Fostamatinib for the treatment of adult persistent and chronic immune thrombocytopenia: Results of two phase 3, randomized, placebo‐controlled trials

Abstract

Spleen tyrosine kinase (Syk) signaling is central to phagocytosis‐based, antibody‐mediated platelet destruction in adults with immune thrombocytopenia (ITP). Fostamatinib, an oral Syk inhibitor, produced sustained on‐treatment responses in a phase 2 ITP study. In two parallel, phase 3, multicenter, randomized, double‐blind, placebo‐controlled trials (FIT1 and FIT2), patients with persistent/chronic ITP were randomized 2:1 to fostamatinib (n = 101) or placebo (n = 49) at 100 mg BID for 24 weeks with a dose increase in nonresponders to 150 mg BID after 4 weeks. The primary endpoint was stable response (platelets ≥50 000/μL at ≥4 of 6 biweekly visits, weeks 14‐24, without rescue therapy). Baseline median platelet count was 16 000/μL; median duration of ITP was 8.5 years. Stable responses occurred in 18% of patients on fostamatinib vs. 2% on placebo (P = .0003). Overall responses (defined retrospectively as ≥1 platelet count ≥50 000/μL within the first 12 weeks on treatment) occurred in 43% of patients on fostamatinib vs. 14% on placebo (P = .0006). Median time to response was 15 days (on 100 mg bid), and 83% responded within 8 weeks. The most common adverse events were diarrhea (31% on fostamatinib vs. 15% on placebo), hypertension (28% vs. 13%), nausea (19% vs. 8%), dizziness (11% vs. 8%), and ALT increase (11% vs. 0%). Most events were mild or moderate and resolved spontaneously or with medical management (antihypertensive, anti‐motility agents). Fostamatinib produced clinically‐meaningful responses in ITP patients including those who failed splenectomy, thrombopoietic agents, and/or rituximab. Fostamatinib is a novel ITP treatment option that targets an important mechanism of ITP pathogenesis.

Phase 2 study of efgartigimod, a novel FcRn antagonist, in adult patients with primary immune thrombocytopenia

“…A high number of patients receiving placebo achieved a single platelet count ≥50 × 10 9 /L during the study (6 [50%] compared to, for example, 14% across two, 24-week fostamatinib Phase 3 studies). 13,43 However, post hoc analyses requiring greater frequency or duration of platelet count ≥50 × 10 9 /L, or increased platelet count to ≥100 × 10 9 /L, demonstrated the efficacy of efgartigimod. Six patients (46%) treated in both efgartigimod groups showed an increase in platelet count >50 × 10 9 /L on at least two occasions.…”

“…[1][2][3] The low platelet count increases the risk of skin and mucosal bleeding, gastrointestinal bleeding complications and rarely, serious intracranial hemorrhages. [7][8][9][10][11][12] Current therapeutic approaches include non-specific immunosuppression (eg, steroids and rituximab), inhibition of platelet clearance (eg, splenectomy, intravenous immunoglobulin [IVIg], anti-D globulin, and the recently FDA-approved Syk inhibitor fostamatinib 13 ) or stimulation of platelet production (eg, thrombopoietin receptor agonist [TPO-RA]). [7][8][9][10][11][12] Current therapeutic approaches include non-specific immunosuppression (eg, steroids and rituximab), inhibition of platelet clearance (eg, splenectomy, intravenous immunoglobulin [IVIg], anti-D globulin, and the recently FDA-approved Syk inhibitor fostamatinib 13 ) or stimulation of platelet production (eg, thrombopoietin receptor agonist [TPO-RA]).…”

“…2,4,5 Patients may suffer from depression and fatigue 6 as well as side effects of existing therapies, impairing their quality of life. [7][8][9][10][11][12] Current therapeutic approaches include non-specific immunosuppression (eg, steroids and rituximab), inhibition of platelet clearance (eg, splenectomy, intravenous immunoglobulin [IVIg], anti-D globulin, and the recently FDA-approved Syk inhibitor fostamatinib 13 ) or stimulation of platelet production (eg, thrombopoietin receptor agonist [TPO-RA]). 4,14 Splenectomy remains the only treatment that provides sustained remission off therapy for one year or longer for a high proportion of patients.…”

“…At later time points, the distribution of platelet counts in both efgartigimod-treated groups generally tended to be higher than in the placebo group, especially in the efgartigimod 10 mg/kg group.A high number of patients receiving placebo achieved a single platelet count ≥50 × 10 9 /L during the study (6 [50%] compared to, for example, 14% across two, 24-week fostamatinib Phase 3 studies) 13,43. At later time points, the distribution of platelet counts in both efgartigimod-treated groups generally tended to be higher than in the placebo group, especially in the efgartigimod 10 mg/kg group.A high number of patients receiving placebo achieved a single platelet count ≥50 × 10 9 /L during the study (6 [50%] compared to, for example, 14% across two, 24-week fostamatinib Phase 3 studies) 13,43.…”

Autoimmune thrombocytopenia: Current treatment options in adults with a focus on novel drugs

“…(NCT02076399) and FIT2 (NCT02076412), patients with refractory ITP were randomized into a fostamatinib (n = 101) or a placebo (n = 49) group. 66 Stable responses were observed in 18% of patients in the fostamatinib arm vs 2% in the placebo arm (P = .0003).…”