Avacopan Helps Vasculitis Patients With Renal Impairment Wean Off Steroids

More patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis and renal disease on avacopan (Tavneos) had recovery of kidney function compared with those on steroids, a subgroup analysis from the phase III ADVOCATE trial found.

For patients with an estimated glomerular filtration rate (eGFR) below 60 mL/min/1.73 m² with or without urinary abnormalities at baseline, the difference in eGFR recovery between those receiving avacopan versus prednisone over the 52-week trial was 5.5 mL/min/1.73 m² (95% CI 1.4-9.6, P<0.01), reported David R. Jayne, MD, of the University of Cambridge in England.

More specifically, patients who had an eGFR below 30 mL/min/1.73 m² at baseline saw the biggest gains in eGFR with avacopan, with a least squares mean increase of 13.7 compared with 8.2 mL/min/1.73 m² among the prednisone group by week 52 (P<0.01), Jayne said in his presentation at the American Society of Nephrology's virtual Kidney Week.

Just looking at the subset of patients with stage IV chronic kidney disease, 50% on avacopan improved one stage, and 5.8% improved by two stages. As for those on prednisone, 44% improved one stage and 2.1% improved two stages (P=0.32).

The benefits of avacopan didn't stop here, as patients receiving this drug also saw more rapid reductions in proteinuria and hematuria. Within the first 4 weeks of treatment, those on avacopan saw a 40% improvement in urinary albumin-to-creatinine ratio, while those on prednisone saw no change.

In previously reported findings from the trial published in the New England Journal of Medicine, which the agent's October FDA approval was based upon, avacopan was found to be noninferior to prednisone in achieving remission at week 26, with sustained remission at week 52. Acting as an oral C5a receptor inhibitor, avacopan now holds an indication as an adjunctive treatment for adult patients with severe ANCA-associated vasculitis -- both granulomatosis with polyangiitis (GPS) and microscopic polyangiitis (MPA) -- in combination with standard therapy including glucocorticoids. The label also notes that it "does not eliminate glucocorticoid use."

"This trial demonstrated clinical efficacy in terms of sustained remission," Jayne explained. "Fixing on the kidney response, we saw earlier falls in proteinuria, hematuria, and MCP-1 across these programs, and better recovery of eGFR in the phase III trial, which was accentuated for those with more severe renal disease."

"We anticipate that this better eGFR recovery with longer-term follow-up will impact on kidney failure and potentially mortality risks," he added.

The trial included 166 patients randomized to the avacopan arm and 164 to the prednisone arm. All participants had a diagnosis of GPS (55%) or MPA (45%), ANCA-PR3 or -MPO positivity, and a Birmingham Vasculitis Activity Score (BVAS) of 1 major or 3+ minor.

Those with severe renal impairment -- defined as an eGFR below 15 mL/min/1.73 m² -- were excluded, as were patients under the age of 12. Patients were also excluded if they received more than 3 g of intravenous glucocorticoids within 4 weeks, or more than 10 mg/day of oral prednisone for more than 6 weeks continuously prior to screening.

About 80% of the total cohort had some degree of renal involvement at baseline, and the average eGFR was 53 mL/min/1.73 m². More than 60% were on intravenous rituximab (Rituxan), and about 30% were on intravenous cyclophosphamide.

Those on avacopan received 30 mg twice daily along with either 4 weeks of rituximab or cyclophosphamide followed by azathioprine. The placebo group received the same background paired with 60 mg/day of prednisone, tapered down to zero by 21 weeks.

All immunosuppressants were stopped prior to trial entry. During the 4-week screening period, glucocorticoid treatment had to be tapered to 20 mg or less of prednisone equivalent before the patient began the trial. However, participants in either study arm who experienced worsening of disease involving a major item on the BVAS could be given rescue therapy with either intravenous glucocorticoids (typically 0.5 to 1 g of methylprednisolone per day for 3 days), oral glucocorticoids, or both, which were tapered according to the patient's condition. The median total prednisone-equivalent dose in the avacopan group was 400 mg versus 2,939 mg in the prednisone group.

Nearly all patients in both study arms experienced some type of adverse event during the trial, and 24% and 25% of the avacopan and prednisone groups experienced a severe adverse event, respectively. There were two deaths in the avacopan group and four deaths in the prednisone group.

"I think the study opens up lots of questions of what we should do in the future," said Jayne. "To me, I think the real value of avacopan -- and this is also something we've seen with rituximab -- is that we can now expect to get patients steroid-free."

"Whether or not we're brave enough to initiate treatment without steroids at all -- I think that will perhaps come with some patients," he said. "But the typical patient coming to us already on steroids, with these sorts of medications we can confidently drive the steroids down to zero, which in the long term is going to save on steroid toxicity."

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