561. Phase 3 Trial of Fostamatinib for the Treatment of COVID-19: Repurposing an Immunomodulatory Drug Previously Approved for Immune Thrombocytopenia

Abstract

Background Key pathologies in severe COVID-19 include immune cell activation, inflammatory cytokine release, and neutrophil extracellular trap release (NETosis), which are mediated by spleen tyrosine kinase (SYK) (Figure 1). Fostamatinib, an oral SYK inhibitor approved for chronic immune thrombocytopenia, has shown activity in vitro using plasma from patients with severe COVID-19, by abrogating the hyperimmune response triggered by anti-spike IgG; 1 inhibiting hyperactivation in platelets; 2 and blocking NETosis in neutrophils.3 R406, active metabolite of fostamatinib, protected against LPS-induced acute lung injury and thrombosis in mice.4,5 In clinical studies, fostamatinib reduced IL-6 in patients with rheumatoid arthritis.6 Therefore, a phase 2 study (NCT04579393) evaluated fostamatinib vs. placebo plus standard of care (SOC) in 59 hospitalized COVID-19 patients (manuscript pending). We initiated a phase 3 clinical study (NCT04629703) of fostamatinib for the treatment of COVID-19. Methods A double-blind, randomized, placebo-controlled, adaptive design, multi-center, Phase 3 study (NCT04629703) is underway to evaluate the safety and efficacy of fostamatinib in 308 adult patients with COVID-19 (Figure 2). Hospitalized patients without respiratory failure (with or without supplemental oxygen) were included. Patients with ARDS or using extracorporeal membrane oxygenation (ECMO) were excluded. Patients will receive fostamatinib 150 mg BID or placebo for 14 days; both arms receive SOC. The primary outcome will be progression to severe/critical disease (worsening in clinical status score on the 8-point ordinal scale) within 29 days of the first dose of study drug. Fostamatinib is investigational for COVID-19. Results Blinded update of trial in progress as of 28 April 2021. 12 patients have been randomized in North and South America. The clinical status score at Baseline was 5 (Hospitalized, requiring supplemental oxygen) in all 12 patients. Five patients had 8 adverse events (AE) (Fig 3). One AE (PE) was serious and is resolving. No deaths have been reported. At least two patients have been discharged (Day 5, Day 13) with continued dosing at home. Conclusion Fostamatinib has the potential to provide a treatment option for the hyperimmune complications of COVID-19. Disclosures Ziad Mallat, MD, PhD, Rigel Pharmaceuticals, Inc. (Consultant) Sandra Tong, MD, Rigel Pharmaceuticals, Inc. (Employee, Shareholder)

Recent advances in understanding spleen tyrosine kinase (SYK) in human biology and disease, with a focus on fostamatinib

“…During COVID-19 disease progression, CLRs and FcγRs on the surface of platelets, macrophages, dendritic cells, and neutrophils are activated by viral antigen antibody immune complexes that trigger an intracellular signaling cascade dependent on SYK recruitment [10,41,42]. The resulting cytokine storm, coagulopathy, and NETosis potentiate disease severity and this is targetable with SYK inhibitors, potentially modifying the severity of COVID-19 infection (Figure 2) [43]. In preclinical studies, SYK inhibition protected mice against LPS-induced acute lung injury and thrombosis [29,44].…”

“…The third study is a double-blind, randomized, placebo-controlled, adaptive, phase 3 study of fostamatinib plus SOC in the treatment of hospitalized adults with COVID-19 in the USA (NCT04629703), with a planned enrollment of 308 patients. Endpoints include progression to severe/critical disease within 29 days of the first dose of treatment, number of patients transferred to ICU, total number of days hospitalized, and mortality [43].…”

Progress, pitfalls, and path forward of drug repurposing for COVID-19 treatment

“…An ongoing phase III clinical trial is expected to provide additional data on the potential of fostamatinib in treating COVID-19. 137 …”