1. Practitioner’s Edge is a registered service mark of Integrity Continuing Education, Inc. © 2014 Integrity Continuing Education, Inc. Sponsored by Integrity Continuing Education Improving Management Strategies for Patients With Multiple Sclerosis: An Evaluation of Current Practice Supported by an educational grant from Novartis

2. 2 Elizabeth Crabtree, MD Associate Professor of Neurology Director of Patient Education and Support University of California San Francisco MS Center San Francisco, California

3. Faculty Disclosures 3

4. Apply the most recent evidence-based criteria toward the diagnosis of multiple sclerosis (MS) Implement management strategies that are personalized to the individual needs of patients with MS Describe the risks and benefits of all approved therapies for the management of patients with MS Monitor response to therapy as recommended by current treatment guidelines, so that changes in a patient’s treatment plan can be implemented if necessary Learning Objectives 4

5. Multiple Sclerosis Overview and Unmet Needs 5

6.  Chronic inflammatory, neuroimmune, demyelinating, and neurodegenerative disease of the central nervous system (CNS)  Characterized by macroscopic and microscopic injury to gray and white matter  Common manifestations are optic neuritis, partial transverse myelitis, and brain stem or cerebellar syndrome  Progressive disability occurs over time  Exact etiology is unknown Multiple Sclerosis Overview 6

7. Affects ~400,000 people 1 Major cause of nontraumatic disability 2 Disease sequelae –Multiple symptoms –Disability (cognitive, motor, vocational) –Psychological stress 3 $8,528 to $54,244 per patient/year in direct plus indirect costs 4 Prevalence and Burden of MS in the United States 7 1. Tullman MJ. Am J Manag Care. 2013;19(2, suppl):S15-S20; 2. Miller AE, et al. Curr Opin Neurol. 2012;25(suppl):S4-S10;3. Kalb R. J Neurol Sci. 2007;256(suppl 1):S29-S33; 4. Adelman G, et al. J Med Econ. 2013;16(5):639-647.

8. Relapsing Remitting (RRMS) Unpredictable exacerbations of new symptoms or worsening of old symptoms Initial onset in 85% of cases Secondary Progressive (SPMS) Initially relapsing remitting course that finally becomes progressive Usually the natural course following RRMS Progressive Relapsing (PRMS) Progressive from onset and is characterized by intermittent relapses Rare Primary Progressive (PPMS) Progressive disease from the onset without relapses Observed in 10% to 15% of cases Clinical Courses of MS 8 Miller AE, et al. Curr Opin Neurol. 2012;25(suppl):S4-S10.

9. Delay in diagnosis and misdiagnosis Lack of biomarkers for disease activity No curative or reparative/restorative therapy Patient compliance with therapeutic protocols Unmet Needs in MS 9

10. Pathophysiology of MS 10

11. Immune-mediated mechanisms damage CNS tissue Inflammatory response (early vs later, gray vs white matter) −B-cell, follicle-like structures in cortical areas Environmental factors (vitamin D, smoking, ultraviolet light) Infectious factors (Epstein-Barr virus) Genetic factors (eg, multiple non-MHC susceptibility genes) −No family history: 1/750 for developing MS −Family history (parent or sibling): 1/40 for developing MS −1st-degree relative (2%-3% chance; sibling > parent) Underlying Pathophysiology of MS 11 Handel ​ ‌ AE, et al. Mult Scler Rel Disord. 2012;1(1):39-42; National MS Society. http://www.nationalmssociety.org/about- multiple-sclerosis/what-we-know-about-ms/who-gets-ms/genetics/index.aspx. MHC, major histocompatibility complex.

12. Focal demyelinated plaques disseminated in CNS Easily visualized in the white matter, but extensive gray matter involvement especially in early MS Predilection for optic nerves, subpial, spinal cord, brain stem, cerebellum and juxtacortical, and periventricular white matter regions Variable degrees of inflammation, gliosis, and neurodegeneration Observed Changes in the CNS in MS 12 Popescu et al. Continuum (Minneap Minn). 2013;19(4):901-921.

13.  Patients with early RRMS showed significantly lower SDGM, but not cortical volumes compared with patients with CIS  Evidence that significant SDGM atrophy (not cortical) occurs rapidly during first 4 years in treatment-naïve patients  Confirms that selective regional, but not global, atrophy occurs from clinical onset to conversion to clinically definite MS Evidence for Gray Matter Involvement 13 Bergsland N, et al. AJNR Am J Neuroradiol. 2012;33:1573–1578. SDGM, subcortical deep gray matter; CIS, clinically isolated syndrome.

