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  • These data are from the placebo arms of several major clinical trials in MS. The graph shows the percentage of patients with residual disability of 0.5 or 1.0 on the EDSS scale at different time points following a relapse. As you can see, over 40% of patients who had a relapse also had a 0.5-point increase in their EDSS score, which was still present >3 months after the relapse. This means that, following an exacerbation of MS, a persistent progression in disability is apparent in a significant portion of patients. It is hoped that effective prevention of MS relapses will result in preservation of MS patients’ functional ability.
  • This slide demonstrates that what we measure by MRI correlates with future disability. If you can prevent these lesions from building up, you can prevent disability progression. These data comes from a study entitled, “A Longitudinal Study of Abnormalities on MRI and Disability from Multiple Sclerosis.” This study explored the association between changing burden of disease and later progressive disease. Twenty-eight patients with clinically probable or definite multiple sclerosis were followed for 14 years after first onset of symptoms. T2 lesion loads were estimated soon after symptom onset and 14 years later. Patients with a higher T2 lesion volume at presentation tended to have a worse EDSS score 14 years later.
  • M-GA 20mg Induction with open-label IV infusion of Mitoxantrone 12mg/m2 at months 0,1,and 2 for a cumulative dose of 36mg/m2 2 week washout Daily GA 20mg SC therapy for 12.5 months + extension GA 20mg Alone Daily GA 20mg SC therapy for 15 months + extension
  • Graphical representation of the data can be made once the numerical values are presented at the AAN
  • Formula for determining when to switch is unproven. Suggested might be any 3 lows, 2 mediums or 1 high, but this would need to be validated.
  • Correct answer is A
  • Correct answer is D

Transcript

  • 1.  
  • 2. New Perspectives on the Pathogenesis of MS Douglas S. Goodin, MD Professor of Neurology Director, Multiple Sclerosis Center University of California, San Francisco
  • 3. Pathogenesis of Multiple Sclerosis Clinical Course Fauci AS. In: Harrison's Internal Medicine, 17th edition. McGraw Hill;2007, with permission from McGraw Hill. RR MS Disability Time Disability Time SP MS Disability Time PP MS RP MS Disability Time
  • 4. Pathogenesis of Multiple Sclerosis Epidemiology Compston A, et al. McAlpine’s Multiple Sclerosis, 4 th ed. Churchill Livingston, London. 2006. Predominantly Caucasian Ethnic origin 20–40 years Age at onset 70%–75% female Sex distribution 5–200/100,000 population Prevalence
  • 5. SLIDE NOT AVAILABLE
  • 6. Pathogenesis of Multiple Sclerosis LFB Stain (Myelin Pathology) LFB = Luxol fast blue. Reprinted from Patrikios P, et al. Brain . 2006;129:3165-3172, with permission from Oxford Journals.
  • 7. Pathogenesis of Multiple Sclerosis In Vivo Pathology (MRI) Courtesy of Douglas S. Goodin, MD.
  • 8. Pathogenesis of Multiple Sclerosis Evidence for Axonal Transection (Axon Bulbs) Doinikow B. Z Gesamt Neurol Psych . 1915;27:151. Reprinted from Trapp BD, et al. N Engl J Med. 1998:338:278. Copyright © 1998. Massachusetts Medical Society. All rights reserved .
  • 9. Pathogenesis of Multiple Sclerosis Microscopic Pathology Courtesy of D.P. Agamanolis, MD. http://neuropathology.neoucom.edu.
  • 10. MOG M Φ I I Type I Lesions Complement M Φ Type II Lesions MOG M Φ Type III Lesions LFB MOG MAG CNPase/ DNA frag Type IV Lesions Similar Except Complement Pathogenesis of Multiple Sclerosis Histopathology Reprinted from Lucchinetti C, et al. Ann Neurol . 2000;47:707, with permission from John Wiley & Sons.
  • 11. Pathogenesis of Multiple Sclerosis Evidence for Genetic and Environmental Basis
    • An individual in the general population (from northern Europe/northern North America) has a lifetime risk of MS of approximately 0.1%–0.2% 1
    • Risk in an individual with an affected family member is increased, roughly in proportion to the degree of shared genetic information 1-5
    • In an identical twin, the relative risk approaches 200 times that in the general population (~ 25%) 1,2,4,5
    • Multiple genes must be involved in susceptibility
    • Environmental factors must also be involved in disease pathogenesis
    1. Compston A, et al. McAlpine’s Multiple Sclerosis, 4 th ed. Churchill Livingston, London. 2006. 2. Ebers GC, et al. Nature. 1995;377:150-151. 3. Sadovnick AD, et al . Lancet. 1996;347:1728-1730. 4. Nielsen NM, et al. Am J Epidemiol. 2005;162:873-874. 5. Compston A, Coles A. Lancet. 2002;359:1221-1231.
  • 12. Timing of Environmental Events New Perspectives
  • 13. Pathogenesis of Multiple Sclerosis Timing of Environmental Events
    • If several environmental events are necessary for MS to develop in an individual, then it is only natural to enquire as to :
      • how many such events are necessary and
      • whether it is important for these events to occur at any particular time or in any particular order
    • 3 pieces of MS epidemiologic evidence bear on these issues
    Courtesy of Douglas S. Goodin, MD.
  • 14. Pathogenesis of Multiple Sclerosis Timing of Environmental Events
    • First, there seems to be a maternal parent of origin effect in MS. Evidence for this includes
      • When half-sibs are concordant for MS, the shared parent is almost twice as likely to be the mother 1,2
      • The concordance rate for MS in full sibs is less than the rate in dizygotic twins 3,4
      • Significantly more MS patients were born in May and fewer in November 5,6
      • Moreover, this may be flipped in the southern hemisphere 5
    • These observations imply an early environmental event (time-locked to the solar cycle), which acts either in utero or in the early postnatal period
    1. Sadovnick AD, et al. Lancet. 1996;347:1728-1730. 2. Ebers GC, et al. Lancet .2004;363:1773-1774. 3. Willer CJ, et al. Proc Natl Acad Sci (U S A). 2003;100:12877-12882. 4. Compston A, Coles A. Lancet. 2002;359:1221-1231. 5. Willer CJ, et al. Br Med J. 2005;330:120. 6. Sadovnick AD, et al. Neurology. 2007;69:60-62.
  • 15. Pathogenesis of Multiple Sclerosis Timing of Environmental Events
    • Second, when individuals migrate (prior to ~15 years) from a region of high MS prevalence to one of low prevalence (or vice versa), they seem to adopt a prevalence similar to that of the region to which they moved.
    • By contrast, when they make the same move after the age 15, they seem to retain the risk of the region from which they moved
    • These observations point to an important environmental event after birth but prior to young adulthood (~15 years)
    1. Dean G, Kurtzke JF. BMJ. 1971;3:725-729. 2. Alter M, et al. Neurol. 1978;28:1089-1093. 3. Elian M, et al. J Neurol Neurosurg Psychiatr . 1990;53:906-911. 4. Kahana E, et al. J Neurol. 1994;241:341-346. 5. Cabre P, et al. Brain. 2005;128:2899-2910.
