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10 Differentiating Disease and the Role of the Immune System Giancarlo Comi, MD Professor of Neurology Director, Department of Neurology Vita-Salute San Raffaele University Milan, Italy

11 Disclosure Consulting Fee: Almirall, Biogen, Excemed, Forward Pharma, Genzyme, Merck, Novartis, Receptos, Roche, Sanofi, Teva Non-CME Services Fees: Almirall, Biogen, Excemed, Forward Pharma, Genzyme, Merck, Novartis, Receptos, Roche, Sanofi, Teva Contracted Research: Biogen, Genzyme, Merck, Novartis, Receptos, Roche, Sanofi, Teva

12 Immune, Genetic, and Environmental Factors Contribute to the Development of RMS Immune Dysregulation Genetics 1,2 Environment 1,3 Many genes associated with increased risk for MS are immune-system related Autoreactive T and B cells Activated Autoreactive T and B cells Environmental risk factors/triggers: Viruses Bacteria Vitamin D levels Smoking Geographic factors Entry Into CNS Development of MS 1. Sospedra M, et al. Annu Rev Immunol. 2005;23: Lill CM. Front Neurol. 2014;5(130): Ramagopalan SV, et al. Lancet Neurol. 2010;9(7):

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14 Immunopathogenesis in MS: Inside-Out Hypothesis Eur J Immunol. 2016; doi: /eji ; Autoimmun Rev. 2016;15(5):457-61; Sci Rep. 2016;6:28484; Nat Commun ;7:12015; J Interferon Cytokine Res. 2014;34(8):615-22; Mol Neurobiol. 2016;doi: /s

15 Immunopathogenesis in MS: Outside-in Hypothesis Eur J Immunol. 2016; doi: /eji ; Autoimmun Rev. 2016;15(5):457-61; Sci Rep. 2016;6:28484; Nat Commun ;7:12015; J Interferon Cytokine Res. 2014;34(8):615-22; Mol Neurobiol. 2016;doi: /s

16 B and T Cells are Drivers of the Neuroinflammatory Process of MS in the Lymph Node and the CNS CNS, central nervous system. Bar-Or A. Semin Neurol. 2008;28(1):29-45.

17 T Cell Mechanisms Sci Transl Med. 2015;7(287):287ra74; Cell. 2015;162(6): ; Cell. 2015;162(6):1212-4; Ann Neurol Jul;78(1):3-20.

18 T Cell Mechanisms Sci Transl Med. 2015;7(287):287ra74; Cell. 2015;162(6): ; Cell. 2015;162(6):1212-4; Ann Neurol Jul;78(1):3-20.

19 Role of B Cells in MS B cells can contribute to the pathogenesis of MS through 1,2 : Cytokine production Focused antigen presentation (APC) B cell CD80/86 MHCII : peptide CD40 OX40L Plasma cell Formation of autoantibodies Antibodies to multiple viruses, ANA, brain antigens, and nonsense antibodies can be detected in MS patients 3-5 High CD80 (B7-1) on the surface of MS B cells allows them to activate antigen-specific T cells 6 1. Lund FE. Curr Opin Immunol. 2008;20(3): Sospedra M, et al. Annu Rev Immunol. 2005;23: Mattson DH, et al. Nature. 1980;287(5780): Barned S, et al. Neurology.1995;45(2): Virtanen JO, et al. Mult Scler. 2014;20(1):27-34; 6. Genc K. J Clin Invest. 1997;99(11):

20 T and B Cells Contribute to MS Pathophysiology, Independently and by Interacting with Each Other Independent T-cell contribution Dendritic cell Independent B-cell contribution B T T B T CD4 + Helper T cell T CD8 + Cytotoxic T cell Regulatory T cell T- and B-cell interactions B Antibody-producing B cell 1. Wiendl H, et al. Nat Rev Neurol. 2013;9(7): Lehmann-Horn K, et al. Ther Adv Neurol Disord. 2013;6(3): Krumbholz M, et al. Nat Rev Neurol. 2012;8(11):

21 Interactions Between T and B Cells Periphery DC (APC) Monocyte Autoreactive B cells serve as APCs for T cells and produce pro- inflammatory cytokines which can further induce T-cell proliferation 1 CNS T T h 2 cells may promote autoreactive B-cell responses in MS 2,3 T B IFN-γ TNF-α T IFN-γ TNF-α IL-10 TNF-β T IL-17 APC CD4 IL-6 TGF-β Th17 TNF-α Th1 Th2 IL-4 IL-5 IFN-γ TNF-α B Mϕ Myelin Sheath CD8 Neuron T reg B B B cells can promote T-cell activation 1 BBB TGF-β and IL-6 secreted by activated B cells promote activity of Th17 cells, leading to further damage to the BBB 1 PC Adapted from Elsevier: Linker RA, et al. Trends Pharmacol Sci. 2008;29(11): Ireland S, et al. Mult Scler Int. 2011;2011:423941; 2. Jiang S, et al. Immunol Rev. 2013;252(1):5-11; 3. Sospedra M, et al. Annu Rev Immunol. 2005;23:

