Safety and Efficacy of Avacopan in Patients with C3 Glomerulopathy: Randomized, Double-Blind Clinical Trial.

Background: Complement 3 (C3) glomerulopathy is a rare autoimmune disorder characterized by activation of the alternative complement pathway with isolated or dominant C3 deposition in glomeruli. Patients with C3 glomerulopathy may develop progressive deterioration in kidney function and kidney failure.

Methods: We studied the safety and efficacy of avacopan 30 mg twice daily in patients with C3 glomerulopathy (N=57) with elevated (> 244 ng/mL) and normal (≤ 244 ng/mL) levels of C5b-9 in a randomized, double-blind, placebo-controlled, phase 2 trial, with kidney biopsies performed pre-randomization and at 26 and 52 weeks. The primary outcome was the percent change from baseline to week 26 in C3 glomerulopathy histologic index for disease activity.

Results: The study was conducted in patients with C3 glomerulopathy, including C3 glomerulonephritis and DDD. The median study duration was 60.0 weeks (interquartile range 59.9 to 61.0). There were no significant differences in the primary outcome between the avacopan and the placebo group; least square mean treatment difference (95% CI) = -0.0 (-1.9 to 1.8). The secondary measures of efficacy including C3 Glomerulopathy Histological Index for disease chronicity, urine protein:creatinine ratio (UPCR), and estimated glomerular filtration rate (eGFR) were not different between treatment groups. The overall incidence and type of adverse events for both treatment groups were comparable. No deaths were reported during the study, and no new safety signals were detected.

Conclusions: The primary end point for the study was not met; other clinical effects of avacopan to improve certain key kidney function parameters and slow disease progression were variable and require further evaluation.