Avacopan trumps steroids for ANCA-associated vasculitis

Avacopan, the oral inhibitor of complement activation, yields significant sustained remission compared with standard treatment with steroids in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), the ADVOCATE study shows.

AAV is a systemic disease caused by the generation of ANCA autoantibodies, which leads to inflammation of small blood vessels. As a result, severe injury to other organs ensues, such as the kidneys and lungs, and even death.

“AAV is associated with increased early mortality and high risk of end-stage renal disease,” said lead author Professor David Jayne from University of Cambridge, UK. “AAV must be treated with immunosuppressants. However, the side effects of these substances can be severe – especially at higher corticosteroid doses.”

“There is a need for safer, more effective treatments of AAV,” he stressed.

Avacopan is a selective inhibitor of complement fragment C5a receptor (C5aR), which is involved in the pathogenesis of AAV.

In the phase III, double-blind, double-dummy trial, 330 patients (mean age 61 years, 56.5 percent male) with new or relapsing AAV were randomized 1:1 to receive avacopan 30 mg twice daily or prednisone 60 mg/day (tapered to zero over 20 weeks) for 52 weeks. Both arms were in addition to cyclophosphamide (followed by azathioprine) or rituximab.

At 26 weeks, remission rates were comparable between the avacopan and the prednisone arms (72.3 percent vs 70.1 percent; p<0.0001 for noninferiority).

Over time, avacopan was not only noninferior, but also superior over prednisone in achieving sustained remission at week 52 (65.7 percent vs 54.9 percent; p=0.0066 for superiority).

Importantly, avacopan significantly reduced requirement for glucocorticoid use and related toxicities, Jayne noted. Glucocorticoid toxicity, as indicated by cumulative worsening score and aggregate improvement score were significantly reduced with avacopan vs prednisone (p<0.05 for both measures at weeks 13 and 26).

In addition, avacopan also improved disease control as reflected better recovery of renal function measured by eGFR (p=0.046 at week 26 and p=0.029 at week 52).

“With avacopan, a drug that could be available in the future, a reduction in corticoid use and more sustained remission is achieved. In the trial, at least 10 percent more patients were still in remission after 1 year,” said Jayne. “The benefit of avacopan in patients with renal involvement was remarkable and it was well-tolerated.”

The avacopan arm also had 54 percent less risk of relapsing compared with the prednisone arm (10.1 percent vs 21.0 percent; hazard ratio for time to relapse, 0.46, 95 percent confidence interval, 0.28–0.83). 

In terms of safety, there was a high number of adverse events (AEs) in both groups but no difference in the rates of severe AEs. No difference was also observed between groups for hepatic system AEs.

“There are trends towards fewer infections, total serious AEs, life-threatening AES and deaths in the avacopan vs the prednisone arms,” reported Jayne.

“Avacopan may fulfill an unmet clinical need by eliminating chronic glucocorticoid dosing and yielding better long-term outcomes for renal and patient survival than current glucocorticoid standard of care,” he highlighted.