Multiple Sclerosis

Multiple Sclerosis

Multiple Sclerosis Multiple Sclerosis (MS) is a chronic inflammatory demyelinating and degenerative disease of the Central Nervous System (CNS) affecting both the Brain and the Spinal Cord. . , Sclerosis en plaque, . Multiple Sclerosis, Multiple Sclerosis MS is the most frequent neurological disease of young age affecting the ages between 20-50 years old It is of unknown aetiology with both genetic and environmental factors playing a major role in its pathogenesis It affects women more than men (3:2, 900 , 1,2:1!) )

( , , , D)) (the main risk allele for multiple sclerosis, HLADRB1*15:01) . Lancet Neurol 2014; 13: 70009 (WGAS) . , , .

, Epstein Barr (EBV). 18 , (OR = 2.17, 95% CI 1.972.39) 1. , 8 , 14 EBV (95% CI 6.331.4) 2. IgG EB (EBNA), EBV , , , . 1. Handel, A.E., et al. PLoS One 2010, 5, e12496. 2. Ascherio, A. et al. Epidemiology 2000, 11, 220224. . 60 , . 60 . 60 .1 1. Sajedi SA, et al. BMC Neurology 2012, 12:100

D , D3 (1, 25- D D) . D3, 1,25- D () 25- D D 7- D ( ) . D . D . . D . , D . Cantorna M, et al 2000, Hayes CE et al 2000, Habeka M et al 2010. Hewer et al. J Clin Neurosci. 2013 Mar 26. Epub ahead of print TH17 CD4+ helper T cells (T H17 cells) interleukin (IL)-17 . TH17 cells IL-23 , T H17 IL-23. TH17 cells . TH17 cells GM-CSF (granulocyte-macrophage colony-stimulating factor), TNF- and IL-2.

, TH17 cells. Kleinewietfeld M, et al. Nature. 2013 Mar 6. doi: 10.1038/nature11868. [Epub ahead of print] ?- D : / : - D

Intracortical lesions on 7T MRI scans 1 2 3 The figure compares the Magnitude (1), R2* (2), and T2* (3) images taken with a 7T scanner. The red arrow points to an intracortical lesion that is barely visible in the Magnitude image, and clearly visible in the R2* and the T2* images. : ; : . (clusters) . T2-FLAIR MRI. / : 240 T2-FLAIR MRI . : 40/240 (17%) 0/10 (P=0.37). . (23/97 cases, 24%, vs. 17/143, 12%; P=0.02). , .

(DMDs). : !) . [S44.001]; AAN, Philadelphia, 2014 (clusters). PLATFORM THERAPIES IFN Efficacy: Pivotal Studies Efficacy: Pivotal Studies Endpoint Annualised relapse rate in RRMS Disability progression in RRMS SC IFN-1b eod-1b eodb eod IM IFN-1b eod-1b eoda qw SC IFN-1b eod-1b eoda tiw 341b eod 322,* 323 29 (N-1b eodS)1b eod, 372,

244, Data is presented as percent (%) reduction vs placebo at 2 years. Conclusions regarding relative efficacy cannot be drawn from results of different clinical trials. General General conclusion: conclusion: IFNb IFNb therapies therapies slow slow disease disease course course by by approximately approximately one-third one-third *For patients completing 2 years of treatment; sustained for 6 months; sustained for 3 months. SC=subcutaneous; eod=every other day; qw=once a week; tiw=three times a week. 1. IFN Mult Scler Study Group, Neurol.1993;43:655; 2. Jacobs LD et al. Ann Neurol. 1996;39:285; 3. PRISMS Study Group. Lancet.1998;352:1498; 4. Rebif EPAR - Scientific discussion 9/8/2006. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000136/ human_med_001018.jsp&mid=WC0b01ac058001d124. DMTs CIS CDMS IM IFN-1b eod-1b eoda 50 50 Placebo IM IFN-1b-1ba Adjusted* HR=0.45, P<0.001b eod Risk Reduction: 55%

