Deconstructing Therapeutic Decision Making: An Expert Analysis of MS Treatment Options

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1 SUPPLEMENT TO JANUARY 2014 FREE 1.5 CME CREDITS Deconstructing Therapeutic Decision Making: An Expert Analysis of MS Treatment Options S3 Introduction Guy J. Buckle, MD, MPH S4 Making Informed Decisions When Screening and Monitoring Thomas P. Leist, MD, PhD S9 Pathology of Multiple Sclerosis and Mechanisms of Multiple Sclerosis Therapies V. Wee Yong, PhD Dr John Zajicek/ /Science Photo Library/Corbis S14 Optimizing Patient Safety and Outcomes by Individualizing Therapy Fred D. Lublin, MD, FAAN, FANA This continuing medical education activity is sponsored by Vindico Medical Education. This activity is supported by an educational grant from Teva Neuroscience, Inc.

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3 TITLE Deconstructing Therapeutic Decision Making: An Expert Analysis of MS Treatment Options SPONSORSHIP STATEMENT This continuing medical education activity is sponsored by SUPPORT STATEMENT This activity is supported by an educational grant from OVERVIEW Since the approval of interferon beta-1b, multiple additional therapies have become available for the treatment of multiple sclerosis. These agents vary in safety and utilize a variety of mechanisms of action, most of which are anti-inflammatory. Therapy for multiple sclerosis must be tailored to each individual patient, while taking into consideration patient-related factors such as disease stage and adherence concerns. Treatment-related issues such as efficacy and safety must also be factored into the decision. This supplement will provide insight on how to use data on available therapies to drive clinical decision making for patients with multiple sclerosis. TARGET AUDIENCE The intended audience for the activity is neurologists and other health care professionals involved in the treatment of patients with multiple sclerosis (MS). LEARNING OBJECTIVES At the conclusion of this activity, participants should be able to: Differentiate new and existing pharmacologic treatments for MS based on their unique mechanisms of action and subsequent therapeutic effects. Discuss the safety profiles, as well as initial and ongoing monitoring requirements, for therapeutic agents used to treat MS. Review recent data on biomarker research and understand its potential impact on patient care. Identify barriers to adherence and discuss strategies to remove those barriers. COURSE CHAIR Guy J. Buckle, MD, MPH Director of Clinical Care Partners MS Center Brigham and Women's Hospital Assistant Professor of Neurology Harvard Medical School Boston, Massachusetts FACULTY Making Informed Decisions When Screening and Monitoring Thomas P. Leist, MD, PhD Associate Professor of Neurology Chief, Division of Clinical Neuroimmunology Director, Comprehensive Multiple Sclerosis Center Jefferson University Philadelphia, Pennsylvania Optimizing Patient Safety and Outcomes by Individualizing Therapy Fred D. Lublin, MD, FAAN, FANA Saunders Family Professor of Neurology Director, The Corinne Goldsmith Dickinson Center for Multiple Sclerosis Mount Sinai Medical Center New York, New York Using Knowledge of Mechanisms of Action and Neuropathology to Drive Clinical Decision Making V. Wee Yong, PhD Professor and Alberta Heritage Foundation for Medical Research Medical Scientist Departments of Clinical Neurosciences and Oncology University of Calgary Canada Research Chair in Neuroimmunology Calgary, Canada ACCREDITATION Vindico Medical Education is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. CREDIT DESIGNATION Vindico Medical Education designates this enduring material for a maximum of 1.5 AMA PRA Category 1 Credit(s). Physicians should claim only the credit commensurate with the extent of their participation in the activity. This enduring material is approved for 1 year from the date of original release, January 1, 2014 January 1, HOW TO PARTICIPATE IN THIS ACTIVITY AND OBTAIN CME CREDIT To participate in this CME activity, you must read the objectives and articles, complete the CME posttest, and complete and return the registration form and evaluation. Provide only one (1) correct answer for each question. A satisfactory score is defined as answering 70% of the posttest questions correctly. Upon receipt of the completed materials, if a satisfactory score on the posttest is achieved, Vindico Medical Education will issue an AMA PRA Category 1 Credit(s) certificate within 4 to 6 weeks. Supplement to Neurology Reviews January 2014 S1

4 PLANNING COMMITTEE AND FACULTY Guy J. Buckle, MD, MPH Thomas P. Leist, MD, PhD Fred D. Lublin, MD, FAAN, FANA V. Wee Yong, PhD REVIEWER Ronald Codario, MD, FACP, FNLA, CCMEP DISCLOSURES In accordance with the Accreditation Council for Continuing Medical Education s Standards for Commercial Support, all CME providers are required to disclose to the activity audience the relevant financial relationships of the planners, teachers, and authors involved in the development of CME content. An individual has a relevant financial relationship if he or she has a financial relationship in any amount occurring in the last 12 months with a commercial interest whose products or services are discussed in the CME activity content over which the individual has control. Relationship information appears on this page. The authors disclose that they do have significant financial interests in products or classes of products discussed directly or indirectly in this activity, including research support. Planning Committee and Faculty report the following relationship(s): Guy J. Buckle, MD, MPH Consulting fees: Acorda Therapeutics, Inc.; Biogen Idec; EMD Serono, Inc.; Genzyme Corporation; Novartis Pharmaceuticals Corporation; Questcor Pharmaceuticals, Inc.; Teva Pharmaceuticals USA, Inc. Thomas P. Leist, MD, PhD Consulting fees: Biogen Idec; EMD Serono, Inc.; Genzyme Corporation; Novartis Pharmaceuticals Corporation; Teva Neuroscience, Inc. Speakers bureaus: Novartis Pharmaceuticals Corporation; Teva Neuroscience, Inc. Fred D. Lublin, MD, FAAN, FANA Contracted research: Acorda Therapeutics, Inc.; Biogen Idec; Celgene Corporation; Genzyme Corporation; National Institutes of Health; National Multiple Sclerosis Society; Novartis Pharmaceuticals Corporation; sanofi-aventis U.S. LLC; Teva Neuroscience, Inc. Consulting agreements/advisory boards/dsmb: Acorda Therapeutics, Inc.; Actelion Pharmaceuticals, US, Inc.; Bayer HealthCare Pharmaceuticals; Biogen Idec; Bristol-Myers Squibb Company; Celgene Corporation; Coronado Biosciences; EMD Serono, Inc.; Forward Pharma A/S; Genentech, Inc.; Genzyme Corporation; Johnson & Johnson; MedImmune, LLC; Novartis Pharmaceuticals Corporation; Questcor Pharmaceuticals, Inc.; Receptos, Inc.; Revalesio Corporation; Roche USA; sanofi-aventis U.S. LLC; Teva Neuroscience, Inc.; XenoPort, Inc. Co-chief editor: Multiple Sclerosis and Related Disorders Current financial interests/stock ownership: Cognition Pharmaceuticals, Inc. V. Wee Yong, PhD Consulting fees: Biogen Idec; Novartis Pharmaceuticals Corporation; Teva Neuroscience, Inc. Speakers bureau: Teva Neuroscience, Inc. Contracted research: Novartis Pharmaceuticals Corporation; Teva Neuroscience, Inc. Reviewer reports the following relationship(s): Ronald Codario, MD, FACP, FNLA, CCMEP No relevant financial relationships to disclose Vindico Medical Education staff report the following relationship(s): No relevant financial relationships to disclose Signed disclosures are on file at Vindico Medical Education, Office of Medical Affairs and Compliance. EDUCATIONAL TOOLS FOR YOUR CLINICAL PRACTICE CAN BE DOWNLOADED AT UNLABELED AND INVESTIGATIONAL USAGE The audience is advised that this continuing medical education activity may contain references to unlabeled uses of FDA-approved products or to products not approved by the FDA for use in the United States. The faculty members have been made aware of their obligation to disclose such usage. All activity participants will be informed if any speakers/authors intend to discuss either non- FDA approved or investigational use of products/devices. COPYRIGHT STATEMENT Published by Neurology Reviews. Created by Vindico Medical Education, 6900 Grove Road, Building 100, Thorofare, NJ Telephone: ; Fax: Printed in the USA. Joint Copyright 2013 Vindico Medical Education and Neurology Reviews. All rights reserved. No part of this publication may be reproduced without written permission from the publisher. The material presented at or in any of Vindico Medical Education continuing medical education activities does not necessarily reflect the views and opinions of Vindico Medical Education. Neither Vindico Medical Education nor the faculty endorse or recommend any techniques, commercial products, or manufacturers. The faculty/authors may discuss the use of materials and/or products that have not yet been approved by the US Food and Drug Administration. All readers and continuing education participants should verify all information before treating patients or utilizing any product. S2 January 2014 Supplement to Neurology Reviews

