Aubagio (teriflunomide tablets) Policy Number: Last Review: 07/2017 Origination: 07/2014 Next Review: 07/2018

Transcription

1 Aubagio (teriflunomide tablets) Policy Number: Last Review: 07/2017 Origination: 07/2014 Next Review: 07/2018 Policy Blue Cross and Blue Shield of Kansas City (Blue KC) will provide coverage for Aubagio (teriflunomide) when it is determined to be medically necessary because the following criteria are met. When Policy Topic is covered Coverage of Aubagio is recommended in those who meet the following criteria. Food and Drug Administration (FDA)-Approved Indications 1. Relapsing Forms of Multiple Sclerosis (MS) in Patients Who Are Not Currently Receiving Aubagio. Approve for patients who meet the following criteria (A, B, and C): A) The patient has a relapsing form of MS (relapsing forms of MS include relapsing-remitting multiple sclerosis [RRMS], secondary-progressive multiple sclerosis [SPMS] with relapses, and progressive-relapsing multiple sclerosis [PRMS]); AND B) The agent is prescribed by, or in consultation with, a neurologist or a physician who specializes in the treatment of MS; AND C) The patient meets ONE of the following conditions (i or ii): i. The patient is unable to administer injections due to dexterity issues or visual impairment; OR ii. The patient has tried one of the following: Avonex, Rebif, Betaseron, Extavia, Copaxone, Glatopa (glatiramer acetate injection for SC use) or Plegridy (peginterferon beta-1a for SC injection). Aubagio is indicated for the treatment of patients with relapsing forms of MS. 1 MS can be a devastating neurological disease and requires extensive follow-up and monitoring of disease activity (e.g., MRI studies to determine axonal damage). Patients are usually followed by a neurologist or a physician who specializes in the treatment of MS, or after consultation with such a specialist if access is limited, to determine the most appropriate care. The interferon beta products and Copaxone have been available in the US since the mid-1990s and have established efficacy and long-term safety. Experience with Aubagio in patients with MS is limited and long-term safety data are not available. Guidelines by the National MS Society, updated in 2008, recommend interferon beta products and Copaxone as first-line therapy as soon as possible after a definite diagnosis of MS with active, relapsing disease, or in those who have experienced a first attack who are at high risk for MS. Extensive, evidence-based, nationallyrecognized updated guidelines are not available that include Aubagio. In general, Copaxone is at least as effective as interferon beta products. 6-7 There are limitations in comparing the more recently performed pivotal trials with Aubagio with the pivotal trials involving interferon beta products and Copaxone (e.g., heterogenous patient populations, use of different MS diagnostic criteria, varying standards of care, different annualized relapse rates at baseline). Although the data are not comparative, in the TEMSO study Aubagio reduced the relapse rate by 30%, which is similar to that observed in the pivotal clinical trials with interferon beta products and Copaxone. 2,6 Also, the TENERE study suggests that Rebif is at least as effective as Aubagio. 3 The pivotal trials with Tecfidera (dimethyl fumarate capsules) and Gilenya (fingolimod capsules) suggest improved efficacy compared

2 with Aubagio. 8-9 However, indirect comparisons among pivotal trials of more recently approved oral disease-modifying agents for MS also should be interpreted cautiously for many of the previously stated reasons. 2. Relapsing Forms of Multiple Sclerosis (MS) in Patients Who Are Currently Receiving Aubagio or Who Have Received Aubagio in the Past. Approve if the patient meets the following criteria (A and B): A) Patient has a relapsing form of MS, (relapsing forms of MS are RRMS, SPMS with relapses, and PRMS); AND B) The agent is prescribed by, or in consultation with, a neurologist or a physician who specializes in the treatment of MS. Aubagio is indicated for the treatment of patients with relapsing forms of MS. 1 MS can be a devastating neurological disease and requires extensive follow-up and monitoring of disease activity (e.g., MRI studies to determine axonal damage). Patients are usually followed by a neurologist or a physician who specializes in the treatment of MS, or after consultation with such a specialist if access is limited, to determine the most appropriate care. When Policy Topic is not covered Aubagio 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. (Note: This is not an exhaustive list of Conditions Not Recommended for Approval.) 