Update on Disease-Modifying Treatments for Multiple Sclerosis

Update on Disease-Modifying Treatments for Multiple SclerosisReview Article
Michael D. Carrithers, MD, PhD
Neurology Service, William S. Middleton Memorial Veterans Hospital, Departments of Neurology and Pathology and Program in Cellular and Molecular Pathology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
ABSTRACT
Purpose: The purpose of this review is to discuss the selection and use of disease- modifying treatments for patients with relapsing forms of multiple sclerosis (MS).
Methods: PubMed was searched (1966–2014) using the terms multiple sclerosis, treatment, interferon, glatiramer acetate, dimethyl fumarate, fingolimod, teri- flunomide, natalizumab, rituximab, and alemtuzumab.
Findings: MS is a chronic neurological disorder that can cause a substantial degree of disability. Because of its usual onset in young adults, patients may require treatment for several decades. Currently available agents include platform injectable therapies, newer oral agents, and second-line monoclonal anti- body treatments. Treatment decisions have become more complex with the introduction of new ap- proaches, and a major goal is to balance perceived efficacy and tolerability in a specific patient with the relative impact of disease activity and adverse events on quality of life. Here the options for disease- modifying treatments for relapsing forms of MS are reviewed, and current and future challenges are discussed.
Implications: An evidence-based approach can be used for the selection of disease-modifying treatments based on disease phenotype and severity, adverse events, and perceived efficacy. (Clin Ther. 2014;36:1938–1945) Published by Elsevier HS Jour- nals, Inc.
Accepted for publication August 17, 2014. http://dx.doi.org/10.1016/j.clinthera.2014.08.006 0149-2918/$ - see front matter
Published by Elsevier HS Journals, Inc.
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Key Words: immune therapy, multiple sclerosis, interferon, glatiramer, natalizumab, fumarate.
INTRODUCTION Multiple sclerosis (MS) is the most common cause of nontraumatic neurological disability in young adults and has a high personal and societal impact on quality of life and health-care costs.1 Many options currently exist to treat relapsing forms of MS. These include platform injectable therapies, newer oral options, and targeted monoclonal antibody agents for those who require more aggressive therapy. All of these approaches have demonstrated efficacy at reducing the number of clinical relapses and appearance of new lesions on imaging. Although effects on long-term outcome are less clear, there is evidence that early treatment can reduce long-term mortality associated with MS disability.2,3
All current disease-modifying treatments modulate or suppress immune function, particularly within lympho- cyte subsets.4 The success of these approaches combined with numerous studies on immunology,5,6 pathogene- sis,7,8 and genetics9 has confirmed that MS is an immune-mediated disorder of the central nervous sys- tem (CNS). Because of the relatively high incidence of MS in some populations and the ability to monitor disease activity clinically and radiologically, the develop- ment of MS therapeutics has been at the leading edge of translational research in autoimmune and neuro-
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logical disorders. Here I review the currently approved agents, discuss the risks and benefits relevant to the aggressiveness of the disease course and perceived efficacy, and outline the longer term goals and challenges.
METHODS Published studies relevant to treatment of MS were identified by a search of PubMed. The literature search was limited to the English language and had no limit on the year of publication.
First-Line Disease-Modifying Treatments Platform Injectable Therapies
The platform injectable therapies include several β interferons* and glatiramer acetate.† The advantage of these agents is that they have 420 years of safety data, and serious adverse events occur rarely. The major disadvantages are that only a subset of patients responds to these treatments and the effect can be modest. Nevertheless, these agents have clearly benefited many patients. Their mechanism of action is targeted primarily at modulation of T lymphocyte differentiation10 and function,11 and, in general, they do not have a marked immunosuppressant effect.
Interferon-β (IFN-β) 1b was the first agent to demonstrate a clear effect on relapse rate reduction. This finding revolutionized treatment of MS patients and encouraged further development of disease- modifying treatments. In a pivotal trial, IFN-β 1b at a dose of 8 MIU every other day reduced the exa- cerbation rate by approximately one third in treated patients compared with the placebo group.12
Subsequently, other IFN-β formulations and dosage schedules have been shown to have similar efficacy,13
and there may be a slight benefit of higher dose preparations during the first year of treatment.14
Their long-term safety profile is relatively favorable. However, because of the possibility of transaminitis and hematological adverse events, laboratory moni- toring of liver functions and blood count needs to be performed on a regular basis. In addition, many patients experience flu-like side effects of variable severity, and some patients may develop a worsening
*Avonexs (Biogen Idec), Betaserons (Bayer Healthcare), Extavias (Novartis Pharmaceutical Corporation, Whippany, New Jersey), and Rebifs (Pfizer).
