ADVOCATE: Avacopan Shows Renal Benefits in ANCA Vasculitis

Nancy A. Melville

November 16, 2021

Dr David R.W. Jayne

Treatment of antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis and renal disease with the oral C5a receptor inhibitor avacopan (Tavneos, ChemoCentryx) provides significant recovery of kidney function compared with prednisone, particularly in patients with severe kidney disease, novel research indicates.

The new analysis underscores that "the real value of avacopan is that we can now expect to get our patients steroid-free," said first author David R.W. Jayne, MD, a professor of clinical autoimmunity at the University of Cambridge, UK, when presenting the findings at ASN Kidney Week 2021.

"Whether or not we're brave enough to initiate treatment without steroids, I think that will perhaps come with some patient experience," he added.

The findings are from a subanalysis of renal effects in the phase 3 ADVOCATE trial, which was published in February in the New England Journal of Medicine and included 330 patients with ANCA-associated vasculitis.

The trial in large part led to the US approval of avacopan by the Food and Drug Administration (FDA) in October as an adjunctive treatment for adults with severe active ANCA-associated vasculitis in combination with standard therapy including glucocorticoids.

The approval was greeted with enthusiasm as suggesting a much-needed option to help reduce, or even potentially eliminate, the need for glucocorticoids and their side effects. Other agents included in treatment regimens for ANCA-associated vasculitis include cyclophosphamide and rituximab.

Jayne emphasized that, before avacopan, treatment options had been limited.

"There is nothing else new in the clinic apart from rituximab, which we have now been using for almost 20 years," he told Medscape Medical News. "Avacopan is new, the mode of action is different from any drugs in use at the moment, and the speed of action is very quick."

Dr J. Charles Jennette, MD

The need to more closely investigate the trial's renal outcomes in this new analysis was important because the high mortality rates in ANCA-associated vasculitis — a rare systemic autoimmune disease causing over-activation of complement resulting in inflammation of small blood vessels — is largely driven by those with MPO and PR3 autoantibody renal vasculitis, Jayne explained.

Commenting on the study, J. Charles Jennette, MD, a professor of pathology and laboratory medicine and professor of medicine at the University of North Carolina at Chapel Hill, said the new findings on renal outcomes, such as proteinuria, may offer key insights on avacopan's efficacy.

"To me, the most impressive outcome of the ADVOCATE Phase 3 trial was the more rapid reduction in hematuria and proteinuria with avacopan compared to conventional prednisone therapy," he told Medscape Medical News.

Recovery of eGFR With Avacopan Best in Those With Severe Renal Disease

In the trial, patients with ANCA-associated vasculitis were randomized 1:1 to treatment with oral avacopan 30 mg twice daily or oral prednisone on a tapering schedule.

All patients also received background immunosuppression — about two thirds received rituximab and a third received cyclophosphamide — followed by azathioprine.

The main study results showed similar rates of remission in both groups at week 26 and a superior remission rate with avacopan, in terms of sustained remission, at week 52 (65.7% vs 54.9%; P < .001).

Approximately 80% of patients in the trial had renal involvement of ANCA vasculitis, the focus of the new analysis, and they had a baseline mean estimated glomerular filtration rate (eGFR) of 45 mL/min/1.73 m2.

Among those with renal involvement, patients treated with avacopan had a significantly greater eGFR recovery compared with the prednisone group at week 26 (P = .046) and week 52 (P < .029).

The strongest improvements were observed among patients with moderate to severe kidney damage, who had a mean eGFR of 21 mL/min/1.73m2 at baseline. Among those patients, the mean increase in eGFR was 13.7 mL/min/1.73m2 in the avacopan-treated group (n = 52) versus 8.2 mL/min/1.73m2 in the prednisone group (n = 48; P < .01) by week 52.

Improvements in urinary albumin:creatinine ratios (UACR) of as much as 40% were also observed in the avacopan group within the first 4 weeks of treatment, while no changes were observed in the same period in the prednisone group.

In other findings, the study also showed more rapid declines in proteinuria within 4 weeks in the avacopan group, and fewer patients had hematuria and there were greater reductions in MCP-1 in avacopan-treated patients at week 52, Jayne reported.

In terms of safety, there were no differences between the groups, with trends of fewer deaths and severe adverse events in the avacopan group.

"We found that the improved recovery of eGFR with avacopan was accentuated among those with more severe renal disease," Jayne said.

He noted that while the study's aim was for the avacopan group to be steroid-free, the patients received brief, reduced doses of about a third of the normal oral steroid dose early in the trial. However, using a Glucocorticoid Toxicity Index, the authors found those in the avacopan group did have fewer glucocorticoid-related adverse events.

Future issues to be examined include what happens when avacopan is discontinued and whether there will be a high relapse rate, Jayne noted.

Overall, however, "we anticipate that with longer-term follow-up, this better eGFR recovery will have a [favorable] effect on kidney failure and potentially mortality risk in these patients," he concluded.

Targeted Therapy Is Good for Patients and Doctors

Expanding upon his comments regarding the new drug, Jennette said it implies "that the C5a receptor inhibitor was targeting an event that blocks injury more quickly and effectively than prednisone."

"This may be because prednisone has more complex pharmacodynamics and less targeted effects than a C5a receptor inhibitor," he said.

Overall, the findings bode well for a potentially beneficial therapy, he added.

"We have entered a new era of more targeted therapies, for example, targeted B-cell therapy using an anti-CD20 antibody, and targeted complement-mediated injury therapy using C5a receptor inhibitor."

"The validation of this targeted therapy to block complement-mediated autoimmune inflammatory injury is another advance toward targeted precision therapy versus empirical therapy. This will be good for the doctors and good for the patients," Jennette concluded.

The study was funded by ChemoCentryx. Jayne has reported receiving grants and/or consulting for AstraZeneca, ChemoCentryx, GSK, MiroBio, Vifor, and Roche/Genentech. Jennette has received funding from ChemoCentryx for preclinical validation studies of avacopan in a mouse model of ANCA glomerulonephritis.

ASN Kidney Week 2021. Abstract 3627697. Presented November 5, 2021.

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