1. Multiple Sclerosis: Clinical Treatment and Current Research Walter Royal, III, MD Associate Professor of Neurology Maryland Center for Multiple Sclerosis Multiple Sclerosis Center of Excellence - East Social Security Administration March 16, 2011

2. Presentation Outline MS Epidemiology, pathogenesis and clinical features General approaches to therapy Currently approved disease modifying therapies Symptomatic therapies Research underway at the Maryland Center for MS

3. Multiple Sclerosis Risk and Geography Wallin MT et al. Ann Neurol 2004;55:65-71.

4. MS is an Immune-Mediated Disease BBB=blood-brain barrier; APC=antigen-presenting cell. Adapted from Miller et al. Continuum: Multiple Sclerosis (Part A). 1999;5:7.

5. The Immune Response in Multiple Sclerosis

6. Pathologic Features of Multiple Sclerosis

7. Gray Matter Lesions in MS Amadio S et a. Cereb Cortex. 2010 Jun;20(6):1263.

8. Multiple Sclerosis Clinical Subtypes Lublin FD et al. Neurology. 1996;46:907-911. Relapsing-remitting Primary-progressive Disability Time Disability Secondary-progressive Progressive-relapsing Time Disability 80% at diagnosis 50% of RR patients after 15 yrs 10-15% at diagnosisRare

9. Diagnosis of Multiple Sclerosis MRI Revised McDonald Criteria – Incorporates previous criteria – Address all MS types RRMS, SPMS Monosymptomatic Primary progressive ↔

10. What Causes MS? Genetics Environmental

11. Major Gene Associations from GWAS Studies in MS Locus HLADRB1*1501 IL-2RA (CD25)* CD58 (LFA3) IL-7R (CD127) HLA-DRB5 Chromosome (Function) 6p21.3(antigen presentation) 10p15 (development of Treg ‡ cells) 1p13 (binds CD2 on T cells) 5p13(T and B cell development) 6p21.3 (decreases risk of SPMS) § * Also associated with Graves Dis., IDDM and RA ‡ Treg = regulatory T cells § Based on data from small number of DRB5*null African American subjects

12. Epstein Barr Virus Ascherio A and Munger K. Ann Neurol 2007;61:288–299 MS Incidence Rate Age Serum IgG Level

13. Currently Available MS Drug Therapies Drug – IFN-β1b (Betaseron ® ) – IFN-β1a (Avonex ® ) – Mitoxantrone (Novantrone ® ) – IFN-β1a (Rebif ® ) – Natilizumab (Tysabri ® ) – IFN-β1b (Extavia ® ) – Fingolimod (Gilenya ® ) Approval Year – 1993 – 1995 – 2000 – (2002; orphan drug act) – 2005 – 2009 – 2010

14. Disease Modifying Therapies: Injections Rebif ® 8.8/22/44 μg SC 3x per week Avonex ® 30 μg IM Weekly Interferon  -1a Betaseron ® /Extavia ® 250 μg SC Every other day Interferon  -1b Copaxone ® 20 mg SC Daily Glatiramer acetate

15. Humanized Monoclonal Antibody Therapies – IV Infusions Natalizumab (Tysabri ® ) –  4 Integrin (T cells ® ) Rituximab (Rituxin ® ) – CD20 (B) cells; Alemtuzamab (Campath ® ) § – CD52 (T+B cells, monocytes) Daclizumab (Zenapax ® ) § – CD25, CD40 ligand (T cells; NK cells) § Not currently FDA approved

16. Mechanisms of Action of Injectable Drugs Interferons (IM, SC) – Induction of Interferon-responsive genes Glatiramer acetate (SC) – ↑ numbers of suppressor cell phenotypes – Neuroprotection via BDNF induction (?) Monoclonal antibodies (IV) – Physical interactions → functional inhibition Oral agents – Inhibition by small molecules

17. Impact of Approved MS Therapies on Annualized Relapse Rate

18. What Works Best? High vs Low Dose IFN-  – High dose was superior IFN-  Low Dose vs Double-dose x 2 – No difference IFN-  vs Glatiramer acetate – No difference IFN-  vs Glatiramer acetate vs IFN+GA – Results pending Approved drug as comparator – E.g., Natalizumab and fingolimod vs IFN-  (natalizumab was superior)

19. More Aggressive Therapies in MS: Efficacy at a Price Higher dose IFN-β: ↑Injection frequency; ↑ side effects (?) Natalizumab: PML Rituximab: Rarer reports of PML Alemtuzamab: ITP; Graves disease S1P1 antagonists: cardiopulmonary, infectious More potent immunomodulation → increased risk of malignancy?

20. Progressive MS No treatments available Recent, current and pending studies – Fingolamod ® (FTY-720; PPMS) – MIS416 (used for pathogen-specific immunization) – Lipoic acid (neuroprotection) – Simvastatin (SPMS) – Mesenchymal stem cell transplantation (autologous; SPMS)

21. Treatment of MS Symptoms (*New Agents) Fatigue: *Armodafinil (Nuvigil®) Poor ambulation: *Dalfampridine (Ampyra®) Pain Spasticity Pseudobulbar affect: *Dextromethorphan/Quinidine sulfate (Nuedexta®) Psychological problems Urinary dysfunction Sexual dysfunction Cognitive impairment

22. Maryland Center for MS: Active Clinical Drug Studies

23. Maryland Center for MS: Pending Clinical Drug Studies

24. Other MS Research at the Maryland Center for Multiple Sclerosis MS Biomarkers – T cell markers (Naïve, memory T cells; CXCR3) – Genetic markers (Response Gene to Complement 32; RGC-32) Vitamin D Cigarette smoke and MS Potassium channels and immune modulation Models of bone marrow transplantation therapy Neuroprotection

25. Maryland Center for Multiple Sclerosis Christopher Bever, MD Kenneth Johnson, MD Walter Royal, III, MD Horea Rus, MD Robert Shin, MD Kerry Naunton, RN Elizabeth Wheeler, RN Valerie Wells, BA Cynthia Dorsey