Dr. Morrow has no disclosures relevant to this presentation.

Sarah A. Morrow M.D., M.S., FRCPC Assistant Professor of Neurology Western University London, ON CANADA Dr. Morrow has no disclosures relevant to this presentation. 1

Treatment of relapses Cognitive relapses Switching therapy Relapse activity MRI activity Clinical worsening (Progression) Standard of Care: High dose corticosteroids Postulated to reduce blood brain barrier abnormalities by decreasing peripheral CD4 lymphocytes, pro-inflammatory cytokines, and inhibit class II receptor on endothelial cells The details.no standard at all 2

Optic Neuritis Treatment Trial (ONTT) - 250mg IV methylprednisolone (IVMP) q6h for 3 days - 1 mg/kg/day oral prednisone (OP) for 14 days - Oral placebo F/U for 2 and 3 years Results: IVMP recovered vision faster than placebo no difference at 6 months Oral prednisone no better than placebo Higher rate of recurrence in oral group in first two years, but no longer significant after 3 years Beck et al NEJM 1992, 1993, Arch Neurol 1995 Not a true comparison of oral and IV treatments - Doses different - IV 1000mg (divided q6h) vs. oral 1mg/kg OD - Dosing schedules different - (IV 3 days vs. oral 14 days) - Only optic neuritis included 3

Morrow et al Neurology 2004 Randomized, single blind pharmacokinetic study of IV 1000mg methylprednisolone vs. 1250mg oral prednisone No difference found on AUC analysis Martenelli et al Neurology 2009 Single blind MRI study No difference in reduction of gad-enhancing lesions or T2 lesions Oral versus Intravenous High Doses of Methylprednisolone in Multiple Sclerosis Relapses, a Double Blinded Randomised Controlled Trial 4

OBJECTIVE: To compare oral versus Intravenous (IV) efficacy and safety of MP 1g/day for 3 days for the treatment of MS relapses. DESIGN/METHODS: Non- inferiority trial French multicenter, double blinded randomized, non inferiority, controlled trial. 200 relapsing MS patients Randomized to receive MP 1g/day for 3 days orally or IV. EDSS scores were measured at 3, 8, 28 and 180 days Tolerance was evaluated at 2, 3, 4, 8 and 28 days and safety data were collected up to 180 days. Primary end-point was the percentage of patients improved at day 28 (decrease by at least 1 point of the most affected functional system) No significant difference between oral and IV Improved at 28 days after treatment (77.7% IV, 77.9% oral) 16% of patients on IV methylprednisolone needed retreatment versus 12.6% on oral treatment 43% on IV treatment totally recovered vs 39% on oral treatment 27.6% of IV treatment had another relapse after a median time of 86 days, vs. 32% of oral treatment after a median of 90.5 days Similar adverse event profiles Metallic tastes Hot flashes Headache Insomnia and agitation -- slightly more frequent in the oral treatment group. 5

Most Common Reddening of the face Transient ankle edema Elevated mood Insomnia Gastrointestinal Only in those w/ history of GI issues (Metz 1999) Rare but worrisome Psychosis Acute pancreatitis Anaphylaxis Transient hyperglycemia Transient hypertension Metz et al Neurology 1999 Sellebjerg and the EFNS guidelines Eur J Neurol 2005 Leary et al Postgrad J Med 2005 Bone demineralization Only seen with multiple pulses per year Objective: To determine the frequency and potential predictors of (hypo)manic and depressive symptoms with HDC treatment for MS relapses. Methods: Consecutive subjects with a relapse)requiring HDC treatment identified. Assessment of before, 3 days post HDC and one month later with: Mood Disorders Questionnaire (MDQ) for hypomania Beck Depression Inventory - Fast Screen (BDIFS) for depressive symptoms Results: Eighty eight subjects completed the study. At relapse diagnosis, mean BDIFS score was 4.2 (SD 3.1); mean number of (hypo)manic symptoms on the MDQ was 4.3 (SD 3.5). Three days after completing HDC treatment, 22.5% had an increase on the BDIFS and 38.2% endorsed more symptoms on the MDQ. A history of depression (p=0.006) and low reported quality of life (p=0.029) predicted an increase on the MDQ; Odds of an increase in (hypo)manic symptoms on HDC was 5.6 times higher with a history of any psychiatric disease/substance abuse (p=0.005). No factor was found to predict worsening on the BDIFS with HDC treatment. 6

Past steroid use? Ask about any symptoms with last treatment Treat symptoms accordingly 1 ST treatment? Hx of insomnia? Hx of GERD? Can prophylactically give perscriptions to be filled as needed Hx of diabetes? Check BG 4x/day and adjust medications accordingly Studies in the past have shown that stopping high doses of corticosteroids after short term use is safe Perumal et al Eur Neurol 2008 Randomized 285 relapses to taper or placebo post relapse treatment No difference between two groups on rate of recovery at 3, 6 and 12 months rebound or relapse recurrence Levic et al J Endo Invest 1996 Chrousos et al JAMA 1993 7