5 Introduction Guy J. Buckle, MD, MPH Multiple sclerosis (MS) remains a challenging disease to treat, despite several new agents approved by the US Food and Drug Administration (FDA) over the past few years marked the 20-year anniversary of the first FDA-approved therapy to treat relapsing-remitting MS, and in the United States we can currently select from 10 products with 7 unique mechanisms of action, all focused on some aspect of the early inflammatory response in the central nervous system (CNS). Despite multiple previous claims, we have as yet no truly neuroprotective agent and no effective treatment for established primary or secondary progressive disease; this is thought by many to be our greatest unmet need. Our best strategy remains an early and aggressive anti-inflammatory approach to stave off (we hope) secondary neurodegeneration. This is especially important for a disease such as MS, which is diagnosed at a relatively young age (typically the second through fifth decades of life) and therefore represents a significant long-term social, economic, and public health burden, imposing a substantial impact on health, quality of life, productivity, and employment over many years. Although disease-modifying agents (DMAs) have revolutionized MS treatment, factors such as dosing, route of administration, convenience, safety, side effects, cost, and adherence must all be taken into account. Additionally, perceived efficacy in terms of reduction in relapses, magnetic Guy J. Buckle, MD, MPH Director of Clinical Care Partners MS Center Brigham and Women's Hospital Assistant Professor of Neurology Harvard Medical School Boston, Massachusetts DISCLOSURES Dr. Buckle reports that he has received consulting fees from Acorda Therapeutics, Inc.; Biogen Idec; EMD Serono, Inc.; Genzyme Corporation; Novartis Pharmaceuticals Corporation; Questcor Pharmaceuticals, Inc.; and Teva Pharmaceuticals USA, Inc. resonance imaging (MRI) activity, and disability progression must be considered when making therapeutic decisions. As new and more effective therapies are approved, the risk of increasingly severe and potentially fatal adverse events continues to rise and therapy selection will only become more complex, with risk-benefit considerations assuming greater importance. This CME supplement has assembled 3 of the best-known experts in the field to address crucial topics that clinicians who manage patients with MS will appreciate. The educational activity begins with a detailed discussion of the diagnosis, choice and initiation of treatment, and assessment of clinical outcomes and treatment responses. This article will enable physicians, patients, and caregivers to make informed decisions when screening, initiating, and monitoring response to therapy. The role and appropriate use of MRI, patient-specific comorbid factors, and key therapeutic considerations based on important clinical trials are discussed in addition to longterm management and treatment modifications. The next article reviews the pathophysiology of the inflammatory, demyelinating, and degenerative aspects of the disease, including mediators of neurodegeneration, detrimental effects on oligodendrocytes, neuronal loss, and axonal injury. This article also includes an in-depth review of the mechanisms of action of the various oral and parenteral agents used to treat MS. The final article discusses optimization of patient safety and outcomes by utilizing an individualized management approach to comprehensive patient care, including whom, when, and how to treat, when not to treat, and who should make treatment decisions. It also reviews the role of the mechanisms of action of various therapies in the individualization of therapeutic regimens. I am confident that clinicians involved in caring for patients with MS will appreciate the practical advice and didactic education surrounding the safety and efficacy of the various therapeutic agents, the role of comorbid conditions, and the concept of care individualization that represents a vital approach to managing this complex and potentially debilitating disease. Supplement to Neurology Reviews January 2014 S3

6 Making Informed Decisions When Screening and Monitoring Thomas P. Leist, MD, PhD Diagnosis, treatment initiation, assessment of treatment response and clinical outcome, and any necessary adjustments to therapy are central parts of the overall management of multiple sclerosis (MS). The diagnosis of MS is predominantly based on clinical findings and often requires exclusion of other conditions with similar presentations. Choice of initial therapy is guided by patient and disease characteristics. Moreover, the initial treatment decision should take into account the notion that disease-modifying therapies appear to have greater benefit early in the disease process; however, in the absence of curative interventions, some form of MS medication will likely need to be continued long-term. The number of therapies approved by the US Food and Drug Administration to treat relapsing forms of MS has significantly increased and additional options will likely become available. However, standardized tests that allow selection of the safest and most effective therapy for an individual patient, initially or at the time of a switch, are not available. Clinical examination and current magnetic resonance imaging (MRI) algorithms used in routine practice help to assess ongoing disease activity and progression of disability, but do so in a retrospective fashion and are not very informative regarding disease activity in the cortical gray matter. While such limitations exist and must be recognized, a significant amount of progress has been made that can help practitioners and their patients make more insightful decisions together. The following article will review aspects of such key decision points. Diagnosis Integration of MRI into the diagnostic process has moved consideration of a relapsing form of MS to the time of the first clinical event. Appropriate findings on an initial MRI of the brain and spinal cord (where indicated), alone or together with changes observed through follow-up MRI studies of the central nervous system (CNS), are the closest approximation to a diagnostic and disease activity biomarker that currently exists for MS. Efforts to establish biomarkers for MS have proven difficult due to the clinical and pathophysiological complexities of the disease. Ideally, biomarkers would correlate with a biological mechanism, accurately reflect clinical activity or status, and predict initiation, reactivation, or progression of disease. They should do so with high sensitivity, specificity, and relative ease of assessment. With MRIs, T2/fluid-attenuated inversion recovery (T2/FLAIR) and enhancing T1-weighted lesions can serve as biomarkers for spatial and temporal dissemination of disease activity in conjunction with a first demyelinating event. Presence of enhancing lesions, oligoclonal banding, and low vitamin D levels are risk markers for a subsequent clinical event (Table 1). 1 Genetic markers, including HLA-DRB1*1501, HLA- DR3/DR4, and HLA-DRB1*04 are associated with a higher TABLE 1 Predictors of subsequent attacks 1 Findings on conventional MRIs at initial attack High number of white matter lesions on T2-weighted MRI Thomas P. Leist, MD, PhD Associate Professor of Neurology Chief, Division of Clinical Neuroimmunology Director, Comprehensive Multiple Sclerosis Center Jefferson University Philadelphia, Pennsylvania DISCLOSURES Dr. Leist reports that he has received consulting fees from Biogen Idec; EMD Serono, Inc.; Genzyme Corporation; Novartis Pharmaceuticals Corporation; and Teva Neuroscience, Inc. He is on the speakers bureaus for Novartis Pharmaceuticals Corporation and Teva Neuroscience, Inc. Presence of any gadolinium-enhancing lesions on T1 imaging Presence of infratentorial or spinal cord lesions at first episode Presence of corpus callosum long-axis perpendicular lesions Increased ventricular volume (progressive brain tissue loss) Abbreviation: MRI, magnetic resonance imaging. Source: Bergamaschi R. Int Rev Neurobiol. 2007;79: S4 January 2014 Supplement to Neurology Reviews