1. Patient has a Non-Relapsing Form of Multiple Sclerosis (MS) [e.g., primary progressive MS]. The efficacy of Aubagio has not been established in patients with MS with non-relapsing forms of MS Concurrent use of Aubagio with Other Disease-Modifying Agents Used for Multiple Sclerosis (MS) [e.g., Avonex, Rebif, Betaseron, Extavia, Copaxone, Glatopa, Plegridy, Tysabri, Gilenya, Tecfidera and Lemtrada {almetuzumab injection for intravenous use}]. These agents are not indicated for use in combination. 1 Some preliminary data have studied Aubagio in combination with interferon beta products 10 and Copaxone in patients with relapsing forms of MS 11. The long-term safety of these combinations in the treatment of MS has not been established. 1 Larger, Phase III investigations need to be completed before combination use can be recommended. 3. Coverage is not recommended for circumstances not listed in the Recommended Authorization Criteria. Criteria will be updated as new published data are available. Considerations Aubagio requires prior authorization through the Clinical Pharmacy Department. 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 Aubagio, a pyrimidine synthesis inhibitor, is indicated for the treatment of patients with relapsing forms of multiple sclerosis (MS). 1 The recommended dose of Aubagio is 7 mg once daily (QD) or 14 mg QD. Aubagio should not be used in patients with severe hepatic impairment, women who are pregnant, or in those concurrently receiving leflunomide. The most common adverse events (AEs) with Aubagio include increases in alanine aminotransferase (ALT), alopecia, diarrhea, influenza, nausea, and paresthesia. Transaminase and bilirubin levels should be obtained 6 months before initiation of

3 Aubagio. Monitor ALT levels at least monthly for 6 months after commencing Aubagio treatment. Obtain a complete blood count (CBC) within 6 months before the initiation of Aubagio therapy. Conduct further monitoring based on signs and symptoms of infection. Prior to starting Aubagio, screen patients for latent tuberculosis (TB) infection with a tuberculin skin test. Monitor blood pressure before initiating Aubagio therapy and periodically thereafter. Elimination of Aubagio can be accelerated by administration of cholestyramine or oral activated charcoal for 11 days. Aubagio is in Pregnancy Category X. Rationale Clinical Efficacy The TEMSO (TEriflunomide Multiple Sclerosis Oral) trial studied Aubagio 7 mg QD and Aubagio 14 mg QD vs. placebo in patients (n = 1,008) with relapsing forms of MS (e.g., relapsing remitting [91.4%], secondary progressive [4.6%], and progressive relapsing [4.0%]). After 108 weeks, Aubagio 7 mg QD and Aubagio 14 mg QD reduced the annualized relapse rate (ARR) compared with patients who received placebo (ARR was 0.54 for placebo vs for Aubagio [both doses]; P < for both comparisons vs. placebo). 1-2 The percent of patients remaining relapse-free at Week 108 was also statistically significantly better for patients receiving Aubagio (53.7% for Aubagio 7 mg and 56.5% for Aubagio 14 mg) compared with placebo (45.6%). The percent of patients with disability progression at Week 108 was reduced with patients given Aubagio 14 mg QD (20.2%) compared with placebo (27.3%) [P = 0.028]. Magnetic resonance imaging (MRI) findings suggested a statistically significant decrease in disease activity with Aubagio compared with placebo. 