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Principal Investigator: Swee Lay Thein
Organization: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
Fiscal Year: 2024
Award: $234,770
Funding agency: National Heart Lung and Blood Institute
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 study has been approved by the NIH Institutional Review Board and will begin accrual in September/October, 2024.
Terms: <AE1 Anion Exchanger><AE1 Chloride-Bicarbonate Exchanger><AE1 Cl- HCO3- Exchanger><AE1 Gene Product><Active Oxygen><Acute><Address><Adverse Experience><Adverse event><Amino Acid Substitution><Animal Disease Models><Animal Model><Animal Models and Related Studies><Animals><Anions><Anticoagulation><Apoplexy><Autoimmune Thrombocytopenias><Autoimmune Thrombocytopenic Purpura><B-globin><Band 3 Protein><Band Cell><Band III Protein><Biochemical><Biological Markers><Bleeding><Blood Neutrophil><Blood Platelets><Blood Polymorphonuclear Neutrophil><Blood erythrocyte><Brain Vascular Accident><COVID-19><CV-19><Capnophorin><Cardiovascular><Cardiovascular Body System><Cardiovascular Organ System><Cardiovascular system><Cell Function><Cell Physiology><Cell Process><Cell membrane><Cellular Function><Cellular Metabolic Process><Cellular Physiology><Cellular Process><Cerebral Stroke><Cerebrovascular Apoplexy><Cerebrovascular Stroke><Clinical><Clotting><Coagulation><Coagulation Process><Complex><Coronavirus Infectious Disease 2019><Cytoplasmic Membrane><Data><Development><Diagnostic Findings><Disease><Disorder><Dose><Dysfunction><Early-Stage Clinical Trials><Enrollment><Erythrocyte Anion Exchange Protein 1><Erythrocyte Anion Exchanger><Erythrocyte Anion Transport Protein><Erythrocyte Membrane Anion Transport Protein><Erythrocyte Membrane Band 3 Protein><Erythrocytes><Erythrocytic><Event><Exhibits><Exposure to><FDA approved><Face><Frequencies><Functional disorder><Genes><Glutamic Acid><Goals><Hb SS disease><HbSS disease><Heart Vascular><Hemoglobin><Hemoglobin S><Hemoglobin S Disease><Hemoglobin sickle cell disease><Hemoglobin sickle cell disorder><Hemolysis><Hemorrhage><Histones><Hypercoagulability><Hypoxia><Hypoxic><IRB><IRBs><Idiopathic Thrombocytopenic Purpura><Immune><Immune thrombocytopenia><Immunes><In Vitro><Incidence><Individual><Inflammatory><Institutional Review Boards><Ischemia-Reperfusion Injury><Kidney><Kidney Urinary System><Kinases><L-Glutamic Acid><L-Valine><Laboratories><Lung><Lung Respiratory System><Marrow Neutrophil><Marrow erythrocyte><Marrow platelet><Mediator><Molecular><Monitor><NIH><National Institutes of Health><Neurologic><Neurological><Neutrophil Activation><Neutrophilic Granulocyte><Neutrophilic Leukocyte><O element><O2 element><Oral><Oxygen><Oxygen Deficiency><Oxygen Radicals><PTK Inhibitors><Patients><Phase 1 Clinical Trials><Phase I Clinical Trials><Phase I Study><Phlebothrombosis><Phosphorylation><Phosphotransferase Gene><Phosphotransferases><Phosphotyrosine><Physiopathology><Plasma Membrane><Platelet Activation><Platelets><Play><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Position><Positioning Attribute><Pro-Oxidants><Process><Production><Protein Phosphorylation><Protein Tyrosine Kinase Inhibitors><Reactive Oxygen Species><Recurrence><Recurrent><Red Blood Cells><Red Cell><Reperfusion Damage><Reperfusion Injury><Risk><Role><SYK><SYK gene><Safety><Sampling><Serine Endopeptidases><Serine Protease><Serine Protein Hydrolases><Serine Proteinases><Serious Adverse Event><Severe Adverse Event><Severities><Severity of illness><Sickle Cell><Sickle Cell Anemia><Sickle Hemoglobin><Signal Pathway><Signs and Symptoms><Specific qualifier value><Specified><Spleen Tyrosine Kinase><Stroke><Study Subject><Subcellular Process><TK Inhibitors><Thrombocytes><Thrombophilia><Thrombosis><Time><Transphosphorylases><Tyrosine Kinase Inhibitor><Tyrosine Phosphorylation><Tyrosine-O-phosphate><Tyrosine-Protein Kinase SYK><United States National Institutes of Health><Valine><Vascular Diseases><Vascular Disorder><Venous><Venous Thrombosis><Werlhof's Disease><beta Globin><bio-markers><biologic marker><biomarker><blood corpuscles><blood loss><blood vessel disorder><brain attack><cell metabolism><cellular metabaolism><cerebral vascular accident><cerebrovascular accident><circulatory system><coronavirus disease 2019><coronavirus disease-19><coronavirus infectious disease-19><design><designing><developmental><disease severity><enroll><erythrolysis><experience><extracellular><faces><facial><hemoglobin polymer><immune cell-mediated thrombosis><immune thrombocytopenic purpura><immune-mediated thrombosis><immunothrombosis><immunothrombotic><injury to the vasculature><life span><lifespan><model of animal><mortality><neutrophil><novel><particle><pathophysiology><phase 1 study><phase I protocol><plasmalemma><pulmonary><renal><research study><safety assessment><serious adverse experience><serious adverse reaction><sickle RBC><sickle cell disease><sickle cell disorder><sickle disease><sickle erythrocyte><sickle red blood cell><sicklemia><sickling><social role><stroked><strokes><symptomatology><thrombogenesis><thrombogenicity><thromboinflammation><thromboinflammatory><thrombotic disease><thrombotic disorder><time interval><vascular dysfunction><vascular injury><vasculopathy><vaso-occlusive crisis><vasoocclusive crisis><venous thromboembolism><β-globin>