7 Making Informed Decisions When Screening and Monitoring risk for MS and, in the case of HLA-DRB1*1501, earlier progression. However, these markers alone are not specific for MS. A number of cytokines have been studied as possible disease activity markers, but these markers are not selective for MS and differences in study subjects with MS versus controls are not typically robust. 2 Findings in cerebrospinal fluid (CSF), visual evoked potentials, other electrophysiologic tests and, more recently, optical coherence tomography, can help support a diagnosis of MS. However, they are subordinate to clinical history and MRI findings and alone are not sufficient to confirm the diagnosis of MS. Cerebrospinal fluid examination may exhibit evidence of intrathecal immunoglobulin production in a majority of patients with MS, but such findings are not specific to MS. On the other hand, the presence of oligoclonal bands restricted to the CSF at the time of a first demyelinating event doubles the risk for a subsequent clinical attack. 3 Criteria for the diagnosis of MS have evolved over time but all, including the most recent update of the McDonald Criteria, 4 emphasize that alternative explanations for the clinical presentation must be considered and excluded. Moreover, the criteria require demonstration of dissemination of disease activity in time and space. Infectious, malignant, congenital, vascular, collagen vascular, rheumatologic, endocrine, and structural conditions of the optic nerve, brainstem, and spinal cord need to be excluded as a first approach, either by history or, when necessary, additional testing. 5 In order for the current MS diagnostic criteria to be applicable, clinical symptoms consistent with a demyelinating event must have occurred. The 2010 McDonald Criteria allow diagnosis of a relapsing form of MS at the time of a first clinical event. For this, the MRI findings have to demonstrate: (1) dissemination in space requirements, exhibiting 1 or more lesions in 2 or more of the telltale locations (periventricular, juxtacortical, posterior fossa, and spinal cord) and (2) a concurrent contrast-enhancing MRI lesion present in an area of the CNS that is distinct from that associated with the clinical symptoms. The current diagnostic criteria also allow counting individual cord lesions when considering the total lesion count (Table 2). While lesions in the cord usually lead to clinical symptoms, they can also be silent. In addition to an MRI of the brain, an MRI of the cervical spine and, where appropriate, the remainder of the spinal cord, should be included in the evaluation of a patient presenting with a suspected first demyelinating event. Most of the MRI data that formed the basis for the dissemination-in-space-and-time imaging requirements in the 2010 McDonald Criteria were from studies utilizing TABLE McDonald criteria 4 Dissemination in space 2 of the following: 1 periventricular T2/FLAIR lesion(s) 1 juxtacortical T2/FLAIR lesion(s) 1 posterior fossa T2/FLAIR lesion(s) 1 spinal cord lesion(s) Dissemination in time Simultaneous presence of asymptomatic enhancing and non-enhancing lesions at any time 1 new T2 or enhancing lesion on subsequent MRI Abbreviation: MRI, magnetic resonance imaging. Source: Polman CM, et al. Ann Neurol. 2011;69: Tesla scanners and slice thicknesses of 3 to 5 mm. Scans obtained in the community may include interspaces between images and thus may not visualize the whole brain. MRI studies obtained using higher field strength (ie, 3 Tesla or higher) may show a greater number of lesions, while scans obtained with a field strength of less than 1.5 Tesla may detect fewer lesions on T2/FLAIR and on contrast-enhanced sequences in particular. 6 The more frequent use of MRIs for unrelated conditions has led to identification of patients with findings concerning for CNS demyelination but without attributable clinical symptoms. Studies following such patients have reported that the presence of suspicious lesions not only in the brain, but particularly also in the spinal cord, is associated with an increased risk for clinical conversion, 7 thus justifying follow-up of such individuals. Determining when such patients with radiographically isolated syndrome should be considered as having MS should be addressed in future revisions of the diagnostic criteria. Although current MRI techniques have helped to secure an earlier diagnosis and can aid in monitoring less clinically apparent disease progression, it should be taken into consideration that the current conventional MRI routinely used for patients with MS does not visualize gray matter lesions, which may have a higher correlation with disability. 8 Lack of appreciation of cortical pathology with current MRI techniques may in part explain the clinical-radiological paradox described in more established MS, where relative stability of T2/FLAIR lesions in the white matter often does not correlate with the clinical picture, which is marked by progression of disability. Supplement to Neurology Reviews January 2014 S5

8 Making Informed Decisions When Screening and Monitoring Once a diagnosis of MS is established, clinical followup should take place regularly but not less than twice a year, even for patients who appear clinically stable. Inclusion of standardized measures in the ongoing evaluations may help to identify progression in the absence of relapses and document degree of recovery after clinical events. Such elements can include individual measures of the revised MS multifunctional composite score (9-hole peg test, 25-foot walk test, symbol-digit modality test, and assessment of low-contrast vision), 9,10 a selfassessment test paralleling the Expanded Disability Status Scale (EDSS) 11 or the EDSS itself, as well as screening tools for depression and cognitive dysfunction. 12,13 Patient-specific factors and therapeutic considerations The body of data available favors early institution of therapy in patients with characteristic CNS lesions on MRI at the time of the first clinical demyelinating event. Six clinical studies in patients with a first clinical demyelinating event and at least 2 characteristic brain lesions on MRI have shown that early institution of MS therapy significantly reduces the likelihood of a subsequent attack over the placebocontrolled study period: CHAMPS (interferon beta-1a intramuscular once weekly [QW]) 14 BENEFIT (interferon beta-1b subcutaneous [SQ] every other day) 15 PreCISe (glatiramer acetate SQ once daily [QD]) 16 REFLEX (interferon beta-1a SQ QW and 3 times per week) 17 ORACLE (cladribine annual cycles orally) 18 TOPIC (teriflunomide QD) 19 In 4 of these studies (BENEFIT, REFLEX, ORACLE, TOPIC), an increased proportion of treated patients who did not develop additional T2/FLAIR lesions during the study period was reported. Open-label extensions to 5 years, during which the original placebo cohort was switched to active therapy, have been reported for the BENEFIT 20 and the PreCISe studies. 21 In both extension studies, the cohort with delayed start of therapy fared worse clinically. Notably, the disease behavior across the placebo cohorts in first demyelinating event trials has been remarkably similar in studies spanning more than a decade. Natural history studies have corroborated the predictive value of MRI at the time of a clinically isolated syndrome. A long-term cohort of untreated patients initially presenting with a first demyelinating clinical event has demonstrated that changes in the T2/FLAIR lesion load over the first 5 years significantly correlated with the degree of disability at 14 and 20 years follow-up. 22 In contrast, patients presenting with a first clinical demyelinating event and with no brain MRI lesions other than the one causing the symptomatology have an approximate 20% lifetime risk for MS, as shown in a study obtained on a machine with 1.5 Tesla. 22 The risk for conversion is highest in the early years after the initial event, but may never decrease to that of the general population. Typically, such patients are currently followed conservatively and initiation of therapy is considered if additional radiographic or clinical disease activity occurs. The prototypical newly diagnosed patient with a relapsing form of MS is a woman in her 20s or 30s. Approximately 70% to 80% of new diagnoses are made in women, most frequently in the third and fourth decade of life. The difference in life expectancy between the general population and patients with MS has diminished over the recent decades, likely because of advances in care, treatment of MS symptoms, and possibly because of disease-modifying therapy, as suggested by the 21-year follow-up of the initial phase III trial with interferon beta-1b. 23 A newly diagnosed individual is therefore likely to live for decades with MS. The difference in life expectancy between the general population and patients with MS has diminished over the decades, likely because of advances in care, treatment of MS symptoms, and possibly because of disease-modifying therapy. With increasing age, patients with MS are also at risk to develop lifestyle and age-related conditions that affect the general population. In addition, patients with MS may experience an increasing number of disease-related symptoms. Approaches to both comorbid conditions and MSassociated symptoms may require institution of therapeutics. Patients with MS are often prescribed relatively complex medication regimens in addition to their disease-modifying therapy. With institution and continuation of diseasemodifying therapy significantly from diagnosis, both early efficacy and long-term safety, particularly with regard to pregnancy, need to be concurrent goals of therapy. Additionally, in the absence of testing modalities that allow prediction of an individual patient s clinical course or response to a given treatment, it is likely that patients will be consecutively treated with different disease-modifying therapies. Prior treatment with certain modes of action may affect safety of subsequent treatment with another mode of action. A prime example for this concept is the observation that prior immunosuppressive therapy raises the risk S6 January 2014 Supplement to Neurology Reviews

