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Clinical Update on Current and Emerging MS Treatment Regimens Harold Moses, Jr., MD Associate Professor of Neurology Neuroimmunology Division Vanderbilt University

Learning Objective • Review the safety, efficacy and other attributes of current and emerging multiple sclerosis (MS) therapies

What is Multiple Sclerosis? • Chronic progressive immune ‐ mediated Healthy Axon disease of the CNS • Associated with demyelination, axonal damage, and subsequent scar or Demyelinated Axon plaque formation • Associated with significant disability Damaged Axon • Primary etiology unknown, but likely multifactorial Calabresi PA, Newsome SD. Multiple sclerosis. In: Weiner WJ et al. Neurology for the Non ‐ Neurologist . 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2010:192 ‐ 221. Ascherio, A. Expert Rev Neurother . 2013;13 Suppl 12:3 ‐ 9.

MS Epidemiology • MS affects an estimated 1 million Americans • It is the most common cause of neurologic disability in 18 ‐ to 60 ‐ year ‐ old population • More prevalent in females • Peak incidence occurs between 20 and 40 years old • Annual cost in the US estimated to be $6.8 to $11.9 billion Calabresi PA, Newsome SD. Multiple sclerosis. In: Weiner WJ et al. Neurology for the Non ‐ Neurologist . 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2010:192 ‐ 221. Ascherio, A. Expert Rev Neurother . 2013;13 Suppl 12:3 ‐ 9. Whetten ‐ goldstein K, Sloan FA, Goldstein LB, Kulas ED. Mult Scler . 1998;4(5):419 ‐ 25. Wallin MT, Culpepper WJ, Campbell JD, et al. Neurology . 2019;92:e1029 ‐ e1040.

MS Disease Subtypes Radiologically or Relapsing ‐ Remitting Secondary Progressive Primary Progressive Clinically Isolated (RRMS) (SPMS) (PPMS) Syndrome (RIS/CIS) First episode of Disability Disability Disability neurologic symptoms; must last for ≥ 24 hours; may not evolve into MS Time Time Time Relapse RRMS Active (relapse or new MRI Active (relapse or new MRI activity) Active without worsening activity) with progression with progression Worsening (incomplete recovery Not active without Active (relapse or MRI activity) from relapse) progression (stable) without progression Stable without activity Not active with progression Not active with progression New MRI activity Active without progression Not active without progression (stable) New MRI activity New MRI activity Types of MS. National Multiple Sclerosis Society. www.nationalmssociety.org/What ‐ is ‐ MS/Types ‐ of ‐ MS. Accessed February 2019. Lublin FD, Reingold SC, Cohen JA, et al. Neurology . 2014;83(3):278 ‐ 286.

Frequency of MS Clinical Subtypes 15% 15% are diagnosed with PPMS at disease onset Left untreated, 85% ~50% diagnosed with RRMS of RRMS cases 50% at disease onset transition to SPMS within 10 years of the initial diagnosis Types of MS. National Multiple Sclerosis Society. www.nationalmssociety.org/What ‐ is ‐ MS/Types ‐ of ‐ MS. Accessed February 2019. Definition of MS. National Multiple Sclerosis Society. www.nationalmssociety.org/What ‐ is ‐ MS/Definition ‐ of ‐ MS. Accessed February 2019.

MS Disease Course Relapsing ‐ Remitting Secondary Progressive Preclinical CIS Age ~10–40 years Primary Progressive Age? Age ~>40 years Clinical Course Disability Opportunity to minimize Brain Volume progression? Lesion Load Contrast enhancing/ CIS: clinically isolated syndrome new MS lesions Hersh CM, Fox RJ. Multiple Sclerosis. Cleveland Clinic Medical School. Time https://teachmemedicine.org/cleveland ‐ clinic ‐ multiple ‐ sclerosis. Published June 2014. Accessed February 2019.

MS Presentation Notable Presentation Features Clinical Presentation • Fatigue • Can be highly variable and often • Imbalance/ataxia reflects areas of active inflammation within the CNS • Optic neuritis • Presentation can be • Transverse myelitis • Focal • Sensory symptoms • Multifocal • Cognitive/mood symptoms • Relapsing • Bowel and bladder dysfunction • Uhthoff’s phenomenon (heat intolerance) • Gradually worsening • Lhermitte’s sign (electrical shocks down the spine) Milo R, Miller A. Autoimmun Rev . 2014;13(4 ‐ 5):518 ‐ 524.

Components of the MS Diagnosis • Clinical: symptoms and exam findings suggestive of MS • MRI: objective evidence of CNS white matter lesions disseminated in time and space • Lab tests: blood work to rule out mimics (e.g., antinuclear antibody and neuromyelitis optica) • CSF studies: findings supportive of MS such as cell count, IgG index, and oligoclonal bands • Neurophysiology: evoked potential supportive of MS (e.g., Lhermitte’s phenomenon) Polman CH, Reingold SC, Banwell B, et al. Ann Neurol . 2011;69(2):292 ‐ 302; Polman CH, Reingold SC, Edan G, et al. Ann Neurol . 2005;58(6):840 ‐ 846.

