New Perspectives on the Pathogenesis of MS

New Perspectives on the Pathogenesis of MS
Douglas S. Goodin, MD Professor of Neurology Director, Multiple Sclerosis Center University of California, San Francisco

Pathogenesis of Multiple Sclerosis
Clinical Course RR MS Disability Time Disability Time PP MS Disability Time SP MS RP MS Disability Time Fauci AS. In: Harrison's Internal Medicine, 17th edition. McGraw Hill;2007, with permission from McGraw Hill.

Pathogenesis of Multiple Sclerosis Epidemiology
Prevalence 5–200/100,000 population Sex distribution 70%–75% female Age at onset 20–40 years Ethnic origin Predominantly Caucasian Compston A, et al. McAlpine’s Multiple Sclerosis, 4th ed. Churchill Livingston, London

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Pathogenesis of Multiple Sclerosis LFB Stain (Myelin Pathology)
LFB = Luxol fast blue. Reprinted from Patrikios P, et al. Brain. 2006;129: , with permission from Oxford Journals.

Pathogenesis of Multiple Sclerosis In Vivo Pathology (MRI)
Courtesy of Douglas S. Goodin, MD.

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 © Massachusetts Medical Society. All rights reserved.

Microscopic Pathology Courtesy of D.P. Agamanolis, MD.

Histopathology Type I Lesions Type II Lesions I I Similar Except Complement MOG MΦ Complement MΦ Type III Lesions Type IV Lesions MOG MΦ LFB MOG MAG CNPase/ DNA frag Reprinted from Lucchinetti C, et al. Ann Neurol. 2000;47:707, with permission from John Wiley & Sons.

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 information1-5 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, 4th ed. Churchill Livingston, London Ebers GC, et al. Nature. 1995;377: Sadovnick AD, et al. Lancet. 1996;347: Nielsen NM, et al. Am J Epidemiol. 2005;162: Compston A, Coles A. Lancet. 2002;359:

Timing of Environmental Events New Perspectives

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.

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 mother1,2 The concordance rate for MS in full sibs is less than the rate in dizygotic twins3,4 Significantly more MS patients were born in May and fewer in November5,6 Moreover, this may be flipped in the southern hemisphere5 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: Ebers GC, et al. Lancet .2004;363: Willer CJ, et al. Proc Natl Acad Sci (U S A). 2003;100: Compston A, Coles A. Lancet. 2002;359: Willer CJ, et al. Br Med J. 2005;330: Sadovnick AD, et al. Neurology.2007;69:60-62.

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: Alter M, et al. Neurol. 1978;28: Elian M, et al. J Neurol Neurosurg Psychiatr. 1990;53: Kahana E, et al. J Neurol.1994;241: Cabre P, et al. Brain.2005;128:

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 place1-6 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, 4th ed. Churchill Livingston, London: Dean G, et al. BMJ. 1971;3: Alter M, et al. Neurol. 1978;28: Elian M, et al. J Neurol Neurosurg Psychiatr. 1990;53:906; Kahana E, et al. J Neurol. 1994;241: Cabre P, et al. Brain. 2005;128:

In summary, there seems to be clear epidemiologic evidence for the operation of at least 3 distinct environmental events in MS Pathogenesis The 1st operates in either in utero or in the early postnatal period The 2nd operates beginning sometime after birth and continues to operate until the age of ~15 years The 3rd (which may be multiple) operates in adulthood, often long after the 1st and 2nd event have already taken place

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: Ebers GC, et al. Lancet. 2004; 363: Ebers GC, et al. Ann Neurol. 2000;48: Sadovnick AD, et al. Lancet Neurol. 2005;4: Dyment DA, et al. J Neurol Neurosurg Psychiatry. 2006;77:

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

Pathogenesis of Multiple Sclerosis Indirect Evidence for EBV
Late EBV infection is associated with MS Symptomatic mononucleosis is associated with MS

