Fostamatinib is a potent SYK inhibitor that targets activation of both the innate and acquired immune systems caused by tissue damage or pathogen signals via C-type lectin receptors (CLR) as well as by antibody-antigen immune complexes via Fc receptors (Figure 1). SYK is also a key modulator of pathways involved in thrombosis formation. Fostamatinib is FDA-approved for chronic immune thrombocytopenia (ITP) and has been evaluated in over 4000 patients for treatment of allergic, autoimmune, and neoplastic disorders. Fostamatinib is well tolerated, with a consistent safety profile across a number of diseases. In rheumatoid arthritis patients, fostamatinib reduced the plasma levels of IL-6.1 The active metabolite (R406) was protective in mouse models of LPS-induced acute lung injury (ALI)2 and LPS- or antibody-induced acute kidney injury (AKI).3 SYK inhibition decreased the incidence of thrombosis in mouse models of thromboembolism,4 and the incidence of thromboembolic events was decreased in patients treated with fostamatinib compared with other treatments for ITP. These immunomodulatory effects suggest that SYK inhibition represents a new therapeutic strategy for the treatment of COVID-19, which led to design of a clinical study of fostamatinib in hospitalized COVID-19 patients.
COVID-19 patients are at risk for a potentially fatal acute respiratory distress syndrome (ARDS), cytokine storm, severe systemic capillary leak syndrome, thromboembolic events, and multi-organ dysfunction/failure. SYK is a master regulator of signal transduction pathways implicated in these COVID-19 associated complications, which involves hyperactivation of both innate and acquired immune systems. Targeting SYK could prevent the cytokine storm, downstream activation of endothelial cells and platelets, and influx of neutrophils and monocytes into lungs or kidney leading to ALI and AKI, respectively.
Methods: A randomized, double-blind, placebo-controlled, multi-center, Phase 3 study will evaluate the efficacy and safety of fostamatinib in adult, hospitalized, high-risk COVID-19 patients. Patients will be treated with fostamatinib 150mg BID for up to 28 days plus standard of care. Improvement in clinical status will be assessed using the 8-point ordinal scale.
References
1. Weinblatt ME et al.Arth Rheum2008;58:3309-18
2. Nadeem A et al.Int Immunopharm2019;68:39-47
3. Al-Harbi NO, et al.Biochimie2019;158: 102-10
4. Van Eeuwijk JMM et al.Arterioscler Thromb Vasc Biol2016;36:1247-53
Results and Conclusions: Trial in Progress
Dummer:Rigel:Current Employment, Current equity holder in publicly-traded company.Markovtsov:Rigel:Current Employment, Current equity holder in publicly-traded company.Tong:Rigel:Current Employment, Current equity holder in publicly-traded company.Masuda:Rigel:Current Employment, Current equity holder in publicly-traded company.
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