†Copaxones (TEVA Neuroscience).
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of depression. Ease of use of IFN-β may be increased in the near future by the introduction of a pegylated form, peginterferon-β 1a,‡ that will allow adminis- tration every other week.15
IFN-β is also approved for use in patients who have had a single clinical demyelination event and are at high risk of experiencing a second one. These patients are classified as having a clinically isolated syndrome. The risk of having a second clinical attack is primarily determined by magnetic resonance imaging (MRI) evidence of demyelinating-type lesions disseminated in space. For this patient group, treatment with once- weekly IFN-β 1a reduced the risk of a second relapse by approximately one third during a 3-year follow- up.16 Subsequent studies demonstrated that treatment of a clinically isolated syndrome with other IFN-β preparations17,18 and glatiramer acetate19 also reduce the risk of a second event.
Unlike IFN-β, which is an endogenous cytokine and a biological agent, glatiramer acetate is a random copolymer synthesized from 4 amino acids that was designed to induce a tolerogenic immune response to myelin basic protein. However, it has a wide range of affinity for T-lymphocyte receptors and was found to suppress an encephalitogenic response to other related immunogens.20 In the pivotal Phase III trial, glatiramer acetate at a daily dose of 20 mg reduced the relapse rate in treated MS patients by 29% compared with the placebo group.21 Trials that compared glatiramer to high-dose IFN-β suggest that the 2 treatments demonstrate similar efficacy on clinical outcomes but that IFN-β may have a more marked effect on imaging outcomes.22,23
For those patients starting on IFN-β or glatiramer acetate, approximately one third will remain on their initial choice and be relapse free within the first 2 years of treatment. Before the approval of newer oral agents, a large subset of patients switched to a second injectable platform treatment because of a lack of efficacy or because of adverse events, and some responded at least partially to the new treatment.24
However, evidence of persistent disease activity while on treatment predicts increased accumulation of disability and suggests that patients with a more severe disease course should be considered for more aggressive treatments. Persistent disease activity in- cludes clinical course and radiological findings; those
‡Plegridys (Biogen Idec, Cambridge, Massachusetts).
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patients on IFN-β who demonstrate gadolinium- enhancing lesions on MRI over the first 1 to 2 years of treatment have a particularly poor long-term prognosis.25
Oral Medications Oral immune suppressive agents, particularly aza-
thioprine, have been extensively used to treat MS worldwide. Despite a relative advantage of cost, aza- thioprine and related medications have not been examined in large, placebo-controlled trials, and their relative benefit compared with that of newer agents is unclear. A meta-analysis of azathioprine studies in MS suggested a relative reduction in relapse rate of 18% to 23% and a 42% reduction in the number of progression-free patients at 3 years.26
Newer drugs that have been more rigorously stu- died and are approved for use in MS patients include dimethyl fumarate, fingolimod, and teriflunomide. These agents tend to have a more global immunosup- pressant mechanism of action compared with inject- able treatments. They have been used for other inflammatory conditions (fumarate compounds in psoriasis), developed to prevent transplant rejection (fingolimod), or synthesized as a more tolerable alter- native (teriflunomide) to existing approaches (lefluno- mide) in other inflammatory diseases.
Dimethyl fumarate is an orally active derivative of fumarate, which is a product of intermediary metabolism in the citric acid cycle. It demonstrates immunomodula- tory effects that can induce lymphopenia in patients treated for psoriasis, alter immune cell cytokine profiles,27
and inhibit inflammatory transcriptional pathways mediated by the transcription factor nuclear factor-κB.28
The latter mechanism of action suggests that dimethyl fumarate may inhibit innate immune function mediated by macrophages and microglia in addition to its effects on lymphocyte function.
In a placebo-controlled Phase III trial, twice-daily dimethyl fumarate reduced annualized relapse rates 50% over 2 years.29 A second Phase III trial included a group treated with glatiramer acetate30
and demonstrated a similar reduction in relapse rate at twice-daily dosing. However, there was a greater reduction of T2 lesions on MRI in the dimethyl fumarate group compared with glatiramer acetate. Potential adverse events include flushing, gastrointes- tinal symptoms ranging from mild to severe, lympho- penia, and transaminitis. Although there have been
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reports of progressive multifocal leukoencephalopathy (PML) developing in patients with psoriasis after treat- ment with fumarate compounds,31 PML did not develop in any MS patients while treated with a formulation of dimethyl fumarate§. In more widespread clinical use for MS, the greatest challenge has been the management of gastrointestinal adverse events, and a variety of approaches are being attempted to increase tolerability and long-term compliance.