30 20 30 20 1b eod0 1b eod0 0 0 1b eod 4 7 1b eod0 1b eod3 1b eod6 Months 1b eod9 22 0 25 31b eod28 34 37 SC IFN-1b eod-1b eoda 44 g QW/TIWg QW/TIW Adjusted QW: HR=0.53, P=0.0023 TIW: HR=0.48, P=0.0004 Risk Reduction: 47%/52% CDMS (%)

40 30 1b eod80 360 540 Time (Days) 720 . Glatiramer Acetate Placebo SC IFN-1b-1ba 44 g TIWg QW SC IFN-1b-1ba 44 g TIWg TIW 50 20 Placebo GA Adjusted HR=0.55, P=0.0005 Risk Reduction: 45% 40 CDMS (%) 50 30 20 1b eod0

1b eod0 0 Placebo SC IFN-1b-1bb Adjusted HR=0.50, P<0.0001b eod Risk Reduction: 50% 40 CDMS (%) 40 CDMS (%) SC IFN-1b eod-1b eodb 0 1b eod80 360 540 Time (Days) 720 0 0 1b eod80 360 540 Time (Days) 720

*Adjusted for age, type of initial event, T2 lesion volume, and number of Gd+ lesions; adjusted for age, sex, type of initial event, steroid use, T2 lesion volume, and number of Gd+ lesions; adjusted for randomisation stratification factors; from HR over 3 years. DMT=disease-modifying therapy; IFN=interferon beta; HR=hazard ratio; CDMS=clinically definite MS; GA=glatiramer acetate. Kinkel RP et al. Presented at AAN; April 28May 5, 2007; Boston, MA. P04.270; Kappos L et al. Neurology. 2006;67:1242-1249; Comi G et al. Lancet. 2009;374:1503-1511; Comi G et al. Presented at AAN; April 916, 2011; Honolulu, HI. P07.194. Time to SPMS from diagnosis (years) Time to SPMS over 16 years Patients on long-term treatment with Interferon beta 1-b had a significant delay of 6.6 years to reach SPMS compared to untreated patients 20 18 +6.6 Years P=0.003 16 14 12 10 8 6 4 N=104 2 0 0 1 2

3 4 Annals of Neurology, Volume 60, Issue S10 (2006) 5 6 7 8 9 10 11 12 Exposure to Betaferon (years) 13 14 15 16 17 N Efficacy: Pivotal StudiesEW ORAL (FIRST LIN Efficacy: Pivotal StudiesE) TREATMEN Efficacy: Pivotal StudiesTS MORE

E E Alemtuzumab N-1batalizumab N-1batalizumab JC Virus + JC Virus EFFICACY Third line Second Line Fingolimod Dimethyl Fumarate First Line LESS Teriflunomide LESS Glatiramer Acetate Interferons DMs SAFETY MORE

Dimethyl fumarate (Tecfidera) N Efficacy: Pivotal Studiesrf2 : Tecfidera DMF or MMF N Efficacy: Pivotal Studiesrf2 N Efficacy: Pivotal Studiesrf2 - / / Keap1 N Efficacy: Pivotal Studiesrf2 N Efficacy: Pivotal Studiesrf2 N Efficacy: Pivotal Studiesrf2 Proteasome ARE Nucleus - D - D

- D - D N Efficacy: Pivotal Studies N Efficacy: Pivotal StudiesA ADPH DPH Cytoplasm Keap1=kelch-like ECH-associated protein 1; ARE=antioxidant response element, Nrf2= nuclear erythroid 2-related factor van Horssen J et al. Biochem Biophys Acta. 2011;1812:141-150; Linker RA et al. Brain. 2011;134:678-692. 0.6 0.5 49% 49% reduction vs placebo P0.0001b eod* reduction vs placebo P0.0001b eod*

P ro p o rtio n R e la p s e d A d ju s te d A n n u a liz e d R e la p s e R a te : DMF bid=43% risk reduction, P0.0001b eod DMF tid=47% risk reduction, P0.0001b eod 0.6 0.437 0.5 0.280 0.4 0.3 0.4 0.251b eod 0.2 0.3 0.2 Placebo DMF bid DMF tid 0.1b eod 0.1b eod 0.0 0.0

