A Phase 1 Study to Evaluate the Safety and Tolerability of Escalating Doses of Fostamatinib in Subjects with stable sickle cell disease

National Heart, Lung, And Blood Institute

Investigators

Abstract

Sickle Cell Disease (SCD) is caused by a single amino acid substitution of valine by glutamic acid at the 6th position of the β-globin gene which results in the production of hemoglobin S (HbS). Under low oxygen conditions, HbS polymerizes and results in sickling of red blood cells (RBCs) triggering a complex cascade of cellular and molecular events leading to the protean manifestations of SCD1. Patients experience clinical symptomatology ranging from relatively mild asymptomatic disease to severe recurrent acute vasoocclusive crises (VOC) that can be debilitating. Moreover, most patients exhibit a slow and inexorable progression to pulmonary, cardiovascular, renal, and neurologic complications that diminishes overall life span2. In addition to stroke from arterial thrombosis, it is now well established that SCD patients face an increased risk of venous thromboembolism (VTE) and VTE associated mortality3. Although RBC sickling is the underlying mechanism triggering VOC, less is known about the direct role of sickling in the development of arterial/venous vasculopathy and thrombosis. Events in SCD pathophysiology i.e., hemolysis and ischemia-reperfusion injury4 induce innate immune dysregulation and facilitate “immunothrombosis” which leads to arterial and venous thrombosis5. Neutrophils, a primary cellular mediator of immunothrombosis appear to be in a heightened state of activation in SCD where they contribute significantly to disease severity. Neutrophils can enable immunothrombosis via their ability to express neutrophil extracellular traps (NETs), reactive oxygen species (ROS), and neutrophil serine proteases, all of which can independently, or collectively, upregulate prothrombotic and proinflammatory processes. Dysregulated NET release is a distinct phenomenon associated with SCD pathophysiology observed in both patients with SCD experiencing acute VOC and in animal models of SCD6,7. Moreover, studies in non SCD animal models in which venous thrombosis is experimentally induced show that NET release plays a central role in initiating and propagating thrombosis8. Animals lacking the ability to form NETs are protected from venous thrombosis highlighting their central role in thrombogenesis. Finally, individual NET components including proteolytic constituents and histones have been identified as initiators or propagators of coagulation activity providing additional evidence that neutrophils are critical cellular effectors of the sickle hypercoagulable state. Central to this hypothesis is the idea that dysregulated neutrophil activation in SCD results in immunothrombosis which supports the notion that decreased neutrophil activation and NET formation will directly inhibit vascular injury and venous thrombosis. Fostamatinib, an FDA approved specific tyrosine kinase inhibitor with demonstrable activity against spleen tyrosine kinase (SYK) reduces NETosis and immunothrombosis in COVID-19. Preliminary data from our laboratory suggests that R406 the active metabolite of Fostamatinib inhibits NET formation by neutrophils from sickle patients in vitro. Importantly, Fostamatinib was not associated with increased bleeding or thrombosis risk in immune thrombocytopenic purpura (ITP), a disorder associated with bleeding, justifying its choice for therapy in SCD. This is an important consideration since patients with SCD exposed to anticoagulation are at a heightened bleeding risk9. Fostamatinib could potentially reduce venous thrombosis without a commensurate increase in bleeding in patients with SCD addressing an important unmet need. Tyrosine phosphorylation of RBC band 3 (the anion exchanger 1, of the SLC4A1 gene) compromises its integrity, leading to shedding of red cell derived microparticles and release of free hemoglobin, key contributors to thrombo-inflammation pathophysiology. By impacting phosphorylation of RBC Band 3 protein, fostamatinib offers the potential for enhanced RBC membrane stability and reduced sickling of RBCs. This phase I study is designed to evaluate the safety and tolerability of fostamatinib in patients with SCD and explore its effect on cellular processes contributing toward immunothrombosis pathophysiology and sickling of RBCs. The overall objective of this study is to assess the clinical safety and tolerability of fostamatinib in subjects with stable sickle cell disease (SCD). Subjects enrolled will receive fostamatinib 100 mg orally twice daily (BID) for 2 weeks then escalate to 150 mg orally BID for an additional four weeks. Throughout the course of the study subjects will be monitored for signs and symptoms of adverse events. The effect of fostamatinib on laboratory biomarkers will be studied at specified timepoints. The first patient was enrolled on 12/18/2024 and have since had a total of 5 subjects who have enrolled with 4 who have completed participation. After RNI and DSMB review in 2025, the IRB confirmed that there was an unanticipated problem (UP) and placed the protocol on hold until an amendment can be submitted to take this UP into consideration for future enrollments. This modification is in process and accrual remains on hold.