9 Making Informed Decisions When Screening and Monitoring TABLE 3 Factors affecting prognosis 1 Favorable Low attack rate Long interval to second relapse Complete recovery after first attack Younger age of onset Female sex Low disability at 2 to 5 years Sensory symptoms only Optic neuritis Unfavorable High attack rate Short interval to second relapse Lack of recovery from first attack Older age of onset Male sex Early development of disability Cerebellar symptoms Insidious motor onset Source: Bergamaschi R. Int Rev Neurobiol. 2007;79: for progressive multifocal leukoencephalopathy (PML) during therapy with natalizumab (see article by Fred D. Lublin, MD, in this supplement). 24 From initial presentation, patients with MS differ significantly with respect to their disease characteristics (Table 3). Presentation before the age of 40 years, monosymptomatic onset, good recovery from the initial attack, low number of MRI lesions, absence of enhancing lesions on the initial study, and long intervals between clinical events are among factors that are usually associated with a more favorable disease course. On the other hand, onset after the age of 40 years (particularly in men), polysymptomatic onset, incomplete recovery from attacks, larger number of lesions on MRI, and evidence of brainstem and cerebellar involvement are consistent with a more severe disease course. While early characteristics may predict prognosis in aggregate, individual patients will follow their own particular courses, and a patient with previously milder-appearing disease may experience a period of more active disease, making it necessary to re-evaluate a given patient s disease behavior at regular intervals. Follow-up scans, particularly in the early years after diagnosis or at the time of new symptoms, can help to identify patients with ongoing disease activity. Significant changes observed with imaging alone or when coupled with clinical occurrences may suggest reevaluation of the current disease-modifying approach. There are currently 9 therapeutic entities approved for the treatment of relapsing forms of MS, belonging to 7 modes of action if the 3 distinct marketed interferon preparations are grouped together (reviewed by V. Wee Yong, PhD). Medications within a mode of action have significantly overlapping side-effect profiles. Side effects and safety profiles across therapeutic modalities are distinct and are reviewed in the article by Dr. Lublin. Three additional products are under regulatory review, including a less frequently administered higher-dose glatiramer acetate and a pegylated interferon beta-1a with an extended in vivo half-life. Alemtuzumab is a therapeutic modality that is new to the MS field and is the first depleting monoclonal antibody being investigated for use in relapsing forms of MS. Alemtuzumab will likely require long-term monitoring of platelet count, thyroid function, and renal function for at least 4 years after the last infusion of the antibody, based on cases of autoimmune thyroid disease, glomerular disease, and thrombocytopenia observed during clinical trials. 25,26 When should a switch of therapy be considered? Treatment side effects can interfere with quality of life and can reduce compliance with a prescribed regimen. With various treatment modalities available, an alternative therapy should be considered when side effects persist despite symptomatic management and retraining regarding administration. In efficacy trials, a therapeutic difference between treatment and control cohorts (active comparator studies) typically begins to be appreciable only beyond the third month or longer of therapy. It may therefore be difficult to evaluate a treatment response early and, in general, at least 6 months of treatment is needed to assess a clinical response. Beyond 6 months, it is the history of new symptoms and progression of disability combined with changes on imaging that drive consideration of a switch in search of higher efficacy. While new therapies may hold promise for greater efficacy, comparison of relative percentage differences within and across clinical trials may overestimate the certainty of the biologic effects. For example, during the development of dimethyl fumarate and laquinimod, 2 phase III trials were conducted for each compound, enrolling subjects with very similar characteristics in each of the sister trials. Comparison of these 2 sets of placebo cohorts may in part address the question of the minimal absolute, not relative, difference that may be biologically relevant in current clinical trials. The difference in the proportion of relapse-free patients was 5% between the 2 dimethyl fumarate trials (54% versus 59%) 27,28 and 9.5% between the 2 placebo cohorts in the laquinimod phase III trials (52.2% versus 61.7%). 29,30 Conclusions Patient factors and disease characteristics influence initial treatment selection. Patients must be continually monitored Supplement to Neurology Reviews January 2014 S7

10 Making Informed Decisions When Screening and Monitoring to assess therapeutic response and clinical outcomes. Modifications to the treatment regimen may be necessary if there are safety or efficacy concerns. In the absence of proven curative treatments, MS management over the long term with disease-modifying therapy will be the standard approach. REFERENCES 1. Bergamaschi R. Prognostic factors in multiple sclerosis. Int Rev Neurobiol. 2007;79: Katsavos S, Anagnostouli M. Biomarkers in multiple sclerosis: an up-to-date overview. Mult Scler Int. 2013;2013: Tintoré M, Rovira A, Río J, et al. Do oligoclonal bands add information to MRI in first attacks of multiple sclerosis? Neurology. 2008;70(13 pt 2): Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011;69(2): Miller DH, Weinshenker BG, Filippi M, et al. Differential diagnosis of suspected multiple sclerosis: a consensus approach. 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Lancet. 2009;374(9700): Comi G, De Stefano N, Freedman MS, et al. Comparison of two dosing frequencies of subcutaneous interferon beta-1a in patients with a first clinical demyelinating event suggestive of multiple sclerosis (REFLEX): a phase 3 randomised controlled trial. Lancet Neurol. 2012;11(1): Leist TP, Comi G, Cree BAC, et al. Oral cladribine delays time to conversion to clinically definite MS in patients with a first demyelinating event: top line results from the Phase III ORACLE MS study. Presented at: The American Academy of Neurology s 65th AAN Annual Meeting; March 16-23, 2013; San Diego, California; P Miller A, Wolinsky J, Kappos L, et al. TOPIC main outcomes: efficacy and safety of once-daily oral teriflunomide in patients with clinically isolated syndrome. Presented at: 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis; October 2-5, 2013; Copenhagen, Denmark; Abstract Kappos L, Freedman MS, Polman CH, et al; BENEFIT Study Group. 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Alemtuzumab vs. interferon beta-1a in early multiple sclerosis. N Engl J Med. 2008;359(17): Cuker A, Coles AJ, Sullivan H, et al. A distinctive form of immune thrombocytopenia in a phase 2 study of alemtuzumab for the treatment of relapsing-remitting multiple sclerosis. Blood. 2011;118(24): Gold R, Kappos L, Arnold DL, et al; DEFINE Study Investigators. Placebocontrolled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med. 2012;367(12): Fox RJ, Miller DH, Phillips JT, et al; CONFIRM Study Investigators. Placebo-controlled phase 3 study of oral BG-12 or glatiramer acetate in multiple sclerosis. N Engl J Med. 2012;367(12): Comi G, Jeffery D, Kappos L, et al; ALLEGRO Study Group. Placebo-controlled trial of oral laquinimod for multiple sclerosis. N Engl J Med. 2012;366: Comi G, Vollmer T, Cutter G, Sasson N, Ladkani D, Gorfine T. Disease progression in relapse-free patients treated with laquinimod. Presented at: 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis; October 2-5, 2013; Copenhagen, Denmark; P1036. S8 January 2014 Supplement to Neurology Reviews

11 Pathology of Multiple Sclerosis and Mechanisms of Multiple Sclerosis Therapies V. Wee Yong, PhD The neuropathology of multiple sclerosis Multiple sclerosis (MS) is an inflammatory, demyelinating, and degenerative condition of the central nervous system (CNS) in which there is significant oligodendrocyte loss and demyelination, as well as neuronal and axonal injury and loss. Classically believed to involve white matter areas, it is now clear that the neurodegenerative processes occur in all areas of the CNS. In the spinal cord, axonal dropout in many tracts is often more than 50%, thalamic neurons are depleted by more than 30%, 1 and the loss of neurons in the cervical spinal cord in a few subjects with MS is comparable to that observed in patients with amyotrophic lateral sclerosis. 2 While these observations are from studies of autopsy specimens with long-term disease, the loss of neuronal populations can be documented using magnetic resonance imaging of living individuals with MS, including early cases. In this regard, the shrinkage of the caudate nucleus, 3 hippocampus, 4 and several other subcortical gray matter nuclei 5 are examples of the ongoing neurodegenerative processes in MS. Cortical lesions are also now amply described in MS. These lesions are particularly important as they may contribute to the cognitive decline observed in MS. Leukocortical, subpial, or intracortical demyelinating lesions are commonly found and are thought to occur from early on in the disease process. 6 While the origin of cortical lesions is debated, microglia and T lymphocytes can be found aggregating around neuronal soma of these demyelinated lesions. 6 In addition to demyelination, the number of cortical neurons V. Wee Yong, PhD Professor and Alberta Heritage Foundation for Medical Research Medical Scientist Departments of Clinical Neurosciences and Oncology University of Calgary Canada Research Chair in Neuroimmunology Calgary, Canada DISCLOSURES Dr. Yong reports that he has received consulting fees from Biogen Idec; Novartis Pharmaceuticals Corporation; and Teva Neuroscience, Inc. He is on the speakers bureau for Teva Neuroscience, Inc., and has performed contracted research for Novartis Pharmaceuticals Corporation and Teva Neuroscience, Inc. across layers 1 to 6 of the cerebral cortex has also been documented to be diminished by the MS disease process. 7 In summary, the pathology of MS involves the white and gray matter at all levels of the CNS. These changes are observed early in the disease course and involve not only demyelination but also neuronal and axonal degeneration. The latter has particular clinical importance as the continuous loss of axons and neurons is believed to be the principal contributor to progression of disability in MS. Mediators of neurodegeneration in multiple sclerosis Regardless of the primary etiology of MS, an invariant feature is the activation of immune cell subsets in the periphery and their migration into the CNS. In addition to the infiltration of leukocytes, CNS-intrinsic microglia are also activated in patients with MS. These activated immune cell subsets are likely mediators of injury and many examples exist in the neuropathology literature of the colocalization of activated macrophages/microglia 8,9 or CD3 + T lymphocytes 10 with markers of axonal injury, including the accumulation of amyloid precursor protein. In several cases of cortical MS lesions, B-cell follicles accumulating in the meningeal space have been described; significantly, the neuronal loss documented to occur in cortical areas of MS are found mostly in those cases that contain meningeal B-cell follicles. 7 While the above are pathological correlations, tissue culture studies emphasize the causative relationship between these elements. For example, activated T cells in culture are very cytotoxic for neurons. 11,12 Microglia activated in tissue culture have also been amply demonstrated to cause neuronal death. Factors released by activated immune cell subsets that lead to the neurodegenerative processes include free radicals; a variety of proteases, including the matrix metalloproteinases (MMPs); cytokines, including tumor necrosis factor-alpha; and glutamate. While the infiltration and activation of immune cell subsets are more difficult to detect by imaging techniques in patients with progressive MS compared to those with the relapsing-remitting form of MS, it should be noted that diffuse inflammation and the significant activation of microglia Supplement to Neurology Reviews January 2014 S9