Evidence for EBV in Adult MS Study EBV+ MS Cases (%) Controls (%) P Value Sumaya, 1980 155/157 (98.7) 76/81 (93.8) .05 Bray, 1983 309/313 (98.7) 363/406 (89.4) .0001 Larson, 1984 93/93 (100) 78/93 (83.9) Sumaya, 1985 104/104 (100) 23/26 (88.5) .007 Shirodaria, 1987 26/26 (100) 24/26 (92.3) - Munch, 1998 137/138 (99.3) 124/138 (89.9) .0004 Myhr, 1998 144/144 (100) 162/170 (95.3) .008 Wagner, 2000 107/107 (100) 153/163 (93.9) .01 Ascherio, 2001 143/144 (99.3) 269/287 (93.7) Sundström, 2004 234/234 (100) 693/702 (98.7) ns Haahr, 2004 153/153 (100) 50/53 (94.3) Ponsonby, 2005 136/136 (100) 252/261 (96.6) Total 1741/1749 (99.5) 2267/2406 (94.2) p < 10-23 Courtesy of Douglas S. Goodin, MD.

Pathogenesis of Multiple Sclerosis Worldwide Prevalence of MS
Reprinted from Kurtzke JF. Acta Neurol Scandinav. 1980;62:65-80, with permission from Blackwell Synergy.

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Pathogenesis of Multiple Sclerosis Indirect Evidence for Vitamin D
Latitude gradient for UVB is strikingly similar to MS prevalence1 Coastal regions of Norway had less MS than inland areas2 (? consumption of fish) Inuit and Sami (very low MS) consume vitamin D in their diet2 No impact on MS from micro-environmental influences, suggesting a population-wide exposure3-5 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 similar6 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, 4th ed. Churchill Livingston, London: Gillie O. Br J Dermatol. 2006;154: Ebers GC, et al. Ann Neurol. 2000;48: Sadovnick. Lancet Neurol. 2005; 4: Bager P, et al. Am J Epidemiol.2006;163: Goldacre MJ, et al. J Epidemiol Community Health.2004;58: Emmons KM, Colditz GA. J Natl Cancer Inst. 1999;91:

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 quintile1 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 MS2,3 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) D3 levels prior to the clinical onset of their illness4 1. Munger KL, et al. Neurology. 2004;62: Van der Mei IA, et al. J Neurol. 2007;254: Van der Mei IA, et al. BJM. 2003;327: Munger KL, et al. JAMA. 2006;296:

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

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 1st environmental factor EBV would seem to be better suited as a candidate for the 2nd 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 1st 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

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Conclusions Pathogenesis of MS involves complex interactions between genetic and environmental factors Multiple genes are involved Timing of environmental factors is important The 1st event: in utero or early postnatal period The 2nd event: after birth to age 15 The 3rd event: in adulthood (may be several) Vitamin D deficiency is a plausible candidate for the 1st factor; EBV infection is a plausible candidate for the 2nd factor MS incidence has increased over the past 30 years due to a change in environmental exposure

Goals of Optimal Therapy
Bruce A. Cohen, MD Professor Davee Department of Neurology Feinberg School of Medicine Northwestern University Chicago, Illinois

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

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 worsens1 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:

Natural History of MS Clinical and MRI Measures
Relapses/Disability MRI Activity MRI T2 Burden of Disease Axonal Loss Secondary Progressive MS Preclinical Relapsing-Remitting MS CIS * Disability Time Reprinted from Trapp BD, et al. Neuroscientist. 1999;5:48-57, with permission from Sage Publications.

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 plaques1 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 degeneration2 Can effective immune therapy early in MS prevent worsening disability? 1. Trapp BD, et al. N Engl J Med. 1998;338: 2. Trapp BD. Neuroscientist. 1999;5:48-57.

Persistent Disability After MS Relapses
 1 pointa  .5 point 50 N=62 N=85 N=77 44 45 42 41 40 35 29 30 30 27 Percentage of Patients 25 20 15 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. 10 5 30–59 60–89 90+ Days Since Exacerbation aExtended Disability Status Scale (EDSS) Reprinted from Lublin FD, et al. Neurology. 2003;61: , with permission from Lippincott, Williams & Wilkins.