1-2 TOWER (Teriflunomide Oral in People With Relapsing Multiple Sclerosis) was a Phase III, international, randomized, double-blind, placebo-controlled trial lasting for up to 40 months in patients with relapsing remitting MS that also showed that Aubagio 7 mg QD and Aubagio 14 mg QD led to a statistically significant 22% and 36% relative risk reduction, respectively, compared with placebo in the annualized relapse rate (n = 1,165). 1,12 For patients who received Aubagio 14 mg QD, there was a significant reduction in the relative risk of disability progression at Week 108 sustained for 12 weeks compared with placebo (15.8% vs. 19.7%; P = 0.044). 1,12 TOPIC was a double-blind, randomized, placebo-controlled trial that assessed Aubagio 7 mg QD and Aubagio 14 mg QD for up to 108 weeks in patients with relapsing MS (n = 614). Patients were required to have experienced a first clinical event consistent with acute demyelination occurring within 90 days of randomization with two or more T2 lesions at least 3 mm in diameter that were suggestive of MS. 1,13 More patients in the Aubagio 7 mg QD group (70.5%) and the Aubagio 14 mg QD group (n = 72.2%) were free of relapses compared with patients in the placebo group (61.7%) [P < 0.05 for both Aubagio groups]. 1 The TENERE (TErifluNomidE and REbif ) study assessed Aubagio 7 mg QD, Aubagio 14 mg QD, and Rebif [interferon beta-1a [subcutaneous {SC}], titrated up to 44 mcg SC three times weekly (TIW), in patients mainly with relapsing-remitting MS (n = 324) for up to 48 weeks. 3 The trial was not performed in the US; therefore, a foreign formulation of Rebif was utilized. Of note, Aubagio was administered in a double-blind fashion whereas Rebif was given open-label. The primary composite endpoint was time to failure, which was defined as the first occurrence of confirmed relapse or permanent treatment discontinuation for any cause. Many secondary endpoints were assessed including the ARR, defined as the number of confirmed relapses during the treatment period per patient-year. No difference was detected between either the Aubagio or Rebif group regarding time to failure. At Week 48, the cumulative percentage of estimated failures utilizing the Kaplan-Meier Method was 37%, 36%, and 33% for Rebif, Aubagio 7 mg QD, and Aubagio 14 mg QD, respectively. Permanent treatment discontinuation rates were higher for patients receiving Rebif (24.0% [n = 25/104]) compared with Aubagio 7 mg QD (6.4% [n = 7/109]) and Aubagio 14 mg QD (13.5% [n = 15/111]). Confirmed relapse was noted in fewer patients receiving Rebif (15.4% [n = 16/104]) compared with Aubagio 7 mg QD (42.2% [n = 46/109]) and Aubagio 14 mg QD (23.4% [n = 26/111]). No difference was noted in adjusted ARR between Rebif and Aubagio 14 mg QD (0.22 vs. 0.26; P = 0.6), although ARR was significantly higher in patients receiving Aubagio 7 mg QD (0.41; P = 0.03 vs. Rebif).

4 Disease Course Four different clinical courses of MS have been described. 4 Relapsing-remitting MS is characterized by acute worsening of neurologic function, usually followed by almost complete recovery with limited progression. Approximately 85% of patients are initially diagnosed with relapsing-remitting MS. Disability progression is usually minimal. However, many patients will experience secondary progression of disability in time and will have a different form of MS. Secondary progressive MS begins as an initial relapsing-remitting course, but the disease transitions in many patients to a steadily progressive form with increased loss of function. Of the 85% of patients who started with relapsingremitting MS, more than 50% will develop secondary progressive MS within 10 years and 90% within 25 years. Primary progressive MS is noted as a continued worsening of disease from onset, without distinct relapses. Approximately 10% of patients are diagnosed with primary progressive MS. Progressive relapsing MS starts with disease progression at onset with occasional acute relapses but continued disease progression. Around 5% of patients appear to have progressive-relapsing MS at diagnosis. Around 10% of patients with MS have a benign MS course, which is generally determined retrospectively. Relapses or exacerbations of MS can vary in severity, duration, and frequency, as well as in the symptomatology. GUIDELINES Evidence-based guidelines that extensively review the clinical literature regarding therapies for MS have not been updated recently. In 2008 the National Clinical Advisory Board of the National MS Society published an expert opinion paper regarding treatment recommendations for physicians. 