MacDonald Diagnostic Criteria: 2017 Revision Clinical Presentation Additional Data Needed for MS Diagnosis • ≥ 2 attacks • Objective clinical evidence of ≥ 2 lesions • None; clinical evidence will suffice • with reasonable historical evidence of a Additional evidence (e.g., brain MRI) desirable, but must be consistent with MS prior attack • ≥ 2 attacks • Dissemination in space demonstrated by MRI OR await further clinical attack • Objective clinical evidence of 1 lesion implicating a different site • One attack • Dissemination in time demonstrated by MRI OR second clinical attack or • Objective clinical evidence of ≥ 2 lesions demonstration of CSF ‐ specific oligoclonal bands • One attack • Dissemination in space demonstrated by MRI or await a second clinical attack • Objective clinical evidence of 1 lesion implicating a different CNS site AND • (clinically isolated syndrome) Dissemination in time, demonstrated by MRI or second clinical attack • One year of disease progression and dissemination in space, demonstrated by 2 of the following: • Insidious neurologic progression • ≥ 1 T2 lesions in brain, in regions characteristic of MS suggestive of MS • ≥ 2 T2 focal lesions in spinal cord • Positive CSF Thompson AJ, Banwell BL, Barkhof F, et al. Lancet Neurol . 2017;17:162 ‐ 173.

MRI Findings Suggestive of MS Periventricular, Juxta ‐ cortical, Posterior Fossa, and Spinal Cord Dawson fingers Subcortical Subcortical Juxtacortical pv Spinal cord lesions Corpus callosum Posterior fossa lesions lesions

Effect of Presence of Spinal Cord Lesions on Time to Conversion From CIS to CDMS Presence of lesions in the spinal cord n=23 1.0 No 1.0 Proportion of patients remaining CIS Proportion of patients remaining CIS Yes n=39 0.8 0.8 0.6 0.6 n=82 n=19 0.4 0.4 0.2 0.2 p =0.005 p =0.001 0.0 0.0 24 48 72 0 96 72 24 48 0 Time in months Time in months CIS=clinically isolated syndrome; CDMS=clinically definite multiple sclerosis Sombekke MH, Wattjes MP, Balk LJ, et al. Neurology . 2013;80(1):69 ‐ 75.

Predictors of Disability: Disease Factors Clinical Factors 1 MS Lesions 2,3 • Younger age at onset • Spinal cord lesions • Longer disease duration • Diffuse abnormalities in the spinal cord • Higher relapse rate • Cortical lesions and atrophy • More frequent early relapses • Poor recovery from relapses 1. Jokubaitis VG, Spelman T, Kalincik T, et al. Ann Neurol . 2016;80(1):89 ‐ 100. 2. KeKearney H, Miszkiel KA, Yiannakas MC, Altmann DR, Ciccarelli O, Miller DH. Mult Scler . 2016;22(7):910 ‐ 20.3. 3. Scalfari A, Romualdi C, Nicholas RS, et al. Neurology . 2018;90(24):e2107 ‐ e2118.

Predictors of Disability: Patient Factors • Higher Patient ‐ derived MS Severity Score (P ‐ MSSS) in Ethnicity 1 African ‐ American and Hispanics vs. Caucasians • Increased risk in males Gender 2 1. Ventura RE, Antezana AO, Bacon T, Kister I. Mult Scler . 2017;23(11):1554 ‐ 1557. 2. Jokubaitis VG, Spelman T, Kalincik T, et al. Ann Neurol . 2016;80(1):89 ‐ 100.

Predicting Disability Profiles of Increasing Disability • Analysis of demographic, clinical and MRI data 100% HR: 2.2 from 542 patients with relapsing MS (baseline HR: 1.52 Risk: 75% 90% Risk: 68% EDSS: 3.0 ‐ 4.0) followed for ≥ 2 years 80% % patients reaching EDSS ≥ 6.0 HR: 1.00 • After 2 years, 63.5% of patients reached EDSS 70% Risk: 56% 6.0 60% 50% • Predictors of disability in patients with disease 40% activity: 30% • Number of relapses before reaching EDSS 3.0– 20% 4.0 Score=0 (age ≤ 45 years and ≤ 6 relapses) Score=1 (age >45 years or >6 relapses) • Age >45 at baseline 10% Score=2 (age >45 years and >6 relapses) 0% • A composite risk score combining age and 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Follow ‐ up (years) number of relapses increased the risk of and shortened the time to EDSS = 6.0 Tomassini V, Fanelli F, Prosperini L, Cerqua R, Cavalla P, Pozzilli C. Mult Scler . 2018;:1352458518790397. [Epub ahead of print].

Treatment Goals in MS Traditional Measures Evolving Measures Reduce relapses End relapses Clinical disease progression and Slow disease relapse Stop progression progression Halt disease activity, reduce Reduce disease Stop MRI MRI disability, burden progression improve QoL Cognitive function Improve function and quality of life and quality of life Smith AL, Cohen JA, Hua LH. Neurotherapeutics . 2017;14(4):952 ‐ 960. Rotstein DL, Healy BC, Malik MT, Chitnis T, Weiner HL. JAMA Neurol . 2015;72(2):152 ‐ 158. Lazibat I, Šamija RK, Rotim K. Acta Clin Croat. 2016;55(1):125 ‐ 133.