Practical Issues in Multiple Sclerosis Disease Overview and Current Perspectives on Patient Management

1. Practical Issues in Multiple Sclerosis Disease Overview and Current Perspectives on Patient Management

2. Learning Objectives Differentiate MS from other similar diagnostic possibilities Identify existing disease-modifying therapies for relapsing-remitting MS (RRMS) and differentiate them in terms of activity, efficacy, safety, and side effect profiles Define patient and disease variables that may alter management approaches

3. Differential Diagnosis of MS Infection Lyme disease Neurosyphilis PML, HIV, HTLV-1 Inflammatory SLE Sj�gren syndrome Other CNS vasculitis Sarcoidosis Beh�et disease

4. Epidemiology of MS Patient characteristics 20 to 50 years of age1 70% are women2 Incidence: 8,500 to 10,000 per year in US3 Prevalence: 400,000 in US Epidemiology of MS MS affects women primarily, although approximately 30% with MS are men.1 Its onset occurs between the ages of 20 and 50.2 The incidence or the number of new cases per year, of MS is between 8,500 and 10,000,3 and the prevalence, or total number of cases, is about 400,000 in the United States.2 References 1. Anderson DW, Ellenberg JH, Leventhal CM, Reingold SC, Rodriguez M, Silberberg DH. Revised estimate of the prevalence of multiple sclerosis in the United States. Ann Neurol. 1992;31:333-336. 2. National Multiple Sclerosis Society. National Multiple Sclerosis Society Information Sourcebook: Epidemiology. Available at: http://www.nationalmssociety.org/sourcebook.asp. Accessed March 31, 2006. 3. Jacobson DL, Gange SJ, Rose NR, Graham NM. Epidemiology and estimated population burden of selected autoimmune diseases in the United States. Clin Immunol Immunopathol. 1997;84:223-243.Epidemiology of MS MS affects women primarily, although approximately 30% with MS are men.1 Its onset occurs between the ages of 20 and 50.2 The incidence or the number of new cases per year, of MS is between 8,500 and 10,000,3 and the prevalence, or total number of cases, is about 400,000 in the United States.2 References 1. Anderson DW, Ellenberg JH, Leventhal CM, Reingold SC, Rodriguez M, Silberberg DH. Revised estimate of the prevalence of multiple sclerosis in the United States. Ann Neurol. 1992;31:333-336. 2. National Multiple Sclerosis Society. National Multiple Sclerosis Society Information Sourcebook: Epidemiology. Available at: http://www.nationalmssociety.org/sourcebook.asp. Accessed March 31, 2006. 3. Jacobson DL, Gange SJ, Rose NR, Graham NM. Epidemiology and estimated population burden of selected autoimmune diseases in the United States. Clin Immunol Immunopathol. 1997;84:223-243.

5. Worldwide Prevalence of MS Varies geographically High prevalence*1,2 Northern US and Canada Most of Europe Southern Australia New Zealand Northern Russia Southern South America Worldwide Prevalence of MS The prevalence of MS varies geographically. Kurtzke developed a classification system based on prevalence: low prevalence is less than 5 cases per 100,000 people; intermediate prevalence is 5 cases to 30 cases per 100,000; and high prevalence is more than 30 cases per 100,000.1 For reasons that are unclear, MS is more common in cooler climates and increases farther from the equator.1 The prevalence is highest in northern Europe, southern Australia, and the northern United States and Canada.2 There is a trend toward increasing prevalence and incidence in southern Europe.3,4 References1. Kurtzke JF. Multiple sclerosis: changing times. Neuroepidemiology. 1991;10:1-8. 2. Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG. Multiple sclerosis. N Engl J Med. 2000;343:938-952. 3. Rosati G, Aiello I, Pirastru MI, et al. Epidemiology of multiple sclerosis in Northwestern Sardinia: further evidence for higher frequency in Sardinians compared to other Italians. Neuroepidemiology. 1996;15:10-19. 4. Bufill E, Blesa R, Galan I, Dean G. Prevalence of multiple sclerosis in the region of Osona, Catalonia, northern Spain. J Neurol Neurosurg Psychiatry. 1995;58:577-581.Worldwide Prevalence of MS The prevalence of MS varies geographically. Kurtzke developed a classification system based on prevalence: low prevalence is less than 5 cases per 100,000 people; intermediate prevalence is 5 cases to 30 cases per 100,000; and high prevalence is more than 30 cases per 100,000.1 For reasons that are unclear, MS is more common in cooler climates and increases farther from the equator.1 The prevalence is highest in northern Europe, southern Australia, and the northern United States and Canada.2 There is a trend toward increasing prevalence and incidence in southern Europe.3,4 References1. Kurtzke JF. Multiple sclerosis: changing times. Neuroepidemiology. 1991;10:1-8. 2. Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG. Multiple sclerosis. N Engl J Med. 2000;343:938-952. 3. Rosati G, Aiello I, Pirastru MI, et al. Epidemiology of multiple sclerosis in Northwestern Sardinia: further evidence for higher frequency in Sardinians compared to other Italians. Neuroepidemiology. 1996;15:10-19. 4. Bufill E, Blesa R, Galan I, Dean G. Prevalence of multiple sclerosis in the region of Osona, Catalonia, northern Spain. J Neurol Neurosurg Psychiatry. 1995;58:577-581.