Fingolimod** is an alternative oral agent. It acts as an agonist of sphinogosine-1-phosphate receptors and induces lymphopenia and causes sequestration of T lymphocytes in peripheral lymph nodes.32 In a 24- month placebo-controlled trial in relapsing MS pa- tients, daily, fingolimod at 2 different doses (1.25 mg and 0.5 mg) reduced relapse rates by 450% and suggested the possibility of a decrease in disease progression. In a comparison trial with once-weekly IFN-β, the fingolimod group demonstrated an im- proved reduction in annualized relapse rate. A more recently completed Phase III confirmed the beneficial effect on relapse rates but did not demonstrate an effect on disability progression.33
In these trials, there was an increased risk of infectious complications, particularly due to herpes zoster, and of skin cancers and other neoplasms. In addition to the risks associated with immunosuppres- sion, fingolimod can induce varying degrees of brady- cardia due to the expression of sphinogosine-1- phosphate receptors in the heart. Findings in the clinical trials included asymptomatic bradycardia and atrioventricular block, and, in clinical practice, there have been subsequent reports of asystole34 and sudden death.35 Currently, cardiac monitoring after the first dose is required but does not necessarily predict delayed cardiac events. An additional potential adverse effect is macular edema,36 and patients should be evaluated by ophthalmologic examination at baseline, 4 to 6 months after initiation, acutely for changes in vision, and annually while on treatment.37
Teriflunomide†† is an oral immunosuppressant and a metabolic derivative of leflunomide,‡‡ which is used in the treatment of rheumatoid and psoriatic forms of arthritis. They inhibit pyrimidine synthesis and
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decrease cell proliferation in rapidly dividing cells such as T lymphocytes. In clinical trials, terifluno- mide reduced exacerbation rates by 30%.38,39
Adverse events include hair loss, nausea, diarrhea, and increased risk of infections.
A major concern with the oral agents is their effects on fertility, pregnancy, and the safety of breastfeeding in a patient population that contains many people of child-bearing age.40 Teriflunomide has been given a pregnancy category X by the US Food and Drug Administration because of the concern of teratogeni- city. However, dimethyl fumarate and fingolimod are also small molecules that can cross the placenta and enter breast milk. IFN-β appears to have a lower risk of teratogenicity but may increase the risk of sponta- neous abortion. Glatiramer acetate is likely the only current agent that can be safely used throughout pregnancy; however, patients are generally advised to stop all disease modifying treatments while they are trying to conceive and during pregnancy.
The emergence of the oral treatments for MS provides patients with greater ease of use and has led to a decline in the use of the platform injectable agents as first-line treatment. The decision to use one of the oral agents as first-line treatment is currently based on a combination of factors that include patient preference, risk of potential adverse events, perceived efficacy, availability, and cost.
Because of its current safety profile and availability, dimethyl fumarate has been used more extensively as a first-line agent in the United States compared with the other oral compounds. Patients who discontinue dimethyl fumarate because of gastrointestinal side effects usually do so within the first 2 to 4 weeks of treatment. For these reasons, one approach for newly diagnosed patients who prefer an oral treatment is to initiate dimethyl fumarate and assess tolerability at a 1-month follow-up visit. If the patient tolerates treatment, clinical response over the following year can be assessed as for the platform injectable therapies. If the patient does not tolerate treat- ment over the first month, then other first-line options can be reconsidered.
Second-Line Disease-Modifying Treatments Natalizumab
Natalizumab§§ is a humanized monoclonal antibody that blocks α4-integrin on the surface of
§§Tysabri (Biogen Idec, Cambridge, Massachusetts).
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mononuclear immune cells and prevents migration of these cells from the peripheral circulation into solid organs at sites of infection or sterile inflammation. Preclinical studies in rodent models of MS directly led to translation of this approach to clinical trials.41 In a Phase III placebo-controlled trial, infusion of natali- zumab every 4 weeks reduced the exacerbation rate by 68% during the first year of treatment, had marked effects on MRI outcomes, and reduced the rate of disability progression over 2 years.42 Although a hypersensitivity to natalizumab early in the course of treatment develops in a small percentage of patients, it is generally well tolerated, and many patients experience a decrease in fatigue and an increase in quality-of-life measures.43,44
The primary drawback to natalizumab therapy is that it is associated with the development of progres- sive PML, particularly in those patients with a detectable humoral response to JC virus and previous immunosuppression. PML is fatal in 20% of pa- tients with MS. The approximate risk of PML is o1 in 1000 for patients with a negative anti-JC virus titer and as high as 11 in 1000 for those with a positive titer and previous exposure to immunosuppressant medications. PML risk increases with prolonged treat- ment 42 years, and risk can be further stratified with the use of newer serological assays to detect relative anti-JC virus levels.
