1. Practical Issues in Multiple Sclerosis Practical Issues in Multiple Sclerosis Disease Overview and Current Perspectives on Patient Management The Science and Medicine of Multiple Sclerosis Kenneth P. Johnson, MD Professor of Neurology Director, Maryland Center for Multiple Sclerosis University of Maryland Medical Center Baltimore, MD

2. Learning Objectives 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 ● Sjögren syndrome ● Other CNS vasculitis ● Sarcoidosis ● Behçet disease  Metabolic –Vitamin B 12 and E deficiencies  CADASIL, other rare familial diseases  CNS lymphoma  Cervical spondylosis  Motor neuron disease  Myasthenia gravis Cohen J, Rensel M. In: Burks J, Johnson K, eds. Multiple Sclerosis: Diagnosis, Medical Management, and Rehabilitation. New York, NY: Demos; 2000:127-138.

4. Epidemiology of MS 1. NMSS. National Multiple Sclerosis Society Information Sourcebook: Epidemiology. Available at: http://www.nationalmssociety.org/sourcebook.asp. Accessed March 31, 2006. 2. Anderson DW et al. Ann Neurol. 1992;31:333-336. 3. Jacobsen DL et al. Clin Immunol Immunopathol. 1997;84:223-243. ► Patient characteristics ● 20 to 50 years of age 1 ● 70% are women 2 ► Incidence: 8,500 to 10,000 per year in US 3 ► Prevalence: 400,000 in US

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 1. Kurtzke JF. Neuroepidemiology. 1991;10:1-8. 2. Noseworthy JH et al. N Engl J Med. 2000;343:938-952. *>30 cases/100,000=high prevalence

6. Trapp BD et al. N Engl J Med. 1998;338:278-285. 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

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 Coyle P. In: Burks J, Johnson K, eds. Multiple Sclerosis: Diagnosis, Medical Management, and Rehabilitation. New York, NY: Demos; 2000:81-97.

8. Symptoms of MS Vision problems Paresthesias Pain Tremor, incoordination Gait problems, spasticity Speech, swallowing difficulties Fatigue Seizures Dizziness, vertigo Itching Depression Hearing loss Cognitive dysfunction Headache Bladder, bowel, sexual dysfunction Less Common Common NMSS. About MS: Symptoms. Available at: http://www.nationalmssociety.org/Symptoms.asp. Accessed March 31, 2006.

9. What Causes Demyelination and 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 CIS 1 ► 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 disability 2 1. Polman CH et al. Ann Neurol. 2005;58:840-846. 2. Brex PA et al. N Engl J Med. 2002;346:158-164.

11. Inflammatory White Matter Lesions Cause Relapses 5 10 Years 15 20

12. Types of Cortical Lesions Peterson JW, Kidd GJ, and Trapp BD. In: Waxman S, ed. Multiple Sclerosis as a Neurodegenerative Disease. 2005:165-184. Type I Lesion in white matter and cortex Type II Intracortical lesions Type III Lesions extending into the cortex from the pial surface

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. Brain Atrophy in MS MS18 MS09 Unpublished data.

15. Brain Atrophy and Its Measures 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. SPMS Disease Type and Disability Progression Time Adapted with permission from JS Wolinsky. Measures of brain volume Relapses and impairment MRI burden of disease MRI activity RRMSPreclinical Disability

17. Progression of Disability*: EDSS Score *Steps are variable. Confined to bed or wheelchair Walks with aid (<5 yards) Walks unaided (≥330-550 yards) Fully ambulatory Death

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.” NMSS. Disease Management Consensus Statement. Available at: http://www.nationalmssociety.org/Sourcebook- Early.asp. Accessed on November 29, 2006.

