SYK Inhibitor (TAVALISSE)

TAVALISSE®​ (fostamatinib disodium hexahydrate) is a potent and selective oral spleen tyrosine kinase (SYK) inhibitor.

In May 2018,​ TAVALISSE was approved by the U.S. Food and Drug Administration (FDA) for use in adult patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to a previous treatment. The patent for TAVALISSE expires in 2026, with an anticipated extension for patent restoration to 2032. We plan to take advantage of this long window of exclusivity and further explore its potential.

Currently, TAVALISSE is in late-stage clinical development in warm antibody autoimmune hemolytic anemia (AIHA) and Rigel expects to launch a Phase 3 clinical trial for the treatment of hospitalized COVID-19 patients in the fourth quarter of 2020.

Autoimmune Hemolytic Anemia (AIHA)

AIHA is a rare, serious blood disorder in which the immune system produces antibodies that result in the destruction (hemolysis) of the body’s own red blood cells (RBC). In AIHA, the body destroys RBCs at a greater rate than it can produce new RBCs, eventually leading to anemia (low levels of red blood cells), with symptoms such as fatigue, pale color, rapid heartbeat, and shortness of breath. In severe cases fever, chest pain, fainting, or heart failure may occur. AIHA affects approximately 45,000 adult patients in the U.S. and approximately 1 to 3 in 100,000 adults are diagnosed each year. Warm antibody AIHA is the most common form of AIHA and can be either primary or secondary to an underlying disease such as systemic lupus erythematosus (SLE) or a lymphoproliferative condition such as or chronic lymphocytic leukemia (CLL) or lymphoma. To date, there are no approved therapies for AIHA, despite the unmet medical need.

Development of TAVALISSE (fostamatinib) in Warm Antibody AIHA:

  • Phase 3 clinical trial (FORWARD) currently enrolling
    • Approximately 90 patients will be enrolled in this 24-week study
  • Announced data from completed Phase 2 clinical trial (SOAR) in November 2019
  • The FDA granted TAVALISSE Orphan Drug designation for the treatment of patients with warm antibody AIHA in January 2018

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

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 (FcyR) 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  Furthermore, SYK inhibition in neutrophils and platelets may lead to decreased thromboinflammation, alleviating organ dysfunction in critically ill patients with COVID-19.

Development of TAVALISSE (fostamatinib) in COVID-19:

  • Rigel plans to launch a randomized, double-blind, placebo-controlled, adaptive Phase 3 clinical trial in over 300 hospitalized COVID-19 patients:
      • 2-arm trial: 1) TAVALISSE + Standard of Care (SOC)  2) Placebo + SOC
  • The National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health (NIH), in collaboration with Inova Health System, initiated a randomized, double-blind, placebo-controlled Phase 2 clinical trial in 60 hospitalized COVID-19 patients:
      • 2-arm trial: 1) TAVALISSE + SOC  2) Placebo + SOC
  • Imperial College London initiated a two-stage, randomized, open label, controlled Phase 2 clinical trial in over 450 hospitalized COVID-19 patients:
      • 3-arm trial: 1) TAVALISSE + SOC  2) ruxolitinib, a Janus Kinase inhibitor, + SOC  3) SOC alone

References:

  1. Berlin DA, Gulick RM, Martinez FJ. Severe Covid-19. N Engl J Med 2020
  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. Anti-SARS-CoV-2 IgG from severely ill COVID-19 patients promotes macrophage hyper-inflammatory responses. bioRxiv July 13, 2020.  DOI: https://doi.org/10.1101/2020.07.13.190140
  4. Sung P-S and Hsieh S-L (2019) CLEC2 and CLEC5A: Pathogenic Host Factors in Acute Viral Infections. Front. Immunol. 10:2867. DOI:https://doi.org/10.3389/fimmu.2019.02867
  5. Behnen M. Immobilized Immune Complexes Induce Neutrophil Extracellular Trap Release by Human Neutrophil Granulocytes via Fcγ RIIIB and Mac-1. The Journal of Immunology July 2014. DOI: https://doi.org/10.4049/jimmunol.1400478