A Phase 1 Study to Evaluate the Safety and Tolerability of Escalating Doses of Fostamatinib in Subjects with Stable Sickle Cell Disease: Trial in Progress
Authors: Conrey Anna , Lovins Dianna , Kimberly Rivers , Lee Yuan Yee , Le Kang , Kruah Britney , Wang Xunde , Metaferia Belhu , Low Philip S. , Jeffries Neal , Eaton William A , Thein Swee Lay 
Published: December 2024

Background:
While the pathology in sickle cell disease (SCD) is initiated by polymerization of deoxygenated hemoglobin S (HbS), the downstream cascade events of vaso-occlusion and hemolysis are caused by changes to the red blood cell (RBC) structure and function (“sickling”). A major source of reactive oxygen species (ROS) and oxidative stress are the contents of the sickle RBCs themselves. Oxidative stress affects the integrity of the RBC membrane; it increases tyrosine phosphorylation of band 3 (tyr-p-bd3) that disrupts its interaction with the ankyrin-spectrin cortical cytoskeleton, leading to membrane destabilization, phosphatidylserine exposure, blebbing of membrane-derived microparticles from the cell surface, and release of hemoglobin into the plasma. Collectively, these processes promote adherence of sickle RBCs to the endothelium, thereby increasing the transit time through the microcirculation with increased probability of vaso-occlusion. All these factors act in a positive feedback-loop driving the pathophysiology of SCD. Restoring integrity of the RBC membrane is thus essential to preventing the vaso-occlusive events that promote SCD. Oxidative stress activates p72 spleen tyrosine kinase (SYK), the major kinase that phosphorylates band 3 tyrosine residues. Fostamatinib is a SYK inhibitor and FDA-approved for treatment in adults with chronic immune thrombocytopenia. To evaluate fostamatinib as an antisickling agent, we incubated HbSS RBCs with fostamatinib and its active metabolite, R406, and showed that both agents reduced tyr-p-bd3 in a dose- and time-dependent manner. We compared the effects of different SYK inhibitors (Imatinib, R112, PRT062607, Endospletinib, Fostamatinib, R406, and cerdulatinib) on the fraction of sickled RBCs vs time following deoxygenation of HbSS RBCs, and showed that R406 slowed the kinetics of sickling while the effect of imatinib on sickling kinetics was minimal. HbSS RBCs treated ex-vivo with fostamatinib and R406 also showed improved deformability. Fostamatinib could have additional benefits in SCD due to its anti-inflammatory effect from inhibition of neutrophil extracellular traps (NETs) as shown in COVID-19.
Objectives: The main objectives of this study (NCT05904093) are to assess the clinical safety and tolerability of fostamatinib and to evaluate its anti-sickling effects in patients with SCD.
Study Design and Methods:
This is an open label, single-center, dose-escalating, phase 1 clinical study of escalating doses of fostamatinib in subjects with stable SCD. Fifteen subjects with SCD will complete two dose levels of fostamatinib, 100 mg twice daily (BID) for 2 weeks escalating to 150 mg BID for four weeks. Timed blood samples for pharmacokinetics will be collected pre-dose and at 1, 2, 4, and 8 hours post-dose on initiation of 100 mg and dose escalation to 150 mg (days 0 and 14). A timed blood sample for pharmacokinetics will also be collected prior to the last dose of fostamatinib on day 42. Eligibility: ≥ 18 years with a documented diagnosis of SCD (HbSS or HbSb0 thalassemia), adequate organ function, baseline Hb ≥ 7 g/dL, and no transfusions or erythropoiesis stimulating agents in the prior 3 months. If taking hydroxyurea (HU), the dose must be stable for ≥ 90 days before starting study drug. Not eligible: history of neutropenia (unrelated to drug suppression), history of poorly controlled blood pressure, currently receiving treatment with SCD therapies (excluding hydroxyurea) or history of gene therapy, bone marrow or stem cell transplantation. The primary objective is to assess the clinical safety and tolerability of a two-dose level dosing regimen of fostamatinib in subjects with stable SCD based on the frequency and severity of adverse events (AEs), and changes in laboratory parameters. Descriptive statistics will include the incidence and severity of AEs with associated confidence intervals for binomial distributions.
Conclusion:
This study will evaluate the safety and tolerability of fostamatinib across the tested dose levels in adults with SCD. The accompanying changes in the active metabolite of fostamatinib, R406, with changes in tyrosine phosphorylation of RBC membrane band 3, sickling kinetics, deformability, and in micro-vesicle release will determine whether fostamatinib treatment could be beneficial by reducing the duration or severity of pain episodes.