1996 vs 2013 MS Phenotype Descriptions of Progressive Disease

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1 Learning Objectives Upon completion, participants should be able to: Describe methods of distinguishing among RRMS, SPMS, and PPMS Incorporate available evidence about emerging and recently approved novel therapeutic strategies for relapsing and progressive forms of MS into individualized decisions about treatment or clinical trial enrollment for appropriate patients 1

2 1996 vs 213 MS Phenotype Descriptions of Progressive Disease 1996 MS Clinical Description Subtypes 213 MS Disease Modifiers and Phenotypes PP Progressive accumulation of disability from onset, with or without temporary plateaus, minor remissions, and improvements Progressive accumulation of disability from onset PP Active a and with progression b Progressive Disease SP Progressive accumulation of disability after initial relapsing course, with or without occasional relapses and minor remissions Progressive Disease Active but without progression Not active but with progression PR Progressive accumulation of disability from onset but clear acute clinical attacks with or without full recovery SP Progressive accumulation of disability after initial relapsing course Not active and without progression (stable disease) a Activity determined by clinical relapses assessed at least annually and/or MRI activity. b Progression measured by clinical evaluation, assessed at least annually. Lublin FD, et al. Neurology. 214;83:278-86; Miller AE. ACTRIMS/ECTRIMS 214; Boston, MA. Abstract TC1.1. Radiologically Isolated Syndrome 5-Year Risk of an Initial Clinical Event From a Multinational Cohort (RISC) Retrospective analysis of 22 databases from 5 countries 451 patients (largest cohort examined to date) 5-year observed conversion rate to first clinical event: 34% In multivariate model, several factors were significantly associated with conversion: Age (younger > older) Sex (M > F) Presence of spinal cord lesions Okuda DT, et al. PLoS One. 214;9:e959. 2

3 Predicting the Course of MS Clinical features associated with poor prognosis Motor symptoms (vs sensory) Polyregional presentation (vs monosymptomatic) Early bladder involvement Incomplete recovery from initial attack Short interval between attacks Minneboo A, et al. Mult Scler. 29;15:632-7; Enzinger C, et al. Mult Scler. 211;17: Prognosis Initial MRI Number of T2 lesions Median EDSS at 2 years was 6 for 1 T2 lesions 3 or 4 Barkhof criteria moderately correlated with EDSS at 5 years % of Patients EDSS > 3 EDSS # of Brain Lesions Fisniku LK. Brain. 28;131:

4 1-CIS: Factors That Determine Disease Course: Early Changes Contribute to Long-Term Prognosis Demographic Factors Topography CSF: OB Baseline Number of T2 New T2 at 12 Months Study was designed to determine factors that add value to clinical and brain MRI changes occurring during the first year to predict conversion to CDMS and disability accumulation N = 1,15 CIS patients (from 1995 to 213) Treatment Factors Decreased Risk Increased Risk HR Key Findings First-year clinical and brain MRI changes further improve the estimation of individual prognosis Independent predictors of additional attacks: Baseline lesions, new T2 during the first year, no DMT before second attack Independent predictors of accumulation of disability: OB, new T2, incomplete recovery Tintore M, et al. ACTRIMS-ECTRIMS 214; Boston, MA. Abstract PS9.4. FDA-Approved Therapies Drug Interferon β-1b Interferon β-1a Peginterferon β-1a Interferon β-1a Glatiramer acetate Glatiramer acetate (generic) Glatiramer acetate Natalizumab Mitoxantrone Fingolimod Teriflunomide Dimethyl fumarate, BG-12 Alemtuzumab Daclizumab Ocrelizumab Route and Frequency of Administration SC every other day IM once per week SC every 14 days SC 3 times per week SC daily SC daily SC 3 times per week IV every 4 weeks IV every 3 months Oral daily Oral daily Oral twice daily IV once daily for 5 days and after 1 year for 3 consecutive days SC once monthly IV once, then 2 nd dose 2 weeks later, then every 6 months Prescribing information for individual agents. 4

