Multiple Sclerosis and Parkinson’s Disease

Multiple Sclerosis and Parkinson’s Disease
New Frontiers and Landmark Practice Advances Optimizing Neurotherapy for Multiple Sclerosis and Parkinson’s Disease Applying Science, Expert Analysis, Guidelines, and Landmark Trials to the Front Lines Patient Care Program Chairman C. Warren Olanow M.D., FRCPC Henry P. and Georgette Goldschmidt Professor and Chairman Emeritus, Department of Neurology Professor, Department of Neuroscience Director, Robert and John M. Bendheim Parkinson’s Disease Center Mount Sinai School of Medicine

Welcome and Program Overview
CME-certified symposium jointly sponsored by the University of Massachusetts Medical School and CMEducation Resources, LLC Commercial Support: Sponsored by an independent educational grant from Teva Neuroscience, Inc. Faculty disclosures: Listed in program syllabus

Program Faculty Program Chairman
C. Warren Olanow M.D., FRCPC Henry P. and Georgette Goldschmidt Professor and Chairman Emeritus, Department of Neurology Professor, Department of Neuroscience Director, Robert and John M. Bendheim Parkinson’s Disease Center Mount Sinai School of Medicine Douglas R. Jeffery, MD, PhD Associate Professor Department of Neurology Wake Forest University Baptist Medical Center Winston-Salem, NC Howard L. Zwibel, MD Founding Medical Director, Emeritus Neuroscience Consultants Comprehensive Multiple Sclerosis Center in affiliation with the National Multiple Sclerosis Center Coral Gables, Florida Baptist Health Doctors Hospital MS Center Coral Gables, FL

Two Diseases in Need of a Neuroprotective Therapy
New Frontiers and Landmark Practice Advances Parkinson’s Disease and Multiple Sclerosis Two Diseases in Need of a Neuroprotective Therapy Program Chairman C. Warren Olanow M.D., FRCPC Henry P. and Georgette Goldschmidt Professor and Chairman Emeritus, Department of Neurology Professor, Department of Neuroscience Director, Robert and John M. Bendheim Parkinson’s Disease Center Mount Sinai School of Medicine

Parkinson’s Disease and Multiple Sclerosis
Two important neurological disorders Primarily affect older individuals (PD) Primarily affect younger individuals (MS) Both have surrogate imaging markers FD-PET (PD) MRI (MS) Treatments are available for both diseases Benefit symptoms (PD) Reduce relapse rate (MS)

Both result in unacceptable disability for many patients despite available treatments Disease-modifying or neuroprotective therapies are urgent priorities Both offer many candidate disease- modifying agents based on laboratory work

Development of a disease modifying therapy in each condition would be enhanced by: Insight into the precise cause of the disease Better animal models Better clinical trial designs with endpoints reflecting the underlying disease process Advances in these areas will be reviewed in the current session

Attempts to Obtain Neuroprotection for Parkinson’s Disease
New Frontiers and Landmark Practice Advances Attempts to Obtain Neuroprotection for Parkinson’s Disease Program Chairman C. Warren Olanow M.D., FRCPC Henry P. and Georgette Goldschmidt Professor and Chairman Emeritus, Department of Neurology Professor, Department of Neuroscience Director, Robert and John M. Bendheim Parkinson’s Disease Center Mount Sinai School of Medicine

Current Therapies for PD
Primarily dopaminergic Highly effective for the classic motor features Tremor, rigidity, bradykinesia Do not satisfactorily control non-dopaminergic features Gait dysfunction, freezing, postural instability, falling, autonomic dysfunction, mood disorders, sensory problems, cognitive impairment, dementia Do not stop disease progression

The Sydney Long Term PD Study
149 PD patients were entered 52 survivors after 15 years None were still employed 40% were in a nursing home 95% had levodopa-induced dyskinesia and wearing off Non-dopaminergic features (falling, dementia) were the primary cause of disability and of nursing home placement

Neuroprotective (Disease-Modifying) Therapy For PD
A treatment intervention that slows, stops or reverses disease progression

Neuroprotective Trials in PD Negative Studies
Agent Mechanism Endpoint Vitamin E Anti-oxidant Time to L-dopa Riluzole Anti-glutamate Minocycline Anti-Inflammatory Δ UPDRS Imunophilin Trophic GDNF/Neurturin Trophic factors TCH346 Anti-apoptotic CEP1347 DA Cell Transplant Cell replacement Δ UPDRS/QOL

Obstacles to Finding a Neuroprotective Therapy for PD
We do not know the precise etiology or pathogenesis of PD—we don’t know what to target We do not have a reliable animal model that is progressive and reflects the etiopathogeneis of PD We do not have a good method for determining the optimal dose to use in a clinical trial

Neuroprotective Trials in PD Positive Studies
Agent Mechanism Endpoint Selegiline (DATATOP) Anti-apoptotic Time to L-dopa Selegiline (SINDEPAR) Wash Out Co-Q10 Bio-energetic Δ UPDRS Creatine Ropinirole Β-CIT-SPECT Pramipexole F-DOPA PET

