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Comparative Clinical and Cost-Effectiveness of Drug Therapies for Relapsing-Remitting Multiple Sclerosis [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2013 Oct. (CADTH Therapeutic Review, No. 1.2B.)

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Comparative Clinical and Cost-Effectiveness of Drug Therapies for Relapsing-Remitting Multiple Sclerosis [Internet].

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1.1. Multiple Sclerosis

Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system.1 It is a demyelinating disease for which the course is variable, it is more common in women by a factor of approximately 3:1 compared with men,4 and it is the leading cause of disability in young adults.39 The prevalence of MS varies geographically and is more common in the northern hemisphere. Canada has the fifth-highest worldwide prevalence, at 240 per 100,000 persons.5,40

MS is classified into four subtypes: primary-progressive, secondary-progressive, progressive-relapsing, and relapsing-remitting (RRMS). Approximately 85% to 90% of MS patients have RRMS,5 which is characterized by clearly defined relapses of impairment, followed by remissions with full recovery or with sequelae and residual deficit. Relapses are defined as acute or subacute onset of clinical dysfunction, followed by a remission. Frequency of relapse is highly variable, but tends to be more frequent in the first few years after disease onset.5 Patients with RRMS typically have earlier onset of disease compared to those with primary-progressive, between 25 and 29 years, which may convert to secondary-progressive disease — typically at a mean age between 40 and 44.41

Early diagnostic criteria for MS required two neurological events to establish a diagnosis of MS;9,42,43 however, the revised criteria currently in use allow for a diagnosis of MS after one neurological event in combination with MRI findings.12,44,45 Markers of MS on MRI are gadolinium-enhancing (GdE) and T2 lesions, which are seen at the early stage of disease.8 T2 lesions represent burden of disease, while GdE lesions are indicative of active inflammation in conjunction with blood-brain barrier disruptions. Biopsy and autopsy histological findings in patients with MS show inflammatory T-cells, B-cells, and macrophages.

MS is a slowly progressing disease, although it can be difficult to determine both the natural history and time to progression of disease because of difficulty in determining the “start time” of the disease — the onset of symptoms as defined by the patient, or the date of diagnosis.46 The natural history in mostly untreated Canadian MS populations has been examined in both Ontario47 and British Columbia.46 Weinshenker et al. followed 1,099 untreated patients in London, Ontario, between 1979 and 1984.47 Sensory impairment was the most common presenting symptom of MS. The median time of sustained progression to mild disability was 7.7 years; to the need to use a cane or other walking aid was 15 years; and to being restricted to a wheelchair or bed was 46 years. The percentage of patients who converted from RRMS to secondary-progressive disease increased steadily over time, with more than half of patients entering the secondary-progressive phase within the first 10 years following the MS diagnosis.

The study from British Columbia by Tremlett et al. examined prospectively collected data from patients at MS clinics in British Columbia.46 The authors followed 2,837 patients, 70% of whom were women, for 22,723 patient-years, and measured disability every 1.1 years; a small number (7.5% of active follow-up) received immunomodulatory drug treatment. Fifteen years after the onset of disease, 21% of their patient population required the use of a cane, and after 40 years, 69% needed a walking aid. The median time of sustained progression requiring a cane was 27.9 years, with 52% of the population requiring a walking aid at age 60.

The longer time to sustained progression (Expanded Disability Status Scale [EDSS 6]) in the population in British Columbia (27.9 years) compared with that of the Ontario population (15.0 years) may have been because of a higher percentage with progressive disease in Ontario (20% versus 12%), which results in more rapid progression.46 Tremlett et al.46 also found that older onset of disease and male sex were not associated with poorer disease outcomes.

1.2. Therapeutic Options

The therapeutic aims of MS drugs are to reduce the frequency of relapses, decrease the lasting effects of relapses, prevent or decrease disability that is the result of disease progression, and promote tissue repair.1,6 In Canada, the earliest available disease-modifying treatments for MS included interferons (interferon beta-1a and interferon beta-1b) and glatiramer acetate, which were approved by Health Canada in the 1990s.

Natalizumab, administered via intravenous infusion, was approved by Health Canada in 2006 for the treatment of RRMS; however, natalizumab treatment is thought to increase the risk for progressive multifocal leukoencephalopathy (PML), a rare demyelinating neurological disorder caused by the reactivation of the JC Virus.7,8 Post-marketing data have estimated the risk of developing PML to be 1 in 500 patients treated with natalizumab.48 The three factors that are known to increase the development of PML are the presence of anti-JC Virus antibodies, longer treatment duration (particularly beyond 24 months), and prior immunosuppressant treatment.49 The Health Canada-approved product monograph for natalizumab states that natalizumab is generally recommended in MS patients who have had an inadequate response to, or are unable to tolerate, other therapies for MS.49

Fingolimod, the first oral agent for the treatment of RRMS, was approved by Health Canada in 2011. The Health Canada-approved product monograph for fingolimod states that fingolimod is generally recommended in MS patients who have had an inadequate response to, or are unable to tolerate, one or more therapies for multiple sclerosis.50 More recently (2013), dimethyl fumarate, another oral agent for the treatment of relapsing-remitting MS, was approved by Health Canada during the conduct of this Therapeutic Review.

While only the interferons have specific product monograph contraindications for pregnancy, animal studies of fingolimod show potential teratogenicity.50 It is unclear as to whether natalizumab is safe during pregnancy;49 and although it is unclear whether glatiramer acetate is safe during pregnancy, it is not recommended for use in pregnant women.51 Further details regarding the approved therapeutic options for the treatment of RRMS, according to their Health Canada product monographs, are included in Table 1.

Table 1. Summary of Health Canada-Approved Therapeutic Options of Interest Based on Product Monographs.

Table 1

Summary of Health Canada-Approved Therapeutic Options of Interest Based on Product Monographs.

1.3. Emerging Treatments

Currently, a number of new disease-modifying therapies are in development for the treatment of MS (both oral and intravenous), including alemtuzumab (intravenous) and teriflunomide (oral), which are expected to enter the Canadian market shortly.

Alemtuzumab, an emerging injectable agent, is a humanized monoclonal antibody that causes depletion of certain T-cells, natural killer cells, and monocytes.14 Teriflunomide, an emerging oral agent for the treatment of RRMS, is a pyrimidine biosynthesis that disrupts the interaction of T-cells with antigen-presenting cells.

1.4. Issue

The comparative effectiveness and safety of current MS treatments is not well-established.1 With the emergence of novel oral and injectable agents, and the uncertainty in the comparative effectiveness of current treatments, the landscape of disease-modifying treatments is evolving and becoming more complex for health care decision-makers. It is therefore important to determine the comparative clinical and cost-effectiveness of currently available and emerging disease-modifying agents for MS, both as monotherapy and in combination. While oral agents may be preferred by patients, their clinical benefit and cost-effectiveness compared with older injectable agents requires evaluation.

Copyright © CADTH March 2013.

Except where otherwise noted, this work is distributed under the terms of a Creative Commons Attribution-NonCommercial- NoDerivatives 4.0 International licence (CC BY-NC-ND), a copy of which is available at

Bookshelf ID: NBK169754


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