22 MS is a Result of Imbalanced Immune Regulatory Networks: T and B Cells 1-3 Reactivated Activated CD8 B CD4 Periphery BBB CNS

23 Mechanisms of Damage and Recovery in MS: Summary Damage Inflammation Demyelination Acute axonal transection Chronic axonal degeneration Recovery Remyelination Brain plasticity Zivadinov R, Cox JL. Int Rev Neurobiol. 2007;79:

24 Disability Progression in Two Phases 7 Natural History 6 EDSS Score Phase 2 Phase Years from clinical onset of MS This is one important factor in deciding to manage patients early to help slow progression, irrespective of initial clinical presentation.

25 Pathological Differences Between RRMS and Progressive MS (SPMS, PPMS) RRMS RPMS SPMS / PPMS New waves of inflammation entering the CNS from circulation Focal demyelinating lesions with variable axonal injury and blood brain barrier injury mainly in the white matter Compartmentalized inflammation in the CNS Slow expansion of preexisting white matter lesions Diffuse inflammation and axonal injury in NAWM Extensive cortical demyelination

26 Pathogenetic Mechanisms Underlying Progression Ontaneda D, 2016.

27 Meningeal B Cell Follicles Immunity. 2011;35(6): Archelos JJ, Hartung HP. Trends Neurosci. 2000;23(7):317-27; Uccelli A, et al. Trends Immunol ;26(5):254-9.

28 B Lymphocyte Roles in Multiple Sclerosis Antibody production Antigen presentation Cytokine production Ectopic lymphoid tissue CIS Relapsing MS Progressive MS Dalakas MC. Nat Clin Pract Neurol. 2008;4(10):

29 Acute Axonal Loss Remains Clinically Silent Until: A critical threshold in a given pathway is reached The compensatory CNS resources are exhausted

30 Disease Activity and Disability Progression in MS: Brain Adaptability is Finite and Individual Structural damage Disease parameter Functional reorganisation High reserve Mean reserve Low Reserve Disability High reserve Mean reserve Low reserve Phase A Phase B Phase C A degree of functional reorganisation compensates for initial structural damage; however, this resource is finite 1

31 Delaying Treatment in MS: What is Lost is Not Regained R Inflammation Degeneration Disability Response to treatment B? R B EDSS 3 B R Clinical onset Time

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33 Dissecting the Data on New and Emerging High-efficacy Agents for RRMS and PPMS Stephen L. Hauser, MD Director, UCSF Weill Institute for Neurosciences Professor and Chair, Department of Neurology University of California, San Francisco San Francisco, CA

34 Disclosure Scientific Advisory Board: Annexon, Bionure, Molecular Stethoscope, Symbiotix Board of Trustees: Neurona

35 Targeting CD20+ B Cells May Preserve B Cell Reconstitution and Long-term Immune Memory v B-cell Reconstitution Preserved 1-3 Long-term Immune Memory Preserved 1,2,4 Ocrelizumab, Ofatumumab, and Ublituximab are monoclonal antibodies that selectively deplete CD20 + B cells

36 Ocrelizumab in Relapsing MS: Reduction in Annualized Relapse Rate Compared With IFN β-1a 0.5 OPERA I 0.5 OPERA II Adjusted ARR at 96 Weeks* % ARR reduction vs IFN β-1a P< Adjusted ARR at 96 Weeks* % ARR reduction vs IFN β-1a P< IFN β-1a 44 μg (n=411) Ocrelizumab 600 mg (n=410) 0.0 IFN β-1a 44 μg (n=418) Ocrelizumab 600 mg (n=417)

37 Ocrelizumab in Relapsing MS: Reduction in Mean Gadolinium-Enhancing Lesions Compared With IFNβ-1a OPERA I OPERA II Mean Number per Patient per MRI Scan* IFN β-1a 44 μg Ocrelizumab 600 mg 91% P< % P<.0001 Week 24 Week 48 Week 96 n IFN β-1a Ocrelizumab % P<.0001 Mean Number Per Patient Per MRI Scan* IFN β-1a 44 μg Ocrelizumab 600 mg 92% P< % P<.0001 Week 24 Week 48 Week 96 n IFN β-1a Ocrelizumab % P<.0001

38 Ocrelizumab in Primary Progressive MS: Reduction in 12-week Confirmed Disability Progression Time to 12-week Confirmed Disability Progression 24% reduction in risk of CDP HR (95% CI): 0.76 (0.59, 0.98); P=.0321 n Placebo Ocrelizumab