Obstacles to Finding a Neuroprotective Therapy for PD
We do not know the precise etiology or pathogenesis of PD –we don’t know what to target We do not have a reliable animal model that is progressive and reflects the etiopathogeneis of PD We do not have a good method for determining the optimal dose to use in a clinical trial We do not have a clinical trial design that can reliably detect a disease-modifying agent

Trial Designs for Neuroprotection in PD
Time to a milestone of disease progression Washout design (change from untreated baseline to final visit performed after drug washout) Change from baseline to final visit in UPDRS score Neuroimaging of surrogate biomarker of dopaminergic function

Delayed Start Design Period I Placebo Early Start Early Start
Intervention

Delayed Start Design Period I Period II Delayed Start Symptomatic
Effect Placebo Early Start Early Start Intervention Delayed Start Intervention

Delayed Start Design Possible Period I Period II Disease Modifying
Effect Period I Period II Delayed Start Placebo Early Start Early study Intervention Delayed Start Intervention

Delayed Start Study Principal Statistical Analyses
I. Superiority of Early Start vs Placebo (UPDRS Slope weeks 12 – 36) II II. Superiority of Early Start vs Delayed Start (UPDRS change from baseline to week 72) Mean UPDRS change from baseline Worsening Improvement III III. Non-Inferiority of Early Start vs Delayed Start (UPDRS slope weeks 48 – 72;) The principal statistical analysis incorporated three primary efficacy hypotheses tests which analyzed in a hierarchical manner the change from baseline in total UPDRS score (sum of parts I, II, and III). The first primary efficacy hypothesis compared the rate (slope estimate) of UPDRS progression during the placebo controlled phase from week 12 to week 36 between the placebo- and rasagiline-treated arms (1 and 2 mg groups). All available post baseline observations in the PC phase of the trial were analyzed (weeks 12, 24 and 36). The placebo groups were combined to one placebo group. Statistical model: Repeated Measures Mixed Linear Model with random intercept and slope The second primary efficacy hypothesis compared the estimate of change from baseline to week 72 in total UPDRS score between the early start and delayed start groups for each dose (1 and 2 mg). The least square means (LSM) at week 72 of the change from baseline in Total UPDRS was compared between the 1mg early-start group and the 1mg delayed-start group and between the 2mg early-start group and the 2mg delayed-start group. The third hypothesis tested for non inferiority of the slope estimates of the early-start and delayed-start rasagiline groups (1 and 2 mg) during the active phase of the trial (weeks 48 to 72). This analysis determines if any separation between the groups at the end of phase I persists, or if the slopes of the curves tend to converge. A non-inferiority margin of 0.15 UPDR S units per week was selected according to power calculation considerations Mixed models repeated measures analysis of covariance was used for all hypothesis statistical tests and parameter estimates. The model included the following fixed effects: treatment group, week in trial, week by treatment interaction, center, and baseline total UPDRS score. To maintain an experiment-wide type I error of .05, the Hochberg-Step up Bonferoni method was used to account for multiple comparisons between treatment groups and the hierarchal method will be used to account for multiple primary analyses. Hierarchal endpoints involve testing multiple hypotheses in a sequential manner. 12 24 36 42 48 54 60 66 72 Week Delayed Start (Placebo-Rasagiline) Early Start (Rasagiline-Rasagiline) Adapted from Olanow et al. Mov Disord

Issues That Must Be Addressed in a Delayed-Start Study
Duration of period 1 and period 2 Long enough for protective effect to occur Long enough for full symptomatic effect to occur Not so long that patients withdraw Drop outs Missing data Need for sensitivity and imputation analyses Sufficient numbers of visits to permit slope analysis in period 1 and 2

The ADAGIO Study

ADAGIO Study Design Placebo 1 mg/day 2 mg/day Untreated PD patients
Week 4 12 24 36 42 54 60 66 72 48 ADAGIO comprised of 2 phases: phase I: 36-week double-blind, placebo-controlled; and phase II: 36-week double-blind, active-treatment phase in which all patients are on active study intervention. After obtaining IRB-approved informed consent, subjects were randomized in a 1:1:1:1 ratio into one of the following four treatment groups, based on a randomization scheme with blocks stratified by center 1 mg/day rasagiline during phase I and phase II (1 mg early start) 2 mg/day rasagiline during phase I and phase II (2 mg early start) Placebo during phase I followed by 1 mg/day rasagiline during phase II (1 mg delayed start) Placebo during phase I followed by 2 mg/day rasagiline during phase II (2 mg delayed start) Thus, ‘early-start’ patients received 72 weeks of treatment with rasagiline (1 or 2 mg once daily) and ‘delayed-start’ patients receive 36 weeks of placebo followed by 36 weeks of rasagiline (1 or 2 mg once daily). If subjects in either treatment group required additional anti-parkinsonian medication during the placebo-controlled phase of the trial, they could proceed directly to Phase II. Once in Phase II, no additional anti-PD therapy was permitted. If the patient required additional medication in this stage they were discontinued from the study. At each visit except at week 4, a UPDRS evaluation was performed. Other evaluations performed at each visit included measures of quality of life, adverse events reporting, and standard laboratory assessments. 36-week (9-month) Double Blind Placebo-Controlled Phase 36-week (9-month) Double Blind Active-Treatment Phase Olanow et al. Mov Disord. 2008