6. Pathology of MS An immune-mediated disease in genetically susceptible individuals Dual nature: inflammatory and neurodegenerative Demyelination leads to slower nerve conduction Axonal injury and destruction are associated with permanent neurological dysfunction Lesions occur in optic nerves, periventricular white matter, cerebral cortex, brain stem, cerebellum, and spinal cord Pathology of MS Inflammation leads to demyelination, the loss of the myelin sheath, which slows conduction along the nerve axon and leads to neurologic symptoms. When the inflammation deceases, the symptoms abate. However, there is evidence that the nerve axons are damaged due to MS and this damage is associated with permanent neurologic dysfunction.1 MS lesions occur in specific areas of the CNS (eg, the optic nerves, periventricular white matter, brain stem, cerebellum, spinal cord). A patient experiences symptoms related to the location of the lesions within the CNS. When acute inflammation decreases, symptoms remit partially or completely. Reference1. Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mork S, Bo L. Axonal transection in the lesions of multiple sclerosis. N Engl J Med. 1998;338:278-285.Pathology of MS Inflammation leads to demyelination, the loss of the myelin sheath, which slows conduction along the nerve axon and leads to neurologic symptoms. When the inflammation deceases, the symptoms abate. However, there is evidence that the nerve axons are damaged due to MS and this damage is associated with permanent neurologic dysfunction.1 MS lesions occur in specific areas of the CNS (eg, the optic nerves, periventricular white matter, brain stem, cerebellum, spinal cord). A patient experiences symptoms related to the location of the lesions within the CNS. When acute inflammation decreases, symptoms remit partially or completely. Reference1. Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mork S, Bo L. Axonal transection in the lesions of multiple sclerosis. N Engl J Med. 1998;338:278-285.

7. Basic Principles of Diagnosing MS Clinical diagnosis; no definitive laboratory test Clinical profile Laboratory evaluation Evidence of dissemination of lesions in space and time Exclusion of other diagnoses Basic Principles of Diagnosing MS MS is a clinical diagnosis; no definitive laboratory test exists.1 The clinical profile consists of symptomatic disease, abnormal examination, and white matter involvement, which are consistent with diagnosis.1 Laboratory evaluation includes MRI to identify lesions and CSF assessment for evidence of intrathecal inflammation.1 Abnormal CSF includes oligoclonal IgG bands in CSF, but not in serum and elevated IgG index. Additionally, evoked potentials may demonstrate evidence of altered conduction in a pattern consistent with demyelination. Evidence of dissemination of lesions in space and time is key to making the diagnosis; there must be at least 2 distinct attacks affecting at least 2 areas of the CNS.1-3 Evaluation should exclude other diagnoses, such as SLE, CNS tumors, vasculitis, and endocrine disturbances.1 Depending on the number of attacks and objective clinical evidence of lesions, MRI is used to assess lesion dissemination in space and time and disease progression. References1. Coyle P. Diagnosis and classification of inflammatory demyelinating disorders. In: Burks J, Johnson K, eds. Multiple Sclerosis: Diagnosis, Medical Management, and Rehabilitation. New York, NY: Demos; 2000:81-97.2. McDonald WI, Compston A, Edan G, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol. 2001;50:121-127.3. Polman CH, Reingold SC, Edan G, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the �McDonald Criteria.� Ann Neurol. 2005;58:840-846.Basic Principles of Diagnosing MS MS is a clinical diagnosis; no definitive laboratory test exists.1 The clinical profile consists of symptomatic disease, abnormal examination, and white matter involvement, which are consistent with diagnosis.1 Laboratory evaluation includes MRI to identify lesions and CSF assessment for evidence of intrathecal inflammation.1 Abnormal CSF includes oligoclonal IgG bands in CSF, but not in serum and elevated IgG index. Additionally, evoked potentials may demonstrate evidence of altered conduction in a pattern consistent with demyelination. Evidence of dissemination of lesions in space and time is key to making the diagnosis; there must be at least 2 distinct attacks affecting at least 2 areas of the CNS.1-3 Evaluation should exclude other diagnoses, such as SLE, CNS tumors, vasculitis, and endocrine disturbances.1 Depending on the number of attacks and objective clinical evidence of lesions, MRI is used to assess lesion dissemination in space and time and disease progression. References1. Coyle P. Diagnosis and classification of inflammatory demyelinating disorders. In: Burks J, Johnson K, eds. Multiple Sclerosis: Diagnosis, Medical Management, and Rehabilitation. New York, NY: Demos; 2000:81-97.2. McDonald WI, Compston A, Edan G, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol. 2001;50:121-127.3. Polman CH, Reingold SC, Edan G, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the �McDonald Criteria.� Ann Neurol. 2005;58:840-846.

