Avacopan Shows Efficacy Signal for Rare Kidney Disease, C3G

Avacopan, recently approved by the US Food and Drug Administration (FDA) for adjunctive treatment of antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, showed a significant benefit in C3 glomerulopathy (C3G) by reducing the disease chronicity score, a secondary endpoint in a randomized, controlled phase 2 trial.

The ACCOLADE trial initially randomized 57 patients with the rare disease who were at least 12 years old to daily oral treatment with avacopan (Taveneos, ChemoCentryx) or placebo for 26 weeks. The primary endpoint was change in a biopsy-based C3G histologic index disease activity score. The 52 evaluable patients showed a nonsignificant trend toward less progression in this score with avacopan versus placebo. These results were presented at the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) 2021 virtual congress and reported by Medscape Medical News.

Results from a secondary analysis now show avacopan was significantly linked with an attenuated rise in patients' disease chronicity score compared with placebo, Andrew S. Bomback, MD, said recently at the World Congress of Nephrology 2022.

This secondary endpoint is notable because a report published in 2021 that validated the C3 histologic index disease activity score as a predictor of kidney failure in patients with C3G also documented that "total chronicity score was the principal histologic correlate of kidney failure."

After 26 weeks of treatment, patients who received avacopan had half the increase from baseline in disease chronicity score compared with placebo, said Bomback, who is director of clinical research in the nephrology division at Columbia University Irving Medical Center in New York City.

Disease Chronicity Correlates With Kidney Failure

"This study is definitely interesting," commented Tejas Desai, MD, a nephrologist with the US Department of Veterans Affairs, Charlotte, North Carolina. He cited recent reports that "the disease chronicity score is the best predictor of time to end-stage kidney disease in patients with C3G."

The results reported by Bomback also showed avacopan led to a significant improvement from baseline in estimated glomerular filtration rate (eGFR) compared with placebo, which correlated with the improvement in disease chronicity.

Other findings he reported were that patients who received avacopan showed larger declines in urinary protein-to-creatinine ratio and urinary MCP-1-to-creatinine ratio compared with placebo, although these differences were mostly not significant. In addition, many patients initially randomized to placebo crossed-over to avacopan treatment after the 26-week randomized study ended, and during the 26 weeks on avacopan following the cross-over, several of these patients had a discernable decline in disease chronicity.

The results also showed that avacopan was well-tolerated, with "no drug-related safety signal identified," Bomback said.

C3G: A Rare Disease, With Fewer Patients Than Researchers

Desai also noted that although a study with 52 evaluable patients is large for a rare disease such as C3G, it is small from a statistical perspective, and this might have contributed to the nonsignificant trend seen for the primary endpoint.

He said there are more authors and reports on C3G than patients with the disease, adding that many nephrologists never see a case during their career.

The National Organization for Rare Diseases estimates the prevalence of C3G is 2 to 3 cases per 1 million people. Desai also highlighted that avacopan is an oral agent, whereas eculizumab (Soliris), "the current treatment for C3G," is delivered intravenously.

Avacopan received FDA approval in October 2021 as an add-on treatment to standard therapy, including glucocorticoids, for adults with severe active ANCA-associated vasculitis. The FDA has also granted avacopan orphan drug designation for ANCA-associated vasculitis and C3G.

Avacopan is a first-in-class, orally administered small molecule that works via a novel, highly targeted mode of action in complement-driven autoimmune and inflammatory diseases.

ACCOLADE received funding from the FDA Office of Orphan Products Development. Bomback has reported receiving consulting and advisory honoraria from ChemoCentryx, Achillion/Alexion, Catalyst, Novartis, and Visterra. Desai has reported no relevant financial relationships.

World Congress of Nephrology 2022. Abstract LBCT-004. Presented February 27, 2022.

Mitchel L. Zoler is a reporter for Medscape and MDedge based in the Philadelphia area. @mitchelzoler

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