20. Immunotherapy of MS ► Selective immunomodulation ● Glatiramer acetate (Copaxone) ► Nonspecific immunomodulation ● IFN  -1a (Avonex, Rebif) ● IFN  -1b (Betaseron) ► Selective adhesion molecule inhibitor ● Natalizumab (Tysabri) ► Immunosuppression ● Mitoxantrone (Novantrone) ● Corticosteroids

21. Glatiramer Acetate: Potential Mechanisms of Action ► Blocks autoimmune T cells ► Induces anergy ► Induces anti-inflammatory T H 2 cells ► Induces bystander suppression ► Upregulates neuronal preservation ► Induction of regulatory T H 2 and T H 3 cells that penetrate CNS 1 ► Enhanced expression of BDNF, IL-10, TGF-β 2 ► Sustained augmentation of BDNF, NT-3, NT-4 in the brain 3 ► Augmentation of processes of neurogenesis: cell proliferation, migration, differentiation 4 1. Aharoni R et al. Proc Natl Acad Sci U S A. 2003;100:14157-14162. 2. Neuhaus O et al. Neurology. 2001;56:702-708. 3. Aharoni R et al. Proc Natl Acad Sci U S A. 2005;102:19045-19050. 4. Aharoni R et al. 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 Noseworthy JH et al. N Engl J Med. 2000;343:938-952. Yong VW. Neurology. 2002;59:802-808.

23. Natalizumab: Potential Mechanisms of Action ► Primary mechanism related to blockade of interaction between the  4  1-integrin and brain receptors ● VCAM-1 ► Alternative mechanisms ● Block VLA-4–fibronectin CS-1 interaction ● Block VLA-4 osteopontin interaction ● Inhibit antigen presentation

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 Glatiramer acetate 1 IM IFN  -1a 2 IFN  -1b 3 SC IFN  -1a 4 Natalizumab 5 011312111098765432 12+ years 2 years 5 years 4 years 2 years 54%* 47%* 1.3%* 77%* 91%* *Percent of patients completing the study. 1. Ford CC et al. Mult Scler. 2006;12:309-320. 2. Jacobs LD et al. Ann Neurol. 1996;39:285-294. 3. IFNB Multiple Sclerosis Study Group. Neurology. 1995;45:1277-1285. 4. PRISMS Study Group. Lancet. 1998;353:1498-1504. 5. Polman CH et al. N Engl J Med. 2006;354:899-910.

26. Data Summary: Long-Term Patients Reaching EDSS Score of 6 Study % Reached EDSS Score of 6 Years Studied Natural history cohort 1 50%15 Glatiramer acetate 2 8%10-12 SC IFN  -1a 3 20%7.4 IFN  -1b 4 (>80) 45%16 IM IFN  -1a 5 35%8 1.Weinshenker BG, Ebers SC. Can J Neurol Sci. 1987;14:255-261. 2. Ford CC et al. Mult Scler. 2006;12:309-320. 3. Kappos L et al. Neurology. 2006;67:944-953. 4. Ebers G et al. 57th AAN Meeting, 2005. 5. Fisher E et al. Neurology. 2002;59:1412-1420.

27. Direct-Comparison Trials

28. Adapted with permission from Panitch H et al. Neurology. 2002;59:1496-1506. EVIDENCE Trial IM IFN β-1a IFN β-1b 0 10 20 30 40 50 04812162024283238404448 Week Cumulative Probability of Patients Experiencing a Relapse (%)

29. Adapted with permission from Durelli L et al. Lancet. 2002;359:1453-1460. INCOMIN Study 0 10 20 30 40 50 60 70 80 90 100 0-67-1213-240-24 Proportion of Patients Relapse Free (%) P=0.23P=0.02 P=0.0013 5% 19% 47% P=0.036 42% IM IFN β-1a IFN β-1b

30. Berlin, Germany 24-Month Open-Label Comparison Adapted with permission from Haas J, Firzlaff M. Eur J Neurol. 2005;12:425-431. IM IFN β-1a SC IFN β-1b Glatiramer acetate SC IFN β-1a 22 μg 1.4 1.2 1.0 0.8 0.4 0.6 0.2 0.0 Before Study 6 Months 6 Months 12 Months 24 Months Mean Number of Relapses

31. Mikol D et al. Lancet Neurol 2008;7:903-914.

32. REGARD: Clinical Outcomes Mikol D et al. Lancet Neurol 2008;7:903-914.

33. REGARD: MRI Outcomes Mikol D et al. Lancet Neurol 2008;7:903-914.

34. REGARD STUDY: MRI Endpoint Change in Brain Volume p = 0.018 Weeks 0-48 Weeks 48-96 Weeks 0-96 Mikol D et al. Lancet Neurol 2008;7:903-914.