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 placebo1 IFN β therapy in RRMS associated with reduced relapses and MRI activity2 IFN β given for 4 years reduced the risk of EDSS progression compared with placebo for 2 years followed by IFN β for 2 years2 IFN β therapy at clinically isolated syndrome (CIS) reduced the risk of subsequent EDSS worsening over 3 years3 However, relapses did not affect the rate of worsening from EDSS scores of 4–6 in a French cohort4 and the authors concluded that relapses do not significantly influence the progression of irreversible disability 1. Jacobs LD, et al. Ann Neurol. 1996;39: PRISMS Study Group. Neurology. 2001;56: 3. Kappos L, et al. Lancet. 2007;370: Confavreux C, et al. N Engl J Med. 2000;343:

T2 Burden at CIS Presentation Predicts Later Disability
7 6 5 4 Median EDSS Score at Year 14 3 2 1 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. 0.6 1-3 0.9 4-10 5.6 >10 Median T2-Weighted MRI Lesion Volume (cm3)/number at CIS presentation CIS = clinically isolated syndrome; EDSS = Extended Disability Status Scale; MRI = magnetic resonance imaging. Brex PA, et al. N Engl J Med. 2002;346:

Dissociation Between Changes in T2 Lesion Burden and EDSS Over Time
P <.001 (cm3) r = correlation coefficient r = 0.41 P = .002 r = 0.35 P = .02 n = 66 n = 66 n = 57 n = 57 n = 45 n = 45 The mechanisms underlying the observed relation between clinical and MRI data are uncertain. Brex PA, et al. N Engl J Med. 2002;346:

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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:

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

Patterns of Cortical Activation Functional MRI
Healthy Volunteers MS Patients Reprinted from Rocca MA, et al. Ann Neurol. 2002;51: , with permission from John Wiley & Sons.

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:

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 HMRS1 (r = , 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:

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.

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.

Suboptimal Response to MS Therapy Potential Causes
Nonadherence Pharmacogenomics: responsiveness to IFN β related to single-nucleotide polymorphism frequencies1 Variable pathologies with differing responses to immune therapies Dosage of an agent2 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: Schwid SR, et al. Arch Neurol. 2005;62:

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

Current Therapies and Role of Emerging Small-Molecule Therapies in MS—Evolving Strategies
Bruce A.C. Cree, MD, PhD, MCR Assistant Professor of Neurology Multiple Sclerosis Center University of California, San Francisco San Francisco, California

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

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

MS Disease Process Believed to be heterogeneous
Multiple damage mechanisms implicated No therapy encompasses all these mechanisms

MS Disease Pathology B L O O D F L O W BRAIN TISSUE a4 Integrin VCAM
Extravasation astrocytes BRAIN TISSUE M Y E L I N oligodendrocyte Circulation Rolling Adhesion B L O O D F L O W B cell Activated T cell LUMEN OF VENULE a4 Integrin Proteases VCAM B A S A L L A M I N A Cytokines and chemokines IL-1, IL-12, chemokines Activated microglia/macrophages Antigen presenting cell (Astrocyte or Microglial cell) T CELL REACTIVATION Activated Macrophage Proteases TNF-a O2•- AXONAL DAMAGE Autoantibodies Complement NO• Courtesy of Sergio Baranzini, PhD.

Oral MS Therapies in Phase III Development
Fingolimod Fumarate Teriflunomide Laquinimod Cladribine

Proof of Concept Phase II Study Design
Months Gad + MRI Scans Placebo Active Treatment Low Dose 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 Active Treatment High Dose Primary outcome measure = cumulative number of gadolinium-DPTA enhanced lesions over 6 months

Fingolimod OH NH2 HO

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: ; Pinschewer DD, et al. J Immunol. 2000;164: ; Chiba K, et al. J Immunol. 1998;160:

Fingolimod Primary Endpoint
16 43% P <0.001 61% P <0.006 12 Cumulative Gad+ Lesion (No. per patient) 8 4 14.8 8.4 5.7 Placebo (n = 81) Fingolimod 1.25 mg (n = 83) Fingolimod 5 mg (n = 77) Adapted from Kappos L, et al. N Engl J Med. 2006;355: Copyright ©2006. Massachusetts Medical Society. All rights reserved.

