On Sept. 17, 2020, Rigel Pharma announced the start of a multicenter, Phase 2 trial to evaluate the safety of fostamatinib, its oral spleen tyrosine kinase (SYK) inhibitor, for treatment of hospitalized COVID-19 patients. The study was sponsored by the National Heart, Lung, and Blood Institute, in collaboration with Inova Health System. Fostamatinib, marketed in the U.S. as TAVALISSE (fostamatinib disodium hexahydrate) tablets, was approved in the U.S. in 2018 as a treatment for adult chronic immune thrombocytopenia (ITP).

The clinical trial is being conducted at the National Institutes of Health Clinical Center in Bethesda, Maryland, the nation’s largest hospital devoted entirely to clinical research, and Inova Fairfax Hospital. COVID-19 is the infectious disease caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2).  SARS-CoV-2 primarily infects the upper and lower respiratory tract and can lead to acute respiratory distress syndrome (ARDS). Additionally, some patients develop other organ dysfunction including myocardial injury, acute kidney injury, shock resulting in endothelial dysfunction and subsequently micro and macrovascular thrombosis. Much of the underlying pathology of SARS-CoV-2 is thought to be secondary to a hyperinflammatory immune response associated with increased risk of thrombosis.

SYK is involved in the intracellular signaling pathways of many different immune cells. Therefore, SYK inhibition may improve outcomes in patients with COVID-19 via inhibition of key Fc gamma receptor (FcγR) and c-type lectin receptor (CLR) mediated drivers of pathology such as pro-inflammatory cytokine release by monocytes and macrophages, production of neutrophil extracellular traps (NETs) by neutrophils, and platelet aggregation. Furthermore, SYK inhibition in neutrophils and platelets may lead to decreased thromboinflammation, alleviating organ dysfunction in critically ill patients with COVID-19.

This is a randomized, double-blind, placebo-controlled trial to evaluate the safety of fostamatinib for the treatment of hospitalized COVID-19 patients. The study will randomly assign fostamatinib or matched placebo (1:1) to approximately 60 evaluable patients who are a 5 to 7 on the 8-point ordinal scale (requiring supplemental oxygen via nasal canula or non-invasive ventilation, requiring mechanical ventilation or extracorporeal membrane oxygenation). Treatment will be administered orally twice daily for 14 days. There will be a follow-up period to day 60. The primary objective of this study is to evaluate the safety of fostamatinib compared to placebo for the treatment of hospitalized COVID-19 patients. The secondary objective will be to assess the early efficacy and clinically relevant measures of disease progression.

Recently, researchers at The Broad Institute of the Massachusetts Institute of Technology (MIT) and Harvard led a screen focused on drug repurposing to identify U.S. Food and Drug Administration (FDA) approved compounds that reduce mucin-1 (MUC1) protein abundance. MUC1 is a biomarker used to predict the development of acute lung injury and ARDS, and it correlates with poor clinical outcomes. Of the 3,713 compounds that were screened, fostamatinib was the only compound identified that both decreased expression of MUC1 and is FDA approved. Additionally, a recent study led by the Amsterdam University Medical Center at the University of Amsterdam, found that anti-Spike IgG from serum of severely ill COVID-19 patients induces a hyperinflammatory response by human macrophages, a response that can be counteracted by SYK inhibition with fostamatinib. This study also found that anti-Spike IgG can break down pulmonary endothelial barriers and induce microvascular thrombosis. Fostamatinib is currently in a Phase 2 trial being conducted by Imperial College London to evaluate the efficacy of fostamatinib for the treatment of COVID-19 pneumonia.