Randomized trial on the effect of an oral spleen tyrosine kinase inhibitor in the treatment of IgA nephropathy

Tam, Frederick W.K., Tumlin, James, Barratt, Jonathan, Rovin, Brad H., Roberts, Ian S.D., Roufosse, Candice, Cook, H. Terence, Bhangal, Gurjeet, Brown, Alison L., Busch, Martin, Dudhiya, Fayaz, Duliege, Anne-Marie, Fraser, Donald J. ORCID: https://orcid.org/0000-0003-0102-9342, Gale, Daniel P., Huang, Chiu-Ching, Lai, Ping-Chin, Lee, Meng, Masuda, Esteban S., McAdoo, Stephen P., Rosenkranz, Alexander R., Sommerer, Claudia, Sunder-Plassmann, Gere, Szeto, Cheuk-Chun, Tang, Sydney C.W., Williamson, Don E., Willcocks, Lisa, Vielhauer, Volker, Kim, Min Jeong, Todd, Leslie, Zayed, Hany, Tong-Starksen, Sandra and Lafayette, Richard 2023. Randomized trial on the effect of an oral spleen tyrosine kinase inhibitor in the treatment of IgA nephropathy. Kidney International Reports 8 (12) , pp. 2546-2556. 10.1016/j.ekir.2023.09.024

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Abstract

Introduction We 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. Methods This 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. Results While 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). Conclusions There 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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Additional Information:	License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by-nc-nd/4.0/, Start Date: 2023-09-20
Publisher:	Elsevier
ISSN:	2468-0249
Date of First Compliant Deposit:	3 October 2023
Date of Acceptance:	18 September 2023
Last Modified:	15 Jan 2024 15:02
URI:	https://orca.cardiff.ac.uk/id/eprint/162903

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