14. Immune-mediated Axonal Injury Mechanisms 14 Dutta R, Trapp BD. Prog Neurobiol. 2011;93(1):1-12. Transection leads to degeneration of the distal end of the axon and the proximal end forms an ovoid due to accumulation of transported organelles Immune-mediated processes lead to axonal transection

15. Cortical Demyelination Patterns 15 Dutta R, Trapp BD. Prog Neurobiol. 2011;93(1):1-12.

16. Common and may represent an early and/or initial target of MS disease process May represent the pathologic substrate of cognitive impairment and seizures in RRMS Highly inflammatory and suggests that neuronal and axonal injury in early cortical demyelination occur on a background of inflammation Meningeal inflammation is present in early MS and topographically associated with cortical lesions –Infiltrates are composed of T cells, B cells, and macrophages Cortical Demyelinated Lesions in Early MS: New Insights 16 Popescu et al. Continuum (Minneap Minn). 2013;19(4):901-921.

17. MRI of Cortical Onset MS 17 Popescu et al. Continuum (Minneap Minn). 2013;19(4):901-921. MRI, magnetic resonance imaging.

18. Very prominent Less inflammatory than white matter lesions −Lack inflammatory infiltrates, complement deposition, and breakdown of blood-brain barrier Characterized by meningeal inflammatory aggregates (B cell follicle-like structures) in primary as well as secondary progressive MS Associated with increased rate of clinical progression Cortical Demyelinated Lesions in Progressive MS: New Insights 18 Popescu et al. Continuum (Minneap Minn). 2013;19(4):901-921; Popescu BF, Lucchinetti CF. BMC Neurol. 2012;12:11; Howell OW, et al. Brain. 2011;134(Pt 9):2755-2771; Choi SR, et al. Brain. 2012;135(Pt 10):2925-2937.

19. Cortical Demyelination in SPMS 19 Howell OW, et al. Brain. 2011;134(Pt 9):2755-2771.

20. New Data on Cortical Pathology and SPMS 20 Calabrese M, et al. Ann Neurol. 2013;74(1):76-83.

21. Other Studies on Cortical Demyelinating Lesions 21 New MRI techniques for visualization (DIR, PSIR, T1- weighted 3D FSPGR) and early diagnosis Correlation between gray matter pathology and patient disability and cognitive impairment Effect of disease-modifying therapy on gray matter pathology Increased cortical demyelinating lesions can indicate evolution of RRMS to SPMS DIR, double inversion recovery; PSIR, phase-sensitive inversion recovery; 3D, three-dimensional; FSPGR, fast spoiled gradient echo. Popescu et al. Continuum (Minneap Minn). 2013;19(4):901-921.

22. Diagnosis of MS 22

23. Exclusion of hereditary, psychological, and other CNS disorders Supplemented by paraclinical tests, including MRI, evaluation of cerebrospinal fluid (CSF) Clinical evaluation of history, symptoms, signs, relapses, and disability progression Recommendations for Diagnosis of MS 23 Pohlman CH, et al. Ann Neurol. 2011;69(2):292-302.

24.  No clinical findings are unique to MS  Difficulty in patient characterization and physician interpretation of symptoms  Numerous differential diagnoses of MS-like symptoms  Imaging is not always specific and there may be an overreliance on MRI  Confounding comorbidities  Unpredictable MS clinical courses Challenges in the Diagnosis of MS 24 Katz S, et al. Continuum (Minneap Minn). 2013;19(4): 922–943.

25. Typically affects young adults (aged 20-45 years) Patient demonstrates signs and symptoms suggestive of CNS demyelination Attacks last for at least 24 hours and reach a peak within 2 to 3 weeks No indication of fever, infection, or encephalopathy Many qualify for definitive diagnosis based on 2010 International Panel diagnostic criteria Clinically Isolated Syndrome 25 Katz S, et al. Continuum (Minneap Minn). 2013;19(4): 922–943; Lo CP, et al. J Neurol Neurosurg Psychiatry. 2009;80(10):1107-1109.

26. Medical history and neurological examination usually indicating CIS MRI to confirm presence of macroscopic lesions CSF analysis Blood tests for ruling out differential diagnoses Steps Toward the Diagnosis of MS 26 Katz S, et al. Continuum (Minneap Minn). 2013;19(4):922–943.

27. Core Requirement: Objective demonstration of dissemination of CNS lesions in both space (DIS) and time (DIT) by MRI Revised criteria simplify DIS and DIT for MS diagnosis Correct interpretation of clinical signs is critical (Patient-reported symptoms or objectively observed signs typical of an acute inflammatory demyelinating event, duration of at least 24 hours, in the absence of fever or infection) Alternative diagnoses need to be considered and excluded McDonald Criteria: 2010 Revision* 27 *Please see detailed 2010 Revised McDonald Criteria to confirm a diagnosis of MS in your handout. Pohlman CH, et al. Ann Neurol. 2011;69(2):292-302.

