Tavalisse (fostamatinib disodium hexahydrate)

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1 Tavalisse (fostamatinib disodium hexahydrate) Policy Number: Last Review: 07/2018 Origination: 07/2018 Next Review: 07/2019 Policy Blue Cross and Blue Shield of Kansas City (Blue KC) will provide coverage for Tavalisse (fostamatinib) when it is determined to be medically necessary because the following criteria are met. When Policy Topic is covered Coverage of Tavalisse is recommended in those who meet the following criteria: FDA-Approved Indication 1. Chronic Immune Thrombocytopenia (ITP). Approve if the patient meets the following criteria (A, B, and C): A) The patient is 18 years of age; AND B) The agent is prescribed by or after consultation with a hematologist; AND C) The patient meets one of the following criteria (i or ii): i. The patient has tried one other therapy (e.g., corticosteroids, intravenous immunoglobulin, anti-d immunoglobulin, Promacta [eltrombopag tablets and oral suspension], Nplate [romiplostim injection for subcutaneous use], or Rituxan [rituximab injection for intravenous use]); OR ii. The patient has undergone splenectomy. The safety and efficacy of Tavalisse have not been established in patients < 18 years of age. 1 Due to the AEs on actively growing bones observed in nonclinical trials, use of Tavalisse is not recommended for patients < 18 years of age. Approval of Tavalisse in ITP is recommended in adults with chronic ITP who have had an insufficient response to previous treatment. 1 Other therapies tried, which are also recommended by guidelines, in the pivotal trials included corticosteroids, IVIG, splenectomy, TPO-RAs (i.e., Promacta, Nplate), and/or Rituxan. 3 When Policy Topic is not covered Tavalisse has not been shown to be effective, or there are limited or preliminary data or potential safety concerns that are not supportive of general approval for the following conditions. Rationale for noncoverage for these specific conditions is provided below. 1. B-Cell Lymphomas. Tavalisse has been investigated in patients with various B-cell lymphomas (e.g., non-hodgkin s lymphoma, diffuse large B-cell lymphoma [DLBCL]). Many other therapies are available for this use 2, Rheumatoid Arthritis. Tavalisse has been studied in patients with rheumatoid arthritis However, other therapies are more well-established and are recommended in guidelines. Considerations Tavalisse requires prior authorization through the Clinical Pharmacy Department.

2 This Blue Cross and Blue Shield of Kansas City policy Statement was developed using available resources such as, but not limited to: Food and Drug Administration (FDA) approvals, Facts and Comparisons, National specialty guidelines, Local medical policies of other health plans, Medicare (CMS), Local providers. Description of Procedure or Service Overview Tavalisse, a tyrosine kinase inhibitor with demonstrated activity against spleen tyrosine kinase, 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. 1 The major metabolite of Tavalisse, R406, inhibits signal transduction by Fc-activing receptors and B-cell receptor. The R406 metabolite reduces antibody-mediated destruction of platelets. The safety and efficacy of Tavalisse have not been established in pediatric patients. Use of Tavalisse is not recommended for patients < 18 years of age because adverse events (AEs) on actively growing bones were observed in nonclinical studies. In subchronic, chronic, and carcinogenicity studies involving Tavalisse, chondrodystrophy of the femoral head was observed in rodents. In a study involving juvenile rabbits, growth plate dysplasia was noted in the proximal femur and femoro-tibial joint, and bone marrow cellularity was reduced in the femur and sternum. Disease Overview ITP is a heterogeneous autoimmune disorder that is hallmarked by low platelet counts (< 100 x 10 9 /L) in the absence of other causes or disorders associated with thrombocytopenia. 2-4 Increased platelet destruction along with decreased platelet production are noted. The condition may happen in isolation (primary) or in association with other disorders (secondary). Some secondary causes are autoimmune diseases (e.g., antiphospholipid antibody syndrome), viral infections (e.g., human immunodeficiency virus [HIV], hepatitis C virus [HCV]), and certain medications (e.g., valproic acid). 2 Most adults (80%) have primary ITP. 4 The incidence reported has ranged from 3.3 to 9.5 per 100,000 adults. 4 The prevalence of ITP increases with age. 2 The incidence appears slightly higher in women of reproductive age and in the elderly. The disease may be persistent, despite treatment. Patients may also be resistant to treatment and experience relapses. 2 The hallmark symptom of ITP is bleeding from various sites (mucosal, gastrointestinal, urinary tract, petechiae). A concern is significant bleeding at selective sites, such as intracranial hemorrhage. Other associated symptoms include fatigue. 2 ITP is categorized into three district phases: newly-diagnosed (within 3 months of diagnosis); persistent (between 3 and 12 months from diagnosis); and chronic (condition present for > 12 months). 3 A noted therapy goal is to achieve a platelet count that is associated with effective hemostasis. Current therapies are intended to inhibit processes that cause destruction or prevent the development of platelets (e.g., corticosteroids, intravenous immunoglobulin [IVIG], anti-d immunoglobulin, Rituxan [rituximab injection for intravenous {IV} use]) or promote the production of new platelets (i.e., thrombopoietin receptor agonists [TPO-RAs] such as Promacta [eltrombopag tablets and oral suspension] and Nplate [romiplostim injection for subcutaneous {SC} use]). 3 Promacta, a TPO-RA, is indicated for the treatment of thrombocytopenia in adult and pediatric patients (aged 1 year) with chronic ITP who have had an insufficient response to corticosteroids, immunoglobulins or splenectomy. 5 Promacta is also indicated for the treatment of thrombocytopenia in patients with HCV, as well as for the treatment of severe aplastic anemia. 5 Nplate, a TPO-RA, is also indicated for the treatment of thrombocytopenia in patients with chronic ITP who have had insufficient response to corticosteroids, immunoglobulins, or splenectomy. 6 Other treatments used second-line for ITP include mycophenoate mofetil, dapsone, sirolimus, vincristine, 6-mercaptopurine, azathioprine, and danazol. 3,7 Although these agents have been used for many years in the management of ITP, rigorous trials that report the effects on bleeding, fatigue, and quality of life are limited. Clinical Efficacy The efficacy of Tavalisse was established in two identical, double-blind, placebo-controlled, multinational, randomized (2:1), 24-week studies (FIT-1 and FIT-2) in patients with persistent or chronic ITP with an insufficient response to previous therapies. 1,8 An open-label extension trial (FIT-3),