5 Initiation of therapy with an interferon beta medication (i.e., Avonex [interferon beta-1a, intramuscular {IM}]), Rebif, Betaseron /Extavia [interferon beta-1b SC]), or Copaxone (glatiramer acetate injection SC) should be considered as soon as possible after a definitive diagnosis of MS with active, relapsing disease, and may be considered for selected patients with a first attack who are at high risk of MS. Therapy should be continued indefinitely unless it is not tolerated or benefit is not obtained. The oral disease-modifying agents approved for relapsing forms of MS have not been incorporated into the expert opinion paper. Tysabri (natalizumab injection for intravenous [IV] use) is generally recommended for patients who have had an inadequate response to, or are unable to tolerate other MS therapies. Treatment with mitoxantrone injection may be considered for selected relapsing patients with worsening disease or patients with secondary-progressive MS with worsening, whether or not relapses are occurring. REFERENCES 1. Aubagio tablets [prescribing information]. Cambridge, MA: Genzyme Corporation (a Sanofi company); October O Connor P, Wolinsky JS, Confavreux C, et al, for the TEMSO Trial Group. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med. 2011;365(14): [Supplementary Appendix]. 3. Vermersch P, Czlonkowska A, Grimaldi LM, et al, for the TENERE Trial Group. Teriflunomide versus subcutaneous interferon beta-1a in patients with relapsing multiple sclerosis: a randomized, controlled phase 3 trial. Mult Scler. 2014;20(6): Clinical bulletin. Information for health professionals. Overview of multiple sclerosis by Rosalind Kalb and Nancy Reitman National Multiple Sclerosis Society. 5. Expert Opinion Paper by the Medical Advisory Board of the National Multiple Sclerosis Society. Treatment recommendations for physicians. Disease management consensus statement Available at n_disease-management-consensus-statement-(under-revision).pdf. Accessed on July 1, McGraw CA, Lublin FD. Interferon beta and glatiramer acetate therapy. Neurotherapeutics. 2013;10(1): Mikol DD, Barkhof F, Chang P, et al. Comparison of subcutaneous interferon beta-1a with glatiramer acetate in patients with relapsing multiple sclerosis (the REbif vs. Glatiramer Acetate in Relapsing MS Disease [REGARD] study): a multicenter, randomized, parallel, open-label trial. Lancet Neurol. 2008;7:

5 8. Tecfidera delayed-release capsules [prescribing information]. Cambridge, MA: Biogen Idec; April Gilenya [package insert]. East Hanover, NJ: Novartis; May Freedman MS, Wolinsky JS, Wamil B, et al, for the teriflunomide multiple sclerosis trial group and the MRI analysis center. Teriflunomide added to interferon-β in relapsing multiple sclerosis. A randomized phase II trial. Neurology. 2012;78: Freedman MS, Wolinsky JS, Wamil B, et al. Oral teriflunomide plus glatiramer acetate in relapsing multiple sclerosis [abstract p17]. Int J MS Care. 2011;13(Suppl 3):9 12. Confavreux C, O Connor P, Comi G, et al, for the TOWER Trial Group. Oral teriflunomide for patients with relapsing multiple sclerosis (TOWER): a randomized, double-blind, placebo-controlled phase 3 trial. Lancet Neurol. 2014;13: Miller AE, Wolinsky JS, Kappos L,e t al, for the TOPIC Study Group. Oral teriflunomide for patients with a first clinical episode suggestive of multiple sclerosis (TOPIC): a randomized, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol. 2014;13(10): Billing Coding/Physician Documentation Information Aubagio is a specialty pharmacy benefit Additional Policy Key Words Policy Policy Implementation/Update Information 07/2016 Policy reviewed-no changes 07/2017 Annual review-no changes to policy statement 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 retrieval system or transmitted, in any form or by any means, electronic, photocopying, or otherwise, without permission from Blue KC.