  • 16. Pathogenesis of Multiple Sclerosis Timing of Environmental Events
    • Third, the onset of clinical symptoms in MS is generally delayed by many years (often decades) after these critical early events (<15 years) have already taken place 1-6
    • This delay implies that some subsequent environmental event or events (i.e., after age 15) are also necessary for disease pathogenesis or, at least, symptomatic onset
    1. Compston A, et al. McAlpine’s Multiple Sclerosis, 4 th ed. Churchill Livingston, London: 2006. 2. Dean G, et al. BMJ. 1971;3:725-729. 3. Alter M, et al. Neurol. 1978;28:1089-1093. 4.Elian M, et al. J Neurol Neurosurg Psychiatr. 1990;53:906;-911. 5. Kahana E, et al. J Neurol. 1994;241:341-346. 6. Cabre P, et al. Brain. 2005;128:2899-2910.
  • 17. Pathogenesis of Multiple Sclerosis Timing of Environmental Events
    • In summary, there seems to be clear epidemiologic evidence for the operation of at least 3 distinct environmental events in MS Pathogenesis
    • The 1 st operates in either in utero or in the early postnatal period
    • The 2 nd operates beginning sometime after birth and continues to operate until the age of ~15 years
    • The 3 rd (which may be multiple) operates in adulthood, often long after the 1 st and 2 nd event have already taken place
  • 18. Pathogenesis of Multiple Sclerosis Micro-Environmental Effects
    • Several studies of the micro-environment (ie, the environment in which a person grows up and lives) have shown that:
      • MS risk is unchanged in adoptees, conjugal couples, individuals of different birth order, and in siblings and half-siblings raised together or apart
    • Thus, these studies suggest that micro-environmental influences (either as an adult or as a child) do not contribute significantly to MS risk
    • Consequently, it seems that, whatever the important environmental factors are, they act at a population level
    1. Sadovnick AD, et al. Lancet. 1996;347:1728-1730. 2. Ebers GC, et al. Lancet. 2004; 363:1773-1774. 3. Ebers GC, et al. Ann Neurol. 2000;48:927-931. 4. Sadovnick AD, et al. Lancet Neurol. 2005;4:611-617. 5. Dyment DA, et al. J Neurol Neurosurg Psychiatry. 2006;77:258-259.
  • 19. Pathogenesis of Multiple Sclerosis Environmental Factors
    • Many environmental factors have been proposed. Two currently popular candidates for involvement in MS pathogenesis are:
          • EBV infection
          • Vitamin D deficiency
  • 20. Pathogenesis of Multiple Sclerosis Indirect Evidence for EBV
    • Late EBV infection is associated with MS
    • Symptomatic mononucleosis is associated with MS
  • 21. Pathogenesis of Multiple Sclerosis Evidence for EBV in Adult MS Courtesy of Douglas S. Goodin, MD. ns 693/702 (98.7) 234/234 (100) Sundström, 2004 .05 252/261 (96.6) 136/136 (100) Ponsonby, 2005 p < 10 -23 2267/2406 (94.2) 1741/1749 (99.5) Total .05 50/53 (94.3) 153/153 (100) Haahr, 2004 .008 269/287 (93.7) 143/144 (99.3) Ascherio, 2001 .01 153/163 (93.9) 107/107 (100) Wagner, 2000 .008 162/170 (95.3) 144/144 (100) Myhr, 1998 .0004 124/138 (89.9) 137/138 (99.3) Munch, 1998 - 24/26 (92.3) 26/26 (100) Shirodaria, 1987 .007 23/26 (88.5) 104/104 (100) Sumaya, 1985 .0001 78/93 (83.9) 93/93 (100) Larson, 1984 .0001 363/406 (89.4) 309/313 (98.7) Bray, 1983 .05 76/81 (93.8) 155/157 (98.7) Sumaya, 1980 P Value EBV+ Controls (%) EBV+ MS Cases (%) Study
  • 22. Pathogenesis of Multiple Sclerosis Worldwide Prevalence of MS Reprinted from Kurtzke JF. Acta Neurol Scandinav. 1980;62:65-80, with permission from Blackwell Synergy.
  • 23. SLIDE NOT AVAILABLE
  • 24. Pathogenesis of Multiple Sclerosis Indirect Evidence for Vitamin D
    • Latitude gradient for UVB is strikingly similar to MS prevalence 1
    • Coastal regions of Norway had less MS than inland areas 2 (? consumption of fish)
    • Inuit and Sami (very low MS) consume vitamin D in their diet 2
    • No impact on MS from micro-environmental influences, suggesting a population-wide exposure 3-5
    • No convincing case of MS prior to 1822  (~onset of industrial revolution in Europe) – indoor work, air pollution ( ↓ UVB)
    • The rate of skin cancer in MS patients is half that in controls; whereas, rates for other cancers are similar 6
    • There is an increasing use of sun-block and sun-avoidance ( ↓ UVB by >94% at SPF = 15) 7
    1. Compston A, et al. McAlpine’s Multiple Sclerosis, 4 th ed. Churchill Livingston, London: 2006. 2. Gillie O. Br J Dermatol. 2006;154:1052-1061. 3. Ebers GC, et al. Ann Neurol. 2000;48:927-931. 4. Sadovnick. Lancet Neurol. 2005; 4:611-617. 5.Bager P, et al. Am J Epidemiol. 2006;163:1112-1117. 6. Goldacre MJ, et al. J Epidemiol Community Health. 2004;58:1032-1035. 7. Emmons KM, Colditz GA. J Natl Cancer Inst. 1999;91:1269-1270.
  • 25. Pathogenesis of Multiple Sclerosis Direct Evidence for Vitamin D
    • Munger et al. followed >185,000 women, interviewed about their diet. The highest quintile for total vitamin D consumption had significantly less new-onset MS compared with lowest quintile 1
    • Van der Mei et al. studied past sun exposure in MS patients and controls from Tasmania. There was a significant negative association between total sun exposure during childhood (especially in those 6–10 year old) and adolescence and the subsequent development of MS 2,3
    • Munger et al. utilized stored serum samples from 257 MS patients (US Military). The risk of MS was significantly decreased with increasing serum 25(OH) D 3 levels prior to the clinical onset of their illness 4
    1. Munger KL, et al. Neurology. 2004;62:60-65. 2. Van der Mei IA, et al. J Neurol. 2007;254:581-590. 3. Van der Mei IA, et al. BJM. 2003;327:316. 4. Munger KL, et al. JAMA . 2006;296:2832-2838.