12 Pathology of Multiple Sclerosis and Mechanisms of Multiple Sclerosis Therapies are features of progressive MS. 13 Indeed, in progressive MS, the extent of axonal injury is correlated with the degree of inflammation. 14 Thus, a case can be made for activated immune cell subsets contributing to the pathology of all forms of MS. In cortical lesions, as noted earlier, microglia and T lymphocytes are found in the vicinity of the neuronal soma. Whether the aggregation of these immune cells is incidental or even protective for neurons is arguable, but it should be considered that pyknotic neurons are found in the vicinity of these cells. 6 In addition to the contents of immune cells, other mediators of neurodegeneration in MS may include CNS-initiated events such as mitochondrial dysfunction within neural cells, 15 energy insufficiency, 16 inactivation of organelles such as peroxisomes, 17 glutamate excitotoxicity, ferrous ionmediated injury, 18 and the elaboration of free radicals by dysfunctional mitochondria within neural cells or of free radicals brought in by activated immune cells. 19 In summary, the robust inflammatory process entering into the CNS, or triggered within the CNS by microglia, contributes significantly to the neurodegenerative processes that occur in MS. Even in the hypothetical context of some cases of MS where the initial insult may be localized to within the CNS and thus may not be immune in origin, the subsequent drainage of damaged CNS elements into the lymphatic system can initiate an inflammatory response that can subsequently spread into the CNS via the peripheral immune system to promote injury. Thus, a vicious cycle of inflammation and neurodegeneration may be initiated, with one driving the other (Figure 1). Multiple sclerosis treatments: Mechanisms of action Given that a strong relationship exists between inflammation and neurodegeneration, immunomodulators are expected not only to reduce inflammation in MS, but they should also attenuate the capacity of inflammatory components to produce neural injury. Moreover, medications that act only in the periphery should still have the capacity to reduce neurodegeneration. Similarly, immunomodulators that enter the CNS to act locally within would be of interest as they would affect both inflammation and neurodegeneration directly (Figure 1). The following sections review the principal mechanisms of immunomodulators (Figure 2); where possible, reference is made to their effects within the CNS. We will begin with medications that have been in long-term use, specifically glatiramer acetate (GA) and the interferon betas, and will transition to the more recently available oral medications. The reader is referred to an excellent recent FIGURE 1 Medications may directly affect inflammation and/or neurodegeneration Inflammation Medication The products of inflammation within the CNS can lead to axonal and neuronal injury; in turn, elements of degeneration can promote an inflammatory response. Because of the cycle of inflammation driving neurodegeneration and vice versa, medications that reduce detrimental inflammation can attenuate neurodegeneration, even if these therapies do not enter the CNS. Therefore, it would seem logical to derive medications that enter the CNS to directly counter neurodegeneration within or to have medications that act in both the peripheral and central compartments. Source: V. Wee Yong, PhD Medication Neurodegeneration Medication review on mechanisms of the many immunomodulators now in use in MS. 20 Medications in long-term use: Glatiramer acetate and interferon betas In the periphery, both GA and interferon betas affect antigen presentation, the process whereby an antigenpresenting cell (APC), such as a dendritic cell, presents a relevant antigen to help activate T cells (Figure 2). The interferon betas reduce the expression of molecules necessary for antigen presentation, thereby decreasing the generation of pro-inflammatory T lymphocytes, including CD4 + T helper (Th) 1 and Th17 cells. Glatiramer acetate also affects antigen presentation, but through mechanisms that are still unclear, glatiramer acetate promotes the generation of Th cells that are regulatory or anti-inflammatory, referred to as Th2 lymphocytes. The reader is referred elsewhere for these discussions. 21 Other mechanisms of GA also exist, such as the generation of APCs, referred to as Type II APCs (including M2 monocytes), that produce antiinflammatory/regulatory cytokines or that polarize T cells towards those that are of the Th2 type. 22 At the level of the blood-brain barrier, the interferon betas are reported to reduce the expression of adhesion molecules on leukocytes and endothelial cells, as well as to decrease the expression of MMPs, thereby helping to block S10 January 2014 Supplement to Neurology Reviews

13 Pathology of Multiple Sclerosis and Mechanisms of Multiple Sclerosis Therapies FIGURE 2 Targets of multiple sclerosis disease-modifying therapies remyelination following lysolecithininduced demyelination. 30 This is a simplified view of the pathogenesis of MS lesions, whereby the (1) activation of immune cells in the periphery leads to the generation of pro-inflammatory Th1 and Th17 lymphocytes and the activation of B cells and monocytes. These activated populations upregulate their expression of adhesion molecules and proteolytic enzymes, including MMPs, that allow their (2) adhesion and (3) infiltration across the blood-brain barrier. Within the CNS, a (4) reactivation process of immune cells is thought to occur and their products contribute to the neurodegeneration in MS lesions. The principal sites of action of MS immunomodulators are displayed and the reader is referred to the text for more information. Abbreviations: APC, antigen-presenting cell; CNS, central nervous system; DMF, dimethyl fumarate; EC, endothelial cell; GA, glatiramer acetate; MMP, matrix metalloproteinase; MS, multiple sclerosis; M2, M2 monocytes; OL, old lesions; Th, T helper; Th2, Th2 lymphocytes. Source: V. Wee Yong, PhD the infiltration of immune cells into the CNS. 21 The interferon betas are not known to enter the CNS directly. Although GA itself is not thought to penetrate the CNS, the Th2 lymphocytes and Type II APCs (or M2 monocytes) that it generates can cross barriers, including the bloodbrain barrier. Immune cells of all types produce a variety of growth factors. 23 In this light, because growth factors can be protective against insults, a significant preclinical literature exists of the capacity of GA-treated animals to have reduced neuropathology not only in models of MS, 24,25 but also models of head trauma, 26 Parkinson disease, 27 stroke, 28 and Alzheimer disease. 29 Attention has also been placed on whether the GAinduced accumulation of nontoxic immune cells in the CNS and the elaboration of trophic growth factors could lead to repair responses. In tissue culture, T cells generated by GA or microglia treated with GA led to the increase in the number of oligodendrocytes from precursor cell populations In animal models of demyelination, GA treatment prevented cuprizone-induced demyelination 32 and improved Monoclonal antibodies Natalizumab is an antibody that reduces the adhesion of leukocytes onto endothelial cells, by virtue of binding to and interfering with the activity of the a 4 b 1 integrin that is expressed on the surface of leukocytes and which mediates cell-cell and cell-extracellular matrix interactions. 33 As a result of natalizumab treatment, leukocytes are excluded from the CNS. As a large monoclonal antibody, it is not known if natalizumab can penetrate the CNS. If so, it could interfere with other a 4 integrin-mediated processes within the CNS and may promote a neuroprotective effect through that mechanism. A group of cytotoxic monoclonal antibodies that bind to particular epitopes on immune cells and then specifically kill these immune cell subsets has been generated; these have promising results in clinical trials in MS. Examples include rituximab, a chimeric antibody which binds to CD20 on B cells; ocrelizumab, a more humanized antibody that binds to CD20; and alemtuzumab, which binds to CD52 on several leukocyte populations. By depleting immune cell subsets, these antibodies reduce inflammation in the periphery as well as in the CNS even if they do not penetrate this tissue. As with natalizumab, whether these antibodies enter the CNS in substantial amounts to directly affect CNS well-being is unclear. Oral medications: Fingolimod Fingolimod binds to sphingosine-1-phosphate (S1P) receptors, and by downregulating these receptors on lymphocytes, prevents these immune cells from exiting the lymph node and entering into the circulation. Thus, there is a reduced availability of leukocytes to migrate into the CNS parenchyma. In experimental models, fingolimod can be detected in the CNS following administration in rats. 34 Cells of the CNS have a spectrum of S1P receptors. 35 Associated with these observations is that fingolimod reduces CNS histopathology in rodent models of MS, 36 ischemic strokes, 37 hemorrhagic strokes, 38 and spinal cord injury. 39,40 Supplement to Neurology Reviews January 2014 S11