Brainstem relapses and relapses with persistent gad-enhancement often rebound after high dose steroids pulse May need steroid taper 60mg X 5 days, followed by 10mg taper q3 days Has patient had rebound in the past? If so, give a perscription for taper, to be used if rebounds occurs What about the first treatment with steroids? Have patient inform you if he/she rebounds after the high dose 1250mg oral prednisone OR 1000mg IV methylprednisolone Depends on setting, convenience for patient, and relapse factors 3 to 5 days of treatment Taper usually not needed Manage adverse events individually 8

Corticotropin (as opposed to corticosteroid) Stimulates the adrenal cortex to secrete Cortisol Corticosterone Aldosterone Approved in 1978 by FDA to treat MS relapses Not used for several years due to limited manufacturing AEs similar to corticosteroids Hoogstraten et al 1990 1 year f/up of 29 MS patients treated with ACTH (IM) vs. placebo ACTH group did better at 1 st assessment, but by 6 and 12 months, there were no longer any significant differences ACTH group had higher risk of relapse in year Barnes et al 1985 14 MS relapses treated with IVMP 1g daily for 7 days vs. IM ACTH (80U, 60U, 40U, 20U daily each for one week) More rapid improvement at 3 and 28 days with IV MP, but no difference at 3 months Thompson et al 1989 61 MS relapses Randomized to IV MP 1X daily for 3 days vs. ACTH (80U for 7 days, 40U for 4 days, 20 U for 3 days) No difference in rate of recovery or final outcome at 12 weeks 9

Considered second line therapy after IVMP or dexamethasone, if Cannot tolerate AEs of high dose corticosteroids Have not responded to corticosteroids in past Have difficulty with IV medications because of poor venous access IM 80-120U daily for 2-3 weeks OR IM 80U daily for a week followed by a taper over a week 10

SDMT Mean Score 57 56 55 54 52 Pre 2 Pre 1 Post 1 Post 2 Post 3 Matched controls without relapses Cases with relapses Between group main effect: P=0.67. Within group main effect: P 0.01. Interaction: P=0.03. SDMT_2 SDMT at Month 2; value 2nd prior to relapse SDMT_1 SDMT at Month 1; value 1st prior to relapse SDMT_1 SDMT at Month 1; value 1st after relapse SDMT_2 SDMT at Month 2; value 2nd after relapse SDMT_3 SDMT at Month 3 Descriptive Statistics D1 D1 D1 D1 D1 Status Case or Control.00 control Mean (SD) 52.45 (11.305) 1.00 case 52.30 (11.645).00 control.39 (11.644) 1.00 case.64 (10.911).00 control 54.70 (11.689) 1.00 case 52.40 (11.093).00 control 55.83 (11.972) 1.00 case 54.85 (11.122).00 control 56.08 (12.205) 1.00 case 55.28 (10.994) Control=MS patients without relapses in STRATA; cases=ms patients with relapses in STRATA; D1=dimension 1. 21 N 115 115 115 115 115 Relapses and cognitive impairment: MSNQ Morrow SA et al. J Neurol. 2011 MSNQ Mean Score 16 15 14 13 12 11 Pre 2 Pre 1 Post 1 Post 2 Post 3 Matched controls without relapses Cases with relapses Between group main effect: P=0.22. Within group main effect: P=0.01. Interaction: P=0.09. MSNQ_2 MSNQ at Month 2 MSNQ_1 MSNQ at Month 1 MSNQ_1 MSNQ at Month 1 MSNQ_2 MSNQ at Month 2 MSNQ_3 MSNQ at Month 3 Descriptive Statistics Status Case or Control D1 D1 D1 D1 D1.00 control Mean (SD) 13.30 (10.959) 1.00 case 14.08 (10.612).00 control 12.95 (10.805) 1.00 case 15.04 (11.1).00 control 12.43 (9.974) 1.00 case 15.64 (12.010).00 control 11.83 (10.010) 1.00 case 14.13 (10.925).00 control 11.86 (10.255) 1.00 case 13.85 (11.661) Control=MS patients without relapses in STRATA; cases=ms patients with relapses in STRATA; D1=dimension 1. 22 N 115 115 115 115 115 11

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Conclusions Changes in cognitive function occur during MS relapses SDMT can be used to detect these changes Morrow SA et al. J Neurol. 2011 258(9):1603-8. 25 13

Disease worsening2 Disease progression 2 NEDA-3 defined as: No confirmed relapses 3,4 (inflammatory disease activity) Disability Relapses MRI activity No confirmed EDSS progression 3,4 Focal Inflammation (relapses / MRI lesions) Diffuse damage accumulation (neurodegeneration / failure of repair; disability / atrophy) No MRI activity (new / enlarging T 2 lesions) 3,4 NEDA-3, 3-component no evidence of disease activity. Adapted from Barten LJ, et al. Drug Des Devel Ther. 2010;4:343-6 1. Bevan CJ and Cree BA. JAMA Neurol. 2014; 2. Lublin FD et al. Neurology. 2014; 3. Havrdova E et al. Lancet Neurol. 2009; 4. Giovannoni G et al. Lancet Neurol. 2011. 27 Treatment Optimization in MS: Canadian MS Working Group Updated Recommendations * Mark S. Freedman 1, Daniel Selchen 2, Douglas L. Arnold 4, Alexandre Prat 5, Brenda Banwell 3, Michael Yeung 6, David Morgenthau 2, Yves Lapierre 4, on behalf of the Canadian Multiple Sclerosis Working Group 1 Ottawa Hospital Research Institute, University of Ottawa, Ottawa 2 St. Michael's Hospital, Toronto 3 The Hospital for Sick Children, Toronto, Ontario 4 Montreal Neurological Institute and Hospital 5 Centre hospitalier de l'université de Montréal, Montreal, Quebec 6 Foothills Medical Centre, Calgary, Alberta, Canada * Freedman et al. Can J Neurol Sci 2013;40:307-323 28 14