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40 Daclizumab-HYP Inhibits High Affinity Interleukin-2 Receptor Signaling Humanized Mab Binds to α-subunit of the interleukin-2 receptor (CD25, IL-2Rα) Selective block of IL-2 signaling through the high-affinity IL-2 receptor Immunomodulatory effects: Inhibits activated effector T cells Expands CD56bright NK Cells Decreased number of regulatory T (Treg) cells DAC-HYP does not have immune depleting or broadly immunosuppressive effects

41 Daclizumab-HYP in Relapsing MS: Primary Endpoint - Annualized Relapse Rate (ARR) Annualized relapse rate % Reduction (95% CI, 35.5%-53.1%) P< IFN Beta-1a (n=922) DAC HYP 150 mg (n=919) Estimated from a negative binomial regression model adjusted for baseline relapse rate, history of prior IFN beta use, baseline EDSS (<=2.5 vs > 2.5) and baseline age (<=35 vs >35). Subjects are censored at the earlier of: 1) start of alternative MS medication, 2) 180 days post treatment discontinuation, or 3) end of treatment period.

42 Mean* number of lesions Daclizumab-HYP in Relapsing MS: Effect on MRI-defined Lesions at Week 96 New/Newly Enlarging T2 Lesions % Reduction P< n=841 n= New Gd+ Lesions 1.0 IFN beta-1a 30 mcg 65% Reduction P<.0001 New T1 Hypointense Lesions black holes Reductions in lesions (T2, Gd+, and T1) were observed as early as 24 weeks for DAC HYP vs IFN beta-1a (P<.001 for all comparisons) *Adjusted mean for T2 and T1 lesions. The number of new/newly enlarging T2 lesions at 96 weeks was a secondary endpoint. Data were adjusted for baseline lesion volume, history of prior IFN beta-1a use and baseline age ( 35 vs >35). Missing data were not imputed and patients with no post baseline MRI were excluded from analysis of new/newly enlarging T2 lesions at 96 weeks. Missing data were imputed for all other analyses % Reduction P< n=909 n=900 n=908 n=899 DAC HYP 150 mg

43 Autologous Stem Cell Transplantation Multistep Procedure: Hematopoietic stem cells harvested from PBL (or BM) Immune system then ablated (varying intensity of conditioning regimen) Harvested stem cells then re-infused, restoring a naïve immune system Greater risk with more intensive conditioning regimens Studies to-date in MS have utilized various regimens, small cohorts, and variable follow-up periods

44 Immunoablation and Autologous Haemopoietic Stem Cell Transplantation for Aggressive MS: Multi-center Single Group Phase 2 Trial Between diagnosis and ahsct, 24 patients had 167 clinical relapses over 140 patient-years with 188 Gdenhancing lesions on 48 pre-ahsct MRI scans Primary outcome, multiple sclerosis activity-free survival at 3 years after transplantation was 69.6% (95% CI ) With up to 13 years of follow-up after ahsct, no relapses occurred and no Gd enhancing lesions or new T2 lesions were seen on 314 MRI sequential scans Rate of brain atrophy decreased to that expected for healthy controls

45 MS Therapies Have Consistent Effects on B cells Therapy Interferon Beta Glatiramer acetate Fingolimod Dimethyl fumarate Teriflunomide Mitoxantrone Natalizumab Alemtuzumab Anti-CD20 RTX, OCR, OFA Effect on B cells* Modulation Differentiation Activation Migration Depletion *In humans and experimental models

46 Therapeutic Decision Making: Relapsing MS 2016 HIGHER Alemtuzumab Natalizumab JC Virus + Natalizumab JC Virus - Oral Parenteral Third Line Second Line Efficacy Mitoxantrone Fingolimod Dimethyl Fumarate First Line Teriflunomide Glatiramer Acetate Interferons LOWER Safety HIGHER Courtesy of Dr. Hauser. Modified from Fig. 1 in Hauser S, et al. Ann Neurol. 2013;74:

47 Therapeutic Decision Making: Relapsing MS 2016 HIGHER E Bone Marrow Transplantation Alemtuzumab Third Line Natalizumab JC Virus + E Natalizumab JC Virus - Ocrelizumab E Oral Parenteral Emerging E Second Line Daclizumab Efficacy Mitoxantrone Fingolimod Dimethyl Fumarate First Line Teriflunomide Glatiramer Acetate Interferons LOWER Safety HIGHER Courtesy of Dr. Hauser. Modified from Fig. 1 in Hauser S, et al. Ann Neurol. 2013;74:

48 Therapeutic Decision Making: Progressive MS 2016 HIGHER Oral Parenteral SPMS PPMS O Off-label Efficacy LOWER Safety O HIGHER Courtesy of Dr. Hauser. Modified from Fig. 1 in Hauser S, et al. Ann Neurol. 2013;74:

49 Therapeutic Decision Making: Progressive MS 2016 HIGHER Oral Parenteral SPMS PPMS O Off-label Efficacy E Siponimod? E Ocrelizumab O LOWER Safety HIGHER Courtesy of Dr. Hauser. Modified from Fig. 1 in Hauser S, et al. Ann Neurol. 2013;74:

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51 Best Practices When Using Selective High-efficacy Agents Prof. Xavier Montalban, MD, PhD Chairman, Dept. of Neurology-Neuroimmunology Director, Multiple Sclerosis Centre of Catalonia Vall d Hebron University Hospital Barcelona, Spain

52 Disclosures Consulting Fee: Almirall, Bayer, Biogen, Genzyme, Merck, Novartis, Receptos, Roche, Sanofi-Genzyme, Teva

53 Key Aspects in the Management of MS Early and Accurate Diagnosis Early Treatment if Indicated Early Identification of Non-responders

54 In November 2016 in Philadelphia, US, the International Panel on Diagnosis of MS will meet for a forth time to.

55 Do We Have Fundamental Treatment in Relapsing MS? CIS/MS Interferon beta 1a SC Interferon beta 1 a pegylated Interferon beta 1b SC RELAPSING- REMITTING YES Interferon beta 1a IM Glatiramer acetate 40 TIW Mitoxantrone Natalizumab Fingolimod Teriflunomide SECONDARY PROGRESSIVE DMF Alemtuzumab Daclizumab Ocrelizumab

56 Do We Have Fundamental Treatment in Progressive MS? SECONDARY PROGRESSIVE PRIMARY PROGRESSIVE NO Interferon beta 1a SC Interferon beta 1 a pegylated Interferon beta 1b SC Interferon beta 1a IM Glatiramer acetate 40 TIW Mitoxantrone Natalizumab Fingolimod Teriflunomide DMF Alemtuzumab Daclizumab Ocrelizumab?

57 Treatment Decision in MS?

58 Treatment Decision Making Process Demographics Male Older than 40 years Smoker Non-caucasian Biological predictors Presence of IgG and IgM oligoclonal bands High levels of NFLl High levels of Chitinase Low levels of Vit D B A D P R O G N O S I S Disease clinical predictors High number of relapses Incomplete recovery from relapses Early progression of disability Cerebellar, cognitive involvement Disease MR predictors High T2 lesion burden 2 Gd+ / new T2 lesions Presence of T1 black holes Early discernable atrophy Infratentorial lesions Spinal cord lesions

59 Treatment Decision Making Process PROGNOSIS Comorbidities: Diabetes Chronic lung disorders Hypertension Cardiac problems Chronic active infections (hepatitis, TB) Concomitant drugs Other concomitant autoimmune disorders (psoriasis, RA, others) Severe depression JCV status T R E A T M E N T D E C I S I O N Pregnancy Patient preferences Other factors: Fatigue Profession Distance from hospitals Travels needs Needle phobia Adherence expectations

60 Assessing Treatment Failure: The Rio Score The Rio Score Relapse: 1 in first 12 months EDSS: increase of 1 point confirmed 6 months MRI: 3 active lesions (T2 or Gd+) PROGRE SSION MRI ACTIVITY RELAPSES Río et al. Ann Neurol 2002, 2006, Mult Scler 2009.

61 Predictors of Long-Term Disability HR (C.I. 95%) Clinical Δ1 EDSS Relapses (y/n) 1 relapse vs ( ) 1.7 ( ) 2 (1-3.9) MRI NewT2 >0 NewT2 > 2 NewT2 >4 NewT2 1-2 vs 0 Gad > 0 Gad 1vs (1-4.2) 2.8 ( ) 3.2 ( ) 0.8 ( ) 2 ( ) 1.2 ( ) Combined Rio score Modified Rio score NEDA 3.5 ( ) 1.6 ( ) 1.7 ( ) HR HR=hazard ratio

62 Treatment Algorithms in Patients with Ongoing Disease Activity Relapsing MS Efficacy Convenience Safety Cost Others Interferon beta 1b Interferon beta 1a SC Interferon beta 1a IM Glatiramer Acetate Teriflunomide DMF Fingolimod Natalizumab Alemtuzumab Rituximab/Ocrelizumab / others

63 Shared Decision Making Patient Experiences Values and Preferences SDM INTERACTION Family, Society Clinician Treatment Options Potential benefits, harms, outcomes Shared decision making combines the measurement of patient preferences with evidence-based practice

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