Multiple Sclerosis: An evolving treatment landscape

1. Multiple Sclerosis:An evolving treatment landscape Oklahoma Academy of Physician Assistants 40th Annual Conference Gabriel Pardo, MD OMRF Multiple Sclerosis Center of Excellence

2. Disclosures Gabriel Pardo, MD Director Multiple Sclerosis Center of Excellence Oklahoma Medical Research Foundation Consultant: Biogen Idec, Genzyme Corporation, Questcor, Teva Neuroscience, Novartis Pharmaceuticals. Honoraria: Acorda Therapeutics, Bayer Healthcare, Biogen Idec, EMD Serono, Genzyme, Novartis Pharmaceuticals, Pfizer, Teva Neuroscience.

3. Learning Objectives • Review the pathophysiology and clinical manifestations of MS.  • Describe the mechanism of action and efficacy data of MS therapeutic agents.  • Emphasize the multidisciplinary approach to the treatment of MS 

4. Multiple Sclerosis • Autoimmune • Chronic • Central nervous system • Mechanisms of disease • Inflammation • Demyelination • Axonal loss • Neurodegeneration

5. Demyelinating Disease Spectrum Radiologically Isolated Syndrome (RIS) Pathologically identified demyelination Clinically Isolated Syndrome (CIS) Multiple Sclerosis Opticospinal MS Fulminant forms: -Tumefactive MS -Marburg MS Benign RRMS SPMS PPMS PRMS Okuda DT. Nat Rev Neurol. 2009.

6. Relapsing Remitting MS (RRMS) • Clearly defined relapse and remission • Relapses: • Typically sudden • Last days, weeks or months • Most patients have this form at diagnosis • ~ 85% of patients with MS • Evolution to progressive MS • Recovery/Remission • May be full or partial • No disease worsening during remission

7. Secondary Progressive MS (SPMS) • More than 50% of Relapsing-Remitting • Secondary-Progressive • May be accompanied by: • Sudden relapses • Minor remissions and plateaus

8. Primary Progressive MS (PPMS) • Gradual increase in symptom severity • No periods of relapse and remission • Less common form of MS • ~ 15% of patients with MS

9. Progressive Relapsing MS (PRMS) • Progressive disease from symptom onset • Acute relapses • Disease progression between relapses • A relatively uncommon form of MS

10. Diagnostic Criteria McDonald 2010 Criteria for Diagnosis of MS

11. MRI in MS

12. MRI IN MS

13. Treatment of MS • Treat the disease • Disease modifying Tx. • Immunomodulators • Immusuppressants • Treat the symptoms • Tailored • Multidisciplinary

14. Approved and Emerging Therapeutic Options LaquinimodDaclizumab Ocrelizumab BAF312 Anti-LINGO (?) Tysabri® (natalizumab) Betaseron® (IFNβ-1b) Avonex®(IFNβ-1a) Extavia® (IFNβ-1b) Alemtuzumab (Lemtrada®) PEG-IFN (Plegridy®) (2014) Copaxone® (glatiramer acetate) Gilenya™ (fingolimod) Novantrone® (mitoxantrone) Aubagio ® (teriflunomide) Tecfidera® (BG12 /DMF) Rebif®(IFNβ-1a) 2013 2001 2014 2004 2009 2010 2011 1993 1995 2000 2012 Estimated launch date Approval date In development Approved therapies

15. Disease Modifying Therapy (DMT) • Without DMT the majority of MS patients become disabled: • 50% of RRMS evolve to SPMS within 10 years • 50% require aid for ambulation after 15 years

16. Disease Modifying Therapy Goals of Disease Modifying Therapy (DMT) • Short-term goals of DMT are to reduce: • Number of MRI lesions • Frequency/severity of relapses • Residual deficits from relapses • Brain atrophy • Physical disability • Long-term goals of DMT are to delay/prevent: • Evolution to SPMS • Development of permanent physical and mental disability

17. Understanding the pathophysiology of MS enables treatment development • MS-specific proinflammatory immune cells cross the blood-brain barrier, secrete proinflammatory cytokines, and eventually destroy myelin and facilitate neuronal death. Proinflammatory cells release destructive cytokines and neurotoxic agents Th1 cell crossing blood-brain barrier Blood-brain barrier Proinflammatory Th1 cells (MS-specific) Proinflammatory cytokines 1. Ziemssen T. J Neurol. 2005;252(Suppl 5):V/38-V/45. 2. Yong VW, et al. Neurology. 2007;68(22 Suppl 3):S32-S37. 3. Dhib-Jalbut S. Neurology. 2007;68(22 Suppl 3):S13-S21. 4. Tzartos JS, et al. Am J Pathol. 2008;172(1):146-155.

18. Activated antigen- presenting cell (astrocytes, microglia, macrophages) Endothelial cells TNF-α, Interferon-γ Class II MHC molecule CD4+ Th1 cell Putative MS antigen ICAM-1, VCAM-1 E-selectins up-regulated TCR Activated antigen- presenting cell (astrocytes, microglia, macrophages) Class II MHC molecule TNF-α, Interferon-γ Interleukin-12 Interferon-γ Cytokine-mediated injury CD4+ Th1 cell Immune mediated injury B7G-1, B7-2 Immune response Putative MS antigen CD28 Anergy CTLA-4 TCR CD4+ T cell CD4+ Th2 cell Interleukin-12 Interferon-γ Microglia Interferon-γ TNF-β Cytokine-mediated injury Autoreactive T cell TNF-α, Antibody/complement mediated injury B7G-1, B7-2 Immune response CD28 Penetration (matrix metalloproteinases) Anergy CTLA-4 Antiinflammatory signaling Interleukin-4, 10, 13 CD4+ T cell Class I MHC molecule CD4+ Th2 cell Astrocyte Demyelinating antibodies Anti-MOG? Interleukin- 4, 5, 6, 10, 13 Interferon-γ TNF-β Class I–restricted CD8+ T cell up-regulated by interferon-γ Antiinflammatory signaling Interleukin-4, 10, 13 TNF-α, Interferon-γ Primary oligodendrogliopathy Interleukin- 4, 5, 6, 10, 13 Oligodendrocyte Antibodies Degeneration of inner glial loop Blood–brain barrier Surface Ig Activated B cell Neuronal cell body Increased sodium-channel density Antibody-mediated remyelination Antibodies Surface Ig Activated B cell Normal myelin sheath Monocyte Remyelinated areas Postsynaptic neuron Oligodendrocyte precursor cell Glial growth factors? Systemic circulation Terminal axon ovoid Proliferation Migration Differentiation Remyelination Basement membrane