The use of natalizumab does not appear to increase the risk of other infections associated with impaired CD4 T-lymphocyte function. This observation sug- gests that a functional, but decreased, level of immune surveillance may remain intact during treatment in the majority of patients. During health, migration of CD4 T lymphocytes into the CNS is mediated in part by the choroid plexus epithelium at the blood cerebrospinal fluid barrier and appears to be α4-integrin independ- ent.45,46 The mechanism of impaired immune surveil- lance in natalizumab-treated patients in whom PML develops remains unclear but is associated with a detectable and persistent systemic humoral response to the JC virus. The possible relevance of this observation is that B cells can be infected with the JC virus and serve as a latent reservoir.47 In sus- ceptible individuals, an unknown regulatory defect may lead to enhanced B-cell mobilization from the bone marrow, a known reservoir for the JC virus.48
Although natalizumab is arguably the most effec- tive agent in the treatment of relapsing forms of MS,
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its use is generally reserved for those patients who have breakthrough disease on a first-line treatment or those who present with very active disease and a high risk of early disability progression. As with the first- line agents, some patients treated with natalizumab experience breakthrough acute exacerbations and can be classified as nonresponders.49 However, few pa- tients with active relapsing disease do not respond to natalizumab, and the lack of a response may suggest an alternative CNS autoimmune syndrome. For exam- ple, natalizumab does not appear to have efficacy in neuromyelitis optica (NMO),50 and identification of a prominent humoral and autoantibody component may identify nonresponders and those with multiple autoimmune processes.51
Rituximab Rituximab is a monoclonal antibody targeted to
CD20 expressed on B lymphocytes and was developed initially as a treatment for B-cell lymphomas. It has been used extensively in the treatment of autoimmune diseases associated with pathogenic autoantibodies, including lupus, classic NMO, and NMO spectrum disorder. Its role in the treatment of MS has been less clear.
In a study of MS patients with relapsing disease, relapse rate reduction was 50% at 48 weeks after a treatment course.52 Although pathological studies support a role for B cells in the pathogenesis of progressive disease,53 the results in patients with primary progressive disease did not demonstrate statistically significant clinical efficacy.54 However, subgroup analysis suggested that it may benefit younger patients.
As with other second-line agents, rituximab needs to be used with caution because of the risk of adverse events. It has been associated with the development of PML and may lead to fulminant reactivation of hepa- titis B in patients with previous infection.55 Although it is not approved for treatment of MS, rituximab may be a viable option as an off-label treatment for some patients with breakthrough disease in whom multiple agents have failed. Studies of rituximab and related monoclonal antibody treatments targeted at B cells are ongoing to assess its potential role in patients with secondary progressive MS.
Alemtuzumab Alemtuzumab is a monoclonal antibody that rec-
ognizes the CD52 epitope on mononuclear cells and,
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as a single intravenous treatment, can cause global immunosuppression that persists for as long as a year. It rapidly depletes monocytes and B and T lympho- cytes with a variable rate of immune reconstitution for each cell population.56 In clinical use, patients usually receive a single yearly dose for 2 consecutive years and are closely monitored for several years to assess for adverse events.
In a 3-year Phase II trial in early MS, annual alemtuzumab infusion was compared with IFN-β 1a preparation.57 Alemtuzumab treatment reduced dis- ability progression, improved disability scores, and decreased relapse rate by 70% compared with BIFN. The trial was terminated early because idiopathic thrombocytopenia developed in 3 patients, and 1 of these patients died. In 23% of alemtuzu- mab patients autoimmune thyroid disease developed, predominantly due to Graves disease. In subsequent Phase III trials, the superiority of alemtuzumab to IFN-β on relapse rates was confirmed, but its effect on disability was not replicated.57,58 In addition to Graves disease, numerous other adverse events were observed including Goodpasture syndrome, neo- plasms, and opportunistic infections.
The goal of alemtuzumab treatment is to halt disease activity in patients with relapsing MS who present with very aggressive disease.59 It is licensed for use in MS patients in Canada and Europe, but approval in the United States is unclear because of safety concerns.
CHALLENGES OF DISEASE-MODIFYING TREATMENTS IN MS Current challenges include initial and subsequent selection of specific agents, potential adverse events, development of approaches to individualize treatment, lack of effective therapies for nonrelapsing forms of progressive disease, and cost.60 Despite the numerous options, all of the medications are only partially effective at preventing relapses and, at best, have a modest effect on limiting accumulation of disability and conversion to a more progressive form of the…