8. Symptoms of MS

9. What Causes Demyelinationand Axonal Loss in MS? Activation of autoreactive CD4+ T cells in peripheral immune system Migration of autoreactive lymphocytes across the BBB into CNS In situ reactivation by myelin autoantigens Activation of macrophages, B cells Secretion of proinflammatory cytokines, chemokines, and antibodies Focal inflammation, demyelination, axonal transection, degeneration

10. Use of MRI in Diagnosis MRI improves confidence in a clinical diagnosis of MS or makes a diagnosis of MS in CIS1 May show dissemination in space and time(e.g., new lesions on follow-up MRI)1 Total lesion load at diagnosis tends to be predictive of future disability2

11. Relapses are caused by inflammatory white matter (WM) lesions. Lesions exceed relapses by as much as 10 to 1. Disability depends on whether lesion hits an articulate region of the WM. Panel A shows T2 lesion burden; Panel B shows Gd-enhanced lesions, which are relatively new and an indication of ongoing disease activity.Relapses are caused by inflammatory white matter (WM) lesions. Lesions exceed relapses by as much as 10 to 1. Disability depends on whether lesion hits an articulate region of the WM. Panel A shows T2 lesion burden; Panel B shows Gd-enhanced lesions, which are relatively new and an indication of ongoing disease activity.

12. Type I lesion is in WM and cortex. Type II lesions are small perivascular lesions. Type III lesions are waves of demyelination that extend from the pial surface and stop at cortical layer 3 or 4. References Peterson JW, Bo L, Mork S, Chang A, Trapp BD. Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions. Ann Neurol. 2001;50:389-400. Peterson JW, Kidd GJ, and Trapp BD. Axonal degeneration in multiple sclerosis: the histopathological evidence. In: Waxman S, ed. Multiple Sclerosis as a Neurodegenerative Disease. 2005:165-184.Type I lesion is in WM and cortex. Type II lesions are small perivascular lesions. Type III lesions are waves of demyelination that extend from the pial surface and stop at cortical layer 3 or 4. References Peterson JW, Bo L, Mork S, Chang A, Trapp BD. Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions. Ann Neurol. 2001;50:389-400. Peterson JW, Kidd GJ, and Trapp BD. Axonal degeneration in multiple sclerosis: the histopathological evidence. In: Waxman S, ed. Multiple Sclerosis as a Neurodegenerative Disease. 2005:165-184.

13. Cortical MS Lesions Significant in most MS brains Hypocellular compared with WM lesions May not be associated with BBB breakdown Cause neuritic transection and neuronal loss Contribute to neurological disability in MS patients Urgent need for noninvasive methods to detect cortical MS lesions

14. These are MRIs (FLAIR) of brain atrophy in patients with MS. BPF on the left is 0.805; BPF on the right is 0.663.These are MRIs (FLAIR) of brain atrophy in patients with MS. BPF on the left is 0.805; BPF on the right is 0.663.

15. Brain Atrophy and Its Measures What is brain atrophy? Brain parenchyma loss is a global process; occurs in MS patients up to 0.5%/y-1.0%/y; pathological parenchyma loss exceeds this rate ? Size of lateral ventricles, CSF spaces ? Anterior-posterior diameter of cervical spinal cord, corpus callosum Appears to correlate with disability Timing Begins as early as disease manifestation; appears essential to study effect of treatments in controlled clinical trials of long duration

16. Disease Type and Disability Progression

18. Goals of MS Therapy Affect the neurodegenerative and inflammatory components Early intervention; initiate therapy as soon as possible for the best chance of controlling damage Reduction of disease activity measured by relapses, MRI findings, and disability Provision of therapy that is well tolerated and safe

19. National Multiple Sclerosis Society Disease Management Consensus Statement �Initiation of therapy with an immunomodulator is advised as soon as possible following a definite diagnosis of MS with a relapsing course and may be considered for selected patients with a first attack who are high risk for MS.�

20. Immunotherapy of MS Selective immunomodulation Glatiramer acetate (Copaxone) Nonspecific immunomodulation IFN b-1a (Avonex, Rebif) IFN b-1b (Betaseron) Selective adhesion molecule inhibitor Natalizumab (Tysabri) Immunosuppression Mitoxantrone (Novantrone) Corticosteroids Immunotherapy of MS Immunomodulators may be classified as selective or nonspecific; immunosuppressants are indiscriminate downregulators of the complete immune system. The immunotherapeutic agents approved by the FDA for RRMS treatment are glatiramer acetate (Copaxone), a specific immunomodulator1; three IFN drugs, IFN �-1b (Betaseron), IFN �-1a (Avonex, Rebif), and natalizumab (Tysabri), nonspecific immunomodulators2,3; mitoxantrone (Novatrone), an antineoplastic agent indicated for MS, PRMS, and worsening RRMS4; and corticosteroids, used to improve the rate of recovery from acute relapses.5 There are no drugs indicated for PPMS. References 1. Copaxone [package insert]. Kansas City, MO: Teva Neuroscience, Inc; 2006. 2. Ann Marrie R, Ruddick RA. Drug Insight: interferon treatment in multiple sclerosis. Nat Clin Pract Neurol. 2006;2:34-44. 3. Tysabri [package insert]. San Diego, CA: Elan Pharmaceuticals, Inc; 2006. 4. Novantrone [package insert]. Rockland, MA: Serono Inc; 2006. 5. Filippini G, Brusaferri F, Sibley WA, et al. Corticosteroids or ACTH for acute exacerbations in multiple sclerosis. Cochrane Database Syst Rev. 2000;4:CD001331.Immunotherapy of MS Immunomodulators may be classified as selective or nonspecific; immunosuppressants are indiscriminate downregulators of the complete immune system. The immunotherapeutic agents approved by the FDA for RRMS treatment are glatiramer acetate (Copaxone), a specific immunomodulator1; three IFN drugs, IFN �-1b (Betaseron), IFN �-1a (Avonex, Rebif), and natalizumab (Tysabri), nonspecific immunomodulators2,3; mitoxantrone (Novatrone), an antineoplastic agent indicated for MS, PRMS, and worsening RRMS4; and corticosteroids, used to improve the rate of recovery from acute relapses.5 There are no drugs indicated for PPMS. References 1. Copaxone [package insert]. Kansas City, MO: Teva Neuroscience, Inc; 2006. 2. Ann Marrie R, Ruddick RA. Drug Insight: interferon treatment in multiple sclerosis. Nat Clin Pract Neurol. 2006;2:34-44. 3. Tysabri [package insert]. San Diego, CA: Elan Pharmaceuticals, Inc; 2006. 4. Novantrone [package insert]. Rockland, MA: Serono Inc; 2006. 5. Filippini G, Brusaferri F, Sibley WA, et al. Corticosteroids or ACTH for acute exacerbations in multiple sclerosis. Cochrane Database Syst Rev. 2000;4:CD001331.

21. Glatiramer Acetate:Potential Mechanisms of Action Blocks autoimmune T cells Induces anergy Induces anti-inflammatory TH2 cells Induces bystander suppression Upregulates neuronal preservation Induction of regulatory TH2 and TH3 cells that penetrate CNS1 Enhanced expression of BDNF, IL-10, TGF-�2 Sustained augmentation of BDNF, NT-3, NT-4 in the brain3 Augmentation of processes of neurogenesis: cell proliferation, migration, differentiation4 Potential Mechanisms of Action of Glatiramer Acetate The putative mechanisms of action of glatiramer acetate incorporate the following processes1-4: Glatiramer acetate avidly binds to major histocompatibility complex (MHC) class II molecules on APCs. This complex competes with myelin basic protein (MBP) and other myelin-associated proteins (ie, proteolipid protein, myelin oligodendrocyte glycoprotein) for binding to APCs. Binding to the APCs induces activation of glatiramer acetate-specific myelin cross-reactive T cells. These activated regulatory T cells may cross the BBB for reactivation in situ by MBP or other myelin antigens. This reactivation inhibits antigen-specific effector functions, such as proliferation and production of proinflammatory TH1 cytokines. The reactivation induces a bystander suppressive effect via anti-inflammatory TH2 cytokines. These actions arrest or slow disease activity. References 1. Aharoni R, Kayhan B, Eilam R, Sela M, Arnon R. Glatiramer acetate-specific T cells in the brain express T helper 2/3 cytokines and brain-derived neurotrophic factor in situ. Proc Nat Acad Sci U S A. 2003;100:14157-14162. 2. Aharoni R, Eilam R, Domev H, Labunskay G, Sela M, Arnon R. The immunomodulator glatiramer acetate augments the expression of neurotrophic factors in brains of experimental autoimmune encephalomyelitis mice. Proc Natl Acad Sci U S A. 2005;102:19045-19050. 3. Neuhaus O, Farina C, Wekerle H, Hohlfeld R. Mechanisms of action of glatiramer acetate in multiple sclerosis. Neurology. 2001;56:702-708. 4. Aharoni R, Arnon R, Eilam R. Neurogenesis and neuroprotection induced by peripheral immunomodulatory treatment of experimental autoimmune encephalomyelitis. J Neurosci. 2005;25:8217-8228.Potential Mechanisms of Action of Glatiramer Acetate The putative mechanisms of action of glatiramer acetate incorporate the following processes1-4: Glatiramer acetate avidly binds to major histocompatibility complex (MHC) class II molecules on APCs. This complex competes with myelin basic protein (MBP) and other myelin-associated proteins (ie, proteolipid protein, myelin oligodendrocyte glycoprotein) for binding to APCs. Binding to the APCs induces activation of glatiramer acetate-specific myelin cross-reactive T cells. These activated regulatory T cells may cross the BBB for reactivation in situ by MBP or other myelin antigens. This reactivation inhibits antigen-specific effector functions, such as proliferation and production of proinflammatory TH1 cytokines. The reactivation induces a bystander suppressive effect via anti-inflammatory TH2 cytokines. These actions arrest or slow disease activity. References 1. Aharoni R, Kayhan B, Eilam R, Sela M, Arnon R. Glatiramer acetate-specific T cells in the brain express T helper 2/3 cytokines and brain-derived neurotrophic factor in situ. Proc Nat Acad Sci U S A. 2003;100:14157-14162. 2. Aharoni R, Eilam R, Domev H, Labunskay G, Sela M, Arnon R. The immunomodulator glatiramer acetate augments the expression of neurotrophic factors in brains of experimental autoimmune encephalomyelitis mice. Proc Natl Acad Sci U S A. 2005;102:19045-19050. 3. Neuhaus O, Farina C, Wekerle H, Hohlfeld R. Mechanisms of action of glatiramer acetate in multiple sclerosis. Neurology. 2001;56:702-708. 4. Aharoni R, Arnon R, Eilam R. Neurogenesis and neuroprotection induced by peripheral immunomodulatory treatment of experimental autoimmune encephalomyelitis. J Neurosci. 2005;25:8217-8228.

