Randomized Trial on the Effect of an Oral Spleen Tyrosine Kinase Inhibitor in the Treatment of IgA Nephropathy

Introduction: We reported increased spleen tyrosine kinase (SYK) expression in kidney biopsies of tients with IgA nephropathy (IgAN) and that inhibition of SYK reduces inflammatory cytokines production from IgA stimulated mesangial cells.Methods: This study was a double-blind, randomized, placebo-controlled phase 2 trial of fostamatinib (an oral SYK inhibitor) in 76 patients with IgAN. Patients were randomized to receive placebo, fosta-matinib at 100 mg or 150 mg twice daily for 24 weeks on top of maximum tolerated dose of renin-angiotensin system inhibitors. The primary end point was reduction of proteinuria. Secondary points included change from baseline in estimated glomerular filtration rate (eGFR) and kidney histology.Results: Although we could not detect significant reduction in proteinuria with fostamatinib overall, predetermined subgroup analysis, there was a trend for dose-dependent reduction in median proteinuria (from baseline to 24 weeks by 14%, 27%, and 36% in the placebo, fostamatinib 100 mg, and 150 groups, respectively) in patients with baseline urinary protein-to-creatinine ratios (UPCR) more than mg/g. Kidney function (eGFR) remained stable in all groups. Fostamatinib was well-tolerated. Side effects included diarrhea, hypertension, and increased liver enzymes. Thirty-nine patients underwent repeat opsy showing reductions in SYK staining associated with therapy at low dose (-1.5 vs. 1.7 SYK+ glomerulus in the placebo group, P < 0.05).Conclusions: There was a trend toward reduction in proteinuria with fostamatinib in a predefined analysis of high risk patients with IgAN despite maximal care, as defined by baseline UPCR greater than 1000 Further study may be warranted.