  • 26. Pathogenesis of Multiple Sclerosis EBV and Vitamin D
    • It is not necessary, however, to decide between the vitamin D and EBV hypotheses. In fact, both factors represent population-wide exposures and both may be critical to MS pathogenesis
      • For example, we have already seen evidence that at least 3 environmental factors must be involved
        • Vitamin D and EBV may be 2 of them
  • 27. Pathogenesis of Multiple Sclerosis EBV and Vitamin D
    • Because EBV infection does not typically occur in utero or in the early postpartum period, this agent unlikely to be the 1 st environmental factor
    • EBV would seem to be better suited as a candidate for the 2 nd factor, which must begin to act sometime after birth and must continue to act until the age of ~15 years
    • By contrast, vitamin D is a much better candidate for the 1 st environmental factor
      • It is known to be involved in immune development and maturation
      • Vitamin D deficiency is associated with autoimmunity
      • Vitamin D production is coupled to the solar cycle
      • There are interactions between the physiologic effects of vitamin D and gender in utero
  • 28. SLIDE NOT AVAILABLE
  • 29. SLIDE NOT AVAILABLE
  • 30. SLIDE NOT AVAILABLE
  • 31. SLIDE NOT AVAILABLE
  • 32. SLIDE NOT AVAILABLE
  • 33. SLIDE NOT AVAILABLE
  • 34. SLIDE NOT AVAILABLE
  • 35. Conclusions
    • Pathogenesis of MS involves complex interactions between genetic and environmental factors
    • Multiple genes are involved
    • Timing of environmental factors is important
      • The 1 st event: in utero or early postnatal period
      • The 2 nd event: after birth to age 15
      • The 3 rd event: in adulthood (may be several)
    • Vitamin D deficiency is a plausible candidate for the 1 st factor; EBV infection is a plausible candidate for the 2 nd factor
    • MS incidence has increased over the past 30 years due to a change in environmental exposure
  • 36. Goals of Optimal Therapy Bruce A. Cohen, MD Professor Davee Department of Neurology Feinberg School of Medicine Northwestern University Chicago, Illinois
  • 37. Therapeutic Goals in MS
    • Prevent disability
    • Prevent relapses
    • Relieve symptoms
    • Maintain well-being
    • Optimize quality of life
    An effective therapy administered early in the disease course can impact all of these goals
  • 38. Relationship Between Relapses and Disability
    • Key question in MS therapeutics
    • Relapses and enhancing MRI lesions are more common early in the disease
    • Relapses decrease over time yet disability worsens 1
    • Current MS therapeutics suppress relapses and enhancing lesions on MRI better than they prevent progressive disability later in the disease course
    • Can optimal early therapy prevent later disability in MS?
    1. Patzold U, Pocklington PR. Acta Neurol Scand. 1982;65:248-266.
  • 39. Natural History of MS Clinical and MRI Measures Time Preclinical MRI Activity Relapses/Disability MRI T2 Burden of Disease Axonal Loss Disability Reprinted from Trapp BD, et al. Neuroscientist. 1999;5:48-57, with permission from Sage Publications. Relapsing-Remitting MS Secondary Progressive MS CIS *
  • 40. Relationship Between Relapses and Disability
    • Loss of axons and neurons considered the substrate of disability in MS
    • Axonal damage has been shown to occur in acute inflammatory plaques 1
    • Axonal damage could be the result of
      • Cumulative inflammatory damage over time
      • A parallel degenerative process related to loss of trophic support or an independent axonal degeneration 2
    • Can effective immune therapy early in MS prevent worsening disability?
    1. Trapp BD, et al. N Engl J Med. 1998;338:278-285. 2. Trapp BD. Neuroscientist. 1999;5:48-57.
  • 41. Persistent Disability After MS Relapses 27 29 30 42 44 41 0 5 10 15 20 25 30 35 40 45 50 30–59 60–89 90+ Days Since Exacerbation Percentage of Patients  1 point a  .5 point Reprinted from Lublin FD, et al. Neurology . 2003;61:1528-1532, with permission from Lippincott, Williams & Wilkins. a Extended Disability Status Scale (EDSS) N=62 N=85 N=77
  • 42. Does Therapy that Reduces Relapses Prevent Disability?
    • IFN β therapy in mild relapsing-remitting multiple sclerosis (RRMS) reduced the risk of Extended Disability Status Scale (EDSS) worsening compared with placebo 1
    • IFN β therapy in RRMS associated with reduced relapses and MRI activity 2
    • IFN β given for 4 years reduced the risk of EDSS progression compared with placebo for 2 years followed by IFN β for 2 years 2
    • IFN β therapy at clinically isolated syndrome (CIS) reduced the risk of subsequent EDSS worsening over 3 years 3
    • However, relapses did not affect the rate of worsening from EDSS scores of 4 – 6 in a French cohort 4 and the authors concluded that relapses do not significantly influence the progression of irreversible disability
    1. Jacobs LD, et al. Ann Neurol. 1996;39:285-294. 2. PRISMS Study Group. Neurology. 2001;56:1628-1636. 3. Kappos L, et al. Lancet. 2007;370:389-397. 4. Confavreux C, et al. N Engl J Med. 2000;343:1430-1438.
  • 43. T2 Burden at CIS Presentation Predicts Later Disability CIS = clinically isolated syndrome; EDSS = Extended Disability Status Scale; MRI = magnetic resonance imaging. Brex PA, et al. N Engl J Med . 2002;346:158-164. 0 1 2 3 4 5 6 7 Median T2-Weighted MRI Lesion Volume (cm 3 )/number at CIS presentation Median EDSS Score at Year 14 0.6 1-3 0 0 0.9 4-10 5.6 >10
  • 44. Dissociation Between Changes in T2 Lesion Burden and EDSS Over Time r = 0.35 P = .02 Brex PA, et al. N Engl J Med. 2002;346:158-164. The mechanisms underlying the observed relation between clinical and MRI data are uncertain. n = 66 n = 66 n = 57 n = 57 n = 45 n = 45 r = correlation coefficient (cm 3 ) r = 0.58 P <.001 r = 0.41 P = .002
  • 45. SLIDE NOT AVAILABLE
  • 46. SLIDE NOT AVAILABLE
  • 47. Measurement of Disability—EDSS
    • 10-step scale of function
    • Steps 0–4 defined by number of neurologic symptoms affected and estimated severity
    • Steps 4.5–8.0 defined by mobility and distance walked
    • Step 10 (death) is rated most consistently across examiners
    Kurtzke JF. Neurology .1983;33:1444-1452.
  • 48. Residual Impairment in MS The Problem of Measurement
    • Current clinical measurement tools are relatively crude
    • These tools emphasize motor changes
    • Limited assessment of cognitive functions
    • Do not discriminate among subtle influences on endurance and fatigability
    • Conventional MRI tools are most useful for prognosis in early stages
    • More-sensitive imaging tools detect change in areas that appear normal on current MRI
  • 49. Patterns of Cortical Activation Functional MRI Reprinted from Rocca MA, et al. Ann Neurol. 2002;51:330-339, with permission from John Wiley & Sons. Healthy Volunteers MS Patients
  • 50. fMRI Measures of Adaptation—Cerebral Reserve?
