Abstract: Introduction: Fostamatinib is an oral, potent inhibitor of spleen tyrosine kinase (SYK) with proven efficacy and a manageable safety profile for the treatment of ITP. SYK is situated in an intracellular signaling pathway upstream of Bruton's tyrosine kinase (BTK). Long-term safety data on fostamatinib at various dosing regimens (up to 150 mg BID) has been collected in & gt;4000 patients with ITP, rheumatoid arthritis (RA), and other autoimmune, allergic and neoplastic disorders. The safety and tolerability of fostamatinib were consistent across different patient populations (apart from disease specific events). We present a summary analysis of the fostamatinib safety data from the ITP and RA studies. Methods: Fostamatinib safety data from 2 randomized, double-blind, placebo-controlled, phase 3 studies and the long-term, open-label, extension (OLE) study in ITP were pooled and are based on a starting dose of 200 mg/day, which was increased to 300 mg/day after 4 weeks in 88% of patients. Fostamatinib safety data from 13 phase 2/3 studies in RA were pooled and are based on a dosing regimen of 100-150 mg/day (n=1232) or 200-300 mg/day (n=2205). Results: The pooled data set for ITP included 146 patients; 60% were female, and the median age was 53 years (range 20-88). The mean duration of fostamatinib treatment was 19 months (range & lt;1-62 months), representing 229 patient exposure years. Adverse events (AEs) were reported in 87% of patients, and 63% were mild to moderate. Serious AEs were reported in 31% of patients. The incidence of diarrhea, hypertension, alanine aminotransferase increase (ALT), and aspartate aminotransferase (AST) increase was evaluated in 58 patients who received fostamatinib for ≥1 year. This enabled a comparison of the incidence of these AEs in quartiles over the first year to assess the cumulative effects of fostamatinib. The AEs were reported with decreasing frequency during the second, third, and fourth quarters of fostamatinib treatment compared with the first quarter of the initial year of treatment in the 58 patients (see Figure 1). In the same 58 patients, the use of rescue therapy decreased while median platelet counts increased each quarter of the first year. The pooled data set for RA included 3437 patients who received fostamatinib; 83% were female, and the median age was 54 (range 18 -87). The mean duration of treatment was 18 months (range & lt;1-81) representing 5134 patient exposure years. AEs were reported in 86% of RA patients and were mild to moderate in 73% of RA patients. Serious AEs occurred in 14%. In the placebo-controlled RA studies, 2414 patients received fostamatinib with 823 patient exposure years and 1169 received placebo with 367 patient exposure years. Despite a two-fold (125%) increase in exposure with fostamatinib vs placebo (823 vs 367 patient exposure years), there was only a 26% increase in AEs with fostamatinib vs placebo (68% vs 54%). The most common events in the ITP and RA studies were diarrhea (36% and 24%), hypertension (22% and 19%) and nausea (19% and 8%), apart from disease-related AEs. Epistaxis (19% and 0.5%), petechiae (15% and 0.3%), contusion (12% and 2%), and fatigue (10% and 2%) are associated with ITP and were uncommon in the RA population. Rheumatoid arthritis was reported as an AE in 9% of patients with RA and in none with ITP. Some AEs may be dose-related, and one-third of the RA patients were on lower dosages (100-150 mg/day) than were generally given in the ITP trials (200-300 mg/day). Conclusions: Fostamatinib has been evaluated in & gt;4000 patients across different disease populations. Fostamatinib has a consistent and manageable safety profile. No new safety signals and no cumulative toxicity were observed with up to 81 months (6.8 years) of continuous treatment. Figure 1 Disclosures Tong: Rigel: Current Employment, Current equity holder in publicly-traded company. Numerof:Rigel: Current Employment, Current equity holder in publicly-traded company. Datangel:Rigel: Current Employment, Current equity holder in publicly-traded company. Masuda:Rigel: Current Employment, Current equity holder in publicly-traded company.

