2013 MS Phenotype Descriptions: Relapsing MS 1

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1 2013 MS Phenotype Descriptions: Relapsing MS 1 Disease-Modifying Therapies? which can be found in its entirety at. Clinically isolated syndrome (CIS) Not Active a Active a,b Relapsing-remitting disease (RRMS) Not Active a Active a a Activity determined by clinical relapse and/or MRI activity (GELs; new/unequivocally enlarging T2 lesions assessed at least annually; if assessments not available, activity indeterminate ). b CIS, if subsequently active fulfilling current MS diagnostic criteria, becomes RRMS. GEL: gadolinium-enhancing lesion; MS: multiple sclerosis. 1. Lublin FD et al. Neurology. 2014;83: ]

2 Worsening or Highly Active MS: Key Definitions 1,2 Disease-Modifying Therapies? which can be found in its entirety at. Active Disease Relapse, acute or subacute episodes of new or increasing neurologic dysfunction followed by full or partial recovery, in absence of fever or infection and/or Occurrence of GEL or new/unequivocally enlarging T2 lesions Worsening Disease Documented increase in neurologic dysfunction/disability as a result of relapses or progressive disease Confirmed Progression/Worsening Increase of neurologic dysfunction confirmed throughout a defined time interval (ie, over 6 mo or 12 mo) RES: Rapidly Evolving Severe Multiple Sclerosis 2 disabling relapses in previous year and 1 GEL or significant in T2-lesion load HAD: High Disease Activity Despite Interferon β 1 relapse in the previous year on interferon β and 1 GEL or 9 T2 lesions on cranial MRI Progressive Disease Steadily increasing, objectively documented, neurologic dysfunction/disability w/out unequivocal recovery (fluctuations and phases of stability may occur) GEL: gadolinium-enhancing lesion. 1. Lublin FD et al. Neurology. 2014;83: Dubey D et al. Neuropsychiatr Dis Treat. 2015;11:

3 2013 MS Phenotype Descriptions: Progressive MS 1 Disease-Modifying Therapies? which can be found in its entirety at. Primary Progressive Progressive accumulation of disability from onset Activea w/ Progression b Progressive Disease Active w/o Progression Not Active w/ Progression Not Active w/o Progression c Secondary Progressive Progressive accumulation of disability after initial relapsing course a Activity determined by clinical relapse and/or MRI activity (GELs; new/unequivocally enlarging T2 lesions assessed at least annually; if assessments not available, activity indeterminate ). b Progression measured by clinical evaluation, assessed at least annually. If assessments are not available, activity and progression indeterminate. c Stable disease. GEL: gadolinium-enhancing lesion. 1. Lublin FD et al. Neurology. 2014;83:

4 Identifying Highly Active MS: Common Features 1 Disease-Modifying Therapies? which can be found in its entirety at. Clinical Radiologic Frequent relapses Severe relapses Incomplete recovery from relapses Frequent clinical disease activity (relapses) despite MS therapy Early accrual of physical or cognitive impairment Heavy T2 lesion burden Presence of multiple GELs at onset High GEL burden Early brain atrophy Continued GELs despite MS therapy Increasing T2 lesion burden despite MS therapy GEL: gadolinium-enhancing lesion Accessed February 1, 2016.

5 Efficacy of Approved Oral DMTs in Highly Active MS: Results of Recent Post Hoc Analyses Disease-Modifying Therapies? which can be found in its entirety at. Trials Highly Active MS Definition Results TEMSO and TOWER 1 1. Subgroup A of mitt (n = 710) Pts with 2 relapses in year before study entry 2. Subgroup B of mitt (n = 1,260) DMT use in prior 2 years and either 1 relapse in year before study entry or 1 GEL on baseline MRI or No DMT use in prior 2 years with EDSS 1.5 and either 2 relapses in year before study entry or 1 relapse with 1 GEL on baseline MRI Teriflunomide vs PBO Subgroup A 7 mg/day and 14 mg/day significantly reduced ARR 14 mg/day significantly reduced 12-week CDP Subgroup B Both doses significantly reduced ARR 14 mg/day significantly reduced 12-week and 24-week CDP FREEDOMS I and FREEDOMS II 2 Equal or greater # of relapses in year before study than in previous year or 1 relapse in year before study and 1 GEL or 9 T2 lesions at baseline Pts Who Maintained NEDA-4 Status for 24 Months PBO = 3.9% Fingolimod 0.5 mg/day = 20.5% NEDA-4: no NEL, no confirmed relapses, no 6-month CDP, and <0.4% mean annual BVL DEFINE and CONFIRM 3 2 relapses w/in 1 year prior to enrollment Dimethyl Fumarate (240 mg 2x/d vs PBO) DMF significantly reduced ARR DMF significantly reduced proportion pts who relapsed DMF significantly reduced 12-week CDP ARR: annualized relapse rate; BVL: brain volume loss; CDP: confirmed disability progression; DMF: dimethyl fumarate; DMT: disease-modifying therapies; GEL: gadolinium-enhancing lesion; mitt: modified intent to treat; NEDA-4: no evidence of disease activity-4; NEL: new/enlarging T2 lesion; PBO: placebo. 1. Kappos L et al. 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS 2013). Abstract P De Stefano N et al American Academy of Neurology Annual Meeting (AAN 2015). Abstract P Phillips JT et al. AAN Abstract P7.228.

6 Efficacy of Approved Monoclonal Antibodies in Highly Active MS: Results of Recent Post Hoc Analyses Disease-Modifying Therapies? which can be found in its entirety at. Trials Highly Active MS Definition Results AFFIRM 1 2 relapses in year before study entry and 1 GEL at study entry Natalizumab vs Placebo Significant reduction in ARR within 3 month tx initiation Significant reduction in cumulative probability of relapse at day 45 CARE-MS II 2 2 relapses in year prior to randomization and 1 GEL on baseline MRI Outcome IFN β-1a SubQ Alemtuzumab ARR Relapse free, (%) Freedom from clinical disease activity, % a Freedom from MRI disease activity, % b Freedom from demonstrable disease activity, % c 0 24 a Relapse free and absence of at 1-point increase over baseline on EDSS for 6 months for 2 years. b No new GEL and no NEL for 2 years. c No clinical or MRI disease activity for 2 years. ARR: annualized relapse rate; EDSS: Expanded Disability Status Scale; GEL: gadolinium-enhancing lesion; NEL: new/enlarging T2 lesion. 1. Kappos L et al. J Neurol. 2013;260: Krieger S et al. 5th Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research In Multiple Sclerosis (CMSC/ACTRIMS 2013). Oral Presentation.