    • Patients with MS and no detectable disability demonstrate increased cortical activation patterns in maintaining simple task performance when compared with normal subjects
      • MS patients within 3 years of diagnosis
      • Multiple Sclerosis Functional Composite (MSFC) scores comparable in subjects and controls
    • Suggests that recruitment of additional neural elements, ie, network expansion, allows the maintenance of “normal” function
    Staffen W, et al. Brain. 2002;125:1275-1282.
  • 51. fMRI Measures of Adaptation—Cerebral Reserve?
    • CIS patients tested within 3 months of presentation show increased cortical activation on a simple repetitive finger flexion-extension motor task (unaffected by their CIS) compared with normal controls
    • Relative activation of the contralateral SMC correlates with decreased WBNAA levels measured with HMRS 1 (r = - 0.78, P <.001)
    • Demonstrates relationship between axonal pathology and recruitment within a network, suggesting adaptations to limit the functional impact from the axonal damage
    CIS = clinically isolated syndrome; SMC = sensorimotor cortex; WBNAA = whole-brain N-acetylaspartate; HMRS = proton magnetic resonance imaging. 1. Rocca MA, et al. Neuroimage. 2003;18:847-855.
  • 52. Relationship between Relapses and Disability—The Cerebral Reserve Hypothesis
    • Early damage in MS is compensated for by expansion of neural networks maintaining performance by our measures for a time: reflecting a cerebral reserve capacity
    • When a critical threshold is exceeded, persistent deficits measurable by EDSS or other performance measures occur
    • Further worsening may result from
      • Cumulative effects of temporally remote injuries
      • Metabolic stress on surviving neurons and axons due to changes in trophic factors and increased performance demands
      • Local pathologic processes within the CNS microenvironment set in motion by earlier pathology
    Courtesy of Bruce A. Cohen, MD.
  • 53. Implications of the Hypothesis
    • Early onset of effective MS immune therapy can alter long-term natural history
    • Since individuals may differ in their response to a particular agent, optimal therapy requires monitoring effectively for a suboptimal response
    • Even with such a strategy, some individuals may do poorly because of factors that favor a more severe disease course and which are not amenable to current therapies
    • Expansion of the therapeutic armamentarium and investigation of potential synergies based on mechanisms of action may further optimize treatment results, particularly when applied in early MS
    Courtesy of Bruce A. Cohen, MD.
  • 54. Suboptimal Response to MS Therapy Potential Causes
    • Nonadherence
    • Pharmacogenomics: responsiveness to IFN β related to single-nucleotide polymorphism frequencies 1
    • Variable pathologies with differing responses to immune therapies
    • Dosage of an agent 2
    • Need for more intense or broader spectrum of immune therapies
    • NAbs
    • Too late in the course of disease
    1. Byun E, et al. Arch Neurol. 2008;65:337-344. 2. Schwid SR, et al. Arch Neurol. 2005;62:785-792.
  • 55. Conclusions
    • To date, treatment has been successful in suppressing relapses and enhancing MRI lesions
    • Early damage in MS appears to be compensated for by expansion of neural networks (“cerebral reserve”)
    • When this reserve is exceeded, persistent deficits result
    • Early treatment with effective immune therapy may alter the course of disease, preventing/ delaying later disability
  • 56. Current Therapies and Role of Emerging Small-Molecule Therapies in MS — E volving Strategies Bruce A.C. Cree, MD, PhD, MCR Assistant Professor of Neurology Multiple Sclerosis Center University of California, San Francisco San Francisco, California
  • 57. Current First-Line MS Therapies
    • Interferon beta-1b
    • 30 mcg Interferon beta-1a once weekly
    • Glatiramer acetate
    • 40 mcg Interferon beta-1a thrice weekly
    • Similar efficacy for relapse rate reduction ~ 30%
    • Generally very safe and well tolerated
    • All require self-injection
  • 58. Second Second-Line MS Therapies
    • Mitoxantrone
    • Natalizumab
    • Generally indicated for persons with suboptimal response to first-line agents
    • Require intravenous infusion
    • Associated with life-threatening adverse events
  • 59. MS Disease Process
    • Believed to be heterogeneous
    • Multiple damage mechanisms implicated
    • No therapy encompasses all these mechanisms
  • 60. MS Disease Pathology  4 Integrin VCAM B L O O D F L O W LUMEN OF VENULE B A S A L L A M I N A Circulation Activated T cell T CELL REACTIVATION IL-1, IL-12, chemokines Proteases TNF -  O 2 • - NO • Courtesy of Sergio Baranzini, PhD. Extravasation astrocytes BRAIN TISSUE M Y E L I N oligodendrocyte B cell Rolling Adhesion Proteases Antigen presenting cell (Astrocyte or Microglial cell) Activated microglia/macrophages Activated Macrophage Autoantibodies Complement Cytokines and chemokines AXONAL DAMAGE
  • 61. Oral MS Therapies in Phase III Development
    • Fingolimod
    • Fumarate
    • Teriflunomide
    • Laquinimod
    • Cladribine
  • 62. Proof of Concept Phase II Study Design Months Gad + MRI Scans Active Treatment High Dose Primary outcome measure = cumulative number of gadolinium-DPTA enhanced lesions over 6 months Active Treatment Low Dose Placebo 0 1 2 3 4 5 6
  • 63. Fingolimod OH NH2 HO
  • 64. Fingolimod
    • Sphingosine-1-phosphate receptor modulator
    • Induces rapid and reversible sequestration of lymphocytes in lymph nodes
      • Prevents activated and autoreactive cells from migrating to target organs
    • Lymphocytes remain functional and may still be activated as part of an immune response
    • Crosses blood brain barrier and may have neuroprotective properties
    Brinkmann V, et al. J Biol Chem. 2002;277:21453-21457; Pinschewer DD, et al. J Immunol . 2000;164:5761-5770; Chiba K, et al. J Immunol . 1998;160:5037-5044.
  • 65. Fingolimod Primary Endpoint 16 12 8 4 0 Cumulative Gad+ Lesion (No. per patient) 14.8 8.4 5.7 Placebo (n = 81) Fingolimod 1.25 mg (n = 83) Fingolimod 5 mg (n = 77) 43% P <0.001 61% P <0.006 Adapted from Kappos L, et al. N Engl J Med. 2006;355:1124-1140. Copyright ©2006. Massachusetts Medical Society. All rights reserved.