28. Important Considerations in Revised 2010 McDonald Criteria Allows diagnosis of MS in patients with CIS Exclusion of neuromyelitis optica (NMO) and NMO spectrum disorders Diagnosis of PPMS Applicability in pediatric, Asian, and Latin American populations 28 Pohlman CH, et al. Ann Neurol. 2011;69(2):292-302.

29. Pediatric MS >95% of pediatric patients with MS have an initial relapsing-remitting disease course PPMS is exceptional ~80% of pediatric cases, and nearly all adolescent-onset cases, present with attacks typical for adult CIS, with a similar or greater total T2 lesion burden MS must be differentiated from acute disseminated encephalomyelitis (ADEM) or NMO 29 Pohlman CH, et al. Ann Neurol. 2011;69(2):292-302.

30.  Confirmation by: –≥2 non–ADEM-like attacks following a first ADEM-like attack OR –1 non-ADEM attack followed by accrual of clinically silent lesions  Serial clinical and MRI observations are required to confirm a diagnosis of MS in children  Accurate diagnosis of pediatric MS is critical Criteria for Diagnosis of MS in Pediatric Patients 30 Pohlman CH, et al. Ann Neurol. 2011;69(2):292-302.

31. DIS can be demonstrated by: −≥1 T2 lesion in at least 2 of 4 regions of the CNS* −Development of further attack implicating different CNS site −In patients with brain stem or spinal cord syndromes, symptomatic MRI lesions are excluded from the criteria and do not contribute to lesion count DIT can be demonstrated by: −Simultaneous presence of asymptomatic gadolinium (Gd)-enhancing and nonenhancing lesions at any time −A new T2 and/or Gd-enhancing lesion(s) on follow-up MRI, irrespective of the timing with baseline scan −The development of a second clinical attack Revised MRI Criteria for DIS and DIT 31 Pohlman CH, et al. Ann Neurol. 2011;69(2):292-302. *Periventricular, juxtacortical, infratentorial, or spinal cord.

32. How have these revised criteria affected your evaluation of clinical and MRI findings toward a diagnosis of MS? Do you use these criteria to make a diagnosis of MS? If not, what do you use? How many of your patients may have been diagnosed with MS prior to 2010 using the revised criteria? Clinical Questions 32

33. Imaging in MS 33

34. MS Lesions on MRI 34 Katz S, et al. Continuum (Minneap Minn). 2013;19(4):922–943.

35. MS Lesions on MRI (cont’d) 35 Katz S, et al. Continuum (Minneap Minn). 2013;19(4):922–943.

36. CSF Findings 36

37. CSF findings such as ≥2 oligoclonal bands or elevated IgG index can support: −Inflammatory demyelinating nature of the underlying condition −Evaluation of alternative diagnoses −Prediction of confirmed diagnosis of MS −PPMS Supportive Role for CSF Findings in MS Diagnosis 37 Pohlman CH, et al. Ann Neurol. 2011;69(2):292-302. IgG, immunoglobulin G.

38. Case Study #1: Kim, 25-year-old Female 38

39. Do you agree with how her physician treated her? Careful history and physical/neurologic exam −Funduscopic exam −Referral to neuroophthalmologist What tests do you order? −Blood work −Brain MRI (with/without contrast, with orbit views) −Spinal MRI (cervical, thoracic, and lumbar) −Lumbar puncture Does she meet 2010 criteria for CIS? Would you have recommended treatment at the initial visit if her symptoms were still present? Approach to counseling on the risk for MS? Clinical Questions 39

40. Depending on level of clinical suspicion, perform tests to exclude: –Autoimmune/demyelinating disorders –Collagen vascular disease and other rheumatologic conditions –Infections (ie, Lyme disease, syphilis, HTLV-1, HIV) –Endocrine abnormalities (eg, thyroid disease) –Vitamin B 12 deficiency –Sarcoidosis Order specific tests? –NMO antibody test –Cadasil gene test –Very long chain fatty acids –Other? Kim’s blood work is normal Diagnosis: CIS Case Study #1, Kim, 25-year-old Female: Blood Work 40 HTLV-1, human T-lymphotropic virus, type 1; HIV, human immunodefiency virus.

41. Management of Patients with MS 41

42. Proposed Algorithm 42 Modified from original in Río J, et al. Nat Rev Neurol. 2009;5(10):553-560. Relapse and/or observed progression Consider change in therapy Treatment with disease-modifying agents commences MRI and clinical assessments at 6 to 12 months Negative MRI result Relapses and/or disease progression Active MRI result Consider change of therapy Periodic clinical and MRI assessment Close clinical and MRI monitoring No relapses and no disease progression

43. 10 DMTs to choose from after diagnosis is confirmed None are curative No “one size fits all” empiric treatment (given variability and unpredictability of MS) Disease, drug, patient factors Prior experience, availability, cost Risk-benefit ratio Choosing a Disease-modifying Therapy (DMT) 43 Freedman MS. Continuum (Minneap Minn). 2013;19(4):968-991.

