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Multiple Sclerosis: Clinical Treatment and Current Research

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. Presentation Outline.

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Multiple Sclerosis: Clinical Treatment and Current Research

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

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

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

  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

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