  • 66. Fingolimod—Long-Term Relapse Rate and MRI Activity (N = 173) a Received 1.25 mg only. b Initially treated with 5.0 mg; dose reduced to 1.25 mg between months 18 and 24. ARR = annualized relapse rate. Comi G, et al. 60 th Annual Meeting AAN 2008; April 12-19, 2008. Abstract S12.005. 173/250 (69%) 189/250 (76%) No subjects retained (%) 75% — No new/newly enlarging T2 lesions since month 24 89% 84% Free of gad-enhanced MRI lesions 73% 68% — Relapse-free 0.21 0.20 0.22 0.20 ARR 5/1.25 mg b 1.25 mg a 5/1.25 mg b 1.25 mg a Month 36 Month 24
  • 67. Fingolimod in MS Conclusions
    • Treatment with fingolimod reduced disease activity
      • MRI activity reduced by up to 61% 1
      • Relapses reduced by >55% 1
      • Up to 73% relapse-free at 36 months 2
      • 89% free of GAD+ MRI lesions at 36 months 2
    • Treatment generally well tolerated 1,2
      • Adverse events were dose dependent and reversible
      • Seven skin cancers including 2 malignant melanomas 2
    • Phase III trials are actively recruiting, expected to conclude late 2010, launch in 2011
    1. Kappos L, et al. N Engl J Med. 2006;355:1124-1140. 2. Comi G, et al. 60th AAN Meeting 2008; April 12-19, 2008. Abstract S12.005.
  • 68. Fumarate O O O O O O O O
  • 69. Fumaric Acid Esters
    • Derived from common fumitory ( Fumaria officinalis ), a plant rich in fumaric acid
    • Used to treat skin disorders since the 17th century
    • Fumaric acid esters used in severe psoriasis
      • First reported by Schweckendiek in 1959
    • Inhibits T-cell activity
      • Induction of activated lymphocyte apoptosis
      • Shift in cytokine profile from Th1 to Th2
    • Effective in chronic experimental autoimmune encephalomyelitis
    • May have neuroprotective properties by activating antioxidant response genes
    Schilling S, et al. Clin Exp Immunol. 2006;145:101-107.
  • 70. Fumarate Phase II Results
    • The 720-mg group had a 69% reduction ( P <0.001) in the mean number of new gadolinium-enhancing lesions vs placebo as measured monthly from weeks 12–24 of the study
    • There was a non-statistically significant trend favoring treatment for relapse reduction by 32% ( P =0.272)
    • The 120-mg and 360-mg treated groups were not statistically significant vs placebo on any endpoints
    Kappos L, et al. 22nd ECTRIMS 2006; September 27-30, 2006. Poster P325. Kappos L et al. 59 th AAN 2007. Boston, Mass. Abstract P06.086.
  • 71. Fumarate Conclusions
    • Fumarate reduced the cumulative number of Gad+ lesions, with a trend toward reduced relapses
    • Adverse effects profile favorable with discontinuations due to nausea, flushing, headache, nasopharingitis (known effects in psoriasis)
    • Phase III trials are actively recruiting, completion expected in 2011, launch in 2012
  • 72. Teriflunomide O N H N F F F OH H 3 C
  • 73. Teriflunomide
    • Leflunomide parent compound used in treatment of rheumatoid arthritis
    • Inhibits pyrimidine synthesis
      • Binds dihydroorotate dehydrogenase, the fourth enzyme in de novo pyrimidine synthesis
    • Inhibits T-cell division
    • Inhibits murine experimental autoimmune encephalomyelitis
    Zeyda M, et al. Arthritis Rheum. 2005;52:2730-2739.
  • 74. Teriflunomide Phase II Primary Outcome 61%, P <0.03 O’Connor PW, et al. Neurology. 2006;66:894-900.
  • 75. Teriflunomide Conclusions
    • Reduced cumulative number of Gad + lesions with favorable trends for relapse rate reduction and disability
    • Overall well tolerated with acceptable adverse effect profile
    • Teriflunomide is teratogenic in animals
    • Reproductive toxicity in humans is not fully understood
      • Women are advised not to become pregnant and men cautioned not to parent children while on therapy
    • Women who wish to become pregnant
      • Washout with cholestyramine or activated charcoal and confirmation of acceptable plasma levels of teriflunomide
      • Without washout up to 2 years before plasma levels decrease sufficiently
    • Phase III trials are actively recruiting, complete enrollment uncertain
    O’Connor PW, et al. Neurology. 2006;66:894-900.
  • 76. Laquinimod Cl OH O N O N CH 3 CH 3
  • 77. Laquinimod
    • Parent compound: roquinimex
      • Suppressed gadolinium-DPTA lesions in phase II/III studies
      • Study stopped due to serositis, myocardial infarction
    • Laquinimod developed to cause less inflammation in dog model
    • In murine experimental autoimmune encephalomyelitis (EAE), laquinimod
      • Suppresses development of EAE; 20x more potent than roquinimex
      • Shifts cytokine balance from Th1 to Th2
    Brunmark C, et al. J Neuroimmunol. 2002;130:163-172; Yang JS, et al. J Neuroimmunool. 2004;156:3-9.
  • 78. Laquinimod Phase IIb Results Comi G, et al. 59th AAN Meeting; April 28-May 5, 2007. Abstract S02.002. Courtesy of Bruce A.C. Cree, MD. Primary End Point: Weeks 24–36 Cumulative No. of Gad-Enhancing T1 Lesions P =0.005 vs placebo -1 4 9 14 19 24 Laquinimod 15.77 0.3 mg Laquinimod 10.53 0.6 mg 16.86 Placebo 0.3 mg Placebo 38% 0.6 mg Placebo
  • 79. Laquinimod Conclusions
    • Reduced the cumulative number of Gad+ lesions
    • No trend in favor of reductions in relapse rate and disability
    • Overall well tolerated without indication of systemic pro-inflammatory effects
    • Phase III trials are under way
  • 80. Cladribine O NH 2 Cl N N HO HO N N
  • 81. Cladribine
    • Cladribine is a purine nucleoside analog prodrug that is resistant to adenosine deaminase degradation and is activated by deoxycytidine kinase
      • Causes failure of DNA damage repair
      • Selective T lymphocyte depleting agent because of high levels of deoxycytidine kinase in T-cells
      • FDA approved for treatment of hairy-cell leukemia
      • Oral cladribine formulation is fast-tracked by the FDA
    • Phase II single center 52 patient study in RRMS
    Sipe JC. Expert Rev Neurother. 2005;5:721-727.
  • 82. Cladribine—RRMS Phase II Relapse Rate Placebo Cladribine 2.1 mg/kg 0 0.5 1 1.5 2 Baseline Months 7–18 P =0.011 32% Months 0–6 Relapses RRMS = relapsing-remitting multiple sclerosis. Adapted from Romine JS, et al. Proc Assoc Am Physicians . 1999;111:35-44, with permission from Blackwell Synergy.
  • 83. Cladribine Conclusions
    • Phase II study single-center, 52 patients 1,2
    • Cladribine was administered subcutaneously 1,2
    • 94% suppression of new enhancing lesions in cladribine group after month 6 ( P <0.001) 2
    • Well tolerated, can cause myelosuppression that is usually reversible 1,2
    • Phase III trial fully enrolled, completion in 12/2008; anticipate launch in 2009
    • Fast-tracked by FDA; expected to be 1st oral treatment for MS
    1. Romine JS, et al. Proc Assoc Am Physicians . 1999;111:35. 2. Sipe J, et al. 60th Annual Meeting AAN 2008; April 12-19, 2008. Abstract S02.004.