35. BEYOND : BE taseron Y ields O utcomes with N ew D ose

36. Randomized N=2,244 IFN β-1b 500 µg n = 899 IFN β-1b 250 µg n = 897 Glatiramer acetate n = 448 EOS reached 81% EOS reached 87% EOS reached 83% premature EOS 19% premature EOS 13% premature EOS 17% EOS = end of study Information presented during a European Charcot Foundation satellite symposium. November 29, 2007. Fiuggi, Italy. BEYOND: Study Design

37. BEYOND: No Group Differences with Respect to Demographics and Baseline Characteristics IFN β-1b 500 µg n = 899 IFN β-1b 250 µg n = 897 Glatiramer Acetate n = 448 Female sex 70%70%68% Age (years, mean) 35.935.835.2 Duration of disease (years, mean) 5.45.35.1 Number of relapses in previous year (mean) 1.61.61.6 EDSS at baseline (mean) 2.42.42.3 Volume of T2 lesions (cm 3, median) 6.05.7 5. 9 Volume of T1 lesions (cm 3, median) 0.50.60.6 Information presented during a European Charcot Foundation satellite symposium. November 29, 2007. Fiuggi, Italy.

38. BEYOND: Annualized Relapse Rate One Year Before and During Treatment -79% -78%-79% IFN β-1b 500 µg 0 0.5 1 1.5 2 Before (retrospective) During Annualized relapse rate Glatiramer Acetate IFN β-1b 250 µg Information presented during a European Charcot Foundation satellite symposium. November 29, 2007. Fiuggi, Italy.

39. BEYOND: Adherence and Tolerability ► No unexpected safety issues ► Discontinuation rate by study arm: ● IFN β-1b 250 mcg: 13% ● Glatiramer acetate: 17% ● IFN β-1b 500 mcg: 19% MedScape Web site. http://www.medscape.com/viewarticle/573185Accessed March 3, 2009.

40. Direct Comparison of Multiple Sclerosis Relapses and Total Medical Costs Over 2 Years: Glatiramer Acetate compared to IFN-β-1b, IFN-β-1a IM, and IFN-β-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-β-1b (n = 110) ● IFN-β-1a IM (n = 331) ● IFN-β-1a SC (n = 143) ● GA: (n = 308) - IFN-β-1b comparison (n = 308) - IFN-β-1b comparison (n = 308) - IFN-β-1a IM comparison (n = 308) - IFN-β-1a IM comparison (n = 267) - IFN-β-1a SC comparison (n = 267) - IFN-β-1a SC comparison Study Design Adapted from Johnson and Lage, ANA 2008; Castelli-Haley, CMSC 2008 and Castelli-Haley, E-ISPOR, 2008

42. Study Design ► Outcomes ● Costs Direct medical costs, including inpatient, outpatient, and prescription drug services. Direct medical costs, including inpatient, outpatient, and prescription drug services. Based upon paid amounts, including insurer and health plan payments, co-payments, and deductibles. 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). 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 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 Adapted from Johnson and Lage, ANA 2008; Castelli-Haley, CMSC 2008 and Castelli-Haley, E-ISPOR, 2008

43. Patient Disposition METINCLUSIONCRITERIA Diagnosis of MS in the i3 LabRx Database July 1, 2001 – June 30, 2006 (N = 51,162) Continuous Use of IFN-β-1b or GA for 24 months (n = 418) Users of IFN-β-1b (n = 1,550) IFN- β -1b (n = 110) GA (n = 308) Users of IFN-β-1a IM (n = 3,949) Continuous Use of IFN-β-1a IM or GA for 24 months (n = 639) Continuous Use of IFN-β-1a SC or GA for 24 months (n =410) Users of GA (n = 3,057) Users of IFN-β-1a SC (n = 1,188) Users of GA (n =2667) IFN-β-1a IM (n =331) IFN-β-1a SC (n =143) GA (n = 267) Users of GA (n = 3,057) GA (n = 308) Adapted from Johnson and Lage, ANA 2008; Castelli-Haley, CMSC 2008 and Castelli-Haley, E-ISPOR, 2008 IFN-β-1b IFN-β-1a IM IFN-β-1a SC