14 Pathology of Multiple Sclerosis and Mechanisms of Multiple Sclerosis Therapies Given that oligodendrocytes and their precursor cells contain S1P receptors, there have been evaluations to determine whether fingolimod impacts oligodendrocyte wellbeing. Indeed, fingolimod in tissue culture has been reported to promote the survival of oligodendrocyte precursor cells, 41 to promote process extension by human oligodendrocytes, 42 and to increase remyelination in slice or aggregate cultures. 42,43 In animal models of demyelination and remyelination, however, fingolimod has thus far not been shown to promote remyelination in the cuprizone model 44 and in other models of demyelination and remyelination. 45 The reader is referred to a publication by Groves and colleagues 46 for a comprehensive summary of the effects of fingolimod on cells within the CNS. Oral medications: Dimethyl fumarate In the periphery, dimethyl fumarate has been reported to alter the activity of APCs and to reduce the subsequent generation of pro-inflammatory Th1 and Th17 cells; levels of Th2 cytokines may also be elevated. 47 Whether dimethyl fumarate enters the CNS in vivo is currently a subject of debate. Upon administration, the action of esterases rapidly generates the monomethyl fumarate form from administered dimethyl fumarate. The monomethyl form is less hydrophobic and this is believed to reduce its potential to accumulate and to cross the blood-brain barrier. Nonetheless, in the malonate model of CNS injury in rats, orally administered dimethyl fumarate led to an increase in levels of monomethyl fumarate not only in plasma, but also in cerebrospinal fluid and the brain. 48 Perhaps the best data available for the direct capacity of dimethyl fumarate to achieve CNS outcomes is in the identification of another target for dimethyl fumarate, the Nrf2 transcription factor system, which leads to the activation of several antioxidative enzymes. 49 Chronic dimethyl fumarate treatment of experimental autoimmune encephalomyelitis (EAE)-affected mice through oral gavage has been demonstrated to increase Nrf2 activation in the CNS of animals. The activated Nrf2 that accumulates in the nucleus of cells was found to be present in several neuronal populations, in gray matter astrocytes, and in white matter oligodendrocytes. 50 With regard to the potential to promote remyelination, a study using the cuprizone model found that dimethyl fumarate treatment did not promote remyelination in that model of injury. 51 Oral medications: Teriflunomide This medication inhibits mitochondrial dihydroorotate dehydrogenase, which regulates the synthesis of pyrimidine nucleotides in cells undergoing proliferation. 20 Since the activation of immune cells usually requires a proliferation step in which immune cell subsets amplify their numbers, the action of teriflunomide reduces the propensity of activated immune cell subsets to be generated. At this time, it is not known if teriflunomide enters the CNS and, thus far, no reports in the published literature exist of its direct impact on events within the CNS. Oral medications in development: Laquinimod Laquinimod, an experimental immunomodulator under investigation for the treatment of MS, has several effects on immune cells in the periphery, including reducing the generation of Th1/Th17 cells, increasing the production of Th2 lymphocytes, and attenuating the activity of dendritic cells and monocytes/macrophages. 52 It has been reported that laquinimod mitigates the infiltration of pro-inflammatory monocytes into the CNS in EAE. 53 Laquinimod enters the CNS 54 and diminishes the histopathology of EAE within the CNS. Laquinimod has been reported to reduce the activity of reactive astrocytes through preventing the activation of the nuclear factor kb (NF-kB) pathway within astrocytes that would normally lead to the production of a spectrum of pro-inflammatory molecules. 55 It has been reported that laquinimod prevents the activation of microglia, which correlates with lowered neuronal death in culture and decreased axonal injury/loss. 56 Therefore, laquinimod appears promising as a medication to reduce neurodegenerative processes within the CNS. With regard to impact on repair, there are currently no available data on whether laquinimod promotes remyelination. Laquinimod has been reported to prevent the demyelination elicited by the toxin cuprizone. 55 Conclusions There are now several immunomodulators in use for the treatment of MS. These medications reduce inflammation in the periphery and may have indirect effects on the CNS by virtue of decreasing the infiltration of pathogenic immune cell subsets into the CNS or they may have additional direct activity within the CNS by entering and acting locally within the CNS milieu. Outcomes of the use of immunomodulators include not only the attenuation of neurodegenerative processes within the CNS; there is also evidence for some immunomodulators for repair within the CNS, such as remyelination. Associated with these beneficial effects is evidence of CNS well-being in treated individuals with MS; the reader is referred to the clinical literature for discussions of MS medications decreasing brain volume loss or improving repair responses. The information on the mechanisms of actions of MS immunomodulators provided in this article can help drive clinical decision making. The treatment of MS has improved significantly over the past 20 years and we S12 January 2014 Supplement to Neurology Reviews

15 Pathology of Multiple Sclerosis and Mechanisms of Multiple Sclerosis Therapies expect further exciting developments in the context of medications aimed principally at eliciting protection and repair of the CNS. REFERENCES 1. Cifelli A, Arridge M, Jezzard P, Esiri MM, Palace J, Matthews PM. Thalamic neurodegeneration in multiple sclerosis. Ann Neurol. 2002;52(5): Schirmer L, Albert M, Buss A, et al. Substantial early, but nonprogressive neuronal loss in multiple sclerosis (MS) spinal cord. Ann Neurol. 2009;66(5): Bermel RA, Bakshi R. The measurement and clinical relevance of brain atrophy in multiple sclerosis. Lancet Neurol. 2006;5(2): Sicotte NL, Kern KC, Giesser BS, et al. Regional hippocampal atrophy in multiple sclerosis. Brain. 2008;131(pt 4): Hulst HE, Geurts JJ. Gray matter imaging in multiple sclerosis: what have we learned? BMC Neurol. 2011;11: Lucchinetti CF, Popescu BF, Bunyan RF, et al. Inflammatory cortical demyelination in early multiple sclerosis. 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Reduced astrocytic NF-kB activation by laquinimod protects from cuprizone-induced demyelination. Acta Neuropathol. 2012;124(3): Mishra M, Silva C, Wang J, Yong V. Mechanisms of laquinimod in multiple sclerosis: focus on microglia. Presented at: 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis, 18th Annual Conference on Rehabilitation in MS; October 2-5, 2013; Copenhagen, Denmark. Supplement to Neurology Reviews January 2014 S13

