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Safety and Efficacy of Avacopan in Patients with Complement 3 Glomerulopathy: Randomized, Double-Blind Clinical Trial
Andrew S Bomback1, Leal C Herlitz2, Priyanka Punit Kedia3
1Division of Nephrology, Department of Medicine, Columbia University Irving Medical Center, New York, New York.
Insights
Avacopan did not significantly improve kidney histology in C3 glomerulopathy patients. The study found no significant differences in disease activity or kidney function between avacopan and placebo groups, indicating variable clinical effects requiring further investigation.
Area of Science:
- Nephrology
- Immunology
- Pharmacology
Background:
- C3 glomerulopathy is a rare autoimmune kidney disease.
- It involves alternative complement pathway activation and C3 deposition in glomeruli.
- This condition can lead to progressive kidney damage and failure.
Purpose of the Study:
- To evaluate the safety and efficacy of avacopan in C3 glomerulopathy.
- To assess avacopan's impact on kidney histology and function.
- To determine if avacopan reduces complement system activation markers.
Main Methods:
- A randomized, double-blind, placebo-controlled phase 2 trial.
- 57 patients with C3 glomerulopathy received avacopan 30 mg twice daily or placebo.
- Kidney biopsies and clinical assessments were performed over 52 weeks.
Main Results:
- The primary outcome, change in C3 Glomerulopathy Histological Index for disease activity, showed no significant difference between groups.
- Secondary efficacy measures, including urine protein:creatinine ratio and eGFR, were also similar.
- Adverse events were comparable between avacopan and placebo groups, with no new safety concerns.
Conclusions:
- The study did not meet its primary endpoint for avacopan efficacy in C3 glomerulopathy.
- Clinical effects on kidney function and disease progression were variable.
- Further research is needed to evaluate avacopan's role in managing C3 glomerulopathy.
Background:
Complement 3 (C3) glomerulopathy is a rare autoimmune disorder characterized by activation of the alternative complement pathway with isolated or dominant complement 3 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 membrane attack complex or terminal complement complex (C5b-9) in a randomized, double-blind, placebo-controlled, phase 2 trial, with kidney biopsies performed prerandomization and at 26 and 52 weeks. The primary outcome was the percent change from baseline to week 26 in C3 Glomerulopathy Histological Index for disease activity.
Results:
The study was conducted in patients with C3 glomerulopathy, including C3 GN and dense deposit disease. The median study duration was 60.0 weeks (interquartile range, 59.9–61.0). There were no significant differences in the primary outcome between the avacopan and the placebo group—least squares mean treatment difference (95% confidence interval)= −0.0 (−1.9 to 1.8). The secondary measures of efficacy including C3 Glomerulopathy Histological Index for disease chronicity, urine protein:creatinine ratio, and 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.