Placebo (n=771b eod) DMF bid (n=769) DMF tid (n=761b eod) BL 0 1b eod2 24 36 48 60 72 Time on Study (weeks) Integrated ITT population; only relapses confirmed by the INEC were included in the analysis. *P value based on Poisson regression (due to underdispersion using negative binomial distribution) adjusted for baseline EDSS score (2.0 vs >2.0), study, region, number of relapses in the 1 year prior to study entry, and baseline age (<40 vs 40 years); P value based on Cox proportional hazards model; Kaplan-Meier estimate of the proportion of subjects relapsed within 2 years. BL=baseline; ITT=intention-to-treat; INEC=independent neurology evaluation committee. Gold R et al. Presented at ECTRIMS; October 1013, 2012; Lyon, France. S151. 84 96 g QW/TIW : g QW/TIW 1b eod2 24 g QW/TIW*

Proportion of Subjects with Sustained Disability Progression (1b eod2-g QW/TIW) 0.3 DMF bid=32% risk reduction, P=0.0034 DMF tid=30% risk reduction, P=0.0059 (24-g QW/TIW) 0.3 DMF bid=29% risk reduction, P=0.0278 DMF tid=32% risk reduction, P=0.01b eod77 0.222 Placebo DMF bid DMF tid 0.2 Placebo DMF bid DMF tid 0.2 0.1b eod55 0.1b eod48 0.1b eod05 0.1b eod46 0.1b eod 0.1b eod

0 BL 1b eod2 24 36 48 60 72 Time on Study (weeks) 84 96 0 BL 0.1b eod04 1b eod2 24 36 48 60 72 84

Time on Study (weeks) Pooled ITT population. *Sustained progression of disability was defined as at least a 1.0-point increase on the EDSS from a baseline EDSS score 1.0 sustained for 12 weeks or at least a 1.5-point increase on the EDSS from a baseline EDSS score of 0.0 sustained for 12 weeks; P value based on a stratified Cox proportional hazards model; Kaplan-Meier estimate of the proportion of subjects sustained progression within 2 years. BL=baseline; ITT=intention-to-treat. Gold R et al. Presented at ECTRIMS; October 1013, 2012; Lyon, France. S151. 96 g QW/TIW : (1b eod0% g QW/TIW) Event, n (%) Placebo (n=836) DMF bid (n=769) DMF tid (n=823) Any adverse event 769 (92) 733 (95) 767 (93) 39 (5) 265 (34) 240 (29) MS relapse

360 (43) 221 (29) 211 (26) N-1b eodasopharyngitis 169 (20) 170 (22) 179 (22) Headache 137 (16) 133 (17) 138 (17) Diarrhea 86 (10) 107 (14) 136 (17) Urinary tract infection 96 (11) 107 (14) 95 (12)

Upper respiratory tract infection 88 (11) 99 (13) 101 (12) N-1b eodausea 72 (9) 93 (12) 115 (14) Fatigue 91 (11) 94 (12) 103 (13) Back pain 92 (11) 94 (12) 84 (10) Abdominal pain upper 47 (6) 76 (10) 94 (11)

Proteinuria* 59 (7) 67 (9) 85 (10) Flushing Indicates 3% higher incidence in either dimethyl fumarate group vs placebo. The overall incidence of any GI event was 31%, 40%, and 43% in the placebo, dimethyl fumarate bid, and dimethyl fumarate tid groups, respectively; *no notable differences in levels of BUN and creatinine, urine 2-microglobulin, and urine microalbumin were observed across treatment groups with monitoring every 4 weeks.GI=gastrointestinal; BUN=blood urea nitrogen. 35 Selmaj K et al. Presented at ECTRIMS; October 1013, 2012; Lyon, France. P484. Teriflunomide Immune system (DHODH),DHODH), de novo Resting lymphocytes Basal demand for pyrimidine nucleotides