16 Optimizing Patient Safety and Outcomes by Individualizing Therapy Fred D. Lublin, MD, FAAN, FANA Therapeutic approaches to multiple sclerosis (MS) entered the modern era 20 years ago with the approval of interferon beta-1b. Since then, 9 additional disease-modifying agents (DMAs) have been approved by the US Food and Drug Administration and have come to market (Table), a remarkable achievement in neurologic therapeutics. The approved agents utilize 7 different mechanisms of action (MOAs), but all work primarily through anti-inflammatory mechanisms. The differences in MOAs allow for a variety of different side effect profiles, safety issues, and individualized decision making. The hallmark of individualizing therapies and optimizing safety for patients with MS revolves around several factors: Whom to treat? When and when not to treat? Does MOA matter? Who makes the decision? How to decide? Whom to treat? Choosing the correct therapeutic approach for each patient may mean selecting 1 of the DMAs, a complex proposition Fred D. Lublin, MD, FAAN, FANA Saunders Family Professor of Neurology Director, The Corinne Goldsmith Dickinson Center for Multiple Sclerosis Mount Sinai Medical Center New York, New York DISCLOSURES Dr. Lublin reports that he has performed contracted research for Acorda Therapeutics, Inc.; Biogen Idec; Celgene Corporation; Genzyme Corporation; National Institutes of Health; National Multiple Sclerosis Society; Novartis Pharmaceuticals Corporation; sanofi-aventis U.S. LLC; and Teva Neuroscience, Inc. He reports consulting agreements and advisory board/data and safety monitoring board membership for Acorda Therapeutics, Inc.; Actelion Pharmaceuticals, US, Inc.; Bayer HealthCare Pharmaceuticals; Biogen Idec; Bristol-Myers Squibb Company; Celgene Corporation; Coronado Biosciences; EMD Serono, Inc.; Forward Pharma A/S; Genentech, Inc.; Genzyme Corporation; Johnson & Johnson; MedImmune, LLC; Novartis Pharmaceuticals Corporation; Questcor Pharmaceuticals, Inc.; Receptos, Inc.; Revalesio Corporation; Roche USA; sanofi-aventis U.S. LLC; Teva Neuroscience, Inc.; and XenoPort, Inc. Dr. Lublin is co-chief editor for Multiple Sclerosis and Related Disorders. He has current financial interests/stock ownership in Cognition Pharmaceuticals, Inc. as described below, or determining that no therapy is appropriate (ie, the risk-to-benefit assessment is unfavorable). The first decision relates to whom to treat. The available therapies (with the exception of mitoxantrone) are all approved for relapsing forms of MS, primarily relapsing-remitting MS. For those forms of MS, the evidence supports sufficient efficacy to outweigh any side effects and safety concerns. The issue becomes less clear with progressive forms of MS, where proven effective therapies are lacking (with the exception of mitoxantrone, where safety concerns have seriously limited use). Nevertheless, the question has been raised as to whether progressive forms of MS, with signs of activity such as ongoing relapses or new magnetic resonance imaging (MRI) activity, might benefit from the currently available agents. This will require additional clinical trials. At the other end of the therapeutic decision-making process are those patients who have a clinically isolated syndrome (CIS), the first attack of what will likely become MS. Here there is compelling evidence to support treating those who clearly have CIS (optic neuritis, brainstem/cerebellar lesion, or partial myelitis) when it is associated with MRI changes that are consistent with MS. 2-5 These patients will benefit from treatment with the same agents used for established relapsing MS. Of note, the latest version of the MS diagnostic criteria allows for approximately 50% of those with a single attack to be diagnosed with MS. 6 When and when not to treat? As discussed above, treatment of relapsing MS and CIS with MRI changes as early as possible has been shown to be beneficial, reducing the risk of subsequent attacks and, in some cases, lessening accrual of disability. 7,8 The studies demonstrating this also showed less development of MRI changes and, for some agents, a slowing of the accelerated loss of brain tissue that occurs with MS. 3,9,10 The key determinant for these treatment decisions is disease activity, the timeframe for which has not yet been determined. There is little debate that activity in the past year would be sufficient to recommend treatment initiation. On the other hand, if someone has been stable for a decade with no relapses or change in S14 January 2014 Supplement to Neurology Reviews

17 Optimizing Patient Safety and Outcomes by Individualizing Therapy TABLE Available disease-modifying agents 1,a Generic name Brand name Dosage Warnings (partial list) Teriflunomide Aubagio Every day; pill taken orally; 7 mg or 14 mg Interferon beta-1a Avonex Once a week; intramuscular injection; 30 µg Rebif 3 times a week; subcutaneous injection; 22 µg or 44 µg Interferon beta-1b Betaseron; Extavia Every other day; subcutaneous injection; 0.25 mg (250 µg) Glatiramer acetate Copaxone Every day; subcutaneous injection; 20 mg (20,000 µg) Fingolimod Gilenya Every day; capsule taken orally; 0.5 mg Mitoxantrone Novantrone 4 times a year by IV infusion in a medical facility (12 mg/m 2 ). Lifetime cumulative dose limit of approximately 8-12 doses over 2-3 years (140 mg/m 2 ) Dimethyl fumarate Tecfidera Twice a day; capsule taken orally; 120 mg for 1 week and 240 mg thereafter Liver damage, birth defects, increased risk of infections, peripheral neuropathy, renal failure/ elevated potassium, increased blood pressure Depression, seizure disorder, cardiac problems, liver abnormalities, anemia, allergic reactions Depression, seizure disorder, liver abnormalities, anemia, allergic reactions Depression, seizures, allergic reactions, injection-site reactions Permanent depressions under the skin at injection sites; skin damage; a post-injection reaction that includes at least 2 of the following: flushing, chest pain, palpitations, anxiety, shortness of breath, constriction of the throat, and transient skin eruptions; these symptoms generally disappear spontaneously after about 15 minutes and have no known longterm effects Bradycardia, increased blood pressure, reduction in blood lymphocyte counts, herpetic infections, respiratory dysfunction, macular edema, liver enzyme elevations Acute myelogenous leukemia (AML); heart damage Reduction in blood lymphocyte counts; nausea, vomiting, diarrhea, abdominal pain; flushing Natalizumab Tysabari Every 4 weeks by IV infusion in a registered infusion facility; 300 mg Increased risk of progressive multifocal leukoencephalopathy (PML); not recommended for persons with weakened immune systems a For more specific recommendations regarding warnings and monitoring, consult prescribing information for each drug. Abbreviation: IV, intravenous. Source: Hilas O, Patel PN, Lam S. Open Neurol J. 2010;4: MRI, there is little reason to think that starting therapy would be of benefit. For progressive disease, especially primary progressive MS, there are no approved therapies and although there may be some logic to treating progressive patients who show evidence of disease activity, either relapses or MRI activity, this needs to be established in carefully controlled clinical trials. Does mechanism of action matter? In general, the key factor in determining the use of an agent is its efficacy and safety profile. All of the currently approved MS agents act primarily through a variety of anti-inflammatory mechanisms. However, there are situations where the MOA and any potential safety issues might influence the choice of an agent. The first consideration relates to comorbid conditions. Obtaining a careful detailed medical history and a physical examination is of paramount importance. Many of the currently available agents have the potential for liver injury by raising levels of liver enzymes. 1,11-17 If an individual with MS also has a concomitant liver disorder, one might want to prescribe a DMA that does not affect the liver. Similarly, if the Supplement to Neurology Reviews January 2014 S15

18 Optimizing Patient Safety and Outcomes by Individualizing Therapy patient is already taking medications that might raise liver enzymes, one should again consider using a DMA that does not affect the liver. Prior immunosuppressive therapy raises the potential for progressive multifocal leukoencephalopathy (PML) in individuals taking natalizumab. 1 Patients with prior uveitis or diabetes mellitus are at greater risk for macular edema when taking fingolimod. 18 Moreover, patients with cardiac conditions, especially conduction problems, are at greater risk of cardiac complications when taking fingolimod. 19 Patients with underlying hematologic conditions require special consideration in their choice of DMA. 1 Another potential issue to contemplate when reviewing comorbidities is whether a DMA might also be beneficial for a concomitant condition. Teriflunomide is the active metabolite for an agent that has been used for treating rheumatoid arthritis and is therefore a reasonable choice when MS is comorbid with rheumatologic conditions. 20 Analogously, dimethyl fumarate has been used to treat psoriasis 21 and natalizumab is used for Crohn disease. 22 Who makes the decision? With so many choices, there are numerous considerations in the selection of a DMA. Ideally, the patient and the physician would collaborate in this process. Among the issues that should be discussed are relative efficacy (when available), safety issues, side effect profiles, route of administration, convenience, adherence, long-term implications, and medical monitoring issues. How to decide? For the efficacy discussion, there are few well-controlled comparative studies to assist in the decision-making process. Several studies suggest that high-dose/high-frequency interferon is more effective than low-dose/low-frequency interferon. 23 There is good evidence to indicate that glatiramer acetate (GA) has a better effect on relapse rate reduction than low-dose/low-frequency interferon. 24 High-dose/ high-frequency interferon appears to have similar efficacy to GA. 25,26 Teriflunomide has similar efficacy to high-dose/highfrequency interferon. 27 Fingolimod is superior to low-dose/ low-frequency interferon in relapse rate reduction. 28 There is an erroneous tendency among some clinicians to try to compare results from different studies. This is fraught with difficulties, as the only rational means to compare different agents is to study them in a well-controlled head-to-head study. For example, natalizumab demonstrated impressive efficacy in its pivotal studies, but there are no direct comparisons with any other agent. Differences in study populations, procedures, placebo groups, follow-up, assessments, and many other factors preclude drawing conclusions across clinical trials. The best evidence for determining efficacy, which at this time is the randomized, prospective, properly blinded clinical trial, should be used. Open-label studies are appropriate for early phase trials and generating hypotheses, but can never be suitable as providing evidence of efficacy. For the safety discussion, there are also many considerations. Every approved agent has a safety database of cumulative available data on human exposure to the agent. When only interferon and GA were available, safety was not a prime consideration, as there are abundant long-term data demonstrating the safety of these agents. With the additions of mitoxantrone and natalizumab, safety became more of an issue. Mitoxantrone, which is currently not used very often, was associated with concerns for cardiac toxicity and secondary leukemias. 1 These concerns have limited its use. Natalizumab had a relatively mild safety profile during the clinical trials that led to its approval. However, shortly after approval, an association with PML was uncovered, leading to the agent s withdrawal from the market for more than 1 year while the association was investigated. 1 To date, there have been approximately 400 cases of PML, 20% of which were fatal. 29,30 Considerable effort has been expended to determine PML risk mitigation strategies for those receiving natalizumab. These mitigation strategies are quite helpful in developing an individualized treatment strategy. There are 3 main factors that affect PML risk. First is duration of natalizumab therapy. 31 The risk is very low in the first 12 months and gradually rises over the next year. After 2 years, the risk increases more dramatically. The second risk factor is any prior exposure to an immunosuppressive agent, such as azathioprine, methotrexate, or cyclophosphamide. Such prior exposure also dramatically increases the PML risk. The third, and perhaps most important risk factor, is evidence of exposure to the virus responsible for PML, the John Cunningham virus (JCV). Of the various ways to assay for JCV, the one that seems to be most useful for risk mitigation is an assay for anti-jcv antibodies in the blood to determine prior exposure to the virus. JCV is a ubiquitous virus that is present in approximately 50% of adults. The infection caused by this virus is latent; neither the route nor symptoms of primary exposure are known. In immunocompromised individuals, the virus can undergo a recombination event that renders it neurotropic and leads to PML. The risk of PML is extremely low in those who do not have antibodies to JCV and is reciprocally much higher in those who have these antibodies. Therefore, assaying for antibodies to JCV is an important part of the screening process prior to determining if an individual is suited for treatment with natalizumab. Evidence to date suggests that if a patient does not have evidence of S16 January 2014 Supplement to Neurology Reviews

