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Avacopan Superior to Steroids in ANCA Vasculitis

— Greater rates of remission and improved renal function seen with oral C5a receptor antagonist

MedpageToday

Inhibition of complement fragment C5a with an investigational drug called avacopan demonstrated efficacy against antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis and might provide an alternative to high-dose glucocorticoids, a new phase III trial suggested.

Among 331 patients enrolled in a randomized trial comparing avacopan versus glucocorticoids plus either cyclophosphamide or rituximab, remission at week 26 was achieved by 72.3% of patients in the avacopan group and by 70.1% of those in the prednisone group (P<0.0001 for noninferiority), reported Peter A. Merkel, MD, of the University of Pennsylvania in Philadelphia, at the European League Against Rheumatism virtual meeting.

"This very clearly was within the margin of noninferiority, so that one of the two primary endpoints was met," Merkel said.

And at week 52, 65.7% of the avacopan group versus 54.9% of patients in the prednisone group had sustained remission (P=0.0066 for superiority). "This difference, which was both clinically and statistically significant, demonstrated the superiority of avacopan over prednisone for the second primary outcome," he said during the opening plenary abstract session.

"ANCA-associated vasculitis is associated with increased early mortality and carries a high risk of end-stage renal disease. The standard of care for induction of remission has been high-dose glucocorticoids with either cyclophosphamide or rituximab, but glucocorticoids are a major cause of treatment-related harm," he said.

C5a has been strongly linked to the pathogenesis of ANCA-associated vasculitis, and avacopan is a highly selective oral inhibitor of the C5a receptor. A demonstrated that avacopan has the potential to minimize the use of glucocorticoids and improve control of renal vasculitis with reduced toxicity.

Eligibility criteria for this phase III trial included a diagnosis of granulomatosis with polyangiitis or microscopic polyangiitis, positivity for the PR3 or MPO subtypes of ANCA, and a high degree of disease activity.

Remission was defined as a Birmingham Vasculitis Activity Score of zero and no use of glucocorticoids.

More than 90% of participants remained in the study for the full 52 weeks.

Glucocorticoid-related toxicities were significantly reduced in the avacopan group as measured on the Glucocorticoid Toxicity Index, with lower scores on the Cumulative Worsening Score and improvements on the Aggregate Improvement Score at both weeks 13 and 26.

There also was improvement in renal function in both groups, but more so in the avacopan group. "Particularly interesting was the fact that even after week 26, when patients were in remission, there was a continued improvement in renal function," he said. At week 52, the mean increase in estimated glomerular filtration rate was 7.3 mL/min/1.73 m2 from baseline in the avacopan group compared with 4 mL/min/1.73 m2 in the prednisone group (P=0.0259).

As to safety, "there were many adverse events -- this was a sick population," Merkel observed. The overall incidence of serious adverse events, similar to what has been seen in previous studies of ANCA-associated vasculitis, was 42.2% in the avacopan group and 45.1% in the prednisone group. Serious infections were reported in 13.3% and 15.2% of the avacopan and prednisone groups, respectively, serious hepatic events occurred in 5.4% and 3.7%, and white blood cell decreases in 2.4% and 4.9%. There were no meningococcal infections.

"In summary, this large randomized trial showed that avacopan was noninferior to glucocorticoids for remission at week 26 and superior for sustained remission at week 52. Important secondary endpoints were also achieved, including reduction of glucocorticoid usage and reduction in glucocorticoid-related toxicities in the avacopan group along with improved recovery of renal function with a very acceptable safety profile," Merkel concluded.

Disclosures

Several co-authors are employees of ChemoCentryx, the manufacturer of avacopan.

Merkel disclosed relevant relationships with, and/or support from, ChemoCentryx, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Forbius, Genentech/Roche, Genzyme/Sanofi, GlaxoSmithKline, InflaRx, Kypha, Terumo BCT, AbbVie, Biogen, CSL Behring, Insmed, Janssen, Kiniksa, Pfizer, Sparrow, and Talaris. Co-authors disclosed multiple relevant relationships with industry including ChemoCentryx.

Primary Source

European League Against Rheumatism

Merkel P, et al "A randomized, double-blind, active-controlled study of avacopan in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis" EULAR 2020; Abstract OP0011.