3 involving patients from FIT-1 and FIT-2 was also performed. 1,9 In FIT-1 (n = 76), a stable platelet response (defined as at least 50 x 10 9 /L on at least four of the six visits between Weeks 14 to 24) was achieved in 18% of patients (n = 9/51) who received Tavalisse compared with none of the patients who received placebo (P = 0.03). 1,8 In FIT-2 (n = 74), a stable platelet response (previously defined) was achieved in 16% of patients (n = 8/50) given Tavalisse vs. 4% of patients (n = 1/24) given placebo (a non statistically-significant difference). In FIT-1 and FIT-2, 47 patients given Tavalisse had received a prior TPO-RA therapy, of which 17% of patients (n = 8/47) achieved a stable response. In FIT-3 (n = 123), 50% of the patients (n = 61/123) discontinued early. Of the 44 patients treated with placebo in the prior study, 23% of patients (n = 10/44) met the criteria for a stable response. Rationale Guidelines The American Society of Hematology (ASH) has an evidence-based practice guideline for immune thrombocytopenia (2011). 3 This summary will focus on recommendations in adults, the population in which Tavalisse is indicated. Refer to the guideline for the management of younger patients or in specialized conditions (e.g., pregnancy, HCV or HIV-associated ITP). Treatment for adults is suggested for newly-diagnosed patients with a platelet count < 30 x 10 9 /L. Therapies should be individualized and consider the bleeding severity, the desired time course for platelet increases, and AEs. For newly-diagnosed adults with ITP, longer courses of corticosteroids are preferred over shortercourses of corticosteroids or IVIG as first-line therapy. When a more rapid increase in platelet count is required, IVIG should be used with corticosteroids. If corticosteroids are contraindicated, either IVIG or anti-d immunoglobulin (in appropriate patients) may be used as first-line treatment. For the treatment of adults who do not respond or relapse following initial corticosteroids therapy, several strategies are employed. Splenectomy is recommended for patients who have failed corticosteroids. For patients at risk of bleeding who relapse following splenectomy or who have a contraindicated to splenectomy and have failed at least one other therapy, TPO-RAs can be given. Also, TPO-RAs may be considered for patients at risk of bleeding who have failed one line of therapy, such as corticosteroids or IVIG, and who have not undergone splenectomy. Rituxan may be an alternative for patients at risk of bleeding who have failed one line of therapy (e.g., corticosteroids, IVIG, or splenectomy). No further treatment is recommended in asymptomatic patients after splenectomy who have achieved platelet counts > 30 x 10 9 /L. Safety The most common AEs) with Tavalisse were diarrhea (31%), hypertension (28%), nausea (19%), respiratory infection (11%), dizziness (11%), alanine aminotransferase (ALT) increases (11%), aspartate aminotransferase (AST) increases (9%), rash (9%), abdominal pain (6%), fatigue (6%), chest pain (6%), and neutropenia (6%). Tavalisse has Warnings/Precautions regarding hypertension, hepatotoxicity, diarrhea, neutropenia, and embryofetal toxicity. POLICY STATEMENT Prior authorization is recommended for prescription benefit coverage of Tavalisse. Due to the specialized skills required for evaluation and diagnosis of patients treated with Tavalisse as well as the monitoring required for AEs and long-term efficacy, approval requires Tavalisse to be prescribed by or in consultation with a physician who specializes in the condition being treated. References 1. Tavalisse tablets for oral use [prescribing information]. South San Francisco, CA and Whitby, Ontario: Rigel Pharmaceuticals and Patheon Whitby; April Newland A, Lee JE, McDonald V, Bussel JB. Fostamatinib for persistent/chronic adult immune thrombocytopenia. Immunotherapy. 2018;10(1): Neunert C, Lim W, Crowther M et al. The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood. 2011;117(16): Lambert MP, Gernsheimer TB. Clinical updates in adult immune thrombocytopenia. Blood. 2017;129(21):