19 Optimizing Patient Safety and Outcomes by Individualizing Therapy exposure to the virus, the other factors (ie, duration of therapy and prior immunosuppression), are not as relevant. 32 Because the nature of the initial JCV infection is unknown and possibly silent, JCV antibody-negative individuals taking natalizumab should undergo repeat testing for development of these antibodies. Repeat testing is also useful for excluding false-negative results. 31 The risks and benefits of continuing treatment with natalizumab should be carefully considered in patients who are found to be anti-jcv antibody positive and have 1 or more additional risk factors. Patients with all 3 known risk factors have an estimated risk of PML of 11 in Other safety issues relate to cardiac concerns with fingolimod and avoidance of concomitant use of certain cardioactive medications. 33 There is also concern for herpetic infections with fingolimod. 33 Risk mitigation includes evaluation for prior exposure to varicella (chicken pox) or immunization. Other safety issues with fingolimod include increased blood pressure, potential adverse effects on asthma, and development of macular edema. 33 With these newer agents, safety has continued to be a concern and is an important part of the discussion with patients. Some patients may prefer to utilize the older agents, despite the need for injections, because of their long-term safety profiles. This highlights the ongoing DMA discussion dynamic. Many patients are delaying the decision to change to a newer, more conveniently dosed or administered agent out of concern for potential safety issues developing as more experience with the agent is acquired. This is not a situation unique to MS, as many agents have been found to have unexpected adverse events after exposure to larger numbers of individuals than typically followed in pivotal clinical trials. Similarly, some safety issues take longer to develop or to be confirmed than is possible within the exposure time of clinical trials. This highlights the unmet need for improved safety monitoring protocols for new agents. This is especially important when considering new molecular entities and first-in-human-use agents such as natalizumab, fingolimod, and dimethyl fumarate. Side effect profiles of the various agents also impact therapy decisions. Interferons may induce flu-like symptoms and injection-site reactions. 1 Glatiramer acetate can produce injection-site reactions and a systemic reaction immediately after an injection. 1 All subcutaneously administered agents can produce subcutaneous atrophy, which is related to the frequency of injection. Therefore, GA is more likely to produce this subcutaneous atrophy as it is administered daily, whereas subcutaneous interferon is administered every other day or 3 times weekly. While this is not a safety concern, it does have cosmetic consequences. Natalizumab may produce infusion reactions. 34 Teriflunomide can induce gastrointestinal symptoms and hair thinning. 35 The latter can lead to some resistance to using this agent, again for cosmetic reasons. Dimethyl fumarate may produce nausea, vomiting, diarrhea, abdominal pain, and dyspepsia. This treatment also can induce flushing, which can be rather intense. 36 Some newer agents have the potential for requiring longterm monitoring. This has been observed with mitoxantrone, for which long-term monitoring of cardiac output has been advised. 37 As more experience with a newer agent accrues, an increased need for long-term monitoring for late complications of therapy may arise. Reproductive issues also affect decision making and individualization of therapy. The risk to the fetus of the various agents ranges from category B to X. The safety during pregnancy has not been determined for any of the agents. Some carry greater potential risk than others. Glatiramer acetate is category B, the lowest risk of the available agents. 38 The others are all category C except for teriflunomide, which is As part of the individualization process, there should be consideration and appropriate discussion of adherence. category X. 35 Furthermore, teriflunomide has been detected in human semen. 35 Whether this can damage fetal tissue has not been studied, but there is potential. Thus, the clinician should have a family planning discussion with the couple. Men and women who wish to have a child must undergo an accelerated elimination procedure to decrease the plasma concentration of teriflunomide to less than 0.02 mg/l (0.02 mg/ml). 35 Teriflunomide can be rapidly eliminated from the body with cholestyramine or activated charcoal. Because MS tends to be less active during pregnancy, 39 initiation of a DMA could be delayed in favor of trying to conceive. Therapy can be restarted or initiated after delivery and after a discussion on whether the mother wishes to breastfeed. Data are limited but suggest that breastfeeding may have some protective effect on MS relapse rate. 40 As part of the individualization process, there should be consideration and appropriate discussion of adherence. No agent will perform as expected unless the patient takes it as prescribed. In general, patients do not like injections. While thousands are receiving injections and have no issues, there are some who will not take them as often as needed or who will develop injection fatigue. If fear of a safety issue or persistent side effects alter adherence, this must be addressed with the patient. Occurrence of relapses is often associated with not taking the DMA as prescribed. 41 Supplement to Neurology Reviews January 2014 S17

20 Optimizing Patient Safety and Outcomes by Individualizing Therapy Perhaps the most significant obstacle in individualizing therapy is financial/insurance constraints. Ideally, a clinician should be able to offer a patient the full range of DMAs so as to best meet the patient s needs. However, all of the DMAs are very expensive. There are no generics or biosimilars available as yet. Some individuals do not have insurance coverage for their medications and some are underinsured. Conclusions The individualization of MS therapies is a complex and timeconsuming process that involves discussions surrounding the efficacy and relative efficacy of the DMAs, the safety profile of each agent and the extent and duration of the safety database, the potential side effects, the role of comorbid conditions, the willingness to take the medications, and the ability to afford expensive medications. REFERENCES 1. Hilas O, Patel PN, Lam S. Disease modifying agents for multiple sclerosis. 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Cambridge, MA: Biogen Idec, Inc.; Mitoxantrone. Medication guide. Rockland, MA: EMD Serono, Inc.; March Accessed October 1, Copaxone [package insert]. Kansas City, MO: Teva Neuroscience, Inc.; Birk K, Smeltzer SC, Rudick R. Pregnancy and multiple sclerosis. Semin Neurol. 1988;8(3): Hellwig K, Haghikia A, Agne H, Beste C, Gold R. Protective effect of breastfeeding in postpartum relapse rate of mothers with multiple sclerosis. Arch Neurol. 2009;66(12): Ivanova JI, Bergman RE, Birnbaum HG, Phillips AL, Stewart M, Meletiche DM. Impact of medication adherence to disease-modifying drugs on severe relapse, and direct and indirect costs among employees with multiple sclerosis in the US. J Med Econ. 2012;15(3): S18 January 2014 Supplement to Neurology Reviews