COVID-19

TAVALISSE® (fostamatinib disodium hexahydrate) is a selective, oral spleen tyrosine kinase (SYK) inhibitor being evaluated for the treatment of hospitalized patients with COVID-19*.

*TAVALISSE is not FDA-approved for use in COVID-19.

Coronavirus Disease 2019 (COVID-19)

COVID-19 is an 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.1 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.2

Scientific Rationale for SYK-Inhibition in COVID-19

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.3,4,5,6 Furthermore, SYK inhibition in neutrophils and platelets may lead to decreased thromboinflammation, alleviating organ dysfunction in critically ill patients with COVID-19.

SYK known to mediate aspects of Covid-19 pathogenesis

1Investigational compound in this indication and has not been submitted for FDA review

2Fu Y. et al. Understanding SARS-CoV-2-Mediated Inflammatory Responses: From Mechanisms to Potential Therapeutic Tools. Virologica Sinica. March 3, 2020

3Nadeem A. et al. Inhibition of spleen tyrosine kinase signaling protects against acute lung injury through blockade of NADPH oxidase and IL-17A in neutrophils and γδT cells respectively in mice. International Immunopharmacology 68 (2019) 39–47.

Peer-reviewed Research

An image titled Fostamatinib Inhibits Neutrophils Extracellular Traps Induced by COVID-19 Patient Plasma: A Potential Therapeutic with a description of The Journal of Infectious Diseases published research from the NIH which demonstrated that R406, the active metabolite of fostamatinib, was able to inhibit NETosis ex vivo in donor plasma from patients with COVID-19.
An image titled High titers and low fucosylation of early human anti-SARS-CoV-2 lgG promote inflammation by alveolar macrophages with a description of A study led by the University of Amsterdam found that anti-Spike lgG from the serum of severely ill COVID-19 patients induces a hyperinflammatory response by human macrophages that can be counteracted by SYK inhibition with fostamatinib.
An image titled A High-Content Screen for Mucin-1-Redicing Compounds Identifies Fostamatinib as a Candidate for Rapid Repurposing for Acute Lung Injury with a description of MIT and Harvard led a screen focused on identifying 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.

Rigel's Clinical Development Program – TAVALISSE in COVID-19

NIH PHASE 2 NIH ACTIV-4 PHASE 3 RIGEL PHASE 3

NIH P2  = National Heart, Lung, and Blood Institute (NHLBI) Phase 2 Trial, part of the National Institutes of Health (NIH), in collaboration with Inova Health System

ACTIV-4 Host Tissue Phase 3 Clinical Trial

ACTIV-4 Host Tissue is a randomized, placebo-controlled Phase 2/3 trial of therapies, including fostamatinib, targeting the host response to COVID-19 in hospitalized patients. More detail on the study can be found on clinicaltrials.gov: NCT04924660.

ACTIV-4 Host Tissue Phase 3 Clinical Trial

1Standard of care includes any treatments currently in use to treat the underlying disease, or comorbidities associated with COVID-19 (eg, remdesivir).

*Following an interim analysis TXA127 and TRV027 study arms were discontinued after meeting the inferiority stopping criteria

Rigel Phase 3 Clinical Trial

Rigel’s multi-center, double-blind, placebo-controlled, Phase 3 clinical trial in hospitalized patients with COVID-19 enrolled 280 patients that were randomly assigned to either fostamatinib plus standard of care (SOC) or matched placebo plus SOC. Top-line results were reported in November 2022. Rigel was awarded $16.5 million by the U.S. Department of Defense to support funding of this trial. More detail on the study can be found on clinicaltrials.gov: NCT04629703.

Rigel Phase 3 Clinical Trial

1Standard of care includes any treatments currently in use to treat the underlying disease, or comorbidities associated with COVID-19 (eg, remdesivir).

NIH/NHLBI Phase 2 Clinical Trial

The National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health (NIH), in collaboration with Inova Health System, sponsored a Phase 2 clinical trial to evaluate fostamatinib in hospitalized patients with COVID-19. The study met its primary endpoint of safety and showed broad and consistent improvement in numerous efficacy endpoints including mortality, ordinal scale assessment, and number of days in the ICU. Results from this study were published in the peer-reviewed journal, Clinical Infectious Diseases.

NIH/NHLBI Phase 2 Clinical Trial

1Standard of care includes any treatments currently in use to treat the underlying disease, or comorbidities associated with COVID-19 (eg, remdesivir).

 

References:

  1. Berlin DA, Gulick RM, and Martinez FJ. Severe Covid-19. N Engl J Med 2020. DOI: https://doi.org/10.1056/NEJMcp2009575
  2. Becker RC. COVID-19 Update: COVID-19 associated coagulopathy. Journal of Thrombosis and Thrombolysis May 15, 2020. DOI: https://doi.org/10.1007/s11239-020-02134-3
  3. Hoepel W et al. High titers and low fucosylation of early human anti–SARS-CoV-2 IgG promote inflammation by alveolar macrophages. Science Translational Medicine 02 Jun 2021. DOI: https://www.doi.org/10.1126/scitranslmed.abf8654
  4. Sung P-S and Hsieh S-L. CLEC2 and CLEC5A: Pathogenic Host Factors in Acute Viral Infections. Frontiers in Immunology December 6, 2019. DOI: https://doi.org/10.3389/fimmu.2019.02867
  5. Bye AP et al. Aberrant glycosylation of anti-SARS-CoV-2 IgG is a pro-thrombotic stimulus for platelets. BioRxiv March 26, 2021. DOI: https://doi.org/10.1101/2021.03.26.437014
  6. Strich J et al. Fostamatinib Inhibits Neutrophils Extracellular Traps Induced by COVID-19 Patient Plasma: A Potential Therapeutic. Journal of Infectious Disease March 15, 2021. DOI: https://doi.org/10.1093/infdis/jiaa789
  7. Kost-Alimova M et al. A High Content Screen for Mucin-1-Reducing Compounds Identifies Fostamatinib as a Candidate for Rapid Repurposing for Acute Lung Injury. Cell Reports Medicine 1 November 17, 2020. DOI: https://doi.org/10.1016/j.xcrm.2020.100137