Rigel Pharmaceuticals announced the initiation of an investigator-sponsored trial (IST) being conducted by Imperial College London to evaluate the efficacy of fostamatinib, its oral spleen tyrosine kinase (SYK) inhibitor, for the treatment of COVID-19 pneumonia. 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).
SYK is a key mediator of immunoreceptor signaling in a host of inflammatory cells. Studies of severe acute respiratory syndrome (SARS) and other acute viral respiratory infections suggest that the pathogenesis relies on a series of SYK-dependent events involving activation of C-type lectin receptors (CLR) and immunoglobulin Fcg receptors (FcgR) in multiple cell types. Such SYK-mediated processes result in excessive cytokine and chemokine release, neutrophil activation associated with extensive NETosis (a highly inflammatory and thrombogenic type of cell death), and endothelial cell stimulation leading to vascular endothelium leakage and edema in the lungs. Together, these events can contribute to acute respiratory distress syndrome (ARDS), micro-thrombosis and associated systemic complications.
The hallmark of severe COVID-19 is hypoxemia and a radiological pattern of acute lung injury (ALI) that shares features with ARDS. By inhibiting SYK, fostamatinib may specifically inhibit the infiltration and activation of monocytes and neutrophils in the lungs that are prominent in COVID-19.
"The COVID-19 global pandemic continues to extract a significant human and economic toll and there remains a serious and immediate need for safe and effective therapies," said Raul Rodriguez, Rigel's president and CEO. "Severe COVID-19 pneumonia can lead to acute respiratory distress syndrome, or ARDS, which can often be fatal. Given encouraging data from pre-clinical models of fostamatinib, we believe there is potential for SYK inhibition to help treat the severity of the disease for these patients and to prevent ARDS.
"We are pleased to be able to support the exciting work being done by our colleagues at Imperial College London. Their efforts will be valuable as we explore fostamatinib in COVID-19 and pursue our plans for a Rigel-led study."
The Imperial College London IST will be a two-stage open label, controlled clinical trial with patients randomized (1:1:1) to fostamatinib, ruxolitinib, or standard of care. Treatment will be administered twice daily for 14 days and patients will receive a follow-up assessment at day 14 and day 28 after the first dose. The primary objective will be to determine the efficacy of fostamatinib and the efficacy of ruxolitinib compared to standard of care to reduce the proportion of hospitalized patients progressing from mild or moderate to severe COVID-19 pneumonia. Rigel will provide support for this trial along with Novartis.
In addition, researchers at The Broad Institute of the Massachusetts Institute of Technology (MIT) and Harvard led a recent screen to identify FDA-approved compounds that reduce mucin-1 (MUC1) protein abundance. MUC1 is a biomarker used to predict the development of ALI and ARDS and correlates with poor clinical outcomes. Of the 3,713 compounds that were screened, fostamatinib was the only compound identified which both decreased expression of MUC1 and is FDA approved, and so allows for rapid repurposing for patients with COVID-19 lung injury. Fostamatinib demonstrated preferential depletion of MUC1 from epithelial cells without affecting cell viability. The research was focused on drug repurposing for the much lower risk of toxicity and the ability of FDA-approved treatments to be delivered on a shortened timescale, which is critical for patients afflicted with lung disease resulting from Read More
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