  • 84. Summary 1. Kappos L, et al. N Engl J Med. 2006;355:1124-1140. 2. O’Connor PW, et al. Neurology. 2006;66:894-900. 3. Comi G, et al. 59th AAN Meeting; April 28-May 5, 2007. Abstract S02.002. 4. Kappos L, et al. 22nd ECTRIMS 2006; September 27-30, 2006. Poster P325. 5. Romine JS, et al. Proc Assoc Am Physicians . 1999;111:35-44. 6. Sipe J, et al. 60th Annual Meeting AAN 2008; April 12-19, 2008. Abstract S02.004. -32%, NS -69%, P <0.001 Fumarate (720 mg) (4-arm study, N = 256) -32%, P =0.01 -94%, P <0.001 Cladribine (2.1 mg) (2-arm study, N = 52) -32%, NS -38%, P =0.005 Laquinimod (0.6 mg) (3-arm study, N = 306) -32%, NS -61%, P <0.03 Teriflunomide (7 mg) (3-arm study, N = 178) -55%, P =0.009 -43%, P <0.001 Fingolimod (1.25 mg) (3-arm study, N = 277) Annualized Relapse Rate Cumulative Number of Gad+ lesions
  • 85. Emerging Oral Therapies Final Thoughts
    • Currently, most oral therapies not available outside of trials
    • Balance between efficacy and tolerability and safety will be crucial
      • Less than equivalent efficacy likely to be acceptable
      • Likely to see switches as soon as an oral therapy becomes available
      • Monotherapy, combination therapy, induction therapy?
    • All studies are very large and placebo controlled, will there be enough subjects to fully enroll all trials?
      • Trials that recruit soonest will be successful, trials recruiting late may not enroll a sufficient number of subjects
  • 86. Controversies in MS Mark S. Freedman, HBSc, MSc, MD Professor of Neurology Director, Multiple Sclerosis Research Clinic University of Ottawa Canada
  • 87. Questions to Address
    • Clinically isolated syndrome
      • To treat or not to treat?
    • Is there a way of choosing patient-specific therapies?
    • How do you identify the suboptimal responder?
    • How long do you treat?
    • Is there a role for combination therapy?
  • 88. Timing of Therapy Key to Preventing Disability First Clinical Attack Time (years) Clinical threshold Axonal loss Demyelination Relapsing-Remitting Transitional Secondary Progressive First Demyelinating Event Pre- clinical Inflammation Courtesy of Mark S. Freedman, MD. Time window for early treatment
  • 89. Rationale for Early Treatment
    • Time is ticking…
    • What is lost by delaying early therapy is not regained by starting later
  • 90. Studies of IFN Beta in CIS ETOMS 2 % of patients with CDMS at 2 years Once-Weekly IFN beta-1a CHAMPS 1 % of patients with CDMS at 2 years Placebo IFN beta-1a Placebo IFN beta-1a 1. Jacobs LD, et al. N Engl J Med. 2000;343:898-904. 2. Comi G, et al. Lancet . 2001:357:1576-1582. 3. Kappos L, et al. Neurology. 2006;67:1242-1249. IFN beta-1b EOD BENEFIT 3 % of patients with CDMS at 2 years Placebo Betaseron IFN = interferon; CIS = clinically isolated syndrome; EOD = every other day; CDMS = Clinically definite MS. P = .002 P = .047 P < .0001 0 10 20 30 40 50 0 10 20 30 40 50 0 10 20 30 40 50 Courtesy of Mark S. Freedman, MD.
  • 91. Results of CIS Treatment
    • Both CHAMPS and ETOMS showed that treating CIS with IFN beta-1a once weekly delays the time to a 2nd attack and reduces MRI lesions
    • Preliminary data from PreCISe indicate that treating CIS with GA also delays the time to the 2nd attack and reduces MRI lesions
    • BENEFIT has shown that treating CIS with high-dose, high-frequency IFN beta-1b has the same effect on 2nd attack and MRI but also delays disability
  • 92. SLIDE NOT AVAILABLE
  • 93. Choosing a Treatment? UG UG Courtesy of Mark S. Freedman, MD.
  • 94. How do any of the disease-modifying agents compare with one another in relapsing MS? The concept of number needed to treat or NNT helps
  • 95. Comparing Efficacy
    • Direct “head-to-head” trials best
    • Cannot simply compare overall results across trials
      • Different populations
      • Different study designs
      • Different behaviour of placebo arms
    • Reduce outcomes to a common independent variable, such as number needed to treat (NNT)
  • 96. SLIDE NOT AVAILABLE
  • 97. Measuring Efficacy Across Trials—Use of NNT
    • To compare results across studies one needs to reduce individual study results to a more common measure
    • The number needed to treat (NNT) is a common measure of the effectiveness of interventions
    • NNT = 1/absolute risk (rate) reduction with intervention vs control
  • 98. Number Needed to Treat
    • Number needed to treat (NNT) = the number of patients needed to receive a treatment over a set period (eg, 2 years) in order for 1 patient NOT to experience 1 negative event (ie, relapse, progression, death, etc.)
    • Therapeutic gain = absolute difference between treatment and placebo groups
    • Absolute risk reduction = therapeutic gain
    • NNT = 1/therapeutic gain or 1/absolute risk reduction
  • 99. Comparing Across Trials—Which to Use? Absolute vs Relative Risk Reduction
    • Assuming all populations are at the same “risk” of having a relapse, then RRR should be constant
    • However, if patients are selected because of their “high” risk but turn out to be at lower risk then can you reliably use RRR?
    • In such cases, using the absolute risk reduction and NNT may be a better comparator
  • 100. Absolute vs Relative Risk Reduction Annualized Relapse Rate  = .5 absolute  = .5 absolute  = .5 absolute 33% relative 50% relative 66% relative Which drug is showing the greatest efficacy? What if all 3 had the same “baseline” RR? Does drug Z really demonstrate twice the efficacy of drug X? Reprinted from Freedman MS, et al. Euro Neurol. 2008;60:1-11, with permission from Karger. 2.0
  • 101. Relationship Between Absolute vs Relative Risk Reduction (Depends on the number of events) # of events Risk Reduction Relative Risk Reduction (RRR) Absolute Risk Reduction When n is small, “relative” changes are large When n is large, “relative” changes are small Relapses in placebo = 10 Relapses in treatment = 5 Absolute difference = 5 RRR = 50% Relapses in placebo = 100 Relapses in treatment = 95 Absolute difference = 5 RRR = 5% Courtesy of Mark S. Freedman, MD.
  • 102. Annualized Relapse Rate Different Placebo Behavior 47% 32% 29% 17% 51% a Copaxone; b Avonex; c Betaseron; d Rebif; e Tysabri. Glatiramer Acetate a IFN beta-1a 30 mcg IM qw b IFN beta-1b c IFN beta-1a 44 mcg SC tiw d Natalizumab e 0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2 Baseline Placebo Treatment Courtesy of Mark S. Freedman, MD.