ADAGIO – Baseline Characteristics
Patients randomised (n) 1,176 Male patients (n, %) 718 (61.1%) Age, years (mean, SD) 62.2 (9.6) PD duration, months (mean, SD) 4.5 (4.6) UPDRS-Total score (mean, SD) Motor ADL 20.4 (8.5) 14,2 (6.4) 5.2 (2.8) Hoehn & Yahr score (mean, SD) 1.5 (0.5) A total of 1,176 patients (61.1% male) from 129 study sites in 14 countries (Argentina, Austria, Canada, France, Germany, Hungary, Israel, Italy, The Netherlands, Portugal, Romania, Spain, the UK and the USA) were enrolled into the study and randomised.1 Overall, the mean age of patients was 62.2 ± 9.6 years, the mean time from diagnosis was 4.5 ± 4.6 months, and mean UPDRS-Total score was 20.4 ± 8.5.1 With a mean disease duration of 4.5 ± 4.6 months and a baseline UPDRS-Total score of 20.4 ± 8.5,1 the population enrolled into the ADAGIO study is one of the earliest PD populations studied to date in a randomised clinical trial. 1. Olanow CW, Hauser R, Jankovic J, et al. Mov Disord In press. Olanow et al. Mov Disord 2008 25

Rasagiline 1mg: Early vs Delayed Start
Olanow et al. NEJM; 2009

Rasagiline 2mg: Early vs Delayed Start
Olanow et al. NEJM; 2009

The ADAGIO Study Summary and Conclusions
Rasagiline 1 mg/day met all 3 primary outcomes of the delayed start study Is this a false positive? Rasagiline 2 mg/day failed to meet all primary outcomes of the delayed start study Is this a false negative?

ADAGIO – Clinical Significance of Positive Result with Rasagiline 1 mg
UPDRS difference of 1.7 units 38% reduction in rate of decline of UPDRS score Reflects only 9 months of active treatment

ADAGIO Trial Clinical Significance
Delayed-start study designed to determine if a study intervention has benefits that cannot be accounted for by symptomatic effects alone Long-term studies are required to assess effect of drug on cumulative disability Extension study Long-term simple study Endpoints that include measures of motor and non-motor function - UPDRS gait, cognitive function, and quality of life

New Dimensions and Landmark Practice Advances The Evidence for First Line Therapy in MS with Immune-Modulating Agents (IMTs) From Mechanisms to Therapy-Landmark Trials, Long-Term Safety Data, and Clinical Experience Howard L. Zwibel, MD Founding Medical Director, Emeritus | Neuroscience Consultants | Comprehensive Multiple Sclerosis Center in affiliation with the National Multiple Sclerosis Center Coral Gables, Florida | Baptist Health Doctors Hospital MS Center | Coral Gables, FL

New Dimensions and Landmark Practice Advances The Evidence for First Line Therapy in MS with Immune-Modulating Agents (IMTs) From Mechanisms to Therapy-Landmark Trials, Long-Term Safety Data, and Clinical Experience NOTE: Both trade and chemic names are used in the presentation to establish clarity, and because many trials use acronyms that employ the brand name. The use of brand names should not be construed as endorsements for these products.

MS: Immune Dysfunction
Proinflammatory immune cells Proinflammatory cytokines Antigen-presenting cell Blood-brain barrier T cells The pathophysiology of MS is 2-fold in that it is both inflammatory and neurodegenerative in nature. In addition to episodes of inflammatory activity, the extent of axonal loss is now believed to be the main determinant of permanent disability An antigen-presenting cell, shown here, activates proinflammatory immune cells, such as the Th1 and Th17 subset of CD4+ cells (shown as red cells in diagram) Th1 and Th17 cells then cross from the bloodstream into the central nervous system (CNS) via the blood-brain barrier (BBB), secrete proinflammatory cytokines, and eventually destroy myelin and facilitate neuronal death 1. Ziemssen T. J Neurol. 2005;252:V/38-V/ Yong VW, et al. Neurology. 2007;68:S32-S Dhib-Jalbut S. Neurology. 2007;68:S13-S Tzartos JS, et al. Am J Pathol. 2008;172:

Based on modifications to McDonald Criteria
Diagnosis of MS Based on modifications to McDonald Criteria Modified from the McDonald criteria. The principle is to establish dissemination in time and place of lesions—ie, that episodes affecting separate sites within the CNS have occurred at least 30 days apart. MRI can substitute for one of these clinical episodes. Dissemination in time of magnetic resonance lesions requires: one gadolinium-enhancing lesion at least 3 months after the onset of the clinical event; or a new T2 lesion compared with a reference scan done at least 30 days after onset of the clinical event. In the case of recurrent stereotyped clinical episodes at the same neurological site, criteria for MRI definition of dissemination in space are three features from: (1) one gadolinium-enhancing lesion or nine T2 MRI lesions; (2) one or more infratentorial lesions; (3) one or more juxtacortical lesions; or (4) three or more periventricular lesions; (a spinal cord lesion can replace some of these brain lesions). Primary progressive multiple sclerosis can be diagnosed after 1 year of a progressive deficit and two of: (1) a positive brain MRI; (2) a positive spinal cord MRI; and (3) positive oligoclonal bands. Patients having an appropriate clinical presentation, but who do not meet all of the diagnostic criteria can be classified as having possible multiple sclerosis. CSF=cerebrospinal fluid. Compston A, Coles A. Lancet. 2008;372: Figure 1 [Caption]. CSF = cerebrospinal fluid Polman CH, et al. Ann Neurol. 2005;58: Compston A, Coles A. Lancet. 2008;372: Figure 1.

Differentiating MS Lesions Using MRI
Note: Scans are not from the same patient. D A B T2 with FLAIR T2 C T1 Precontrast Black Holes Differentiating MS Lesions Using MRI These images are derived from the conventional MRI techniques used in assessing MS disease activity. Panel A is a T2-weighted MRI scan that indicates total BOD1; Panel B is a FLAIR image, an MRI technique designed to demonstrate specific aspects of lesions by revealing tissue T2 prolongation with CSF suppression. Panel C is a T1-weighted MRI without Gd contrast, which reveals black holes; black holes do not enhance with Gd in subsequent scans and are not active lesions. These areas indicate severe axonal damage and permanent CNS damage. Black holes (ie, T1-weighted hypointensities that reflect areas of axonal loss) correlate with the progression of disability and are areas of permanent damage when not associated with a new lesion. Panel D is a T1-weighted MRI scan with Gd contrast; this technique reflects active lesions and shows the level of disease activity. These representative MRI scans do not come from the same patient. References Images courtesy of Jerry S. Wolinsky, MD. 1. Miller DH, Kesselring J, McDonald WI, Paty DW, Thompson AJ. Magnetic Resonance in Multiple Sclerosis. Cambridge, England: Cambridge University Press; 1997. 2. Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG. Multiple sclerosis. N Engl J Med. 2000;343: T1 Post-Gd Contrast Active Inflammation FLAIR = Fluid Attenuated Inversion Recovery Slide courtesy of JS Wolinsky. 35

Clinically Isolated Syndrome (CIS)
Clinical episode consistent with demyelination Characterized by MRI and lab data Patient may or may not develop clinically definite MS (CDMS) Features of CIS suggestive of a first MS attack include: Appropriate age; female gender Abnormal brain MRI Optic neuritis Typically unilateral, retrobulbar, and painful Brainstem/cerebellar dysfunction Most commonly ocular motor syndromes (INO, nystagmus), ataxia, dysarthria, sensory or motor signs Myelitis Partial sensory more common than partial motor Bowel and bladder dysfunction common INO: Internuclear ophthalmoparesis Frohman, et al. Neurology. 2003;61: 36

Clinically Isolated Syndrome (CIS)
The challenge for physician is to determine the likelihood that person experiencing this type of demyelinating event is going to experience a second demyelinating event in the future, thereby meeting the criteria for a definite diagnosis of MS. When the CIS is accompanied by MRI-detected brain lesions consistent with those seen in MS, there is a high risk of a second neurologic event and diagnosis of clinically definite MS within several years. Individuals who experience CIS with no evidence of MRI- detected lesions are at relatively low risk of developing MS. National MS Society. Clinically isolated syndrome. Accessed 12/08. 37

CIS: MRI Lesions at Baseline Associated with Development of CDMS Over Next 20 Years
85% 82% 81% 21% In another study,1 results were similar to those shown on the slide. At the 14-year follow-up of a cohort of 71 patients with CIS, 4 of 21 (19%) patients with normal baseline MRI had developed CDMS and 44 of 50 (88%) patients with abnormal MRI (ie, lesions) at baseline had developed CDMS. Reference 1. Brex PA, Ciccarelli O, O’Riordan I, et al. A longitudinal study of abnormalities on MRI and disability from multiple sclerosis. N Engl J Med. 2002;346: (n = 34) (n = 22) (n = 20) (n = 31) Fisniku LK, et al. Brain. 2008;131: 38