4 5. Promacta tablets and oral suspension [prescribing information]. East Hanover, NJ: Novartis; October Nplate injection for subcutaneous use [prescribing information]. Thousand Oaks, CA: Amgen; October Grace RF, Neunert C. Second-line therapies in immune thrombocytopenia. Hematology Am Soc Hematol Educ Program. 2016;2016(1): 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 April 26. [Epub ahead of print]. 9. Bussel JB, Arnold DM, Cooper N, et al. Long-term maintenance of platelet responses in adult patients with persistent/chronic immune thrombocytopenia treated with fostamatinib: 1-year efficacy and safety results. Blood. 2017;130(Suppl 1):16. Available at: Accessed on May 14, Flinn IW, Bartlett NL, Blum KA, et al. A phase II trial to evaluate the efficacy of fostamatinib in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). Eur J Cancer. 2016;54: Friedberg JW, Sharman J, Sweetenham J, et al. Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-hodgkin lymphoma and chronic lymphocytic leukemia. Blood. 2010;115(13): Genovese MC, van der Heijde DM, Keystone EC, et al. A phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study of 2 dosing regimens of fostamatinib in patients with rheumatoid arthritis with an inadequate response to a tumor necrosis factor-α antagonist. J Rheumatol. 2014;41(11): Weinblatt ME, Genovese MC, Ho M, et al. Effects of fostamatinib, an oral spleen tyrosine kinase inhibitor, in rheumatoid arthritis patients with an inadequate response to methotrexate: result from a phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Arthritis Rheumatol. 2014;66(12): Weinblatt ME, Kavanaugh A, Genovese MC, et al. An oral spleen tyrosine kinase (SYK) inhibitor for rheumatoid arthritis. N Engl J Med. 2010;363(14): Taylor PC, Genovese MC, Greenwood M, et al. OSKIRA-4: a Phase IIb randomized, placebocontrolled study of the efficacy and safety of fostamatinib monotherapy. Ann Rheumat Dis. 2015;74(12): Kunwar S, Davkota AR, Ghimire DK. Fostamatinib, an oral spleen tyrosine kinase inhibitor, in the treatment of rheumatoid arthritis: a meta-analysis of randomized controlled trials. Rheumatol Int. 2016;36(8): Billing Coding/Physician Documentation Information N/A Tavalisse is considered a pharmacy benefit Additional Policy Key Words Policy Number: Policy Implementation/Update Information 07/2018 New policy titled Tavalisse (fostamatinib disodium hexahydrate) State and Federal mandates and health plan contract language, including specific provisions/exclusions, take precedence over Medical Policy and must be considered first in determining eligibility for coverage. The medical policies contained herein are for informational purposes. The medical policies do not constitute medical advice or medical care. Treating health care providers are independent contractors and are neither employees nor agents Blue KC and are solely responsible for diagnosis, treatment and medical advice. No part of this publication may be reproduced, stored in a

5 retrieval system or transmitted, in any form or by any means, electronic, photocopying, or otherwise, without permission from Blue KC.