Alternative "Salvage" pathway Immune surveillance and protective immune responses DHODH = dihydroorotate dehydrogenase Gold and Wolinsky. Acta Neurol Scand 2011;124:7584 Stimulated myelinspecific lymphocytes Increased demand for pyrimidine nucleotides DHO-DH X X De novo pathway Pro-inflammatory autoimmune response TERIFLUN-1b eodOMIDE g QW/TIW vs. Placebo TOWER2 TEMSO1b eod

0.6 0.54 RRR: 31% p<0.001 0.4 0.37 0.3 RRR: 31b eod% 0.37 p<0.001 0.2 0.1 0.0 0.5 Annualized Relapse Rate Annualized Relapse Rate 0.5 0.6 0.50 RRR: 22% p=0.0183 0.4 0.39 RRR:

36% p=0.0001 0.32 0.3 0.2 0.1 0.0 Placebo 7 mg 1b eod4 mg Placebo 7 mg n=363 n=365 n=358 n=388 n=407 RRR=relative risk reduction, 1. O'Connor P et al. N Engl J Med 2011;365:1293-303;.2 .Confavreux C, et al. Lancet Neurol 2014. 1b eod4 mg n=370 g QW/TIW 1b eod4 mg g QW/TIW vs. Placebo

TEMSO1b eod TOWER2 1b eod4 mg vs. placebo: HR 0.702, p=0.0279 40 Teriflunomide 14 mg Teriflunomide 7 mg Placebo 30 27% 22% 20 20% 10 0 30% P<0,05 Sustained Disability Progression (%) Sustained Disability Progression (%) 7 mg vs. placebo: HR 0.763, p=0.0835 7 mg vs. placebo: HR 0.955, p=0.7620 40

30 1b eod4 mg vs. placebo: HR 0.685, p=0.0442 Teriflunomide 14 mg Teriflunomide 7 mg Placebo 22% 21b eod% 20 1b eod6% 10 0 0 12 24 36 48 60 Weeks 72 84 96 108

0 12 24 36 48 60 72 84 96 108120132 Weeks HR=hazard ratio 1. O'Connor P et al. N Engl J Med 2011;365:1293-303, 2. Confavreux C, et al. Lancet Neurol 2014. 32% P<0,05 g QW/TIW 1b eod4mg ARR g QW/TIW g QW/TIW Annualized Relapse Rate ARR 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 TEMSO/TOWER : 2 / 0.728 Placebo

1b eod2-week SAD Disability Progression Confirmed for 1b eod2 Weeks (%) 34% Risk reduction (p=0.001b eod) 31% Risk reduction (p<0.001) 0.499 0.484 Teriflunomide 7 mg Teriflunomide 1b eod4 mg Risk reduction Teriflunomide 7 mg Teriflunomide 14 mg 40 p value 29% 0.088 46% 0.004

Placebo Teriflunomide 7 mg Teriflunomide 14 mg 35 30 31b eod% 25 20 23% 1b eod8% 15 10 5 0 0 12 24 36 48 60 72 Weeks Kappos L et al. ECTRIMS 2012, S0153. 84 96 108 120 132

ARR = Annualised Relapse Rate, TEMSO Placebo TOWER Teriflunomide (n=360) 7 mg (n=368) 1b eod4 mg (n=358) Diarrhea 8.9 1b eod4.7 N-1b eodausea 7.2 Elevated ALT Placebo Teriflunomide (n=385) 7 mg (n=409)

1b eod4 mg (n=371b eod) 1b eod7.9 7.3 1b eod2.0 1b eod1b eod.1b eod 9.0 1b eod3.7 8.8 8.3 1b eod0.2 6.7 1b eod2.0 1b eod4.2 8.3 1b eod1b eod.2 1b eod4.0 Hair thinning/ decreased hair density 3.3