CIS or First Demyelinating Event: Phase III, Placebo-Controlled Studies
Acronym Full name Primary Endpoint(s) Status PreCISe Study to Evaluate the Effect of Early Glatiramer Acetate (GA, Copaxone®) Treatment in Delaying the Conversion to CDMS of Subjects Presenting with a CIS Time to clinically definite MS (CDMS) Completed BENEFIT Betaferon® (IFNb-1b) in Newly Emerging MS for Initial Treatment Time to CDMS Time to McDonald MS CHAMPS Controlled High-Risk Subjects (IFNb-1a) Avonex® Multiple Sclerosis Prevention Study Probability of developing CDMS Changes in MRI ETOMS Early Treatment of MS Study (IFNb-1a) Conversion to CDMS REFLEX Rebif® (IFNb-1a) FLEXible Dosing in Early MS Time to conversion to MS (McDonald criteria) Ongoing Trade names are included in this presentation to reduce confusion regarding medication formulations and in no way endorses the use of the product with the trade name. Comi G, et al. Lancet. 2009;Published online 10/7/09, DOI: / (09) Kappos L, et al. Neurology. 2006;67(7): Jacobs LD, et al. N Engl J Med. 2000;343(13): Comi G, et al. Lancet. 2001;357:

Completed CIS Clinical Trials: Demographics and Key Results
Parameter PreCISe (GA) BENEFIT (IFNb-1b SC) CHAMPS (IFNb-1a IM) ETOMS (IFNb-1a SC) Duration 3 yrs (stopped early) 2 yrs Patients (N) 481 468 383 308 Patient age 31 ± 7 yrs 30 yrs 33 ± 7 yrs 28 ± 6 yrs EDSS (mean) NA 1.5 1.17 ± 1.2 % Reduction in CDMS Risk 45% 50% 44% 39% P-value 0.0005 < 0.002 0.047 NA = not available EDSS= expanded disability status score Comi G, et al. Lancet. 2009;Published online 10/7/09, DOI: / (09) Kappos L, et al. Neurology. 2006;67(7): Jacobs LD, et al. N Engl J Med. 2000;343(13): Comi G, et al. Lancet. 2001;357:

BENEFIT 5-Year Extension Data: Early Versus Delayed IFNβ-1b
57% 37% reduction in risk of developing CDMS 46% CDMS = clinically definite multiple sclerosis HR 0.63, 95% Cl 0.48–0.83; P = 0.003 Kappos L, et al. Lancet. 2009; published online September 11, 2009 DOI:1016/S (09)

CHAMPIONS (CHAMPS Open-label Extension): Early Versus Delayed IFNβ-1a
Incidence of CDMS by Treatment Group: 10-year extension data Delayed Treatment (n = 190) 40% reduction in risk of developing CDMS Immediate Treatment (n = 193) Univariate HR (95% CI) = 0.64 (0.47–0.86), P = 0.003 Adjusted HR (95% CI) = 0.60 (0.44–0.81), P < 0.001 Kinkel RP, et al. Presented at the 25th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), Düsseldorf, Germany, September 9-12, Poster # 446.

“Initiation of treatment with an interferon beta medication or glatiramer acetate should be considered as soon as possible following a definite diagnosis of MS with active, relapsing disease, and may also be considered for selected patients with a first attack who are at high risk of MS.” National Clinical Advisory Board of the National Multiple Sclerosis Society (2007). Accessed 01/14/09.

Summary Early treatment of CIS with DMTs (GA, IFNβ formulations) delays progression to CDMS Early treatment of CIS or MS Reduces rate of relapses Delays the development of disability May reduce the overall cost of care

Current MS Therapies Immunosuppressants or Immunomodulators?
Generally considered to be immunomodulators Glatiramer acetate [GA] injection IFNβ products Natalizumab (?) Uses of these immunomodulators GA and IFNβ products are first-line therapies for the long-term treatment of CIS and RRMS Natalizumab for patients who are unresponsive or who cannot tolerate first-line DMTs, first-line use in very active RRMS It is important to consider how existing therapies and the new therapeutic approaches to MS will reset and suppress multiple components of the immune system. We will be discussing how some of the emerging therapies, which have long lasting consequences on immune cell populations, compare to the current therapies and how their mechanism of action may influence treatment decisions. Today, most of the first-line therapies used to treat MS patients are considered Immunomodulators. These include GA and the interferon products, both of which are routinely used as treatments in CIS and MS populations. Chan A, et al. J Neuron. 2008;255(suppl 6):22-27.

Glatiramer Acetate Dose: 20 mg sc daily (pre-filled syringes)
Pregnancy Category: B Drug Interactions: None noted in clinical trials Laboratory monitoring: None needed Adverse events: Injection site reaction, immediate post-injection reaction

