S307: cevidoplenib (ski-o-703), a novel syk inhibitor, reduces antiphospholipid antibody titers and prevents intramyocardial small arterial thrombosis in a mouse model of antiphospholipid syndrome

Background: Antiphospholipid syndrome (APS) is an autoantibody-mediated blood disorder where the antiphospholipid antibodies (APLs) may cause blood clots to form in arteries and veins potentially leading to life-threatening conditions such as a heart attack or strokes and obstetric complications. There is no disease-modifying medication currently available other than anti-thrombotic treatments. Cevidoplenib (SKI-O-703) is a potent and selective inhibitor of spleen tyrosine kinase (SYK). It recently completed Phase II study in patients with immune thrombocytopenia (ITP; the data presented in this meeting). Aims: By inhibiting antiphospholipid antibody-induced activation of B cell receptor (BCR) and Fc receptor (FcR), it is anticipated that inhibition SYK might be an effective strategy to lower the levels of autoantibodies and the risk of blood clot formation. This study aims to test the hypothesis in a mouse model of APS. Methods: A mouse model of primary APS was established by subcutaneous injection of human beta2GP1 in BALB/c mice, where dramatic increases in the level of anti-beta2GP1 and anti-cardiolipin IgG antibodies as well as significant pan-cytopenia were observed at 12-week post-immunization, along with evident histopathologic changes in cardiac tissues such as intramyocardial small arterial thrombosis and epicardial calcification. In the therapeutic model, the mice were administered with cevidoplenib (42 and 84 mg/kg qd, po) from day 3 post-immunization for 16 weeks. Blood samples were collected at weeks 5, 9, 11, and 14 for analysis of autoantibody levels by ELISA and, at the end of treatment, cardiac tissues were examined by IHC and spleen cells by FACS. In addition, lupus anticoagulant testing was also performed. Results: Cevidoplenib treatment was effective at lowering the levels of APLs and it dramatically reduced the incidence of histological findings in cardiac tissue. Although spleen cells were not noticeably altered, prothrombin time and fibrinogen levels were significantly reduced. Summary/Conclusion: Most pathological signs of APS, especially that of cardiac histology, were significantly improved by administration of cevidoplenib in the mouse model. Specific inhibition of SYK appears to be a promising immunotherapeutic, disease-modifying approach to lowering the risk of thrombotic events in APS patients. Keywords: Antiphospholipid syndrome, SYK, Antiphospholipid antibody