1b eod0.3 1b eod3.1b eod 4.4 1b eod0.3 1b eod3.5 Hypersensitivity or skin disorders 7.2 1b eod0.3 1b eod1b eod.2 Adverse Event, % N-1b eodot Reported Less than 1% of patients discontinued treatment due to hair loss or thinning and 85% recovered without sequelae; most diarrhea and nausea occurred in the first 3 months of the study and resolved without intervention. OConnor PW et al. N Engl J Med. 2011;365:1293-1303; Kappos L et al. MS Presented at ECTRIMS; October 1013, 2012; Lyon, France. P153. Freedman MS et al. Presented at CMSCACTRIMS; May 30June 2, 2012: San Diego, CA. P7; Freedman MS et al. Presented at CMSC ACTRIMS; May 30June 2, 2012: San Diego, CA. P8. MORE N-1batalizumab EFFICACY JC Virus Second Line

Fingolimod Dimethyl Fumarate First Line Glatiramer Acetate LESS Teriflunomide LESS SAFETY Interferons MORE N-1b eodatalizumab (Tysabri) In the Inflammatory Process, N-1b eodatalizumab Could Intervene at Multiple Points 1b eod. Leukocyte migration from blood to tissue Natalizumab 2. Leukocyte priming and activation 3. Modulation of leukocyte apoptosis Natalizumab VCAM-1=vascular cell adhesion molecule 1. 1. Cannella B et al. Ann Neurol. 1995;37:424-435; 2. TYSABRI [prescribing information]. Cambridge, MA: Biogen Idec; 2012; 3. Yednock TA et al. Nature. 1992;356:63-66; 4. TYSABRI [EMA product information]. Denmark: Biogen Idec A/S; 2012.

AFFIRM - 68% 1b eod.0 0.9 ARR (95% CI) 0.8 Placebo n=31b eod5 0.78 0.73 0.67 P<0.001b eod P<0.001b eod P<0.001b eod `` 0.7 N-1b eodatalizumab n=627 0.6 0.5 66% 68% 0.4 0.3 0.27

0.23 70% 0.20 0.2 0.1b eod 0 Years 02 Year 01b eod Year 1b eod2 FDA per-subject mean relapse rate at 2 years = 0.67 for placebo and 0.22 for natalizumab (67% reduction) ARR=annualized relapse rate; CI=confidence interval. Polman CH et al. N Engl J Med. 2006;354:899-910; Polman CH et al. Presented at AAN; April 916, 2005; Miami, FL. AFFIRM - 42%54% vs. Placebo 6 Hazard ratio=0.58 P<0.001b eod 0.4 Placebo 29% 0.3 42% 0.2 0.1

TYSABRI 1b eod7% 0.0 0 12 24 36 48 60 72 Week 84 96 108 120 g QW/TIW g QW/TIW g QW/TIW g QW/TIW 3 Hazard ratio=0.46 P<0.001b eod 0.4 0.3 Placebo 23% 0.2

54% 0.1 TYSABRI 1b eod1b eod% 0.0 0 12 24 Number of Patients at Risk Placebo TYSABRI 315 627 296 601 283 582 264 567 248 546 240 525 229 517 Polman CH, et al. N Engl J Med. 2006;354:899-910.

216 503 208 490 200 478 199 473 Placebo TYSABRI 315 627 298 611 287 594 36 48 60 72 Week 84 Number of Patients at Risk 269 253 246 237 225 581 559 540 532 521 96

216 509 108 211 503 120 211 502 AFFIRM Study K Natalizumab g QW/TIW N-1b eodatalizumab Hypersensitivity Suspend dosing Often associated with anti-natalizumab antibodies PML Risk stratification by anti-JCV antibody testing TYSABRI (natalizumab) [summary of product characteristics]. Maidenhead, Berkshire, UK: Biogen Idec Ltd; October 2013. 47 g QW/TIW g QW/TIW JC- PML Anti-JCV Antibody Status N-1b eodegative