Presumed MOA of Glatiramer Acetate: Immunomodulation
Proinflammatory immune cells Proinflammatory cytokines Anti-inflammatory cytokines Regulatory T-cell types Antigen-presenting cell Neurotrophic factors T cells Blood-brain barrier Induces a population of regulatory T-cell types (Th2,Treg) Anti-inflammatory cytokines and neurotrophic factors are released May prevent nerve damage and lead to remyelination* COPAXONE® (glatiramer acetate injection) is thought to work with the immune system by inducing a population of peripheral CD4+ COPAXONE®-reactive regulatory T-cell types, including Th2 and regulatory T (Treg) cells (shown in diagram as blue cells). It is believed that these cells accumulate in the CNS of patients with MS and release anti-inflammatory cytokines (shown in diagram as small blue circles) These regulatory T-cell types are believed to reduce harmful inflammation inside the CNS and produce neurotrophic factors that may prevent nerve damage and lead to remyelination* It is not known if these effects play an important role in the observed clinical activity of glatiramer acetate in MS T cells derived from MS patients receiving therapy with COPAXONE® have been shown to produce neurotrophic factors including brain-derived neurotrophic factor, and to prevent nerve damage and enhance in situ remyelination and repair in animal models. * It is not known if these effects play an important role in the observed clinical activity of COPAXONE® in MS. T cells derived from MS patients receiving therapy with COPAXONE® have been shown to produce neurotrophic factors, including brain-derived neurotrophic factor, and to prevent nerve damage and enhance in situ remyelination and repair in animal models. Weber MS, et al. Neurotherapeutics. 2007;4: Aharoni R, et al. Proc Natl Acad Sci U S A. 2008;105: *

Interferons Avonex®, Betaseron®, Rebif®
Doses: Avonex ® : 30 mcg IM once weekly Betaseron ® : 250 mcg SC every other day Rebif ® : 22 mcg, or 44 mcg, SC TIW Pregnancy Category: C Drug Interactions: Possible with hepatically active drugs Laboratory monitoring: CBC, LFT, thyroid Adverse events: Flu-like symptoms, injection site reaction, depression, hepatic injury May be beneficial to address IFN-statin drug-drug interaction from AAN 2007 (Dhawan & Birnbaum).

Presumed MOA of IFNβ: Immunomodulation
Proinflamatory immune cells Proinflammatory cytokines Eliminated immune cell T cells Antigen-presenting cell Blood-brain barrier Reduces proinflammatory cytokine levels Reduces lymphocyte trafficking into the central nervous system (CNS) IFNβ is thought to work primarily by reducing both proinflammatory cytokine levels (shown in diagram as dark-red circles) and lymphocyte trafficking into the CNS while remaining on the peripheral side of the BBB It is not known what role these effects play in the observed clinical activity of IFNβ in MS Betaseron® prescribing information. Bayer HealthCare Pharmaceuticals Inc.

Monoclonal Antibody Natalizumab
Dose: 300 mg iv infusion monthly Pregnancy Category: C Drug Interactions: Immunosuppressants, corticosteroids Safety Issues: Progressive Multifocal Leukoencephalopathy (PML) Hypersensitivity Reaction / NAbs Melanoma / Other Cancers Liver Injury Reactivation of Latent Viruses

Presumed MOA of Natalizumab: Reduction of Cell Trafficking
Proinflammatory immune cells Proinflammatory cytokines Antigen-presenting cells Blood-brain barrier T cells Inhibits the α4-mediated adhesion of leukocytes to vascular cell adhesion molecule-1 Strongly reduces proinflammatory cell recruitment to the CNS Natalizumab binds to the α4 subunit of α4β1 and α4β7 expressed on the surface of all leukocytes, with the exception of neutrophils. This inhibits the α4-mediated adhesion of leukocytes to the vascular cell adhesion molecule-1 counter-receptor expressed on activated vascular endothelial cells Thus, natalizumab helps prevent proinflammatory cells from being recruited to the CNS It is not known if these effects play an important role in the observed clinical activity of natalizumab in MS Tysabri® (natalizumab) prescribing information. Biogen Idec Inc.

Head to Head Clinical Trials

Head to Head Clinical Studies
EVidence of Interferon Dose-response: European North American Comparative Efficacy (The EVIDENCE Trial)

Results : Primary Endpoint Proportion Relapse Free at 64 Weeks
56.3% % Relapse Free 48.2% Panitch H, et.al. J Neurol Sci. 2005;239:67-74.

Results : Mean T2 Active Lesions at 64 Weeks Secondary Endpoint
1.4 P < 0.001 0.9 Mean T2 Lesions Panitch H, et.al. J Neurol Sci. 2005;239:67-74.

REbif® vs. Glatiramer Acetate in Relapsing MS Disease (The REGARD Study) Phase IV Multicenter, Open Label, Randomized Study of Rebif® 44 µg Administered Three Times Per Week by Subcutaneous Injection Compared with Copaxone® 20 mg Administered Daily by Subcutaneous Injection in the Treatment of RRMS

Time to First Relapse (Primary Endpoint)
672 days (96 weeks) IFNβ-1a Hazard ratio (95% CI): (0.74, 1.21) p = 0.643 GA Survival distribution function 460/736 planned patients (63%) were expected to have  1 relapse 258/764 patients (34%) experienced  1 relapse Time to first relapse (days) Adapted from an analyst report by Bernstein Research, October 15, 2007. 57