5 Hypothesized Immunomodulatory Effect of Daclizumab Treatment Daclizumab treatment increases CD56 bright NK cell proliferation and cytotoxicity via intermediate-affinity IL-2 signaling TCR Activation TCR CD4 Anti-CD25 CD25 CD4 IL-2 NK CD56 hi NK CD56 hi NK CD56 hi NK CD56 hi NK cells are activated and expanded by IL-2 binding to the intermediateaffinity IL-2R IL-2 not consumed by T cells Bielekova B, et al. Neurology. 21;74:S31-4; Martin JF, et al. J Immunol. 21;185: Daclizumab HYP vs IFNβ-1a: DECIDE Study Findings 1:1 Randomization 96- to 144-Week Treatment Period RRMS Patients (N = 1,841) IM IFNβ-1a 3 mcg Q1W (n = 922) SC DAC HYP 15 mg Q4W (n = 919) Follow-Up 45% reduction in ARR:.22 for DAC vs.39 for IFN 54% reduction in NE T2 lesions 65% reduction in Gd+ lesions 52% reduction in new T1 black holes.2.1 IFNβ-1a 3 mcg (n = 922) DAC HYP 15 mg (n = 919) 6-month disability progression risk reduction: 27% P =.332 Cutaneous events: Any AE: 37% DAC vs 19% IFN SAEs: 2% DAC vs < 1% IFN Proportion with progression Wk 48: 4% vs 7% Wk 96: 9% vs 12% Wk 144: 13% vs 18% BL Kappos L, et al. N Engl J Med. 215;373:

6 OPERA I and OPERA II: Trial Design RMS diagnosis Age: years 2 clinical relapses within last 2 years or 1 relapse in last year EDSS of :1 Randomization Ocrelizumab Dose 1: 3 mg IV x 2 (Days 1, 15) Doses 2-4: 6 mg IV x 1 IFNβ-1a 44 µg SC 3 x per week OLE Screening Period OLE Ocrelizumab Dose 1 Dose 2 Dose 3 Dose 4 Baseline Week 24 Week 48 Week 72 Dose 4 Week 96 Safety Follow-Up ~48 Weeks From Date of Last Infusion B Cell Monitoring a a Continued monitoring occurs if B cells are not replete. Kappos L, et al. N Engl J Med. 215;373: ; Ocrelizumab Superior to IFNβ-1a in Reducing ARR: Phase 3 Results of OPERA I and II Adjusted ARR at 96 Weeks, % Primary Endpoint: ARR at 96 Weeks.292 OPERA I OPERA II IFNβ-1a 44 μg.29 46% ARR P < % ARR P < n = 411 n = 418 n = 41 n = 417 Ocrelizumab 6 mg Compared with IFNβ-1a, ocrelizumab reduced: ARR 12- and 24-week CDP (by 4% ) T1 Gd+ lesions (by 94%-95%) NE T2 lesions (by 77%-83%) Safety profile of ocrelizumab: Similar to IFNβ-1a Most common: IRR (at first dose) IFNβ-1a Ocrelizumab SAE 8.7% 6.9% Malignancies n = 2 (lymphoma, squamous cell carcinoma) Deaths n = 2 (suicide, mechanical ileus) n = 4 (renal cancer, melanoma, breast cancer) n = 1 (suicide) 6

7 Autologous HSCT in MS: Meta-Analysis 15 studies (n = 764), Transplant-related mortality: 2.1% (95% CI, 1.3%-3.4%) Progression rate at 2 years: 17.1% (95% CI, 9.7%-24.5%) Proportion of NEDA patients: After 2 years: 83% (95% CI, 7%-9%) After 5 years: 67% (95% CI, 59%-7%) Proportion of NEDA Patients, % 1% 9% 8% 7% 6% 5% Pooled Estimation of NEDA Over Time Since Transplant Time, months Weighted average Hamerschlak 21 (n = 41) Burman 214 (n = 41) Burt 215 (n = 145) Nash 215 (n = 24) Atkins 216 (n = 23) 6 72 Suggests autologous HSCT may be an effective approach for treating aggressive forms of MS Sormani MP, et al. Neurology. 217;88: Steps of Shared Decision Making Engage patient participation Explore and compare treatment options Assess patient values and preferences Reach a decision on treatment with the patient Evaluate the decision 7