22. IFN-?: Potential Mechanisms of Action Induces an antiproliferative effect Blocks T cell activation Induces apoptosis of autoreactive T cells IFN-? antagonistic Induces cytokine shifts Has antiviral effect Acts in periphery (ie, does not cross BBB) Indirect effects on CNS

23. Natalizumab:Potential Mechanisms of Action Primary mechanism related to blockade of interaction between the ?4b1-integrin and brain receptors VCAM-1 Alternative mechanisms Block VLA-4�fibronectin CS-1 interaction Block VLA-4 osteopontin interaction Inhibit antigen presentation Potential Mechanisms of Action of Natalizumab The presumed MOA for natalizumab involves blockade of the molecular interaction between the ?4�1-integrin expressed by inflammatory cells and VCAM-1 at the BBB.1 It is likely that other actions play a role as well. Other proposed MOAs include Blocking VLA-4 antigen from binding to fibronectin CS-1, a surface protein Blocking VLA-4 from binding to osteopontin, a protein expressed by brain parenchymal cells Inhibiting antigen presentation1-3 References 1. Tysabri [package insert]. San Diego, CA: Elan Pharmaceuticals; 2006. 2. Rice GP, Hartung HP, Calabresi PA. Anti-alpha4 integrin therapy for multiple sclerosis: mechanisms and rationale. Neurology. 2005;64:1336-1342. 3. Mould AP, Askari JA, Craig SE, Garratt AN, Clements J, Humphries MJ. Integrin alpha 4 beta 1-mediated melanoma cell adhesion and migration on vascular cell adhesion molecule-1 (VCAM-1) and the alternatively spliced IIICS region of fibronectin. J Biol Chem. 1994;269:27224-27230.Potential Mechanisms of Action of Natalizumab The presumed MOA for natalizumab involves blockade of the molecular interaction between the ?4�1-integrin expressed by inflammatory cells and VCAM-1 at the BBB.1 It is likely that other actions play a role as well. Other proposed MOAs include Blocking VLA-4 antigen from binding to fibronectin CS-1, a surface protein Blocking VLA-4 from binding to osteopontin, a protein expressed by brain parenchymal cells Inhibiting antigen presentation1-3 References 1. Tysabri [package insert]. San Diego, CA: Elan Pharmaceuticals; 2006. 2. Rice GP, Hartung HP, Calabresi PA. Anti-alpha4 integrin therapy for multiple sclerosis: mechanisms and rationale. Neurology. 2005;64:1336-1342. 3. Mould AP, Askari JA, Craig SE, Garratt AN, Clements J, Humphries MJ. Integrin alpha 4 beta 1-mediated melanoma cell adhesion and migration on vascular cell adhesion molecule-1 (VCAM-1) and the alternatively spliced IIICS region of fibronectin. J Biol Chem. 1994;269:27224-27230.

