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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

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Practical Issues in Multiple Sclerosis

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  1. 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. 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 Learning Objectives

  3. Infection Lyme disease Neurosyphilis PML, HIV, HTLV-1 Inflammatory SLE Sjögren syndrome Other CNS vasculitis Sarcoidosis Behçet disease Differential Diagnosis of MS • Metabolic • Vitamin B12 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. 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 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. ClinImmunolImmunopathol. 1997;84:223-243.

  5. 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 *>30 cases/100,000=high prevalence • Kurtzke JF. Neuroepidemiology.1991;10:1-8. • 2. Noseworthy JH et al. N Engl J Med. 2000;343:938-952.

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

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

  9. 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 What Causes Demyelinationand Axonal Loss in MS?

  10. 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 Use of MRI in Diagnosis 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. 20 10 5 15 Years Inflammatory White Matter Lesions Cause Relapses

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

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

  14. Brain Atrophy in MS MS09 MS18 Unpublished data.

  15. 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 Brain Atrophy and Its Measures

  16. Measures of brain volume SPMS Relapses and impairment MRI burden of disease MRI activity Preclinical RRMS Disability Disease Type and Disability Progression Time Adapted with permission from JS Wolinsky.

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

  18. 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 Goals of MS Therapy

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

  20. 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

  21. 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-β2 Sustained augmentation of BDNF, NT-3, NT-4 in the brain3 Augmentation of processes of neurogenesis: cell proliferation, migration, differentiation4 Glatiramer Acetate:Potential Mechanisms of Action 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. 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 IFN-: Potential Mechanisms of Action Noseworthy JH et al. N Engl J Med. 2000;343:938-952. Yong VW. Neurology. 2002;59:802-808.

  23. 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 Natalizumab:Potential Mechanisms of Action

  24. 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 MS Trials

  25. 0 1 2 3 4 5 6 7 8 9 10 11 12 13 Prospective RRMS Pivotal Trial Durations Glatiramer acetate1 12+ years 47%* IM IFN -1a2 2 years 54%* IFN -1b3 1.3%* 5 years SC IFN -1a4 77%* 4 years Natalizumab5 91%* 2 years *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 1. Weinshenker BG, Ebers SC. Can J Neurol Sci. 1987;14:255-261. 2. Ford CC et al. MultScler. 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. 50 IM IFN β-1a IFN β-1b 40 30 Cumulative Probability of Patients Experiencing a Relapse (%) 20 10 0 0 4 8 12 16 20 24 28 32 38 40 44 48 Week EVIDENCE Trial Adapted with permission from Panitch H et al. Neurology. 2002;59:1496-1506.

  29. INCOMIN Study IM IFN β-1a IFN β-1b 100 P=0.23 P=0.02 19% 90 5% P=0.0013 80 47% 70 P=0.036 60 Proportion of Patients Relapse Free (%) 42% 50 40 30 20 10 0 0-6 7-12 13-24 0-24 Adapted with permission from Durelli L et al. Lancet. 2002;359:1453-1460.

  30. Glatiramer acetate IM IFN β-1a 1.4 SC IFN β-1a 22 μg 1.2 SC IFN β-1b 1.0 0.8 Mean Number of Relapses 0.6 0.4 0.2 0.0 Before Study 6 Months 12 Months 24 Months Berlin, Germany24-Month Open-Label Comparison Adapted with permission from Haas J, Firzlaff M. Eur J Neurol. 2005;12:425-431.

  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 Weeks 0-48 Weeks 48-96 Weeks 0-96 p = 0.018 Mikol D et al. Lancet Neurol 2008;7:903-914.

  35. BEYOND: BEtaseronYields Outcomes with New Dose

  36. BEYOND: Study Design Randomized N=2,244 IFN β-1b500 µg n = 899 IFN β-1b250 µg n = 897 Glatiramer acetate n = 448 premature EOS 19% premature EOS 13% premature EOS 17% EOS reached 81% EOS reached 87% EOS reached 83% EOS = end of study Information presented during a European Charcot Foundation satellite symposium. November 29, 2007. Fiuggi, Italy.

  37. BEYOND: No Group Differences with Respect toDemographics and Baseline Characteristics 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 IFN β-1b 500 µg IFN β-1b 250 µg Glatiramer Acetate 2 1.5 Annualized relapse rate 1 -79% -79% -78% 0.5 0 Before (retrospective) During Information presented during a European Charcot Foundation satellite symposium. November 29, 2007. Fiuggi, Italy.

  39. No unexpected safety issues Discontinuation rate by study arm: IFN β-1b250 mcg: 13% Glatiramer acetate: 17% IFN β-1b 500 mcg: 19% BEYOND: Adherence and Tolerability 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-1a IM 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. 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 Study Design Adapted from Johnson and Lage, ANA 2008; Castelli-Haley, CMSC 2008 and Castelli-Haley, E-ISPOR, 2008

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

  44. US Managed Care Database Analysis • All US regions were included in the database • There were no significant differences among immunomodulators in their regional distribution Adapted from Johnson and Lage, ANA 2008; Castelli-Haley, CMSC 2008 and Castelli-Haley, E-ISPOR, 2008

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

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

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

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

  49. 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. Conclusion 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

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