Baseline Clinical Characteristics and Complement Biomarkers of Patients with C3 Glomerulopathy Enrolled in Two Phase 2 Studies Investigating the Factor D Inhibitor Danicopan

Abstract

<b><i>Introduction:</i></b> C3 glomerulopathy (C3G) is a rare, progressive kidney disease resulting from dysregulation of the alternative pathway (AP) of complement. Biomarkers at baseline were investigated in patients with C3G who participated in two phase 2 studies with the factor D (FD) inhibitor, danicopan. <b><i>Methods:</i></b> Patients with biopsy-confirmed C3G, proteinuria ≥500 mg/day, and estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m² were enrolled into two studies (NCT03369236 and NCT03459443). Biomarker analysis was performed for patients with C3G confirmed by central pathology laboratory re-evaluation. Complement and clinical biomarkers, biopsy composite score, and activity and chronicity indices were assessed at baseline and analyzed by pairwise Spearman correlation analysis. <b><i>Results:</i></b> Twenty-nine patients were included in the analysis (median [interquartile range] age: 24.0 [10.0] years). Systemic complement AP activation was evident by reduced median concentrations of C3 and C5, elevated sC5b-9, and normal C4, relative to reference ranges. C3 showed strong pairwise correlations with C5 and sC5b-9 (<i>r</i> = 0.80 and −0.73, respectively; <i>p</i> &#x3c; 0.0001). Baseline Ba and FD concentrations were inversely correlated with eGFR (<i>r</i> = −0.83 and −0.87, respectively; <i>p</i> &#x3c; 0.0001). Urinary concentrations of sC5b-9 were correlated with both plasma sC5b-9 and proteinuria (<i>r</i> = 0.69 and <i>r</i> = 0.83, respectively; <i>p</i> &#x3c; 0.0001). Biopsy activity indices correlated strongly with biomarkers of systemic AP activation, including C3 (<i>r</i> = −0.76, <i>p</i> &#x3c; 0.0001), whereas chronicity indices aligned more closely with eGFR (<i>r</i> = −0.57, <i>p</i> = 0.0021). <b><i>Conclusion:</i></b> Associations among complement biomarkers, kidney function, and kidney histology may add to the current understanding of C3G and assist with the characterization of patients with this heterogenous disease.