24. MS Trials Short-term, class I placebo-controlled studies (�2 years) do not guarantee long-term effectiveness Neutralizing antibodies Intolerable side effects Change from RRMS to SPMS Safety issues Unknown factors Ethical considerations of placebo-controlled trials

25. Prospective RRMS Pivotal Trial Durations

26. Data Summary: Long-Term Patients Reaching EDSS Score of 6

27. Direct-Comparison Trials

28. EVIDENCE Trial EVIDENCE Trial The most effective dose regimen for IFN � remains controversial. To shed light on this issue, the EVIDENCE trial randomized 677 patients with RRMS to receive SC IFN �-1a 44 �g 3 times weekly or IM IFN �-1a 30 �g once weekly.1 Over 24 weeks, 75% of the SC IFN �-1a group and 63% of the IM IFN �-1a group remained relapse free. The odds ratio was 1.9 (95% CI, 1.3-2.6; P=0.0005), indicating a relative increase of 90% in the odds of remaining relapse free for patients receiving high-dose SC IFN �-1a as opposed to lower-dose IM IFN �-1a. Over 48 weeks, 62% of the SC IFN �-1a group and 52% of the IM IFN �-1a group remained relapse free. The odds ratio was 1.5 (95% CI, 1.1-2.1; P=0.009), indicating a relative increase of 50% in the odds of remaining relapse free for patients receiving SC IFN �-1a compared with IM IFN �-1a. Patients receiving SC IFN �-1a had fewer active lesions on MRI assessments (P<0.001 at Weeks 24 and 48). Reference 1. Panitch H, Goodin DS, Francis G, et al. Randomized, comparative study of interferon �-1a treatment regiments in MS. The EVIDENCE trial. Neurology. 2002;59:1496-1506.EVIDENCE Trial The most effective dose regimen for IFN � remains controversial. To shed light on this issue, the EVIDENCE trial randomized 677 patients with RRMS to receive SC IFN �-1a 44 �g 3 times weekly or IM IFN �-1a 30 �g once weekly.1 Over 24 weeks, 75% of the SC IFN �-1a group and 63% of the IM IFN �-1a group remained relapse free. The odds ratio was 1.9 (95% CI, 1.3-2.6; P=0.0005), indicating a relative increase of 90% in the odds of remaining relapse free for patients receiving high-dose SC IFN �-1a as opposed to lower-dose IM IFN �-1a. Over 48 weeks, 62% of the SC IFN �-1a group and 52% of the IM IFN �-1a group remained relapse free. The odds ratio was 1.5 (95% CI, 1.1-2.1; P=0.009), indicating a relative increase of 50% in the odds of remaining relapse free for patients receiving SC IFN �-1a compared with IM IFN �-1a. Patients receiving SC IFN �-1a had fewer active lesions on MRI assessments (P<0.001 at Weeks 24 and 48). Reference 1. Panitch H, Goodin DS, Francis G, et al. Randomized, comparative study of interferon �-1a treatment regiments in MS. The EVIDENCE trial. Neurology. 2002;59:1496-1506.

29. INCOMIN Study INCOMIN Study In the 24-month prospective INCOMIN study, 188 patients with RRMS were randomized to receive IM IFN �-1a or SC IFN �-1b.1 The relative difference in the proportion of patients free from relapse was marginal during the first 6 months; 19% higher in the IFN �-1b group during the second 6 months; and 47% higher in this group during the second year. Overall, 42% more patients remained relapse free with SC IFN �-1b than with IM IFN �-1a in the 24-month study (P<0.036). Reference 1. Durelli L, Verdun E, Barbero P, et al. Every-other-day interferon beta-1b versus once-weekly interferon beta-1a for multiple sclerosis: results of a 2-year prospective randomised multicentre study (INCOMIN). Lancet. 2002;359:1453-1460.INCOMIN Study In the 24-month prospective INCOMIN study, 188 patients with RRMS were randomized to receive IM IFN �-1a or SC IFN �-1b.1 The relative difference in the proportion of patients free from relapse was marginal during the first 6 months; 19% higher in the IFN �-1b group during the second 6 months; and 47% higher in this group during the second year. Overall, 42% more patients remained relapse free with SC IFN �-1b than with IM IFN �-1a in the 24-month study (P<0.036). Reference 1. Durelli L, Verdun E, Barbero P, et al. Every-other-day interferon beta-1b versus once-weekly interferon beta-1a for multiple sclerosis: results of a 2-year prospective randomised multicentre study (INCOMIN). Lancet. 2002;359:1453-1460.

30. Berlin, Germany24-Month Open-Label Comparison 24-Month Open-Label Comparison Data from a nonrandomized open-label study1 show the ARRs (arithmetic mean and SEM) for 4 immunomodulators after Months 6, 12, and 24. For all groups, changes in relapse rates at Months 6, 12, and 24 improved (P<0.05) compared with rates before the study. Reference1. Haas J, Firzlaff M. Twenty-four month comparison of immunomodulatory treatments�a retrospective open label study in 308 RRMS patients treated with beta interferons or glatiramer acetate (Copaxone�). Eur J Neurol. 2005;12:425-431.24-Month Open-Label Comparison Data from a nonrandomized open-label study1 show the ARRs (arithmetic mean and SEM) for 4 immunomodulators after Months 6, 12, and 24. For all groups, changes in relapse rates at Months 6, 12, and 24 improved (P<0.05) compared with rates before the study. Reference1. Haas J, Firzlaff M. Twenty-four month comparison of immunomodulatory treatments�a retrospective open label study in 308 RRMS patients treated with beta interferons or glatiramer acetate (Copaxone�). Eur J Neurol. 2005;12:425-431.