44.  Current disease activity and disability  Disease prognostic profile  Patient lifestyle and expected longevity  Preference for route of treatment administration  Patient's ability to self-treat  Need for therapy to be delivered by a healthcare professional  Reproductive status  Other expectations Important Considerations Before Making Therapeutic Decisions 44 Miller AE, et al. Curr Opin Neurol. 2012;25(suppl):S4-S10.

45. First-line option involves glucocorticoids Glucocorticoids may speed up recovery time frame Most common regimen –1000-mg IV methylprednisolone daily for 5 days without an oral taper –Excellent bioavailability –High-dose oral could be substituted Second-line options involve corticotropin gel, plasma exchange, IVIG Recommendations for Treatment of Acute MS Exacerbations 45 Goodin DS, et al. Neurology. 2002;58:169-178. IV, intravenous; IVIG, intravenous immunoglobulin.

46. First-line AgentsSecond-line Agents Interferon beta-1a Interferon beta-1b Glatiramer acetate Oral therapies: Fingolimod Teriflunomide Dimethyl fumarate Mitoxantrone Natalizumab Oral therapies: Fingolimod DMTs Approved for RRMS 46 Río J, et al. Curr Opin Neurol. 2011;24(3):230-237; Coyle PK. CNS Drugs. 2013;27(4):239-247.

47. ClinicalTrials website. www.clinicaltrials.gov. Accessed December 2, 2013.  Safety and efficacy of Siponimod (BAF312) versus placebo for variable treatment durations in patients with SPMS  Double Blind Combination of Rituximab by Intravenous and Intrathecal Injection Versus Placebo in Patients With Low- Inflammatory Secondary Progressive Multiple Sclerosis (RIVITaLISe)  Study of Tcelna (Imilecleucel-T) in Secondary Progressive Multiple Sclerosis (Abili-T)  Masitinib for the treatment of patients with PPMS or relapse-free SPMS  Safety, Tolerability and Activity Study of Ibudilast in Subjects With Progressive Multiple Sclerosis Current Trials in SPMS 47

48. Overview of Available Agents for MS 48

49. Relapse Response Rate to Interferons 49 Freedman MS. Continuum (Minneap Minn). 2013;19(4):968-991. INTERFERONS INF β-1a subcutaneous ‘94 ‘07 INF β-1a intramuscular ‘93 ‘11 INF β-1b ‘88 ‘07

50. Glatiramer acetate vs placebo 2-year relapse rate (1.19 vs 1.68) Reduced disability (22%) Significant reduction in the number of new T1 Gd-enhancing lesions over 9 months Study 1 (N=50) Study 2 (N=251) Study 3 (N=239) (RRMS) Results similar to IFNβ-1a for time to first relapse, relapse rates, disease progression, or number and change in volume of T2 active or Gd+ lesions REGARD trial (RRMS) Results similar to IFNβ-1b for relapse risk, disease progression, or MRI measures of lesion burden BEYOND trial (RRMS) Clinical Evidence for Glatiramer Acetate 50 Mikol DD, et al. Lancet Neurol. 2008;7(10):903-914; O'Connor P, et al. Lancet Neurol. 2009;8(10):889-897; McGraw CA, et al. Neurotherapeutics. 2013;10(1):2-18. IFN, interferon.

51. Relapse Response Rate to Therapies 51 GLATIRAMER ACETATE Freedman MS. Continuum (Minneap Minn). 2013;19(4):968-991. 1991 2011

52. 3, 6 mg of IV natalizumab per kg of body weight every 28 days compared with placebo Fewer inflammatory brain lesions and fewer relapses over a 6-month period Study 1 (RRMS or relapsing SPMS) 300 mg of natalizumab every 4 weeks compared with placebo for over 2 years 68% ↓ in rate of clinical relapse 83% ↓ in new or enlarging hyperintense lesions 92% fewer Gd-enhancing lesions over 2 years 42% ↓ in risk of sustained disability progression Study 2 (RRMS) Clinical Evidence for Natalizumab (mAb against leukocyte integrin α4) 52 Miller DH, et al. N Engl J Med. 2003;348(1):15-23; Polman CH, et al. N Engl J Med. 2006;354(9):899-910; Río J, et al. Curr Opin Neurol. 2011;24(3):230-237. mAb, monoclonal antibody.

53. Newer Oral Therapies 53

54. Would you switch to a new therapy that was oral or injectable and was associated with mild or severe risk and vigilance? Survey of Patients Taking Self-injected DMT: Route of Administration 54 Giovannoni G, et al. Curr Opin Neurol. 2012;25(suppl):S20-S27.

