Introduction: Immune thrombocytopenia(ITP) is characterized by platelet (plt) phagocytosis, predominantly autoantibody-directed, mediated by activated monocyte Fc receptors which signal via spleen tyrosine kinase (syk). This, and T cell-mediated mechanisms, lead to suboptimal plt production. The safety and efficacy of investigational fostamatinib, an oral syk inhibitor, was evaluated in adult persistent/chronic ITP in two parallel, multi-center, randomized, placebo-controlled (2 active:1 placebo), double-blind phase 3 studies, each 24 weeks in duration; one performed in North America, Australia and Europe (047) and one in Europe (048). The median duration of ITP at study entry was 8.5 years and patients (pts) were heavily pretreated with ITP therapies: 94% of pts had received corticosteroids, 47% thrombopoietin-receptor agonists, 32% rituximab and 35% splenectomy. Pts from either study were eligible to enroll in an ongoing open-label extension study (049). Pts initially received fostamatinib 100 mg BID, which could be increased to 150 mg BID if the pt did not have a plt response. A stable response (SR) was achieved in 18/101 (18%) fostamatinib vs 1/49 (2%) placebo pts in 047/048 (p=0.007). We report safety and durability of response among pts who achieved an SR to fostamatinib across studies 047, 048, and 049 including pts on placebo in the 047/048 studies who received active drug in 049.
Methods: SR was defined as a plt count ≥50/nL at 4 of 6 evaluations every 2 weeks during weeks 14-24 (in 047/048) or as a plt count ≥50/nL within 12 weeks of starting treatment without the need for rescue therapy and ≥50/nL at 2 of the 3 subsequent monthly evaluations (in 049). Loss of response was prospectively defined as 2 plt counts at least 4 weeks apart <50/nL. Plt counts within 28 days of rescue therapy were assumed to be <50/nL at those visits.
Results: 123 of 150 pts (82%) who participated in 047/048, enrolled in 049. Pts first received fostamatinib in 047 (n=36), 048 (n=43) or 049 (n=44); a total of 27 (22%) pts achieved an SR. Among pts who received placebo during the 047/048 studies and then received fostamatinib in 049, 10 of 44 (23%) pts achieved an SR compared to only one (2%) pt when these same pts were treated with placebo (p=0.0039). As of April 14, 2017, ≥12 months had elapsed since fostamatinib therapy initiation in 117 of 123 pts, including 25 of 27 pts achieving SRs as well as those who did not respond or who have discontinued therapy. Seventeen of 25 (68%) pts maintained their response, with a median plt count of 23/nL at the last evaluation before starting fostamatinib treatment and a median plt count of 111/nL and 115/nL after 12 and 52 weeks of fostamatinib treatment, respectively. Among the 8 pts who achieved an SR but did not maintain it, 4 continued on study and elected to remain on drug and 4 discontinued early (2 adverse events [AEs], 1 lack of efficacy, and 1 pt decision). The Kaplan-Meier median duration of response (months; [min, max]) for the 17 pts who maintained an SR has not yet been reached, and is estimated as >28 months (12, >28). Ninety-two of 123 (75%) pts experienced ≥1 AE with the majority (72%) being mild or moderate in severity; 64 (52%) pts experienced ≥1 treatment-related AE. The most common AEs were: diarrhea (28%), hypertension (15%), petechiae (15%), and epistaxis (14%). Serious AEs were reported in 27 of 123 pts (22%); bleeding-related SAEs were experienced by 11 pts, 10 of whom were nonresponders. AEs leading to study drug withdrawal occurred in 15 of 123 pts (12%) including diarrhea (n=5), liver enzyme elevations (n=3), and neutropenia (n=2), which occurred in more than one pt.
Conclusions: Most heavily pre-treated adult persistent/chronic ITP pts with long disease duration who achieved an SR to fostamatinib maintenance therapy in studies 047, 048, and 049 were able to maintain an SR for ≥12 months and up to >24 months in some pts. The majority of AEs were mild or moderate in severity, and consistent with those observed in previous ITP and rheumatoid arthritis studies with fostamatinib.
Bussel: Boehringer Ingleheim: Research Funding; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; UpToDate: Honoraria, Patents & Royalties; Momenta: Membership on an entity's Board of Directors or advisory committees; Rigel: Membership on an entity's Board of Directors or advisory committees, Research Funding; Protalex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prophylix: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Physicians Education Resource: Speakers Bureau. Arnold: UCB: Consultancy; Dova: Consultancy; Novartis: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Rigel: Consultancy; Bristol Myers Squibb: Research Funding. Cooper: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ghanima: Amgen: Honoraria; Novartis: Research Funding. Zayed: Rigel Pharmaceuticals, Inc.: Employment. Cadieux: Rigel Pharmaceuticals, Inc.: Employment. Duliege: Rigel Pharmaceuticals, Inc.: Employment.
Asterisk with author names denotes non-ASH members.