COVID-19

TAVALISSE® (fostamatinib disodium hexahydrate) is a selective, oral spleen tyrosine kinase (SYK) inhibitor being evaluated in clinical trials 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.


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

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

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

The TAVALISSE COVID-19 program covers a broad range of hospitalized patients. Clinical trials are being conducted to address the full spectrum of patient clinical status, from mild to severe.


1NIH P2 Study = National Heart, Lung, and Blood Institute (NHLBI) Study, part of the National Institutes of Health (NIH), in collaboration with Inova Health System; MATIS = Imperial College of London Study

2NOTE: MATIS study uses WHO scale of 3-4 and ACTIV-4 uses WHO scale of 4-7

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 study 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).

Rigel Phase 3 Clinical Trial

Rigel is enrolling a randomized, double-blind, placebo-controlled, adaptive Phase 3 clinical trial in hospitalized patients with COVID-19. 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).

ACTIV-4 Host Tissue Phase 3 Clinical Trial

ACTIV-4 Host Tissue is a multi-site, randomized, placebo-controlled Phase 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).

ICL (MATIS) Phase 2 Clinical Trial

Imperial College London (ICL) is enrolling a two-stage, randomized, open label, controlled Phase 2 clinical trial, also known as MATIS, in hospitalized patients with COVID-19. More detail on the study can be found on clinicaltrials.gov: NCT04581954.

ICL (MATIS) Phase 2 Clinical Trial Design

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

 

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