55. Oral dimethyl fumarate 240 mg 2 or 3 times daily compared with placebo over 2 years Significantly reduced annualized relapse rates (ARRs; 0.22, 0.20, placebo 0.4) and new or enlarging T 2 – weighted hyperintense lesions Trend towards decreased disability compared with placebo CONFIRM trial (RRMS) Oral dimethyl fumarate 240 mg 2 or 3 times daily compared with placebo over 2 years Reduction in relapse rates (27%, 26% vs 46%), ARRs (0.17, 0.19 vs 0.36), ↓number of Gd-enhancing lesions and of new or enlarging T 2 -weighted hyperintense lesions, and ↓progression of disability (16%-18%) compared with placebo (27%) DEFINE trial (RRMS) Results similar to glatiramer acetate in CONFIRM trial Long-term benefits unclear Long term Clinical Evidence for Dimethyl Fumarate 55 Fox RJ, et al. N Engl J Med. 2012;367:1087-1097; Gold R, et al. N Engl J Med. 2012;367:1098-1107; Freedman MS. Continuum (Minneap Minn). 2013;19(4):968-991.

56. Indicated for relapsing forms of MSDosing: 240 mg twice-a-day, oralWarnings and Precautions May cause lymphopenia and flushing Recent complete blood cell count (< 6 months) before starting treatment and annually or as clinically indicated Liver function tests Administration with food may decrease flushing (ASA but watch GI effects) Withholding treatment should be considered in patients with severe infections Practice Recommendations for Dimethyl Fumarate 56 National MS Society. http://www.nationalmssociety.org/ms-clinical-care-network/clinical-resources-and-tools/core- curriculum/managing-ms/comprehensive-care/disease-modification/indications-dosing-etc/index.aspx; http://www.nationalmssociety.org/ms-clinical-care-network/clinical-resources-and-tools/core-curriculum/managing- ms/comprehensive-care/disease-modification/warnings-safety-management/index.aspx.

57. Oral fingolimod at a dose of 0.5 mg or 1.25 mg daily compared with placebo over 2 years Reduced ARRs (0.18, 0.16 vs 0.4) Statistically significant reductions in both the risk of sustained disability progression (hazard ratio, 0.70 and 0.68, respectively; P=.02 vs placebo, for both comparisons) Superior MRI-related measures (number of new or enlarged lesions on T(2)-weighted images, Gd-enhancing lesions, and brain-volume loss; P<.001 for all comparisons at 24 months) FREEDOMS trial (RRMS) Compared oral fingolimod (1.25 or 0.5 mg) with IFNβ-1a daily over 1 year ↓ ARR (0.2, 0.16 vs 0.33) and reduced MRI lesions Effect on disability progression was unclear TRANSFORM MS trial (RRMS) Survey showed that more than 80% of patients reported the first dose of fingolimod was moderately/very/extremely manageable, convenient, and easy to take. 4-year data show that continued fingolimod treatment improved brain volume loss Long term Clinical Evidence for Fingolimod 57 Kappos L, et al. N Engl J Med. 2010;362(5):387-401; Cohen JA, et al. N Engl J Med. 2010;362(5):402-415; Freedman MS. Continuum (Minneap Minn). 2013;19(4):968-991; Hanson KA, et al. Patient Prefer Adherence. 2013;7:309-318.

58. Adherence with Fingolimod Therapy 58 Agashivala N, et al. BMC Neurol. 2013;13(1):138. [Epub ahead of print] Naïve disease-modifying therapy users 1.0 0.9 0.8 0.7 0.6 0.5 0.4 Probability of Staying on Index Medication 5 25 4565 85105 125 145 165185205225 245 265 285 305 325 345 365 Days Fingolimod Subcutaneous interferon beta-1a Interferon beta-1b Glatiramer acetate Intramuscular interferon beta-1a

59. Adherence with Fingolimod Therapy (cont’d) 59 Agashivala N, et al. BMC Neurol. 2013;13(1):138. [Epub ahead of print] Experienced disease-modifying therapy users 1.0 0.9 0.8 0.7 0.6 0.5 0.4 Probability of Staying on Index Medication 1 31 61 91 121151 181 211 241 271 301 331 361 Days Fingolimod Subcutaneous interferon beta-1a Interferon beta-1b Glatiramer acetate Intramuscular interferon beta-1a

