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 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, randomized, placebo...
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Elsevier
2023-12-01
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| Series: | Kidney International Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2468024923015176 |
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| author | Frederick W.K. Tam James Tumlin Jonathan Barratt Brad H. Rovin Ian S.D. Roberts Candice Roufosse H. Terence Cook Gurjeet Bhangal Alison L. Brown Martin Busch Fayaz Dudhiya Anne-Marie Duliege Donald J. 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 C.W. Tang Don E. Williamson Lisa Willcocks Volker Vielhauer Min Jeong Kim Leslie Todd Hany Zayed Sandra Tong-Starksen Richard Lafayette |
| author_facet | Frederick W.K. Tam James Tumlin Jonathan Barratt Brad H. Rovin Ian S.D. Roberts Candice Roufosse H. Terence Cook Gurjeet Bhangal Alison L. Brown Martin Busch Fayaz Dudhiya Anne-Marie Duliege Donald J. 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 C.W. Tang Don E. Williamson Lisa Willcocks Volker Vielhauer Min Jeong Kim Leslie Todd Hany Zayed Sandra Tong-Starksen Richard Lafayette |
| author_sort | Frederick W.K. Tam |
| collection | DOAJ |
| description | 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, randomized, placebo-controlled phase 2 trial of fostamatinib (an oral SYK inhibitor) in 76 patients with IgAN. Patients were randomized 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. The primary end point was reduction of proteinuria. Secondary end 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, in a 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 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 vs. 1.7 SYK+ cells/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 mg/g. Further study may be warranted. |
| first_indexed | 2024-03-09T02:57:00Z |
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| institution | Directory Open Access Journal |
| issn | 2468-0249 |
| language | English |
| last_indexed | 2024-03-09T02:57:00Z |
| publishDate | 2023-12-01 |
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| series | Kidney International Reports |
| spelling | doaj.art-66982ca5bf66483cb14ee295eaf075262023-12-05T04:15:34ZengElsevierKidney International Reports2468-02492023-12-0181225462556Randomized Trial on the Effect of an Oral Spleen Tyrosine Kinase Inhibitor in the Treatment of IgA NephropathyFrederick W.K. Tam0James Tumlin1Jonathan Barratt2Brad H. Rovin3Ian S.D. Roberts4Candice Roufosse5H. Terence Cook6Gurjeet Bhangal7Alison L. Brown8Martin Busch9Fayaz Dudhiya10Anne-Marie Duliege11Donald J. Fraser12Daniel P. Gale13Chiu-Ching Huang14Ping-Chin Lai15Meng Lee16Esteban S. Masuda17Stephen P. McAdoo18Alexander R. Rosenkranz19Claudia Sommerer20Gere Sunder-Plassmann21Cheuk-Chun Szeto22Sydney C.W. Tang23Don E. Williamson24Lisa Willcocks25Volker Vielhauer26Min Jeong Kim27Leslie Todd28Hany Zayed29Sandra Tong-Starksen30Richard Lafayette31Centre for Inflammatory Disease, Department of Immunology and Inflammation, Imperial College London, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK; Correspondence: Frederick Wai Keung Tam, Centre for Inflammatory Disease, 9th floor, Commonwealth Building, Hammersmith Hospital Campus, Imperial College London, Du Cane Road, London W12 0NN, UK.Department of Nephrology, Emory University School Medicine, Atlanta, Georgia, USADepartment of Cardiovascular Sciences, University of Leicester, Leicester, UKDivision of Nephrology, Ohio State University Wexner Medical Center, Columbus, Ohio, USADepartment of Cellular Pathology, John Radcliffe Hospital, Oxford University Hospital NHS FT, Oxford, UKCentre for Inflammatory Disease, Department of Immunology and Inflammation, Imperial College London, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UKCentre for Inflammatory Disease, Department of Immunology and Inflammation, Imperial College London, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UKCentre for Inflammatory Disease, Department of Immunology and Inflammation, Imperial College London, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UKFreeman Hospital, Newcastle upon Tyne, UKDepartment of Internal Medicine III, University Hospital Jena, Friedrich Schiller University, Jena, GermanyCentre for Inflammatory Disease, Department