Abstract: Introduction. Immune thrombocytopenia (ITP) is characterized by autoantibody-mediated platelet destruction resulting in thrombocytopenia and often at least a degree of bruising and bleeding. Platelet destruction occurs within activated macrophages that signal via spleen tyrosine kinase (SYK) following Fcγ receptor engagement by platelet-bound IgG antibodies. Fostamatinib is a SYK inhibitor, taken orally twice daily with or without food. In the three phase 3 clinical studies (2 randomized, controlled trials and 1 open-label extension study), 145 adults with ITP received fostamatinib. These patients had a median of 3 prior therapies (range 1-13) and a median of 8.4 years (range 〈 1-53 years) since ITP diagnosis, making them the most difficult-to-treat ITP population studied thus far in registration trials. Since gaining FDA approval in April 2018, fostamatinib has been prescribed to a wide range of ITP patients, including those with persistent disease and those for whom fostamatinib is second-line therapy. We conducted a post hoc analysis of the phase 3 clinical study data in patients for whom fostamatinib was second-line therapy as well as in patients with earlier stage disease, eg ITP of duration 〈 2 years. Methods. The phase 3 trials included patients with persistent or chronic ITP, who had failed ≥1 prior treatment and had ≥3 platelet counts 〈 30,000/μL at screening. Patients were initiated on fostamatinib at 100mg BID PO and increased to 150mg BID based on tolerability and if platelets were 〈 50,000/μL after 4 weeks. An overall platelet response was defined as achieving ≥1 platelet count of ≥50,000/µL (without rescue therapy) at any visit. Patients who had previously received corticosteroids (+/- immunoglobulins) but no other therapies for ITP were included in this analysis of fostamatinib as second-line therapy. Patients were also categorized by duration of ITP: 3 months to 〈 1 year (persistent), 1 to 〈 2 years, and ≥2 years duration of ITP. Results. Of 145 patients, 32 (22%) received fostamatinib as second-line therapy. Baseline characteristics of the 32 patients included median age of 50 years (range 20-88), median duration of ITP of 2.7 years, and median platelet count of 21,000/μL. Of these 32 patients, 25 (78%) had an overall platelet response, which compares favorably with the 47% response rate in the 113 patients who received fostamatinib as 3rd line or later therapy. The most commonly reported adverse events (AEs) in the 32 fostamatinib-as-second-line-therapy patients were hypertension, diarrhea, upper respiratory tract infection, nausea, vomiting, elevated liver enzymes, petechiae, and headache. AEs were primarily mild to moderate in severity and resolved or were managed by dose reduction, dose interruption, and/or secondary medication. The type and frequency of AEs in the second-line patients were consistent with that of the overall study population. We also assessed the subgroup of 29 patients with early-stage disease (of whom 11 received fostamatinib as second-line therapy). An overall response to fostamatinib was achieved by 9 of 10 (90%) patients with persistent ITP ( 〈 1 year), 11 of 19 (57%) patients with one to 〈 2 years of ITP, and 58 of 116 (50%) patients with 2 to 53 years of ITP. The overall response rate in the entire phase 3 population was 54% (78/145). Conclusions. A higher percentage of patients had an overall response to fostamatinib as second-line therapy for ITP (78%) compared with later lines of therapy (47%), and a higher percentage with persistent ITP (90%) responded than those with earlier stage (1-2 years) chronic ITP (57%) or later stage chronic ITP (50%). These data suggest that higher response rates may be seen with the use of fostamatinib as second-line therapy for ITP and in persistent ITP patients as compared with later lines of therapy and later stage ITP. Disclosures Boccia: SecuraBio: Consultancy; AMAG: Consultancy; Bristol Myers Squibb: Consultancy, Speakers Bureau; Celgene: Speakers Bureau; Rigel: Speakers Bureau; Daiichi Sankyo, Inc.: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau. Boxer:Takeda: Honoraria, Speakers Bureau; Arizona Oncology: Employment; Incyte: Speakers Bureau; Best Doctors: Consultancy; Abbvie: Honoraria, Speakers Bureau; Gerson Lerman: Consultancy; Rigel: Speakers Bureau. Ghanima:Bayer: Honoraria, Research Funding; Pfizer/BMS: Research Funding; Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding. Hill:Bioverativ, a Sanofi company: Honoraria; Apellis: Honoraria; Novartis: Speakers Bureau; Alexion: Research Funding. Sholzberg:Amgen: Honoraria, Research Funding; Novartis: Honoraria. Tarantino:Michael Tarantino, MD SC: Other: President, Owner- Private Practice ; Magellan Healthcare: Consultancy; Roche: Consultancy; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Octapharma: Consultancy, Speakers Bureau; Grifols: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novo Nordisk: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bleeding and Clotting Disorders Institute: Employment. Kreychman:Rigel: Employment, Equity Ownership. Numerof:Rigel: Employment, Equity Ownership. Olender:Rigel: Employment, Equity Ownership. Todd:Rigel: Employment, Equity Ownership. Tong:Rigel: Employment, Equity Ownership. Duliege:Rigel: Employment, Equity Ownership. Cooper:Principia: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees. Bussel:Dova Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Momenta Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kezar Life Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tranquil: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; 3S Bio: Speakers Bureau; Physician Education Resource: Speakers Bureau; Regeneron: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; RallyBio: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; argenx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; UCB: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Fostamatinib is a tyrosine kinase (SYK) inhibitor for the treatment of adult patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to a previous treatment. The use of fostamatinib in other diseases is off-label.

Abstract: Patients with relapsed warm antibody autoimmune hemolytic anemia (wAIHA) have limited treatment options. Fostamatinib is a potent, orally administered spleen tyrosine kinase inhibitor approved in the United States and Europe for the treatment of adults with chronic immune thrombocytopenia (ITP). This phase 2 study evaluated the response to fostamatinib, administered at 150 mg BID orally with or without food in adults with wAIHA and active hemolysis with hemoglobin (Hgb) 〈 10 g/dL who had failed at least one prior treatment. Hemoglobin levels and safety assessments were performed at visits every 2 weeks. The primary endpoint was Hgb 〉 10 g/dL with an increase of ≥2 g/dL from baseline by week 24 without rescue therapy or red blood cell transfusion. Eleven of 24 (46%) patients achieved the primary endpoint. Increases in median Hgb were detected at week 2 and sustained over time. Median lactate dehydrogenase levels and reticulocyte counts generally declined over time with little change in median haptoglobin levels. The most common adverse events (AEs) were diarrhea (42%), fatigue (42%), hypertension (27%), dizziness (27%), and insomnia (23%). AEs were manageable and consistent with the fostamatinib safety database of over 3900 patients across multiple diseases (rheumatoid arthritis, B‐cell lymphoma, COVID‐19, and ITP). No new safety signals were detected. Fostamatinib may be a promising therapeutic option for wAIHA. A randomized, double‐blind, phase 3 study is nearing completion.