Fingolimod—Long-Term Relapse Rate and MRI Activity (N = 173)
Month 24 Month 36 1.25 mga 5/1.25 mgb ARR 0.20 0.22 0.21 Relapse-free — 68% 73% Free of gad-enhanced MRI lesions 84% 89% No subjects retained (%) 189/250 (76%) 173/250 (69%) No new/newly enlarging T2 lesions since month 24 75% aReceived 1.25 mg only. bInitially treated with 5.0 mg; dose reduced to 1.25 mg between months 18 and 24. ARR = annualized relapse rate. Comi G, et al. 60th Annual Meeting AAN 2008; April 12-19, Abstract S

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 months2 89% free of GAD+ MRI lesions at 36 months2 Treatment generally well tolerated1,2 Adverse events were dose dependent and reversible Seven skin cancers including 2 malignant melanomas2 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: 2. Comi G, et al. 60th AAN Meeting 2008; April 12-19, Abstract S

Fumarate O O

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:

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 Graphical representation of the data can be made once the numerical values are presented at the AAN Kappos L, et al. 22nd ECTRIMS 2006; September 27-30, Poster P325. Kappos L et al. 59th AAN Boston, Mass. Abstract P

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

Teriflunomide O N H F OH H3C

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:

Teriflunomide Phase II Primary Outcome
O’Connor PW, et al. Neurology. 2006;66:

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:

Laquinimod Cl OH O N N O CH3 CH3

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: ; Yang JS, et al. J Neuroimmunool. 2004;156:3-9.

Laquinimod Phase IIb Results
Primary End Point: Weeks 24–36 24 P =0.005 vs placebo 19 38% 16.86 14 15.77 Placebo Placebo Cumulative No. of Gad-Enhancing T1 Lesions 0.3 mg 9 0.6 mg 10.53 4 -1 Placebo 0.3 mg 0.6 mg Laquinimod Laquinimod Comi G, et al. 59th AAN Meeting; April 28-May 5, Abstract S Courtesy of Bruce A.C. Cree, MD.

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

Cladribine O NH2 Cl N HO

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:

Cladribine—RRMS Phase II Relapse Rate
2 P =0.011 Placebo 1.5 Relapses 32% Cladribine 2.1 mg/kg 1 0.5 Baseline Months 0–6 Months 7–18 RRMS = relapsing-remitting multiple sclerosis. Adapted from Romine JS, et al. Proc Assoc Am Physicians. 1999;111:35-44, with permission from Blackwell Synergy.

Cladribine Conclusions
Phase II study single-center, 52 patients1,2 Cladribine was administered subcutaneously1,2 94% suppression of new enhancing lesions in cladribine group after month 6 (P <0.001)2 Well tolerated, can cause myelosuppression that is usually reversible1,2 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, Abstract S

Cumulative Number of Gad+ lesions Annualized Relapse Rate
Summary Cumulative Number of Gad+ lesions Annualized Relapse Rate Fingolimod (1.25 mg) (3-arm study, N = 277) -43%, P <0.001 -55%, P =0.009 Teriflunomide (7 mg) (3-arm study, N = 178) -61%, P <0.03 -32%, NS Laquinimod (0.6 mg) (3-arm study, N = 306) -38%, P =0.005 Fumarate (720 mg) (4-arm study, N = 256) -69%, P <0.001 Cladribine (2.1 mg) (2-arm study, N = 52) -94%, P <0.001 -32%, P =0.01 1. Kappos L, et al. N Engl J Med. 2006;355: O’Connor PW, et al. Neurology. 2006;66: Comi G, et al. 59th AAN Meeting; April 28-May 5, Abstract S Kappos L, et al. 22nd ECTRIMS 2006; September 27-30, Poster P Romine JS, et al. Proc Assoc Am Physicians. 1999;111: Sipe J, et al. 60th Annual Meeting AAN 2008; April 12-19, Abstract S

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

Mark S. Freedman, HBSc, MSc, MD
Controversies in MS Mark S. Freedman, HBSc, MSc, MD Professor of Neurology Director, Multiple Sclerosis Research Clinic University of Ottawa Canada

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?