32. REGARD: Clinical Outcomes

33. REGARD: MRI Outcomes

34. REGARD STUDY: MRI Endpoint Change in Brain Volume

35. BEYOND: BEtaseron Yields Outcomes with New Dose

37. BEYOND: No Group Differences with Respect toDemographics and Baseline Characteristics

38. BEYOND: Annualized Relapse Rate One Year Before and During Treatment

39. BEYOND: Adherence and Tolerability No unexpected safety issues Discontinuation rate by study arm: IFN �-1b 250 mcg: 13% Glatiramer acetate: 17% IFN �-1b 500 mcg: 19%

40. Direct Comparison of Multiple Sclerosis Relapses and Total Medical Costs Over 2 Years: Glatiramer Acetate compared to IFN-�-1b, IFN-�-1a IM, and IFN-�-1a SC

41.  Data Direct analysis of insurance claims for patients taking either interferon-beta or glatiramer acetate. Outcomes data from a health-claims database, i3 LabRx, which contains laboratory test results, hospitalization and pharmacy data, and demographic information for more than 20 million de-identified individuals from a major US managed care organization. Data for multiple sclerosis spanned the period from July 1, 2001 through June 30, 2006. Continuous Use (CU) Cohorts of patients on individual DMT for at least 24 months IFN-�-1b (n = 110) IFN-�-1a IM (n = 331) IFN-�-1a SC (n = 143) GA: (n = 308) - IFN-�-1b comparison (n = 308) - IFN-�-1a IM comparison (n = 267) - IFN-�-1a SC comparison

42. Study Design Outcomes Costs Direct medical costs, including inpatient, outpatient, and prescription drug services. Based upon paid amounts, including insurer and health plan payments, co-payments, and deductibles. All costs converted to 2006 values (medical component of the Consumer Price Index). Relapse Defined as either a hospitalization with a primary diagnosis of MS or an outpatient visit with a diagnosis of MS accompanied by a prescription for steroids within 7 days after the outpatient visit.14 Regression Analyses Logistic regression analyses were used to examine the impact of immunomodulatory therapy on the probability of relapse in the 24 month study period. Ordinary least squares regression analyses were used to examine the impact of specific MS therapy on costs, using the log of costs as the dependent variable. All regressions controlled for the independent variables listed in Table 1 and were conducted using SAS version 9.1.Regression Analyses Logistic regression analyses were used to examine the impact of immunomodulatory therapy on the probability of relapse in the 24 month study period. Ordinary least squares regression analyses were used to examine the impact of specific MS therapy on costs, using the log of costs as the dependent variable. All regressions controlled for the independent variables listed in Table 1 and were conducted using SAS version 9.1.

43. Patient Disposition Inclusion Criteria: MS Diagnosis (ICD 9 Code 340.xx) First date of drug use between March 28, 2002 and July 1, 2004 Continuous insurance coverage 6 months prior through 24 months after first drug code Inclusion Criteria: MS Diagnosis (ICD 9 Code 340.xx) First date of drug use between March 28, 2002 and July 1, 2004 Continuous insurance coverage 6 months prior through 24 months after first drug code

44. US Managed Care Database Analysis

45. Impact of Medication on Probability of Relapse during 2 Years of Continuous Use of Single Drug

46. Impact of Medication on Probability of Relapse during 2 Years of Continuous Use of Single Drug

47. Results For the Continuous Use cohorts, the risk of relapse in the 2 years after medication initiation is significantly lower for patients on GA vs. on an interferon. In the Continuous Use cohorts, the 2-year total direct medical costs with GA use are significantly lower than those using an interferon. Prior research found lower annual costs associated with GA than with IFN-�-1b. This study relied on data collected throughout the United States. Practicing physicians made all treatment decisions free of influence by drug company sponsored studies or known bias. Prescott JD, Factor S, Pill M, Levi GW. Descriptive analysis of the direct medical costs of multiple sclerosis in 2004 using administrative claims in a large nationwide database. J Manag Care Pharm. 2007 Jan-Feb;13(1):44-52. Prescott JD, Factor S, Pill M, Levi GW. Descriptive analysis of the direct medical costs of multiple sclerosis in 2004 using administrative claims in a large nationwide database. J Manag Care Pharm. 2007 Jan-Feb;13(1):44-52.