8 ORATORIO Phase 3 Study Results: Ocrelizumab in PPMS Proportion of Patients With CDP, % Primary Endpoint: Significant Reduction in 12-Week CDP 6 Placebo (n = 244) Ocrelizumab 6 mg (n = 488) % reduction in risk of CDP HR,.76 (95% CI, ); P = Key Secondary Endpoints 24-week CDP 25% reduction in risk of CDP (P =.4) Progression rate of walking time 29% reduction vs placebo (P =.4) Rate of BVL 17.5% reduction vs placebo (P =.2) T2 lesion volume 7.4% increase on placebo -3.4% decrease on ocrelizumab (P <.1) Safety: Similar incidence of severe AEs and serious infections with ocrelizumab and placebo. Most common events were mild-tomoderate IRRs. Possible malignancy signal. Montalban X, et al. N Engl J Med. 217;376:29-2. Efficacy and Safety of Siponimod in SPMS: Results From EXPAND Phase 3 Trial Patients Free of 3-Month CDP, % Primary Endpoint: Time to 3-Month CDP vs Placebo 21% Risk Placebo (n = 546) Siponimod (n = 1,99) HR,.79 (95% CI, ) P = Study Month Secondary Endpoints: 6-month CDP: 26% risk (P =.6) Consistent effects on ARR, T2 lesion volume, and change in brain volume No significant effect on T25FW AEs Occurring in 5% of Patients Siponimod Placebo n = 1,99 n = 546 AEs by System Organ Class N % N % Infections and infestations Nervous system disorders Musculoskeletal and connective tissue disorders Gastrointestinal disorders General disorders and administration site conditions Investigations Injury, poisoning, and procedural complications Skin and subcutaneous tissue disorders Psychiatric disorders Vascular disorders Cardiac disorders Respiratory, thoracic, and mediastinal disorders Neoplasms (benign, malignant, and unspecified) Eye disorders Metabolism and nutrition disorders Renal and urinary disorders Ear and labyrinth disorders Frequency Higher Lower Kappos L, et al. ECTRIMS 216; London, England. Abstract 25. 8

9 Efficacy of Biotin (MD13) in Progressive MS Primary Endpoint: Proportion Improved at Month 9, Confirmed at Month 12 (EDSS/T25FW) MD13 n (%) ITT 13 (12.6%) n = 13 Placebo n (%) (%) n = 51 P Value.5 Outcomes: 12.6% achieved primary endpoint in MD13 arm % in placebo arm Primary endpoint confirmed by significant decrease in EDSS progression Effect may be greater in SPMS vs PPMS Safety profile of MD13 was similar to that of placebo Can interfere with thyroid assays Upcoming trial: Effect of MD13 in Progressive Multiple Sclerosis (SPI2) NCT Tourbah A, et al. Mult Scler. 216;22: ; ClincialTrials.gov. Simvastatin a in SPMS The phase 2 MS-STAT study showed that simvastatin can reduce the rate of brain atrophy in SPMS Patients who took simvastatin (8 mg daily for 2 years) had a 43% lower rate of brain atrophy and better EDSS and MSIS-29 scores Change in WBV, % per year a Use of simvastatin is off-label BSI-Derived Change in WBV -25 Months Placebo group Simvastatin group Chataway J, et al Lancet. 214;383:

10 Acknowledgment of Commercial Support This activity is supported by an educational grant from Genentech. Contact Information Call (toll-free) Please visit us online at for additional activities provided by Med-IQ. To receive credit, click the Get Credit tab at the bottom of the Webcast for access to the evaluation, attestation, and post-test. 217 Unless otherwise indicated, photographed subjects who appear within the content of this activity or on artwork associated with this activity are models; they are not actual patients or doctors. 1

11 Abbreviations/Acronyms AE = adverse event ARR = annualized relapse rate BSI = boundary shift integral BVL = brain volume loss CDMS = clinically definite multiple sclerosis CDP = confirmed disability progression CIS = clinically isolated syndrome CSF = cerebrospinal fluid DMT = disease modifying therapy EDSS = Expanded Disability Status Scale FDA = Food and Drug Administration GD+ = gadolinium enhancing HR = hazard ratio HSCT = hematopoietic stem cell transplantation HYP = high yield process IFN = interferon IL = interleukin IM = intramuscular IRR = infusion related reaction ITT = intent to treat IV = intravenous MSIS 29 = Multiple Sclerosis Impact Scale NE = new or enlarging NEDA = no evident disease activity NK = natural killer OB = oligoclonal bands OLE = open label extension PP = primary progressive PR = progressive relapsing RISC = Radiologically Isolated Syndrome Consortium RMS = relapsing multiple sclerosis RR = relapsing remitting SAE = serious adverse event SC = subcutaneous SP = secondary progressive TCR = T cell receptor T25FW = timed 25 foot walk WBV = whole brain volume