Randomized Trial on the Effect of an Oral Spleen Tyrosine Kinase Inhibitor in the Treatment of IgA Nephropathy
Frederick W.K. Tam, James A. Tumlin, Jonathan Barratt, Brad H. Rovin, S. A. Roberts, Candice Roufosse, H. Terence Cook, Gurjeet Bhangal, Alison L. Brown, Martin Busch, Fayaz Dudhiya, Anne‐Marie Duliège, Donald Fraser, Daniel P. Gale, Chiu‐Ching Huang, Ping‐Chin Lai, Meng Lee, Esteban S. Masuda, Stephen P. McAdoo, Alexander R. Rosenkranz, Claudia Sommerer, Gere Sunder‐Plassmann, Cheuk‐Chun Szeto, Sydney Tang, Don Williamson, Lisa Willcocks, Volker Vielhauer, Min Jeong Kim, Leslie Todd, Hany Zayed, Sandra Tong-Starksen, Richard Lafayette
Abstract
IntroductionWe reported increased spleen tyrosine kinase (SYK) expression in kidney biopsies of patients with IgA nephropathy (IgAN) and that inhibition of SYK reduces inflammatory cytokines production from IgA stimulated mesangial cells.MethodsThis study was a double-blind, randomised, placebo-controlled phase 2 trial of fostamatinib (an oral SYK inhibitor) in 76 patients with IgAN. Patients were randomised to receive placebo, fostamatinib at 100 mg or 150 mg twice daily for 24 weeks on top of maximum tolerated dose of renin-angiotensin system inhibitors (RASi). The primary end point was reduction of proteinuria. Secondary endpoints included change from baseline in eGFR and kidney histology.ResultsWhile we could not detect significant reduction in proteinuria with fostamatinib overall, in a pre-determined 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 mg groups respectively) in patients with baseline urinary protein to creatinine ratios (UPCR) more than 1000 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 biopsy showing reductions in SYK staining associated with therapy at low dose (-1.5 v 1.7 SYK+ cells/glomerulus in the placebo group, p<0.05).ConclusionsThere was a trend towards 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 mg/g. Further study may be warranted.