Rigel Announces NIH/NHLBI-Sponsored Trial of Fostamatinib in Hospitalized COVID-19 Patients

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

"With the ongoing pandemic continuing to cause tens of thousands of new daily cases of COVID-19 across the U.S., there is a critical need to not only stop the spread of the virus, but to also develop new and effective therapies to treat the infected population, including those with severe and life-threatening disease," said Richard Childs, M.D., clinical director of the NHLBI. "As we work with the broader community to identify safe and effective therapeutic options for COVID-19 patients, we are hopeful that the investigation of fostamatinib will potentially aid in the fight against this pandemic."

The clinical trial is being conducted at the NIH Clinical Center in Bethesda, Maryland and Inova Fairfax Hospital.

"Working with Dr. Childs and his team at the NIH provides an excellent platform to further explore the potential of fostamatinib to treat and prevent conditions caused by an overactive immune system in COVID-19 patients," said Raul Rodriguez, Rigel's president and CEO. "COVID-19 infection can lead to dangerous and potentially life-threatening immune responses that can attack not only the lungs, but potentially other organs. Based on our understanding of SYK's role in the pathogenesis of the virus and fostamatinib's mechanism of action, we believe expanding our clinical effort into this second trial in COVID-19 related lung injuries is critical."

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.