  • 103. Annualized Relapse Rate Comparing Risk Outcomes Baseline Placebo Treatment 28% 18% 34% 32% 68% a Copaxone; b Avonex; c Betaseron; d Rebif; e Tysabri. Glatiramer Acetate a IFN beta-1a 30 mcg IM qw b IFN beta-1b c IFN beta-1a 44 mcg SC tiw d Natalizumab e 0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2 Courtesy of Mark S. Freedman, MD. Marked difference in “on study” RR Can you really therefore compare these differences? ~ same baseline RR
  • 104. Change in MS Study Populations in Trials Patients relapse-free (%) 30 th %tile time to first relapse (months) Annualized relapse rate IFN beta-1a IFN beta-1a IFN beta-1a GA GA GA ‘ 94 ‘ 04 ‘ 94 ‘ 04 ‘ 94 ‘ 04 ‘ 91 ‘ 04 ‘ 91 ‘ 04 ‘ 91 ‘ 04 a Median; IFN beta-1a = 44 mcg TIW except for OWIMS (44 mcg QW). OWIMS = Once Weekly Interferon for MS. Study start Courtesy of Mark S. Freedman, MD.
  • 105. Relapses NNT (2 years) Lower NNT denotes greater efficacy Number Needed to Treat a Copaxone; b Avonex; c Betaseron; d Rebif; e Tysabri. NNT = number needed to treat. Freedman MS, et al. Euro Neurol. 2008;60:1-11. Glatiramer Acetate a IFN beta-1a 30 mcg IM qw b IFN beta-1b c IFN beta-1a 44 mcg SC tiw d Natalizumab e Courtesy of Mark S. Freedman, MD.
  • 106. % Relapse Free (95% CI) NNT (2 years) Lower NNT denotes greater efficacy Number Needed to Treat a ns = not significant; b Copaxone; c Avonex; d Betaseron; e Rebif; f Tysabri. Freedman MS, et al. Euro Neurol. 2008;60:1-11. (3–5) (6– ∞ ) (4– ∞ ) (4–11) (4–23) Glatiramer Acetate a IFN beta-1a 30 mcg IM qw b IFN beta-1b d IFN beta-1a 44 mcg SC tiw d Natalizumab f Courtesy of Mark S. Freedman, MD.
  • 107. % Progression-Free (95% CI) Over 2 Years Lower NNT denotes greater efficacy Number Needed to Treat (7– ∞ ) (6– ∞ ) (4–38) (5–53) (6–17) a ns = not significant; b Baseline expanded disability status score 1–3.5; c Copaxone; d Avonex; e Betaseron; f Rebif; g Tysabri. Freedman MS, et al. Euro Neurol. 2008;60:1-11. Glatiramer Acetate a IFN beta-1a 30 mcg IM qw b IFN beta-1b e IFN beta-1a 44 mcg SC tiw f Natalizumab g Courtesy of Mark S. Freedman, MD.
  • 108. MRI Activity-Free (No T2 Active Scans Over 2 Years) Lower NNT denotes greater efficacy Number Needed to Treat NA NA (3–7) (3–11) (2–3) Glatiramer Acetate a IFN beta-1a 30 mcg IM qw b IFN beta-1b c IFN beta-1a 44 mcg SC tiw d Natalizumab e NA = not available. c Copaxone; b Avonex; c Betaseron; d Rebif; e Tysabri. Freedman MS, et al. Euro Neurol. 2008;60:1-11. Courtesy of Mark S. Freedman, MD.
  • 109. Optimizing Therapy How do you determine when there is a suboptimal response?
  • 110. Canadian Multiple Sclerosis Working Group (CMSWG) Recommendations on Optimizing Treatment with Disease-Modifying Therapy
  • 111. Optimizing Therapy Important Relapse Features
    • Rate
      • Probably the least sensitive index
    • Severity
      • Steroids required
      • Effects on activities of daily living
      • Mono/multiple systems involved
      • Motor (pyramidal/cerebellar)
    • Recovery
      • Prompt vs delayed
      • Complete vs residual deficit
  • 112. Determining the Level of Concern to Consider Treatment Modification Based on Relapse Outcomes a Rate of change is relative to the baseline. Reference time frame for baseline ≥2 years prior to treatment initiation. Ideally, prospective and objective relapse data should be obtained during the reference period (minimum 6/12). ADL = activities of daily living; FS = functional systems. Adapted from Freedman MS, et al. Can J Neurol Sci . 2004:31:157-168, with permission from the Canadian Journal of Neurological Sciences. Incomplete at 6/12 Incomplete at 3/12 Prompt Recovery
    • Severe
    • Steroids/hospital
    • Severe effect on ADL
    • >1 FS involved
    • Severe motor/cerebellar involvement
    • Moderate
    • Steroids required
    • Moderate effect on ADL
    • >1 FS involved
    • Moderate motor/cerebellar involvement
    • Mild
    • No Steroids
    • Minimal effect on ADL
    • 1 FS involved
    • No motor/cerebellar involvement
    Severity Minimal reduction <35% (= result of all clinical trials) Modest reduction 35%–75% Moderate reduction 75%–100% Rate a High Medium Low
  • 113. Determining the Level of Concern to Consider Treatment Modification Based on Progression Outcomes EDSS = expanded disability status scale. Adapted from Freedman MS, et al. Can J Neurol Sci . 2004:31:157-168, with permission from the Canadian Journal of Neurological Sciences.
    • Pronounced motor, cerebellar, or cognitive
    • Multiple domains affected
    • Some motor, cerebellar or cognitive
    • Multiple domains affected
    • No motor
    • Minor sensory
    Clinically documented progression
    • >0.5 point confirmed at 6/12
    • 0.5 point confirmed at 6/12
    ≥ 5.5
    • >1 point confirmed at 6/12
    • 1 point confirmed at 1 year
    • 1 point confirmed at 6/12
    • <1 point
    4 – 5
    • >2 points confirmed at 6/12
    • 2 points confirmed at 1 year
    • 2 points confirmed at 6/12
    • <2 points
    ≤ 3.5 High Medium Low Baseline EDSS
  • 114. Determining the Level of Concern to Consider Treatment Modification Based on MRI Outcomes Adapted from Freedman MS, et al. Can J Neurol Sci . 2004:31:157-168, with permission from the Canadian Journal of Neurological Sciences. Atrophy Enlarging T1 hypointense lesions New T1 hypointense lesions Enlarging T2 (BOD) New T2 lesions Increase in >2 MRI categories Any new lesion New Gd-enhancing lesions Medium Low Change in MRI Categories
  • 115. The Optimization Model Assessing the Concern Whether to Modify a Treatment Regimen Adapted from Freedman MS, et al. Can J Neurol Sci . 2004:31:157-168, with permission from the Canadian Journal of Neurological Sciences. Each gauge represents a continuum from no concern ( 0 on the dial ) to a low , medium , or high level of concern Consider 3 “ low ”, any 2 “ medium ”, or any 1 “ high ” as an indication of suboptimal treatment that might warrant a change in management Relapse Progression MRI
  • 116. Applying TOR to Year 1 of PRISMS 4 IFN beta-1a SC Patients (%) TOR = Treatment Optimization Recommendations. Freedman MS, Forrestal. Multiple Sclerosis . 2008 (in press). 32% 39% 29% 22% 27% 29% 12% 10% 0 0.05 0.1 0.15 0.2 0.25 0.3 0.35 0.4 0.45 22 mcg sc tiw (n = 180) 44 mcg sc tiw (n = 182) None Low Medium High Level of Concern: n = 58 n = 52 n = 49 n = 21 n = 70 n = 41 n = 52 n = 19 Courtesy of Mark S. Freedman, MD.