of Immunology and Inflammation, Imperial College London, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UKDepartment of Clinical Development, Rigel Pharmaceuticals, Inc., South San Francisco, California, USAWales Kidney Research Unit, Cardiff University, School of Medicine, Heath Park, Cardiff, UKDepartment of Renal Medicine, University College London, London, UKDivision of Nephrology, China Medical University Hospital, Taichung, TaiwanDivision of Nephrology, China Medical University Hospital, Taichung, Taiwan; School of Medicine, Chang Gung University, Taoyuan, TaiwanDepartment of Clinical Development, Rigel Pharmaceuticals, Inc., South San Francisco, California, USADepartment of Clinical Development, Rigel Pharmaceuticals, Inc., South San Francisco, California, USACentre for Inflammatory Disease, Department of Immunology and Inflammation, Imperial College London, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UKDivision of Nephrology, Department of Internal Medicine, Medical University of Graz, Graz, AustriaNephrology, University Hospital Heidelberg, Heidelberg, GermanyDivision of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, AustriaDepartment of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong SAR, ChinaDivision of Nephrology, Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Queen Mary Hospital, Hong KongSoutheastern Clinical Research Institute, Augusta, Georgia, USAAddenbrookes Hospital, Cambridge, UKMedizinische Klinik und Poliklinik IV, Nephrologisches Zentrum, Klinikum der Universität München, Munich, GermanyDivision of Nephrology, Cantonal Hospital Aarau, Aarau, SwitzerlandDepartment of Clinical Development, Rigel Pharmaceuticals, Inc., South San Francisco, California, USADepartment of Clinical Development, Rigel Pharmaceuticals, Inc., South San Francisco, California, USADepartment of Clinical Development, Rigel Pharmaceuticals, Inc., South San Francisco, California, USADepartment of Nephrology, Stanford University Medical Center, Stanford, California, USAIntroduction: 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, randomized, placebo-controlled phase 2 trial of fostamatinib (an oral SYK inhibitor) in 76 patients with IgAN. Patients were randomized 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. The primary end point was reduction of proteinuria. Secondary end 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, in a 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 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 vs. 1.7 SYK+ cells/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 mg/g. Further study may be warranted.http://www.sciencedirect.com/science/article/pii/S2468024923015176glomerulonephritisIgA nephropathyinflammationkidneymacrophagesignaling |
| spellingShingle | Frederick W.K. Tam James Tumlin Jonathan Barratt Brad H. Rovin Ian S.D. Roberts Candice Roufosse H. Terence Cook Gurjeet Bhangal Alison L. Brown Martin Busch Fayaz Dudhiya Anne-Marie Duliege Donald J. 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 C.W. Tang Don E. Williamson Lisa Willcocks Volker Vielhauer Min Jeong Kim Leslie Todd Hany Zayed Sandra Tong-Starksen Richard Lafayette Randomized Trial on the Effect of an Oral Spleen Tyrosine Kinase Inhibitor in the Treatment of IgA Nephropathy Kidney International Reports glomerulonephritis IgA nephropathy inflammation kidney macrophage signaling |
| title | Randomized Trial on the Effect of an Oral Spleen Tyrosine Kinase Inhibitor in the Treatment of IgA Nephropathy |
| title_full | Randomized Trial on the Effect of an Oral Spleen Tyrosine Kinase Inhibitor in the Treatment of IgA Nephropathy |
| title_fullStr | Randomized Trial on the Effect of an Oral Spleen Tyrosine Kinase Inhibitor in the Treatment of IgA Nephropathy |
| title_full_unstemmed | Randomized Trial on the Effect of an Oral Spleen Tyrosine Kinase Inhibitor in the Treatment of IgA Nephropathy |
| title_short | Randomized Trial on the Effect of an Oral Spleen Tyrosine Kinase Inhibitor in the Treatment of IgA Nephropathy |
| title_sort | randomized trial on the effect of an oral spleen tyrosine kinase inhibitor in the treatment of iga nephropathy |
| topic | glomerulonephritis IgA nephropathy inflammation kidney macrophage signaling |
| url | http://www.sciencedirect.com/science/article/pii/S2468024923015176 |
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