Timing of Therapy Key to Preventing Disability
First Demyelinating Event Secondary Progressive Pre- clinical Relapsing-Remitting Transitional Time window for early treatment First Clinical Attack Axonal loss Clinical threshold Demyelination Inflammation Time (years) Courtesy of Mark S. Freedman, MD.

Rationale for Early Treatment
Time is ticking… What is lost by delaying early therapy is not regained by starting later

Studies of IFN Beta in CIS
Once-Weekly IFN beta-1a IFN beta-1b EOD ETOMS2 % of patients with CDMS at 2 years BENEFIT3 % of patients with CDMS at 2 years CHAMPS1 % of patients with CDMS at 2 years 50 50 50 P = .047 40 40 40 P < .0001 30 30 30 P = .002 20 20 20 10 10 10 Placebo IFN beta-1a Placebo IFN beta-1a Placebo Betaseron IFN = interferon; CIS = clinically isolated syndrome; EOD = every other day; CDMS = Clinically definite MS. 1. Jacobs LD, et al. N Engl J Med. 2000;343: Comi G, et al. Lancet. 2001:357: Kappos L, et al. Neurology. 2006;67: Courtesy of Mark S. Freedman, MD.

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

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Choosing a Treatment? UG UG Courtesy of Mark S. Freedman, MD.

The concept of number needed to treat or NNT helps
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

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)

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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

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

Comparing Across Trials—Which to Use
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

Absolute vs Relative Risk Reduction
What if all 3 had the same “baseline” RR? 2.0 Annualized Relapse Rate D = .5 absolute 33% relative D = .5 absolute 50% relative D = .5 absolute 66% relative Does drug Z really demonstrate twice the efficacy of drug X? Which drug is showing the greatest efficacy? Reprinted from Freedman MS, et al. Euro Neurol. 2008;60:1-11, with permission from Karger.

Relationship Between Absolute vs Relative Risk Reduction (Depends on the number of events)
Relative Risk Reduction (RRR) Absolute Risk Reduction 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% # of events When n is small, “relative” changes are large When n is large, “relative” changes are small Courtesy of Mark S. Freedman, MD.

Annualized Relapse Rate Different Placebo Behavior
29% 2 17% 51% 47% 1.8 Baseline Placebo 1.6 32% Treatment 1.4 1.2 1 0.8 0.6 0.4 0.2 Glatiramer Acetatea IFN beta-1a 30 mcg IM qwb IFN beta-1bc IFN beta-1a 44 mcg SC tiwd Natalizumabe aCopaxone; bAvonex; cBetaseron; dRebif; eTysabri. Courtesy of Mark S. Freedman, MD.

Annualized Relapse Rate Comparing Risk Outcomes
2 Baseline 1.8 Placebo 32% Treatment 1.6 34% ~ same baseline RR 1.4 1.2 Marked difference in “on study” RR 68% 28% 1 18% 0.8 Can you really therefore compare these differences? 0.6 0.4 0.2 Glatiramer Acetatea IFN beta-1a 30 mcg IM qwb IFN beta-1bc IFN beta-1a 44 mcg SC tiwd Natalizumabe aCopaxone; bAvonex; cBetaseron; dRebif; eTysabri. Courtesy of Mark S. Freedman, MD.

Change in MS Study Populations in Trials
Patients relapse-free (%) 30th %tile time to first relapse (months) Annualized relapse rate IFN beta-1a GA IFN beta-1a GA IFN beta-1a GA Study start ‘94 ‘04 ‘91 ‘04 ‘94 ‘04 ‘91 ‘04 ‘94 ‘04 ‘91 ‘04 aMedian; IFN beta-1a = 44 mcg TIW except for OWIMS (44 mcg QW). OWIMS = Once Weekly Interferon for MS. Courtesy of Mark S. Freedman, MD.

Relapses NNT (2 years) Lower NNT denotes greater efficacy
Number Needed to Treat Glatiramer Acetatea IFN beta-1a 30 mcg IM qwb IFN beta-1bc IFN beta-1a 44 mcg SC tiwd Natalizumabe aCopaxone; bAvonex; cBetaseron; dRebif; eTysabri. NNT = number needed to treat. Freedman MS, et al. Euro Neurol. 2008;60:1-11. Courtesy of Mark S. Freedman, MD.