19. RRMS treatment: Different mechanistic approaches1-6 Immune modulation Reduction in cell trafficking Immune cell ablation Immune cell sequestration 1. Weber MS, et al. Neurotherapeutics. 2007;4(4)647-653. 2. Aharoni R, et al. ProcNatlAcadSci U S A. 2008;105(32):11358-11363. 3.Betaseron® prescribing information. Bayer HealthCare Pharmaceuticals Inc. 4. Tysabri® prescribing information. Biogen Idec Inc. 5. Lopez-Diego RS, et al. Nat Rev Drug Discovery. 2008;7(11):909-920. 6. Giovannoni G, et al. N Engl J Med. 2010;362(5):416-426.

20.  1 2  3 4 Proinflammatory cytokines Proinflammatory Th1 cells (MS-specific) × Anti-inflammatory Th2 cells (MS-specific) Anti-inflammatory cytokines Naïve T cells Neurotrophic factors

21. Interferons

22. Interferons • Interferon beta 1b • Betaseron SC (250 mcg) QOD • Extavia SC (250 mcg) QOD • Interferon beta 1a • Avonex IM (30 mcg) QW • Rebif SC (22 or 44 mcg) TIW

23. Interferons

24. gLATIRAMER

25. Copaxone SC (20mg) QD Proinflammatory cytokines Proinflammatory Th1 cells (MS-specific) Anti-inflammatory Th2 cells (MS-specific) Anti-inflammatory cytokines Naïve T cells Neurotrophic factors

26. Natalizumab

27. Tysabri IV (300mg) Q 4 weeks  Proinflammatory cytokines Proinflammatory Th1 cells (MS-specific) Anti-inflammatory Th2 cells (MS-specific) Anti-inflammatory cytokines Naïve T cells Neurotrophic factors

28. Fingolimod

29. Gilenya PO (0.5mg) QD Proinflammatory cytokines Proinflammatory Th1 cells (MS-specific) Anti-inflammatory Th2 cells (MS-specific) Anti-inflammatory cytokines Naïve T cells Neurotrophic factors

30. Teriflunomide

31. Aubagio® PO (7 or 14 mg) QD • Selective dihydro-orotatedehydrogenase (DHO-DH) inhibitor • Blocks de novo pyrimidine synthesis, reducing proliferation of autoreactive T- and B-cells • Preserves replication and function of cells (e.g., hematopoietic and memory T-cells) via salvage pathway • Reversed with cholestyramine O'Connor P, et al. Presented at: 26th Congress of the European Committee for Treatment and Research in Multiple Sclerosis; October 13-16, 2010; Gothenburg, Sweden. Platform Presentation 79.

32. Dimethyl fumarate(DMF / BG12)

33. Tecfidera® PO(240 mg) BID • Dimethylfumarate (DMF) • Rapidly metabolized to monomethylfumarate (active) • MOA • Release of transcription factor Nrf-2 from Keap-1 • Decrease in: inflammatory cytokines chemokines adhesion molecules (iCAM / vCAM) • Neuroprotection • Reduction of oxidative stress: • myelin • oligodendrocytes • axons • neurons

34. Emerging MS Therapies Alemtuzumab

35. Alemtuzumab (Lemtrada®) • Humanized monoclonal antibody to CD52 • Alters circulating lymphocyte pool • Prolonged T and B lymphocyte depletion • CD52 also expressed by monocytes, macrophages, NK cells, and some granulocytes • Indicated as a single agent for the treatment of B-cell chronic lymphocytic leukemia • Approved by the US Food and Drug Administration since May 2001 • Studied for use in MS since 1991 • Two Phase III trials have been completed, and regulatory filing was presented in 2012

36. Emerging MS Therapies Pegylated interferon

37. PEG Interferon (Plegridy®) • Pegylation allows lower administration frequency • Interferon beta 1a. • Results support use once every other week • Subcutaneous

38. Symptom management Visual Blurry vision Blindness Double vision Oscillopsia Bladder / bowel Frequency Urgency Incontinence • Motor / Gait • Weakness • Spasticity / contractures • Ataxia • Tremors • Sensory • Numbness • Paresthesias • Pain

39. Symptom management Symptoms Pain Trigeminal neuralgia Central neuropathic Musculoskeletal Bulbar Dysarthria Dysphagia Fatigue • Sexual • Erectile dysfunction • Painful intercourse • Inability to achieve climax • Decreased interest • Cognitive • Attention span • Concentration • Multitasking • Decision making

40. FatigueDepression Cognitive Function Exercise Sleep SpasticityConstipation BladderProblems Impact of MS Symptoms • Many MS symptoms are interrelated and interdependent: • One untreated symptom may trigger additional symptoms

41. Discussion & questions