive," said panel member C. John Sperati, MD, of Johns Hopkins University in Baltimore.

Of her vote in favor of approval, panel member Margrit Wiesendanger, MD, PhD, of the Icahn School of Medicine at Mount Sinai in New York City, said, "The FDA could recommend judicious use and additional guidance as to which patients might be suitable candidates."

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