  • 117. Relapses During Years 2–4 in “High” Concern Year 1-Treated Patients Patients (%) Freedman MS, Forrestal. Multiple Sclerosis. 2008 (in press). 14% 16% 10% 11% 29% 21% 48% 53% 0 10 20 30 40 50 60 22 mcg sc tiw (n = 21) 44 mcg sc tiw (n = 19) None ≤ 0.5 >0.5 and ≤1.0 >1.0 Relapses per Year: n = 3 n = 2 n = 6 n = 10 n = 3 n = 2 n = 4 n = 10 Courtesy of Mark S. Freedman, MD.
  • 118. Annualized Relapse Rates During Years 2–4 vs Year 1 Level of Concern Annualized Relapse Rate Freedman MS, Forrestal. Multiple Sclerosis . 2008 (in press). 0.29 1.18 0.45 0.6 0.68 1.08 1.08 1.26 0 0.2 0.4 0.6 0.8 1 1.2 1.4 22 mcg sc tiw 44 mcg sc tiw Inactive Low Medium High n = 58 n = 52 n = 49 n = 21 n = 70 n = 41 n = 52 n = 19 Courtesy of Mark S. Freedman, MD.
  • 119. EDSS Progression During Years 2–4 in Patients of “High” Concern in Year 1 Patients (%) Freedman MS, Forrestal. Multiple Sclerosis . 2008 (in press). 43% 58% 29% 32% 10% 5% 19% 5% 0 10 20 30 40 50 60 70 22 mcg sc tiw 44 mcg sc tiw None ≤ 0.5 >0.5 and ≤1.0 >1.0 Progressions per Year: n = 9 n = 6 n = 2 n = 4 n = 11 n = 6 n = 1 n = 1 Courtesy of Mark S. Freedman, MD.
  • 120. Results of Using Canadian TOR to Monitor Response to Therapy
    • 89% (125/141) of medium/high concern year 1 patients had ≥ 1 relapse/progression in years 2–4
    • 11% (16/141) of this same group had no clinical disease activity
      • They may well have had MRI activity
      • Further follow-up may well have demonstrated continued activity
    TOR = Treatment Optimization Recommendations . Freedman MS, Forrestal. Multiple Sclerosis . 2008 (in press).
  • 121. Length of Treatment When do you consider stopping treatment?
  • 122. How Long is the Carry-Over Benefit After Stopping IFN beta? Courtesy of N. Richert, MD. Patient 1 Patient 2 Month 0 1 2 3 -15 -10 -5 0 5 10 15 20 25 30 35 40 45 IFN 0 5 10 15 20 25 30 -30 -25 -20 -15 -10 -5 0 5 10 15 20 25 30 35 40 IFN Total No. Contrast Enhancing Lesions/T2-LL (cc)
  • 123. What is the Effect of First-Line Agents in SPMS? Proportion of Patients with Confirmed Progression P >.05 in all studies (ie, insignificant). SPMS = secondary progressive MS. Courtesy of Mark S. Freedman, MD. 32% 34% 939 NA SPMS (IFN beta-1b) 29% 59% 39% IFN beta 34% 65% 50% Placebo 436 618 718 N IMPACT (IFN beta-1a IM) SPECTRIMS (IFN beta-1a SC) EUSPMS (IFN beta-1b)
  • 124. Combination Therapy
    • When?
      • Early vs late
    • What?
      • Whole array of agents tried, nothing proven but mostly uncontrolled or observational studies
    • Are they safe?
      • Lessons from SENTINEL (IFN beta + natalizumab)
  • 125. Combination Therapy
    • How?
      • Induction
        • Combine with first-line agent for a short period, then stop & continue with first-line agent alone
      • Pulse
        • Add agent to first-line agent for short periods but at regular intervals
      • Long-term combination
        • Maintain both agents
  • 126. Panel Discussion Question and Answer Session
  • 127. Fingolimod and Fumarate Both
    • May have neuroprotective effects
    • Are immune suppressants
    • Induce Th1 to Th2 cytokine shifts
    • Are lymphocyte-sequestering agents
  • 128. Which of the Following Statements Best Characterizes Your Approach to Clinically Isolated Syndrome (CIS)?
    • CIS patients may not progress to MS; starting treatment at this stage may commit them to long-term therapy they do not need
    • This is the earliest stage we can reasonably introduce treatment
    • Studies show that treatment leads to a short delay to next relapse but doesn’t prevent MS, so what’s the point?
    • It is better to wait until patients demonstrate disease activity before starting an expensive treatment
  • 129. The “Cerebral Reserve” Hypothesis Suggests that
    • Early damage of MS is compensated for by an expansion of neural networks
    • Treatment is largely ineffective in preventing disability if given before the cerebral reserve is exceeded
    • Both 1 and 2
  • 130. Evidence that the Timing of Environmental Events is Important in the Development of MS Includes
    • Studies in immigrants
    • The maternal parent-of-origin effect
    • The delay in clinical symptoms after 15 years
    • All of the above
  • 131. Cladribine
    • Is a prodrug metabolized by deoxycytodine kinase
    • Is a FDA-approved drug
    • Can cause bone marrow suppression
    • All of the above
  • 132. Which of the Following Statements is TRUE Regarding MS Treatment Trials?
    • Results from different studies cannot be directly compared
    • Results of different studies can be directly compared by using the NNT, which definitely identifies the agent with the greatest efficacy
    • Therapeutic gain measured across studies is less apt to be affected by a low event rate than is relative reduction
    • Without direct comparative studies, there is no way of knowing if one agent is more efficacious than another
  • 133. You have Started an RRMS Patient on a DMT. Over the Next 1-2 Years Which of the Following Would Prompt You to Consider Changing Treatment?
    • Recurrent relapses without worsening residual impairment
    • Recurrent relapses with cumulative residual disability
    • Slowing progressive worsening neurologic disability
    • 1 or 2
    • Any of the above
  • 134. There is Some Evidence Suggesting That the Increased Incidence of MS Observed Over the Last 30 Years Maybe Due to
      • A change in the genetic susceptibility to MS
      • A change in the environmental exposure
      • Both