60. Indicated for relapsing forms of MS Dosing: 0.5 mg once daily (qd), oral Warnings and Precautions Infection; macular edema; dose-dependent decreased pulmonary function; elevated serum hepatic transaminases; hypertension Screening white blood cell count (WBC), serum transaminase determination, serum bilirubin determination, serum varicella zoster antibody testing (in patients with no history of chicken pox), baseline electrocardiogram, and ophthalmologic evaluation; baseline pulse/blood pressure prior to first dose and observation of all patients for 6 hours after the first dose for signs and symptoms of bradycardia; ophthalmologic evaluation after 3 to 4 months of treatment and in the event of new visual symptoms Withholding treatment in patients with severe infections Women of childbearing age should use effective contraception during and for 2 months after stopping therapy Cardiac contraindication Practice Recommendations for Fingolimod 60 Singer BA. Ther Adv Neurol Disord. 2013;6(4):269-275; National MS Society. http://www.nationalmssociety.org/ms- clinical-care-network/clinical-resources-and-tools/core-curriculum/managing-ms/comprehensive-care/disease- modification/indications-dosing-etc/index.aspx; http://www.nationalmssociety.org/ms-clinical-care-network/clinical- resources-and-tools/core-curriculum/managing-ms/comprehensive-care/disease-modification/warnings-safety- management/index.aspx.

61. Teriflunomide (7/14 mg po qd) vs placebo over 108-week treatment period 31% reduction in ARRs 67% reduction in MRI lesion volume 30% reduction in disability progression TEMSO trial (RRMS) Teriflunomide (7/14 mg po qd) vs placebo over 48 weeks 36% reduction in annual relapse rates 32% reduction in disability progression TOWER trial (RRMS) History not well established to date However, have long history of leflunomide use in rheumatoid arthritis (black boxed warnings for leflunomide) Long term Clinical Evidence for Teriflunomide 61 O’Connor, et al. N Engl J Med. 2011;365(14):1293-303; Freedman MS. Ther Adv Chronic Dis. 2013;4(5):192-205. po, by mouth.

62. Oral teriflunomide 7 or 14 mg or subcutaneous IFNβ-1a 44 µg No difference in time to failure was observed No difference in ARR between teriflunomide 14 mg and IFNβ-1a (0.26 vs 0.22) TENERE trial (RRMS) Comparison of Teriflunomide with IFNβ-1a 62 Freedman MS. Ther Adv Chronic Dis. 2013;4(5):192-205; Vermersch et al. Mult Scler. 2013 Oct 14. [Epub ahead of print].

63. Indicated for relapsing forms of MSDosing: 7 mg or 14 mg; qd oralWarnings and Precautions Infection; elevated serum hepatic transaminases (“black boxed” warning); fetal death and malformations (“black boxed” warning); skin reactions; blood pressure increase; respiratory effects Screen for tuberculosis Pre-treatment: evaluation for infection, pregnancy, renal failure, peripheral neuropathy, interstitial pulmonary disease and hypertension; WBC, serum transaminase determination, and serum bilirubin determination During treatment: blood pressure monitoring; serum transaminase determinations, renal function Women of childbearing age should not be started on therapy until pregnancy is excluded and confirmation of reliable contraception (category X) Practice Recommendations for Teriflunomide 63 National MS Society. http://www.nationalmssociety.org/ms-clinical-care-network/clinical-resources-and-tools/core- curriculum/managing-ms/comprehensive-care/disease-modification/indications-dosing-etc/index.aspx; http://www.nationalmssociety.org/ms-clinical-care-network/clinical-resources-and-tools/core-curriculum/managing- ms/comprehensive-care/disease-modification/warnings-safety-management/index.aspx.

64. Superior efficacy Ease of administration Good tolerability Long-term safety data Differs from patient to patient (therefore must be individualized based on risk-benefit ratio) Ideal Therapy 64 Fox EJ, et al. Curr Opin Neurol. 2012;25(suppl):S11-S19.

65. AgentMode of Action Route of Administration Promising Outcomes Current Status Glatiramer acetate Immunomodulatory agent SubcutaneousResults available on double-dose (20 vs 40 mg) administration Under FDA review LaquinimodImmunomodulatory agent OralALLEGRO and BRAVO trials— modest outcomes in annual relapse rates Ongoing phase 3 trial AlemtuzumabHumanized monoclonal antibody against CD52 IntravenousCARE-MS I and II trials—reduced annual relapse rate Under FDA review Pegylated interferon PEG-IFN beta-1aSubcutaneousPhase 3 trial— reduced annual relapse rate Ongoing phase 3 trials Investigational Agents 65 Tullman MJ. Am J Manag Care. 2013;19(2, suppl):S21-27; Peru al J, Khan O. Curr Treat Options Neurol. 2012;14(3):256-263; Castro-Borrero et al. Ther Adv Neurol Disord. 2012;5(4):205-220; Clinicaltrials website. www.clinicaltrials.gov. Accessed December 2, 2013. FDA, US Food and Drug Administration.