% Relapse Free (95% CI) NNT (2 years)
(6–∞) Lower NNT denotes greater efficacy (4–∞) Number Needed to Treat (4–23) (4–11) (3–5) Glatiramer Acetatea IFN beta-1a 30 mcg IM qwb IFN beta-1bd IFN beta-1a 44 mcg SC tiwd Natalizumabf a ns = not significant; bCopaxone; cAvonex; dBetaseron; eRebif; fTysabri. Freedman MS, et al. Euro Neurol. 2008;60:1-11. Courtesy of Mark S. Freedman, MD.

% Progression-Free (95% CI) Over 2 Years
(7–∞) Lower NNT denotes greater efficacy Number Needed to Treat (6–∞) (5–53) (4–38) (6–17) Glatiramer Acetatea IFN beta-1a 30 mcg IM qwb IFN beta-1be IFN beta-1a 44 mcg SC tiwf Natalizumabg a ns = not significant; bBaseline expanded disability status score 1–3.5; cCopaxone; dAvonex; eBetaseron; fRebif; gTysabri. Freedman MS, et al. Euro Neurol. 2008;60:1-11. Courtesy of Mark S. Freedman, MD.

MRI Activity-Free (No T2 Active Scans Over 2 Years)
Lower NNT denotes greater efficacy (3–11) (3–7) Number Needed to Treat (2–3) NA NA Glatiramer Acetatea IFN beta-1a 30 mcg IM qwb IFN beta-1bc IFN beta-1a 44 mcg SC tiwd Natalizumabe NA = not available. cCopaxone; bAvonex; cBetaseron; dRebif; eTysabri. Freedman MS, et al. Euro Neurol. 2008;60:1-11. Courtesy of Mark S. Freedman, MD.

How do you determine when there is a suboptimal response?
Optimizing Therapy How do you determine when there is a suboptimal response?

Canadian Multiple Sclerosis Working Group (CMSWG) Recommendations on Optimizing Treatment with Disease-Modifying Therapy

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

Determining the Level of Concern to Consider Treatment Modification Based on Relapse Outcomes
Low Medium High Ratea Moderate reduction 75%–100% Modest reduction 35%–75% Minimal reduction <35% (= result of all clinical trials) Severity Mild No Steroids Minimal effect on ADL 1 FS involved No motor/cerebellar involvement Moderate Steroids required Moderate effect on ADL >1 FS involved Moderate motor/cerebellar involvement Severe Steroids/hospital Severe effect on ADL Severe motor/cerebellar involvement Recovery Prompt Incomplete at 3/12 Incomplete at 6/12 aRate 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: , with permission from the Canadian Journal of Neurological Sciences.

Determining the Level of Concern to Consider Treatment Modification Based on Progression Outcomes
Baseline EDSS Low Medium High ≤3.5 <2 points 2 points confirmed at 6/12 >2 points confirmed at 6/12 2 points confirmed at 1 year 4 – 5 <1 point 1 point confirmed at 6/12 >1 point confirmed at 6/12 1 point confirmed at 1 year ≥5.5 0.5 point confirmed at 6/12 >0.5 point confirmed at 6/12 Clinically documented progression No motor Minor sensory Some motor, cerebellar or cognitive Multiple domains affected Pronounced motor, cerebellar, or cognitive EDSS = expanded disability status scale. Adapted from Freedman MS, et al. Can J Neurol Sci. 2004:31: , with permission from the Canadian Journal of Neurological Sciences.

Determining the Level of Concern to Consider Treatment Modification Based on MRI Outcomes
Change in MRI Categories Low Medium New Gd-enhancing lesions Any new lesion Increase in >2 MRI categories New T2 lesions Enlarging T2 (BOD) New T1 hypointense lesions Enlarging T1 hypointense lesions Atrophy Adapted from Freedman MS, et al. Can J Neurol Sci. 2004:31: , with permission from the Canadian Journal of Neurological Sciences.

The Optimization Model Assessing the Concern Whether to Modify a Treatment Regimen
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 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. Adapted from Freedman MS, et al. Can J Neurol Sci. 2004:31: , with permission from the Canadian Journal of Neurological Sciences.

