Supplement

An Update on New and Emerging Therapies for Relapsing-Remitting Multiple Sclerosis

Published Online: November 30, 2013
Bianca Weinstock-Guttman, MD
Disease-modifying therapies (DMTs), known to actively reduce relapses and delay disability progression, have been used for the treatment of relapsing-remitting multiple sclerosis (RRMS) for over a decade. These well-known therapies include intramuscular (IM) interferon (IFN) beta-1a (Avonex), subcutaneous (SC) IFN beta-1a (Rebif), SC IFN beta- 1b (Betaseron; Extavia), and SC glatiramer acetate (Copaxone). These first-line therapies have shown only partial benefits for controlling multiple sclerosis (MS) disease activity and are often associated with inadequate patient adherence. Low patient adherence to therapy may be related to the mode of administration or to the side effects associated with treatment. The intravenous DMT natalizumab (Tysabri; dosed monthly) provides high therapeutic efficacy and good compliance but is considered a second-line intervention because of the associated increased risk for progressive multifocal leukoencephalopathy. In 2010, fingolimod (Gilenya), the first oral DMT, was approved by the US Food and Drug Administration (FDA) for the treatment of MS. Recently, 2 new oral DMTs received FDA approval for the treatment of RRMS: teriflunomide (Aubagio) and dimethyl fumarate (Tecfidera). In addition, oral laquinimod, several monoclonal antibodies (eg, alemtuzumab, daclizumab, and ocrelizumab), and other agents have shown preliminary beneficial results in relapsing MS in phase 3 clinical trials. These new and emerging DMTs may provide a more efficacious individualized therapeutic approach, more favorable methods of administration (eg, oral administration), and/or a lower frequency of infusions (eg, annually, 3-5 daily infusions over a year for alemtuzumab) that may improve patient adherence and clinical outcomes.

(Am J Manag Care. 2013;19:S343-S354)
I n 1993, the US Food and Drug Administration (FDA) approved the first disease-modifying therapy (DMT), interferon (IFN) beta-1b, marking a major change in the management of multiple sclerosis (MS).1 Prior to the development of DMTs, MS was considered an untreatable disease, and management strategies for MS were primarily focused on treating the acute attacks (relapses) that are characteristic of the disease course for the majority of MS patients1 and on diminishing the associated neurological symptoms (symptomatic therapies).2,3 DMTs, which include immunomodulatory, anti-inflammatory, and immunosuppressive drugs,4 are used to slow the development of MS-related neurological damage and disability progression and to reduce the occurrence of relapses.1,5 By providing a more effective approach to MS treatment, DMTs may improve quality of life for individuals with MS.4

Following the first IFN product (subcutaneous [SC] IFN beta- 1b [Betaseron, Bayer HealthCare Pharmaceuticals Inc; Extavia, Novartis Pharmaceuticals, Inc]), additional interferon products (IFN beta-1a intramuscular [IM], Avonex, Biogen Idec; and IFN beta-1a SC, Rebif, EMD Serono, Inc), glatiramer acetate (GA) (Copaxone, Teva Pharmaceutical Industries Ltd), natalizumab (Tysabri, Biogen Idec), fingolimod (Gilenya, Novartis Pharmaceuticals Corporation), and more recently, teriflunomide (Aubagio, Genzyme Corporation) and dimethyl fumarate (DMF; Tecfidera, Biogen Idec), have received FDA approval for the treatment of relapsing MS.1,4,6,7 Mitoxantrone is approved for the treatment of secondary-progressive MS (SPMS), progressiverelapsing MS, or worsening relapsing-remitting MS (RRMS).8 A stepwise approach was generally followed for MS DMTs used in the pre-oral era; therapy was usually initiated with IFN beta or GA, and patients who did not respond to these first-line agents were treated with natalizumab or, more rarely, mitoxantrone.9,10 First- and second-line DMTs have been shown to reduce the rate of MS relapses, slow the progression of disability, and reduce magnetic resonance imaging (MRI) measures of disease activity.1,5,11 Despite the demonstrated efficacy of DMTs, patient adherence to DMTs remains problematic.12,13 Poor patient adherence to therapy may result in reduced treatment efficacy in delaying MS progression and in poorer patient outcomes.14 There is some evidence that poor patient adherence to DMT may be related to the fact that some of these agents are administered via SC or IM injection.10,14-16 In a study of 2648 patients receiving IFN beta or GA, the most common reasons for nonadherence to treatment were forgetting to administer the injection (50.2%) and other injection-related reasons (32.0%).15 To improve adherence to DMTs and outcomes associated with long-term DMT use, recent attention has focused on the development of DMTs with improved tolerability and efficacy and those that are orally administered or require less frequent administration.17-22 This review will briefly describe the efficacy and safety of established DMTs, including IFN beta, GA, natalizumab, and fingolimod; data from large phase 3 trials of the 2 DMTs that most recently received FDA approval (teriflunomide and DMF) are also described. Efficacy, quality of life, and tolerability data for new and emerging DMTs will also be discussed. Mitoxantrone, approved as treatment for SPMS and worsening RRMS, is not detailed further due to the relative infrequency of its use, mostly related to the side effects associated with its administration, including cardiotoxicity and leukemia, which developed even after administration of lower than the maximum recommended dose (ie, 140 mg/m2).23

Established DMTs

IFN Beta


IFN beta, which has numerous immunomodulatory activities, was the first DMT approved for the management of MS and remains the foundation of many MS treatment algorithms.5,9,10 Three formulations of IFN beta are currently approved for the treatment of RRMS24-27: SC IFN beta-1b (administered every other day), SC IFN beta-1a (administered 3 times weekly), and IM IFN beta-1a (administered once weekly).5,28 In randomized, controlled, phase 3 studies, all formulations of IFN beta have been associated with an approximate 30% reduction in the annualized relapse rate compared with placebo, as well as significant decreases in MRI markers of disease activity compared with placebo (P <.05) in patients with RRMS (Table 1).29-41 In addition, in short, controlled studies, significant delays in the time to sustained progression of disability have been observed with IFN beta-1a treatment compared with placebo (P <.05).29,30 The efficacy of different IFN beta formulations for decreasing the relapse rate and delaying disability progression in patients with MS is generally comparable; however, direct comparative studies have shown some differences in relapse outcomes, favoring the more frequent SC formulations over IM IFN beta-1a.42-45 In patients with a first demyelinating event (ie, patients with clinically isolated syndrome [CIS]), IFN beta- 1b treatment has been shown to significantly delay the time to development of clinically definite MS (CDMS) compared with placebo (P <.0001),33 and IM IFN beta-1a has been associated with a significant decrease in the probability of developing CDMS compared with placebo (P = .002).34 Flulike symptoms and injection site reactions are 2 of the most common side effects associated with IFN beta therapy.29-31

GA

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