66. AgentMode of ActionRoute of Administration Promising Outcomes Current Status DaclizumabHumanized monoclonal antibody against IL2- R SubcutaneousSELECT trial— reduction in annual relapse rate Ongoing phase 3 trials OcrelizumabRecombinant human anti-CD20 monoclonal antibody Intravenous infusion Phase 2 trial— reduction in annual relapse rate Ongoing phase 3 trials BAF312Selective modulator of sphingosine 1- phosphate receptor types 1 and type 5 OralBOLD trial—reduction in active lesions Ongoing phase 3 trials MasitinibTyrosine kinase inhibitor OralPromising in PPMS and SPMS Ongoing phase 2b/3 trials Investigational Agents (cont’d) 66 Tullman MJ. Am J Manag Care. 2013;19(2,suppl):S21-S27; Peru al J, Khan O. Curr Treat Options Neurol. 2012;14(3):256-263; Castro-Borrero et al. Ther Adv Neurol Disord. 2012;5(4):205-220.

67. Case Study #2: Carl, 40-year-old Male 67

68. New Imaging Results—New Strategy for Treatment? T2-weighted image Recent scans show multiple new lesions What are the next steps for this patient? 68

69. For this patient with changes on imagery, what is your management strategy: Do you switch medications? If so, to what? What criteria do you use to make this decision? How many relapses are enough in 1 year to consider switching therapies? How do you monitor disease status/progression following a relapse? −Set new baseline MRI at time of relapse −Frequency of MRI? Image results—one new enhancing lesion Case Discussion 69

70. Considerations for Switching Medications 70

71. Proposed Algorithm 71 Modified from original in Río J, et al. Curr Opin Neurol. 2011;24(3):230-237. Relapse and/or observed progression Consider change in therapy Treatment with disease-modifying agents commences MRI and clinical assessments at 6 to 12 months Negative MRI result Relapses and/or disease progression Active MRI result Consider change of therapy Periodic clinical and MRI assessment Close clinical and MRI monitoring No relapses and no disease progression

72. IndicationCategoryExample Intolerable side effects Adverse reactions Injection site reaction, infusion reaction, infections Persistent symptoms Flu-like symptoms, headache, nausea Significant and persistent laboratory abnormality Increased liver enzymes, low WBC Detection of antibodies JC (John Cunningham) virus antibody positivity Pertinent for natalizumab use Persistent neutralizing antibodies Pertinent for natalizumab and IFNβ (high-titer antibodies) Unacceptable breakthrough activity Clinical activity Relapses, disability, cognitive status, transition to progressive disease Neuroimaging activity Brain MRI, spinal cord MRI abnormalities Indications for Switching Therapies 72 Coyle PK. CNS Drugs. 2013;27(4):239-247.

73. African American, Hispanic, older age (≥35 years), male gender Clinical and MRI features Baseline prognostic factors Tolerability history Clinical parameters (relapse, disability, cognitive deterioration, conversion to progressive disease) MRI parameters (contrast-positive lesions, T2 lesions, T1 lesions, atrophy) Careful analysis of breakthrough disease activity Considerations for Switching Therapies 73 Coyle PK. CNS Drugs. 2013;27(4):239-247.

74. Switch between approved first-line agents Side effects or poor adherence Switch from first- to second- line agent (natalizumab) Poor prognosis or significant breakthrough activity Switch to off-label use, investigational gents Failed therapy with approved DMTs or restricted Switching Recommendations 74 Coyle PK. CNS Drugs. 2013;27(4):239-247.

75. Natalizumab to fingolimod –JC virus antibody–negative patients Few weeks –JC virus antibody–positive patients 4 to 8 weeks after MRI for progressive multifocal leukoencephalopathy lesions Fingolimod to natalizumab –JC virus antibody–negative patients Few weeks –JC virus antibody–positive patients Until WBC count improves Washout Considerations 75 Coyle PK. CNS Drugs. 2013;27(4):239-247.

76. Individualized Treatment and Patient Education Are Necessary 76

77. Patient’s adherence to monitoring or drug regimen Individualized treatment Roadmap for Individualized Treatment 77 Giovannoni G, et al. Curr Opin Neurol. 2012;25(suppl):S20-S27. Increasingly complex environment Treatment strategy Economic factors Patient’s treatment goals Patient’s risk/benefit tolerance Other Patient’s disease profile and characteristics

78. Pharmacological and nonpharmacological management of symptoms such as: –Fatigue, spasticity, bladder problems, bowel problems, cognitive dysfunction, pain, paroxysmal symptoms, sexual dysfunction, tremor, heat intolerance, and optic neuritis Rehabilitation (physical and occupational therapy) Surgery as indicated to alleviate symptoms Supportive Treatments 78 National MS Society. http://www.nationalmssociety.org/ms-clinical-care-network/clinical-resources-and- tools/core-curriculum/managing-ms/comprehensive-care/symptom-management/index.aspx.