Positive 0.1b eod 0.1b eod//1b eod1b eod0000 00 Risk is similarly low, regardless of exposure time or prior IS treatment Medical information website. Boston, MA, USA: Biogen Idec Inc. https://medinfo.biogenidec.com/medinfo. Accessed August 5, 2013. JCV=JC virus; PML=progressive multifocal leukoencephalopathy. g QW/TIW g QW/TIW JC Anti-JCV Antibody Status N-1b eodegative Positive* N-1b eodo Prior IS Use N-1b eodatalizumab Exposure 1b eod24 months 2548 months 4972 months PML Risk 0.7/1b eod000 5.3/1b eod000 6.1b eod/1b eod000

Risk Risk of of PML PML is is 1b eod 1b eod//1b eod1b eod0000 00 for for all all patients patients with with no no prior prior IS IS use use in in the the first first 22 years years 1b eod in 1b eod89 Consider Consider increasing increasing frequency frequency of of brain brain MRI MRI *https://medinfo.biogenidec.com/medinfo. Accessed August 5, 2013. Data as of March 2013 indicate estimated risk of PML patients with prior immunosuppressant use is 1.8/1000 for natalizumab exposure of 124 months and 11.2/1000 for exposure of 2548 months. IS=immunosuppressant. Phan-Ba R et al. Neurology. 2012;79:1067-1069; Blair NF et al. Neurology. 2012;79:1067-1069; Ayzenberg I et al. J Neurol. 2012;259:1732-1733; Nicholas JA et al. Ther Adv Chronic Dis. 2014;5:62-68. g QW/TIW

g QW/TIW JC Anti-JCV Antibody Status N-1b eodegative Positive* Prior IS Use N-1b eodatalizumab Exposure 1b eod24 months 2548 months 4972 months PML Risk 1b eod.8/1b eod000 1b eod1b eod.2/1b eod000 Insufficient Data 1b eod in 89 Monitor Monitor by by frequent frequent brain brain MRI MRI *https://medinfo.biogenidec.com/medinfo. Accessed August 5, 2013. Phan-Ba R et al. Neurology. 2012;79:1067-1069; Blair NF et al. Neurology. 2012;79:1067-1069; Ayzenberg I et al. J Neurol. 2012;259:1732-1733; Nicholas JA et al. Ther Adv Chronic Dis. 2014;5:62-68.

Fingolimod Fingolimod Targets S1P Receptors, Which Are Widely Expressed throughout the Body N-1b eodeural cells express S1b eodP receptors known to modulate neuropathological processes relevant to MS Permeability of vessels in the eye Macular edema Smooth bronchial muscles Respiratory flow restriction Smooth vascular musculature Increased vascular tone Atrial myocytes Lowering heart rate Disturbed AV conduction Blood Risk of elevated LFTs in 8%, usually early Efferent Lymph S1b eodP Gradient

Autoaggressive lymphocytes remain in the lymph nodes, away from the CN-1b eodS reversible REDISTRIBUTION-1b eod, not depletion Lymphoid Organ S1P=sphingosine 1-phosphate; LFT=liver function test; MS=multiple sclerosis; AV=atrioventricular; CNS=central nervous system. Adapted from Marsolais D, Rosen H. Nat Rev Drug Disc. 2009;8:297-307; Comi G et al. Mult Scler. 2010;16:197-207. >70% reduction in lymphocyte count, 1b eod8% grade 4 g QW/TIW g QW/TIW 0.5 0.4 0.4 0.3 54% reduction vs placebo P<0.001b eod 0.2 0.1b eod8

60% reduction vs placebo P<0.001b eod 0.1b eod6 0.1b eod n=41b eod8 0 Placebo n=425 n=429 Fingolimod Fingolimod 0.5 mg 1b eod.25 mg FREEDOMS II2 Adjusted* Annualised Relapse Rate Adjusted* Annualised Relapse Rate FREEDOMS1b eod 0.5 0.4 0.4 48% reduction vs placebo P<0.001b eod 0.3 0.21b eod

