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TREATING CHRONIC IMMUNE THROMBOCYTOPENIA

IMMUNE THROMBOCYTOPENIA IS A HETEROGENEOUS DISEASE WITH A COMPLEX, MULTIFACTORIAL PATHOGENESIs

Immune thrombocytopenia (ITP) is driven by two factors: immune-mediated platelet destruction and limited platelet production1

  • Dysregulation of the immune system leads to
    production of anti-platelet antibodies2

    Anti-platelet antibodies
  • Macrophage recognition of antibody-coated platelets results in
    unregulated platelet destruction3

    Antibody-coated platelets
  • Lysis process results in an amplified production
    of anti-platelet antibodies3

    Anti-platelet antibodies
  • Platelet destruction causes decreased levels
    of thrombopoietin (TPO)1

    Anti-platelet antibodies
  • Anti-platelet antibodies may also target megakaryocytes,
    resulting in impaired megakaryocyte function3

    Antibody-coated platelets
  • Irregular T-cell response may destroy platelets in bone
    marrow and impede platelet production4

    Anti-platelet antibodies

Conventional itp treatment options are defined by complexities

Current ITP treatment approaches either decrease platelet destruction or stimulate platelet production3

  • Corticosteroids
  • Suppress systemic function and reduce antibody production, resulting in decreased platelet destruction1
  • Standard first-line therapy for recently diagnosed patients5
  • Over time, treatment side effects may outweigh the potential benefits5
  • Most patients relapse upon discontinuation of treatment5
  • TPO-RAs
  • Stimulate megakaryocytes in bone marrow to produce platelets3
  • Associated with potential increases in bone marrow fibrosis5
  • Evidence of increased thrombotic events with use of certain TPO-RA agents5
  • Anti-CD20
  • Depletes B cells3
  • Increased response when used with concomitant corticosteroids5
  • A meta-analysis of 5 trials showed that rituximab was not associated with reductions in bleeding5
  • In a study of response durability, only 21% maintained remission at 5 years5

TPO-RAs=thrombopoietin receptor agonists.

An individualized treatment strategy is needed for patients since ITP is a distinctly heterogeneous disease.

—Shih et al. Presse Med. 2014.2

THE INTERNATIONAL CONSENSUS REPORT ON ITP ENDORSES FOSTAMATINIB AS A SECOND-LINE TREATMENT FOR CHRONIC ITP

After first-line treatments fail in adults with ITP, the International Consensus Report recommends5,*,†:

Subsequent treatment

*Adapted from the 2019 publication of the International Consensus Report on ITP.

Recommended first-line treatments are defined as corticosteroids, intravenous immune globulin, and anti-D.

TAVALISSE presents an opportunity to redefine the treatment landscape

Limiting platelet destruction with the targeted mechanism of TAVALISSE is a novel way to treat chronic ITP6,7

Tavalisse Targeting Mechanisms

[TAVALISSE] has a unique mechanism of action, dissimilar to other approved ITP therapies, and produced responses in patients who had relapsed or not responded to TPO-RA agents, rituximab, and/or splenectomy.

—Bussel et al. Am J Hematol. 2018.6

TAVALISSE is the first spleen tyrosine kinase (SYK) inhibitor indicated for the treatment of thrombocytopenia in adult patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to a previous treatment6,7

References: 1. Raj AB. Immune thrombocytopenia: pathogenesis and treatment approaches. J Hematol Transfus. 2017;5(1):1056-1065. 2. Shih A, Nazi I, Kelton JG, Arnold DM. Novel treatments for immune thrombocytopenia. Presse Med. 2014;43:e87-e95. 3. Newland A, Lee E, McDonald V, et al. Fostamatinib for persistent/chronic adult immune thrombocytopenia. Immunotherapy. 2018;10(1):9-25. 4. Olsson B, Ridell B, Carlsson L, et al. Recruitment of T cells into bone marrow of ITP patients possibly due to elevated expression of VLA-4 and CX3CR1. Blood. 2008;112(4):1078-1084. 5. Provan D, Arnold DM, Bussel JB, et al. Updated international consensus report on the investigation and management of primary immune thrombocytopenia. Blood Adv. 2019;3(22):3780-3817. 6. Bussel J, Arnold DM, Grossbard E, et al. Fostamatinib for the treatment of adult persistent and chronic immune thrombocytopenia: results of two phase 3, randomized, placebo-controlled trials. Am J Hematol. 2018;93(7):921-930. 7. TAVALISSE® [package insert]. South San Francisco, CA: Rigel Pharmaceuticals, Inc.; April 2018. 8. Ghanima W, Godeau B, Cines DB, et al. How I treat immune thrombocytopenia: the choice between splenectomy or a medical therapy as a second-line treatment. Blood. 2012;120(5):960-969. 9. Mizutani H, Furubayashi T, Imai Y. Mechanisms of corticosteroid action in immune thrombocytopenic purpura (ITP): experimental studies using ITP-prone mice, (NZW x BXSB) F1. Blood. 1992;79(4):942-947. 10. Kistanguri G, McCrae KR. Immune thrombocytopenia. Hematol Oncol Clin North Am. 2013;27(3):495-520. 11. WinRho® SDF [package insert]. Berwyn, PA: Aptevo BioTherapeutics, LLC.; August 2016. 12. Stasi R, Pagano A, Stipa E, Amadori S. Rituximab chimeric anti-CD20 monoclonal antibody treatment for adults with chronic idiopathic thrombocytopenic purpura. Blood. 2001;98(4):952-957. 13. Rituxan® [package insert]. South San Francisco, CA: Genentech, Inc.; April 2019. 14. Doptelet® [package insert]. Durham, NC: Dova Pharmaceuticals, Inc.; June 2019. 15. Nplate® [package insert]. Thousand Oaks, CA: Amgen, Inc.; October 2017. 16. Promacta® [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; April 2019.