79. Encourage patients to discuss diagnosis, voice concerns, and share feelings about treatment progress Help patients access information Recognize opportunities to discuss treatment strategies Manage adverse events Facilitate optimal monitoring of disease progression Improving patient concordance Patient Education 79 Giovannoni G, et al. Curr Opin Neurol. 2012;25(suppl):S20-S27.

80. Improve quality of life by relieving symptoms caused by exacerbations and reduce number of events Reduce MRI activity Delay/prevent the onset of SPMS Slow or stop the course of disease progression Minimize treatment-associated adverse events Treatment Goals 80 Giovannoni G, et al. Curr Opin Neurol. 2012;25(suppl):S20-S27.

81. Updated diagnostic criteria to facilitate early and accurate diagnosis of MS Unbiased communication of clinical evidence to support decision making and to accommodate patient preferences Effective strategies to monitor therapeutic progress and switch therapies Individualizing treatment goals and interventions for patients with MS Summary 81

82. Questions & Answers 82

83. Thank You! 83

84. Revised 2010 McDonald Criteria to Confirm Diagnosis of MS— Reference Slides 84

85. Clinical Attacks LesionsAdditional Criteria for Diagnosis 1Objective clinical evidence of 1 lesion DIS, demonstrated by: 1 T2 lesion in at least 2 MS-typical CNS regions OR Await further clinical attack implicating a different CNS site AND DIT, demonstrated by: Simultaneous asymptomatic contrast-enhancing and non-enhancing lesions at any time OR New T2 and/or contrast-enhancing lesions(s) on follow-up MRI, irrespective of its timing OR Await a second clinical attack Revised 2010 McDonald Criteria to Confirm Diagnosis of MS 85 Pohlman CH, et al. Ann Neurol. 2011;69(2):292-302.

86. Clinical Attacks LesionsAdditional Criteria for Diagnosis 1Objective clinical evidence of 2 or more lesions DIT, demonstrated by: Simultaneous asymptomatic contrast-enhancing and non- enhancing lesions at any time OR New T2 and/or contrast-enhancing lesions(s) on follow-up MRI, irrespective of its timing OR Await a second clinical attack Revised 2010 McDonald Criteria to Confirm Diagnosis of MS (cont’d) 86 Pohlman CH, et al. Ann Neurol. 2011;69(2):292-302.

87. Clinical Attacks LesionsAdditional Criteria for Diagnosis 2 or moreObjective clinical evidence of 2 or more lesions or objective clinical evidence of 1 lesion with reasonable historical evidence of a prior attack None. Clinical evidence alone will suffice; additional evidence desirable but must be consistent with MS 2 or moreObjective clinical evidence of 1 lesion DIS, demonstrated by: 1 T2 lesion in at least 2 MS-typical CNS regions (periventricular, juxtacortical, infratentorial, spinal cord) OR Await further clinical attack implicating a different CNS site Revised 2010 McDonald Criteria to Confirm Diagnosis of MS (cont’d) 87 Pohlman CH, et al. Ann Neurol. 2011;69(2):292-302.

88. Clinical AttacksLesionsAdditional Criteria for Diagnosis 0 (progression from onset) One year of disease progression (retrospective or prospective) AND at least 2 out of 3 criteria: DIS in the brain based on ≥1 T2 lesion in periventricular, juxtacortical, or infratentorial regions DIS in the spinal cord based on ≥2 T2 lesions Positive CSF Revised 2010 McDonald Criteria to Confirm Diagnosis of MS (cont’d) 88 Pohlman CH, et al. Ann Neurol. 2011;69(2):292-302.

89. Back-up 89

90. The defining features of NMO are transverse myelitis and optic neuritis with ≥2 of the following: MRI results nondiagnostic for MS A spinal cord lesion extending over 3 or more vertebral segments (short-segment lesions are typical of MS) A serologic test result positive for NMO-IgG Criteria for Diagnosing NMO and NMO Spectrum Disorders 90 Mayo Clinic. Neuromyelitis optica. http://www.mayoclinic.org/medicalprofs/neuromyelitis-optica.html.

91. Current Trials in PPMS Clinicaltrials website. www.clinicaltrials.gov. Accessed December 2, 2013.  Fingolimod in Patients With Primary Progressive Multiple Sclerosis (INFORMS)  Safety and Efficacy of Rituximab in Adults With Primary Progressive Multiple Sclerosis (OLYMPUS)  Ocrelizumab in Patients With Primary Progressive Multiple Sclerosis  Idebenone in Patients With Primary Progressive Multiple Sclerosis (IPPoMS)  Masitinib for the Treatment of Patients With Primary Progressive or Relapse-free Secondary Progressive Multiple Sclerosis  Safety, Tolerability and Activity Study of Ibudilast in Subjects With Progressive Multiple Sclerosis 91