Safety and Efficacy of Avacopan in Patients with Complement 3 Glomerulopathy
In a phase 2 randomized trial, avacopan did not improve the primary histologic disease-activity endpoint in patients with C3 glomerulopathy, though it was generally well tolerated.
Background
Complement 3 glomerulopathy is a rare autoimmune disorder characterized by activation of the alternative complement pathway with dominant C3 deposition in glomeruli, and patients may progress to kidney failure. Avacopan is an orally administered C5a receptor antagonist that blocks the proinflammatory effects of C5a.
Study design
This randomized, double-blind, placebo-controlled phase 2 trial enrolled 57 patients with C3 glomerulopathy, including C3 glomerulonephritis and dense deposit disease, with elevated or normal levels of the terminal complement complex (C5b-9). Patients received avacopan 30 mg twice daily, with kidney biopsies before randomization and at 26 and 52 weeks. The primary outcome was the percent change from baseline to week 26 in the C3 Glomerulopathy Histological Index for disease activity; median study duration was about 60 weeks.
Key findings
There was no significant difference between the avacopan and placebo groups in the primary outcome, with a least-squares mean treatment difference of essentially zero. Secondary measures, including the histological index for chronicity, urine protein-to-creatinine ratio, and estimated glomerular filtration rate, also did not differ between groups. The overall incidence and type of adverse events were comparable between groups, with no deaths and no new safety signals.
Clinical implications
The primary endpoint was not met, so avacopan did not demonstrate a benefit on histologic disease activity in C3 glomerulopathy in this trial. Other potential clinical effects on kidney function parameters were variable and require further evaluation, leaving an unmet need for effective targeted therapy in this disease.
Category
Research
Source
Journal of the American Society of Nephrology
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