Of mice and men: an open-label pilot study for treatment of immune thrombocytopenic purpura by an inhibitor of Syk

Abstract

To determine whether inhibition of Syk would be useful in Fc␥R-dependent cytopenias such as immune thrombocytopenic purpura (ITP) or autoimmune hemolytic anemia, mouse models were used to evaluate efficacy of R406, an inhibitor of Syk function, in treating cytopenia. Both disease models responded favorably to treatment, with amelioration of ITP being more dramatic. Thus, phase 2 clinical trial was initiated to study the effects of Syk inhibition in humans with ITP. Sixteen adults with chronic ITP were entered into an open-label, single-arm cohort doseescalation trial beginning with 75 mg and escalating as high as 175 mg twice daily. Doses were increased until a persistent response was seen, toxicity occurred, or 175 mg twice daily was reached. Eight patients achieved persistent responses with platelet counts greater than 50 ؋ 10 9 /L (50 000 mm 3 ) on more than 67% (actually 95%) of their study visits, including 3 who had not persistently responded to thrombopoietic agents. Four others had nonsustained responses. Mean peak platelet count exceeded 100 ؋ 10 9 /L (100 000 mm 3 ) in these 12 patients. Toxicity was primarily GI-related with diarrhea (urgency) and vomiting; 2 patients had transaminitis.

Spleen tyrosine kinase (Syk) is a potent target for GvHD prevention at different cellular levels

“…In clinical trials Syk inhibitions was effective in immune thrombocytopenic purpura 54 and rheumatoid arthritis. 19,20 In summary, we demonstrate that pharmacological Syk inhibition targets several key events of GvHD pathogenesis including expansion and migration of Tcs as well as costimulation by and migration of DCs.…”

Fostamatinib for Persistent/Chronic Adult Immune Thrombocytopenia

“…Syk is a key regulator in signal transduction pathways involved in development and progression of autoimmune diseases, such as rheumatoid arthritis and ITP [35][36][37][38]. It is a member of the cytoplasmic protein tyrosine kinase family that is expressed extensively in hematopoietic cells, including macrophages, B cells, T cells, dendritic cells and platelets [39].…”

Spleen Tyrosine Kinase Is Important in the Production of Proinflammatory Cytokines and Cell Proliferation in Human Mesangial Cells following Stimulation with IgA1 Isolated from IgA Nephropathy Patients

“…This result confirms the expression of SYK in murine mesangial cells. R406 (the active component of fostamatinib) is a novel SYK inhibitor, and its therapeutic potential has been investigated in a range of animal models of allergy, autoimmunity, and inflammation and also in a limited number of clinical trials (21)(22)(23)(24). Our group has recently shown that treatment with fostamatinib prevents the development of disease, and dramatically reduces glomerular injury and proteinuria in established disease, in a rat model of Ab-mediated crescentic glomerulonephritis (25).…”