48. Limitations Analysis was done on an administrative claims database and included only patients with medical and prescription benefit coverage. Studies used different method of defining relapses than traditional clinical studies; however the algorithm used to define relapses was applied equally to all treatment groups. The use of medical claims data precludes the use of physician or patient-reported functioning. The studies focused only on direct medical costs. Other research has indicated that indirect costs (worker productivity, lost work days) from MS are also large. Kobelt G, Berg J, Atherley D, Hadjimichael O. Costs and quality of life in multiple sclerosis: a cross-sectional study in the US. Neurology 2006;66:1696-1702. Whetten-Goldenstein K, Sloan FA, Goldenstein LB, Kulas ED. A comprehensive assessment of the cost of multiple sclerosis in the United States. Multiple Sclerosis 4 (1998), 419-425. Kobelt G, Berg J, Atherley D, Hadjimichael O. Costs and quality of life in multiple sclerosis: a cross-sectional study in the US. Neurology 2006;66:1696-1702. Whetten-Goldenstein K, Sloan FA, Goldenstein LB, Kulas ED. A comprehensive assessment of the cost of multiple sclerosis in the United States. Multiple Sclerosis 4 (1998), 419-425.

49. Conclusion This outcomes multivariate analysis indicates that patients with MS who use glatiramer acetate have significantly lower chances of relapse and significantly lower two-year direct medical costs than patients who use beta interferon. These data represent practicing physicians� treatment decisions nationwide and do not rely on drug company sponsored clinical studies. Analysis includes the broad range of treated MS patients in the U.S. rather than narrowly defined cohorts from clinical trials. These studies probably best mirror unbiased clinical and cost related outcomes of MS treatment in the U.S.

50. Pharmacoeconomic Evaluation of New Treatments: Efficacy versus Effectiveness Current pivotal phase III trials ��.. are designed to test safety and efficacy (does the drug work under optimal circumstances?) and not to answer questions about the effectiveness of a drug ��..(does the drug work in usual care?)

51. Natalizumab: Humanized Monoclonal Antibody Against ?4 Integrins CDR grafted from murine antibody Human IgG4 framework Retains full potency

52. Selective Adhesion Molecule Inhibition: Implications for MS Therapy

53. Potential Mechanisms of Action of Natalizumab Primary mechanism related to blockade of interaction between the ?4b1 integrin and brain receptors VCAM-1 Alternative mechanisms Block VLA-4�fibronectin CS-1 interaction Block VLA-4�osteopontin interaction Inhibit antigen presentation The presumed MOA for natalizumab involves blockade of the molecular interaction between the ?4�1 integrin expressed by inflammatory cells and VCAM-1 at the BBB.1 It is likely that other MOAs play a role as well. Other proposed mechanisms of action include the following:1-3 Blocking very late activation antigen (VLA)-4 from binding to fibronectin CS-1, a surface protein Blocking VLA-4 from binding to osteopontin, a protein expressed by brain parenchymal cells Inhibition of antigen presentation References1. Tysabri [package insert]. San Diego, CA: Elan Pharmaceuticals, Inc; 2006. 2. Rice GP, Hartung HP, Calabresi PA. Anti-alpha4 integrin therapy for multiple sclerosis: mechanisms and rationale. Neurology. 2005;64:1336-1342. 3. Mould AP, Askari JA, Craig SE, Garratt AN, Clements J, Humphries MJ. Integrin alpha 4 beta 1-mediated melanoma cell adhesion and migration on vascular cell adhesion molecule-1 (VCAM-1) and the alternatively spliced IIICS region of fibronectin. J Biol Chem. 1994;269:27224-27230.The presumed MOA for natalizumab involves blockade of the molecular interaction between the ?4�1 integrin expressed by inflammatory cells and VCAM-1 at the BBB.1 It is likely that other MOAs play a role as well. Other proposed mechanisms of action include the following:1-3 Blocking very late activation antigen (VLA)-4 from binding to fibronectin CS-1, a surface protein Blocking VLA-4 from binding to osteopontin, a protein expressed by brain parenchymal cells Inhibition of antigen presentation References1. Tysabri [package insert]. San Diego, CA: Elan Pharmaceuticals, Inc; 2006. 2. Rice GP, Hartung HP, Calabresi PA. Anti-alpha4 integrin therapy for multiple sclerosis: mechanisms and rationale. Neurology. 2005;64:1336-1342. 3. Mould AP, Askari JA, Craig SE, Garratt AN, Clements J, Humphries MJ. Integrin alpha 4 beta 1-mediated melanoma cell adhesion and migration on vascular cell adhesion molecule-1 (VCAM-1) and the alternatively spliced IIICS region of fibronectin. J Biol Chem. 1994;269:27224-27230.

55. The Interferons and Glatiramer Acetate Delay the Risk of CDMS

56. Partial List of MS Drugs Under Development

57. Partial List of MS DrugsUnder Development

58. Summary Understanding of multiple sclerosis is expanding rapidly yet remains incomplete Current therapies provide clinically equivalent benefit but glatiramer acetate is best tolerated New era emerged with natalizumab when risk vs. benefit ratio required consideration Numerous new therapies in Phase III trials. Practice decisions may become more complicated