Betaseron Efficacy Yielding Outcomes of a New Dose (The BEYOND Study) Friday, 12 October 2007 Immunomodulation 1 (Poster topic 2) 15:30 – 17:00 [P181] First phase of the BEYOND Programme: analysis of 3- year data from an open-label, extension study comparing 500 mcg and 250 mcg interferon beta-1b S. Kirzinger, B. Arnason, G. Bigley, P.K. Coyle, D. Goodin, B. Hurwitz, D.R. Jeffery, S. Lynch, R. Mandler, D. Mikol, K. Rammohan, R. Sater, S. Sriram, B. Thrower, F. Boateng, S. Grossova-Garie, T. Bogumil on behalf of the BEYOND Programme Backgound: Data suggest that doses of interferon beta-1b (IFNB-1b; Betaferon®/ Betaseron®) higher than the currently approved, 250 mcg every other day (eod) may provide greater efficacy in treating patients with relapsing remitting multiple sclerosis (RRMS) without compromising tolerability or safety. Objective: The BEYOND (Betaferon®/ Betaseron® Efficacy Yielding Outcomes of a New Dose) programme was established to assess the safety, tolerability and efficacy of 500 mcg IFNB-1b eod. This programme consists of a small-scale first phase (pilot study) and a larger scale second phase (phase IIIb trial). The extension of the first phase of the programme is reported here. Methods: The first phase was a double-blind, randomised, parallel group, multicentre pilot study comparing IFNB-1b 500 mcg and 250 mcg eod in patients with RRMS; the 500 mcg dose was shown to be well tolerated and safe over the titration and treatment period of 12 to 28 weeks. Results: Sixty three of 71 patients who completed this pilot study opted to enter the extension. Treatment was unblinded at Week 10 of the extension study and the 61 remaining patients chose their therapeutic dose: 22 chose the 250 mcg dose and 39 chose the 500 mcg dose. After 3 years of follow-up, 42 patients are still participating: 12 in the 250 mcg group and 30 in the 500 mcg group returned for the follow-up visit. After 3-years, no relevant change from baseline in alanine aminotransferase (ALT) or aspartate aminotransferse (AST) levels was observed in any of the dose groups. Pre-planned MRI evaluations up to year 2 of the follow-up study will be presented. Conclusion: The extension data show that IFNB-1b is well tolerated and has a safety profile similar to that of the approved 250 mcg dose over a 3-year period. The second phase of the BEYOND programme is currently investigating the efficacy and safety of the 500 mcg dose of IFNB-1b in a larger number of patients to confirm the conclusions of this pilot study. Disclosure:The BEYOND Pilot study is financially supported by Bayer Schering Pharma AG

Annualized Relapse Rate 1 Year Before and During Treatment
0.5 1.0 1.5 2.0 Before During IFNβ-1b 500 ug 250 ug GA -79% -78% *No significant differences Comi G. Presented at: The European Charcot Foundation Symposium 2007; Nov 29 – Dec 1, 2007; Fiuggi, Italy.

BEtaseron® vs. COpaxone® in MS with Triple-Dose Gadolinium and 3-T MRI Endpoints (The BECOME Study)

The BECOME Study “This protocol is optimized to detect enhancement…”
Study Design Investigator-initiated study (single site) N = 75 RRMS (61) and CIS (14) patients Triple dose Gd with 40 min post-injection delay 3-Tesla MRI “This protocol is optimized to detect enhancement…” Sponsored by Berlex/Schering AG Primary Outcome Measure The mean number of combined active lesions (CALs) per scan CALs were defined as Gd-enhancing lesions + new T2/FLAIR lesions unassociated with enhancement Patients were recruited from the MS Centers at New Jersey Medical School and Holy Name Hospital (both in NJ) IFNb cohort – 31/36 had RRMS, GA cohort – 30/39 had RRMS Using a 3-T MRI, a 21% increased sensitivity for MS lesion detection and a 30-50% increase in lesion volume has been reported when compared to 1.5-T MRI This triple dose Gd/3-T MRI protocol demonstrated an increase in lesion detection rate of 123% Wolansky L, et al. Presented at: 22nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis; September 27-30, 2006; Madrid, Spain.

BECOME: Summary Primary Outcome (CAL Count)
“The primary outcome of the BECOME study demonstrates that IFNβ-1b and GA have similar efficacy and onset of action for suppression of blood–brain barrier (BBB) breakdown in MS” No significant differences on the following secondary outcomes New enhancing lesions Black Holes (acute hypointensities and persistent black holes) Clinical: ARR, sustained disability progression, cognitive function It is difficult to generalize from one set of cohorts, however, the implication of the BECOME trial is that “the superiority of IFNβ-1b over GA for reducing the incidence of active inflammation in MS may have been overestimated” Wolansky L, et al. Presented at: 23rd Congress of the European Committee for Treatment and Research in Multiple Sclerosis; October 11-14, 2007; Prague, Czech Republic. Cheriyan J, et al. Presented at: 132nd Annual Meeting, American Neurological Association; October 7-10, 2007; Washington, D.C. Cadavid D, et al. Presented at: 23rd Congress of the European Committee for Treatment and Research in Multiple Sclerosis; October 11-14, 2007; Prague, Czech Republic.