0.2 0.1b eod 0 *Adjusted for study group, region, number of relapses and EDSS score at baseline. 1. Kappos L et al. N Engl J Med. 2010;362:387-401. 2. Calabresi PA et al. Presented at AAN; April 2128, 2012; New Orleans, LA, USA. ESS.015. n=355 n=358 Placebo Fingolimod 0.5 mg (1b eod2 g QW/TIW) 40 FREEDOMS II2 Sustained Disability Progression* (%) Placebo Fingolimod 0.5 mg HR=0.70; P=0.02 Fingolimod 1b eod.25 mg HR=0.68; P=0.02 30 30 25 24.1b eod% 20

20 1b eod7.7% 1b eod6.6% 1b eod5 1b eod0 27-31b eod% reduction 1b eod0 5 00 0 0 90 1b eod80 270 360 450 540 630 720 1b eod80 360 Days 540 720 Sustained Disability Progression* (%) FREEDOMS1b eod 40

Placebo Fingolimod 0.5 mg HR=0.83; P=0.227 30 29.0% 25.3% 20 1b eod3% reduction 1b eod0 0 0 1b eod80 360 540 720 900 Days *Time to sustained disability progression based on Kaplan-Meier method; based on Cox proportion hazards model, adjusted for treatment, region, baseline EDSS score, and age. HR=hazard ratio; NS=not significant. 1. Kappos L et al. N Engl J Med. 2010;362:387-401; 2. Agius M et al. Presented at CMSC, May 29June 1, 2013, Orlando, FL. DX09. g QW/TIW Fingolimod Cardiovascular

disease risk Macular edema Bradycardia AV block Teratogenic potential Lymphopenia and risk of infection Approximately 6 weeks for lymphocyte counts to return to LLN Use of attenuated live vaccines not possible prolonged treatment with corticosteroids! http://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/022527Orig1s000riskr.pdf. Accessed April 24, 2012; Comi G et al. Mult Scler. 2010;16:197-207; Gilenya (fingolimod) [summary of product characteristics]. Horsham, West Sussex, UK: Novartis Europharm Ltd. 2011; Francis G et al. Presented at ECTRIMS, October 13-16 2010; Gothenburg, Sweden; P442; Karlsson G. Neurol. 2014;82:674-680. Circulating Lymphocyte Count Markedly and Rapidly Decreased Fingolimod 0.5 mg (n=425) Fingolimod 1b eod.25 mg (n=429) Placebo (n=41b eod8) Change in Mean White Blood Cell Counts over Time in Patients Receiving Fingolimod Therapy or Placebo (FREEDOMS Core Study Group) Lymphocyte Count ( 1b eod09/L) 2.8 2.4 Rapid reduction in circulating lymphocytes

2.0 >70% reduction in lymphocyte count within 7 days1 Steady state levels reached within 2 weeks2 1b eod.6 1b eod.2 0.8 Lower limit of normal 0.4 0 0 0.5 1b eod 2 3 6 9 1b eod2 1b eod5 Time Point (months) 1b eod8 21b eod 24 Data are mean (standard deviation [SD]). In EU: Fingolimod is indicated for the treatment of patients with highly active RRMS.

1. Comi G et al. Mult Scler. 2010;16:197-207; 2. Francis G et al. Presented at ECTRIMS; October 1316, 2010; Gothenburg, Sweden. P442. MORE E E Alemtuzumab N-1batalizumab N-1batalizumab JC Virus + JC Virus EFFICACY Third line? Second Line Fingolimod Dimethyl Fumarate First Line LESS Azathioprine LESS Glatiramer Acetate Teriflunomide SAFETY

Interferons MORE Alemtuzumab Alemtuzumab: 1b eod. CD52 Monocytes 2. B B 3. g QW/TIW Stem cell B B CD52 Macrophages Neutrophils TT Lymphocyte precursor TT Pre/Pro B cell