44. US Managed Care Database Analysis Percent of Patients per Drug per Region NortheastMidwestSouthWest IFNβ-1b8%38%44%10% IFNβ-1a IM10%35%42%12% IFNβ-1a SC13%48%28%11% GA12%39%34%15% Adapted from Johnson and Lage, ANA 2008; Castelli-Haley, CMSC 2008 and Castelli-Haley, E-ISPOR, 2008  All US regions were included in the database  There were no significant differences among immunomodulators in their regional distribution

45. Impact of Medication on Probability of Relapse during 2 Years of Continuous Use of Single Drug Adapted from Johnson and Lage, ANA 2008; Castelli-Haley, CMSC 2008 and Castelli-Haley, E-ISPOR, 2008 Continuous Use Cohorts % IFN-β-1b GA IFN-β-1a IMGA IFN-β-1a SC P=0.0018P=0.0048P=0.0049

46. Impact of Medication on Probability of Relapse during 2 Years of Continuous Use of Single Drug Adapted from Johnson and Lage, ANA 2008; Castelli-Haley, CMSC 2008 and Castelli-Haley, E-ISPOR, 2008 Continuous Use Cohorts $ IFN-β-1b GA IFN-β-1a IMGA IFN-β-1a SC P=0.0018P=0.0048P=0.0049 P < 0.05

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-β-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. Adapted from Johnson and Lage, ANA 2008; Castelli-Haley, CMSC 2008 and Castelli-Haley, E-ISPOR, 2008

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. Adapted from Johnson and Lage, ANA 2008; Castelli-Haley, CMSC 2008 and Castelli-Haley, E-ISPOR, 2008

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. Adapted from Johnson and Lage, ANA 2008; Castelli-Haley, CMSC 2008 and Castelli-Haley, E-ISPOR, 2008

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?) Bombardier C, Maetzel A Ann Rheum Dis 1999, 58:182-185

51. Human IgG4 Framework Complementarity-Determining Complementarity-DeterminingRegions(CDRs) Natalizumab: Humanized Monoclonal Antibody Against  4 Integrins ► CDR grafted from murine antibody ► Human IgG 4 framework ► Retains full potency Reprinted with permission from Dr. P Calabresi.

52. Selective Adhesion Molecule Inhibition: Implications for MS Therapy Reprinted with permission from Dr. P Calabresi.

53. Potential Mechanisms of Action of Natalizumab ► Primary mechanism related to blockade of interaction between the  4  1 integrin and brain receptors ● VCAM-1 ► Alternative mechanisms ● Block VLA-4–fibronectin CS-1 interaction ● Block VLA-4–osteopontin interaction ● Inhibit antigen presentation Rice GP, Hartung HP, Calabresi PA. Neurology. 2005;64(8):1336-42.12

54. Panzara M, et al. P488 Presented at WCTRIMS September 2008. Natalizumab Utilization and Safety in Patients with Relapsing MS: Updated Results from TOUCH and TIGIRS Number of Patients a) 13,900 treated for ≥ 1 year b) 6,600 treated for ≥ 18 months c) 31,800 patients receiving natalizumab worldwide d) 21,099 in TOUCH (median # of doses = 8) a b,c d

55. The Interferons and Glatiramer Acetate Delay the Risk of CDMS Study Conversion to CDMS in the Placebo Group CHAMPS50% ETOMS45% BENEFIT45% PreCISe41% Kappos L, et al. Neurology 2006; 67:1242-1249 Jacobs L, et al NEJM 2000;343:989-904 Comi G, et al. Lancet 2001;357:1576-1582 Comi G, et al. AAN Annual Meeting 2008

56. Partial List of MS Drugs Under Development Drug Monoclonal Antibody PhaseMOA 1.Alemtuzumab (Campath) (Campath)III Anti CD 52 2.Rituximab (Rituxan) (Rituxan)III B cell inhibitor Anti CD 20 3.Daclizumab (Zenapax) (Zenapax)II IL-2 receptor Antagonist 4.Ustekinumab CNTO 1275 CNTO 1275II Anti IL12/IL23

57. Partial List of MS Drugs Under Development Drug Oral PhaseMOACladribineIIIImmunosuppressant LaquinimodIIIImmunomodulator FTY-720 (fingolimod) (fingolimod)IIIImmunosuppressant BG12IIIImmunomodulator EstriolIII Estrogen agonist Other MBP 8298 III Altered Peptide Ligand TeriflunomideIIIImmunosuppressant

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