Applying TOR to Year 1 of PRISMS 4 IFN beta-1a SC
0.45 Level of Concern: 0.4 None 39% Low 0.35 Medium 32% High Patients (%) 29% 29% 0.3 27% 0.25 22% 0.2 0.15 12% 10% 0.1 0.05 n = 58 n = 52 n = 49 n = 21 n = 70 n = 41 n = 52 n = 19 22 mcg sc tiw (n = 180) 44 mcg sc tiw (n = 182) TOR = Treatment Optimization Recommendations. Freedman MS, Forrestal. Multiple Sclerosis (in press). Courtesy of Mark S. Freedman, MD.

Relapses During Years 2–4 in “High” Concern Year 1-Treated Patients
60 Relapses per Year: 53% 50 48% None ≤0.5 >0.5 and ≤1.0 40 Patients (%) >1.0 29% 30 21% 20 16% 14% 11% 10% 10 n = 3 n = 2 n = 6 n = 10 n = 3 n = 2 n = 4 n = 10 22 mcg sc tiw (n = 21) 44 mcg sc tiw (n = 19) Freedman MS, Forrestal. Multiple Sclerosis (in press). Courtesy of Mark S. Freedman, MD.

Annualized Relapse Rates During Years 2–4 vs Year 1 Level of Concern
1.4 Inactive 1.26 Low 1.18 1.2 Medium 1.08 1.08 High 1 0.8 Annualized Relapse Rate 0.68 0.6 0.6 0.45 0.4 0.29 0.2 n = 58 n = 52 n = 49 n = 21 n = 70 n = 41 n = 52 n = 19 22 mcg sc tiw 44 mcg sc tiw Freedman MS, Forrestal. Multiple Sclerosis (in press). Courtesy of Mark S. Freedman, MD.

EDSS Progression During Years 2–4 in Patients of “High” Concern in Year 1
70 Progressions per Year: None 58% 60 ≤0.5 50 >0.5 and ≤1.0 43% >1.0 Patients (%) 40 32% 29% 30 19% 20 10% 10 5% 5% n = 9 n = 6 n = 2 n = 4 n = 11 n = 6 n = 1 n = 1 22 mcg sc tiw 44 mcg sc tiw Freedman MS, Forrestal. Multiple Sclerosis (in press). Courtesy of Mark S. Freedman, MD.

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 (in press).

When do you consider stopping treatment?
Length of Treatment When do you consider stopping treatment?

How Long is the Carry-Over Benefit After Stopping IFN beta?
Month 1 2 3 -15 -10 -5 5 10 15 20 25 30 35 40 45 IFN -30 -25 -20 Total No. Contrast Enhancing Lesions/T2-LL (cc) Patient 1 Patient 2 Courtesy of N. Richert, MD.

What is the Effect of First-Line Agents in SPMS?
Proportion of Patients with Confirmed Progression EUSPMS (IFN beta-1b) SPECTRIMS (IFN beta-1a SC) NA SPMS (IFN beta-1b) IMPACT (IFN beta-1a IM) N 718 618 939 436 Placebo 50% 65% 34% IFN beta 39% 59% 32% 29% P >.05 in all studies (ie, insignificant). SPMS = secondary progressive MS. Courtesy of Mark S. Freedman, MD.

Combination Therapy When? What? Are they safe? Early vs late
Whole array of agents tried, nothing proven but mostly uncontrolled or observational studies Are they safe? Lessons from SENTINEL (IFN beta + natalizumab)

Combination Therapy How? Induction Pulse Long-term combination
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

Question and Answer Session
Panel Discussion Question and Answer Session

Fingolimod and Fumarate Both
May have neuroprotective effects Are immune suppressants Induce Th1 to Th2 cytokine shifts Are lymphocyte-sequestering agents Correct answer is A

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

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

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

Cladribine Is a prodrug metabolized by deoxycytodine kinase
Is a FDA-approved drug Can cause bone marrow suppression All of the above Correct answer is D

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

You have Started an RRMS Patient on a DMT
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

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

New Perspectives on the Pathogenesis of MS

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