T-cell precursor CD52 CD52 Lymphocyte precursor T B g QW/TIW 1b eod CD52, alemtuzumab2 Lymphocyte precursor g QW/TIW TT B B Alemtuzumab T B 2,3

alemtuzumab2,4,5 2,3 T- B , 2,4,5 1. Weber MS et al. Results Probl Cell Differ 2010;51:115-26; 2. Hu Y et al. Immunology 2009;128;260-70; 3.Turner MJ et al. J Neuroimmunol 2013;261:29-36; 4. Cox AL et al. Eur J Immunol 2005;35:3332-42; 5. Fox EJ. Exp Rev Neurother 2010;10:1789-97. Alemtuzumab Phase 3 Clinical Trials: g QW/TIW CARE-MS I (N-1b eod=581b eod) Annualised relapse rate at 2 years1,2 55% vs SC IFN-1a Disability progression (6-month sustained)1,2 30% vs SC IFN-1a 0.18 alem vs 0.39 SC IFN-1a 8% alem vs 11% SC IFN-1a Disability improvement

(6-month sustained)3 Not assessed Patients MRI and clinically disease free1,4 Odds ratio 1.75 39% alem vs 27% SC IFN-1a CARE-MS II (N-1b eod=840) P<0.0001 P=0.22 49% vs SC IFN-1a 0.26 alem vs 0.52 SC IFN-1a 42% vs SC IFN-1a 13% alem vs 20% SC IFN-1a 157% vs SC IFN-1a 29% alem vs 13% SC IFN-1a P=0.006 Odds ratio 3.03 32% alem vs 14% SC IFN-1a P<0.0001

P=0.0084 P=0.0002 P<0.0001 1. Cohen JA et al. Lancet. 2012;380:1819-1828; 2. Coles AJ et al. Lancet. 2012;380:1829-1839; 3. Giovannoni G et al. Presented at AAN; March 1623, 2013; San Diego, CA. P07.120; 4. Hartung HP et al. Presented at AAN; March 1623, 2013; San Diego, CA. P07.093. CARE-MS I1b eod CARE-MS II2 SC IFN-1b eod-1b eoda (n=1b eod87) Alemtuzumab 1b eod2 mg/day (n=386) SC IFN-1b eod-1b eoda (n=202) Alemtuzumab 1b eod2 mg/day (n=426) Alemtuzumab 24 mg/day (n=1b eod70) Infusion-associated reactions* NA 90

NA 90 97 Infection -Nasopharyngitis -UTI -Herpes infection -URTI 45 13 4 2 13 67 20 17 16 15 66 24 11 4 12 77 29 21 16 16 83 32 23

16 21 Autoimmune -Thyroid disorder -Serious thyroid event -ITP 6 0 0 18 1 1 5 0 0 16 <1 1 19 1 1 Event, % *Infusion associated reactions for the 12 mg/day dose included headache (43%), rash (39%41%), pyrexia (16%33%), nausea (14%17%), urticaria (11%15%), chills (7%10%). Patients received acyclovir prophylaxis for herpes infections and were monitored for immune cytopenias and thyroid or renal disorders. NA=not applicable; UTI=urinary tract infection; URTI=upper respiratory tract infection; ITP=idiopathic thrombocytopenic purpura. 1. Cohen JA et al. Lancet. 2012;380:1819-1828; 2. Coles AJ et al. Lancet. 2012;380:1829-1839. g QW/TIW Alemtuzumab During Treatment

Counsel patients to Monitor Avoid live attenuated vaccines (until 48 months after last infusion) Report any adverse event, signs, or symptoms (especially fever, chills, swollen glands, bleeding gums, bruising, rashes) Monthly CBC with differential Use contraception Keep the Patient Alert Card with them and read Patient Guide Monthly renal function tests Serum creatinine levels Urinalysis with microscopy Quarterly thyroid function tests (TSH) Annual HPV screening for female patients Report adverse events by HCPs via the national reporting system TSH=thyroid-stimulating hormone; HPV=human papillomavirus; HCPs=healthcare professionals. Lemtrada (alemtuzumab) [summary of product characteristics]. Oxford, UK: Genzyme Therapeutics Ltd. 2013. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003718/WC500150521.pdf. Accessed February 21, 2014.

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