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Indication and Important Safety Information

Indication

TAVALISSE is indicated for the treatment of thrombocytopenia in adult patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to a previous treatment.

Important Safety Information

Warnings and Precautions

  • Hypertension can occur with TAVALISSE treatment. Patients with pre-existing hypertension may be more susceptible to the hypertensive effects. Monitor blood pressure every 2 weeks until stable, then monthly, and adjust or initiate antihypertensive therapy for blood pressure control maintenance during therapy. If increased blood pressure persists, TAVALISSE interruption, reduction, or discontinuation may be required.
  • Elevated liver function tests (LFTs), mainly ALT and AST, can occur with TAVALISSE. Monitor LFTs monthly during treatment. If ALT or AST increase to >3 x upper limit of normal, manage hepatotoxicity using TAVALISSE interruption, reduction, or discontinuation.
  • Diarrhea occurred in 31% of patients and severe diarrhea occurred in 1% of patients treated with TAVALISSE. Monitor patients for the development of diarrhea and manage using supportive care measures early after the onset of symptoms. If diarrhea becomes severe (≥Grade 3), interrupt, reduce dose or discontinue TAVALISSE.
  • Neutropenia occurred in 6% of patients treated with TAVALISSE; febrile neutropenia occurred in 1% of patients. Monitor the ANC monthly and for infection during treatment. Manage toxicity with TAVALISSE interruption, reduction, or discontinuation.
  • TAVALISSE can cause fetal harm when administered to pregnant women. Advise pregnant women the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for at least 1 month after the last dose. Verify pregnancy status prior to initiating TAVALISSE. It is unknown if TAVALISSE or its metabolite is present in human milk. Because of the potential for serious adverse reactions in a breastfed child, advise a lactating woman not to breastfeed during TAVALISSE treatment and for at least 1 month after the last dose.

Drug Interactions

  • Concomitant use of TAVALISSE with strong CYP3A4 inhibitors increases exposure to the major active metabolite of TAVALISSE (R406), which may increase the risk of adverse reactions. Monitor for toxicities that may require a reduction in TAVALISSE dose.
  • It is not recommended to use TAVALISSE with strong CYP3A4 inducers, as concomitant use reduces exposure to R406.
  • Concomitant use of TAVALISSE may increase concentrations of some CYP3A4 substrate drugs and may require a dose reduction of the CYP3A4 substrate drug.
  • Concomitant use of TAVALISSE may increase concentrations of BCRP substrate drugs (eg, rosuvastatin) and P-Glycoprotein (P-gp) substrate drugs (eg, digoxin), which may require a dose reduction of the BCRP and P-gp substrate drug.

Adverse Reactions

  • Serious adverse drug reactions in the ITP double-blind studies were febrile neutropenia, diarrhea, pneumonia, and hypertensive crisis, which occurred in 1% of TAVALISSE patients. In addition, severe adverse reactions occurred including dyspnea and hypertension (both 2%), neutropenia, arthralgia, chest pain, diarrhea, dizziness, nephrolithiasis, pain in extremity, toothache, syncope, and hypoxia (all 1%).
  • Common adverse reactions (≥5% and more common than placebo) from FIT-1 and FIT-2 included: diarrhea, hypertension, nausea, dizziness, ALT and AST increased, respiratory infection, rash, abdominal pain, fatigue, chest pain, and neutropenia.

 

Please see full Prescribing Information.

To report side effects of prescription drugs to the FDA, visit www.fda.gov/medwatch or call 1-800-FDA-1088 (1-800-332-1088).

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Indication and Important Safety Information

Indication

TAVALISSE is indicated for the treatment of thrombocytopenia in adult patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to a previous treatment.

Important Safety Information

Warnings and Precautions

  • Hypertension can occur with TAVALISSE treatment. Patients with pre-existing hypertension may be more susceptible to the hypertensive effects. Monitor blood pressure every 2 weeks until stable, then monthly, and adjust or initiate antihypertensive therapy for blood pressure control maintenance during therapy. If increased blood pressure persists, TAVALISSE interruption, reduction, or discontinuation may be required.
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September is ITP Awareness month

Join Rigel in helping to raise awareness of immune thrombocytopenia (ITP) and showing support for ITP patients, care partners, and healthcare providers

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