558 MS patients 483 (87%) IFN, 75 (13%) GA Compared non-switchers 1) switchers for ongoing disease activity vs 2) switchers for other reasons 15

CARRA EUR NEUROL 2008 CASTILLO PLOS ONE 2011 Without switching, MS pts with high ARR on DMTs will continue to have ongoing relapses - For inadequate efficacy, the second treatment had a lower ARR (the smallest change was from IFN to IFN) - For AEs, little change in ARR but this was low before and after (ARR 1.1 pre-switch) Relapse criteria Rate Severity Recovery Level of concern* Low Medium High 1 relapse in second year of treatment 1 relapse in first year of treatment Mild Moderate Severe >1 relapse in first year of treatment Steroids not required Steroids required Steroids/hospitalization required Minimal effect on ADL Moderate effect on ADL Severe effect on ADL 1 FS affected >1 FS affected >1 FS affected No/mild motor or cerebellar Prompt recovery Moderate motor/cerebellar involvement Incomplete recovery at 3 mo. Severe motor/cerebellar involvement Incomplete recovery at 6 mo. No functional deficit Some functional impairment Functional impairment * Level of concern determined by meeting at least 1 criterion ADL=activities of daily living; FS=functional systems 32 16

50 subjects in cladribine RCT with monthly MRIs Gadolinium injected 10 minutes before imaging Used presence of new lesions to predict new clinical activity (relapse) 17

Using 2 relapses as the baseline for comparison (known to increase risk of progression) 2 new GdE lesions were 2x more predictive of EDSS progression 3 new T2 lesions were 3x more predictive 4 3 2 1 0 Relative Ability to Predict EDSS Progression 1.05 2 relapses 2.05 2 new GdE lesions 3.41 3 T2 new lesions 6 Prospective, longitudinal study of RRMS treated with IFN-β. N=152 patients followed for 2 years Evaluation of predictive value of MRI after 1 year of treatment Active lesions at 1 year Odds ratio 95 % CI p value 2 1.0 - >2 8.3 3.1 to 21.9 <0.0001 MRI activity after 1 year predicts an increase in disability increase in the first 2 years of therapy 7 18

MRI criteria Level of concern* Activity on MRI* Low Medium High New Gd-enhancing lesions OR Accumulation of new T2 lesions per year 1 lesion 2 lesions 3 lesions Routine follow-up MRI with gadolinium is recommended 12 months after treatment initiation * Gd-enhancing lesions more reliable than new T2 lesions. New T2 lesion counts require high-quality comparable MRI scans and interpretation by qualified individuals. 37 19

Predictor of progression (1 year after starting therapy) Proportion of the Treatment Effect on Disability Progression Active T2 lesions 63% Clinical relapses 61% New and enlarging T2 lesions + clinical relapses 100% Caveat: These are short-term data; lesions and relapses predict disability over 2 years only. There remains a need to integrate brain atrophy for more meaningful, longer-term assessment.* MRI, magnetic resonance imaging. *Faculty expert opinion. Adapted from Sormani MP, et al. Neurology. 2011;77(18):1684-90. 8 Progression criteria Level of concern* EDSS score Low Medium High 3.5 1 point 2 points at 6 mo.* >2 points at 6 mo.* 2 points at 12 mo.* 4.0 to 5.0 <1 point 1 point at 6 mo.* >1 points at 6 mo.* 1 point at 12 mo.* 5.5 - - 0.5 points at 6 mo.* >0.5 points at 6 mo.* Clinically documented progression No motor Minor sensory Some motor, cerebellar or cognitive Multiple EDSS domains affected Pronounced motor, cerebellar or cognitive Multiple EDSS domains affected T25FW** 20% confirmed at 6 mo. >20% and <100% increase confirmed at 6 mo. 100% increase confirmed at 6 mo. * If EDSS progression alone is used to assess treatment response, any change requires subsequent confirmation at 3-6 months. ** Timed 25-foot walk tested at baseline; with aid, if required 40 20

Prompt treatment with high dose corticosteroids will lead to improvement of relapse symptoms Equivalent high doses of IV or oral appropriate Can use ACTH if poor tolerance corticosteroids Cognitive relapses can occur and respond to treatment similar to physical symptom relapses MRI activity and progression are also indicators of poor response to treatment Consider switching treatment if: More than one mild relapse One moderate to severe relapse Evidence of multiple new T2 or gad lesions on MRI Significant short term progression due to underlying inflammation 21