Trends Across Clinical Trials: % Reduction in ARR – ~2 Years
59 44 51 42 79 85 71 69 78 84 86 20 40 60 80 100 GA Avonex Betaseron Rebif 44 FTY720 Tysabri % Reduction in ARR vs Baseline This slide shows a graphic representation of the % reduction in ARR that was shown in the last column of the table on the previous slide. Within group comparison vs baseline GA ARR: 2.9 relapses in prior 2 yrs at baseline; 2.9/2 = 1.45 ARR at baseline Avonex 2-yr ARR: used the ‘all pts’ value Betaseron ARR: 3.4 relapses in prior 2 yrs at baseline; 3.4/2 = 1.70 ARR at baseline Rebif 44 ARR: 3.0 relapses in prior 2 yrs at baseline; 3.0/2 = 1.50 ARR at baseline; ARR 2-yr: at 2 yrs; 1.73/2 = 0.87 ARR at 2-yrs FTY720: 1.9 relapses in prior 2 yrs at baseline; 1.9/2 = 0.95 ARR at baseline; only used continuous FTY720 pts (not PBO-active pts) BEYOND: baseline ARR and % reduction vs baseline reported; calculated ARR 2-yrs by: (ARR pre-entry) * (100-% reduction) BECOME: used ‘confirmed relapse’ ARR value from Cadavid ECTRIMS 2007 poster for this graph Reduction vs Baseline values derived by: (ARR pre-entry) – (ARR 2 yrs) / (ARR pre-entry) FTY720: used the values for the 1.25mg dose because this is the dose they’re pursuing (not the 5mg dose); baseline value obtained from NEJM pub – this study (same pt pop) extended to 24mos and data presented at ECTRIMS 2006 so the 2-yr ARR for FTY720 comes from the Kappos ECTRIMS 2006 poster REFERENCES: Johnson KP, et al. Neurology. 1995;45: 2. Jacobs LD, et al. Ann Neurol. 1996;39: 3. IFNB-1b Study Group. Neurology. 1993;43: 4. PRISMS-2. Lancet. 1998; 5. Polman CH, et al. NEJM. 2006;354: 6. Kappos L, et al. NEJM. 2006;355: 7. Kappos L, et al. Presented at: 22nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis; September 28th-30th, 2006; Madrid, Spain. Multiple Sclerosis 12 (Suppl 1):S101. 8. Mikol DD, et al. The REGARD Trial: A randomized, assessor-blinded trial comparing interferon beta-1a and glatiramer acetate in relapsing remitting multiple sclerosis. Presented at: ECTRIMS October 15, Cited in Multiple Sclerosis. 2007;13(suppl2):S269. 9. Comi G, et al. Presented at The European Charcot Foundation Symposium, November 29th, 2007; Fiuggi, Italy. 10. Cadavid D, et al. Betaseron vs Copaxone in MS with Triple-dose gadolinium and 3T MRI Endpoints (BECOME): announcement of secondary clinical outcomes. Presented at: ECTRIMS, October 11-14, P207. Cited in Multiple Sclerosis. 2007;13(suppl 2):S58. Johnson 1995 Jacobs 1996 IFNβ-1b study group,1993 PRISMS-2 1998 Kappos ECTRIMS 2006, NEJM 2006 Polman 2006 REGARD 2007 REGARD 2007 BEYOND 2007 BEYOND 2007 BECOME 2007 BECOME 2007

Trends Across Clinical Trials: Annualized Relapse Rate – ~2 Years
Annualized Relapse Rate – 2-yrs Avonex 2-yr ARR: used the ‘all pts’ value Rebif 44 ARR 2-yr: at 2 yrs; 1.73/2 = 0.87 ARR at 2-yrs BECOME: used ‘confirmed relapse’ ARR value from Cadavid ECTRIMS 2007 poster for this graph REFERENCES: Johnson KP, et al. Neurology. 1995;45: 2. Jacobs LD, et al. Ann Neurol. 1996;39: 3. IFNB-1b Study Group. Neurology. 1993;43: 4. PRISMS-2. Lancet. 1998; 5. Kappos L, et al. Presented at: 22nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis; September 28th-30th, 2006; Madrid, Spain. Multiple Sclerosis 12 (Suppl 1):S101. 6. Polman CH, et al. NEJM. 2006;354: 7. Mikol DD, et al. The REGARD Trial: A randomized, assessor-blinded trial comparing interferon beta-1a and glatiramer acetate in relapsing remitting multiple sclerosis. Presented at: ECTRIMS October 15, Cited in Multiple Sclerosis. 2007;13(suppl2):S269. 8. Comi G, et al. Presented at The European Charcot Foundation Symposium, November 29th, 2007; Fiuggi, Italy. 9. Cadavid D, et al. Betaseron vs Copaxone in MS with Triple-dose gadolinium and 3T MRI Endpoints (BECOME): announcement of secondary clinical outcomes. Presented at: ECTRIMS, October 11-14, P207. Cited in Multiple Sclerosis. 2007;13(suppl 2):S58. Johnson 1995 Jacobs 1996 IFNB-1b study group,1993 PRISMS-2 1998 Kappos ECTRIMS 2006 Polman 2006 REGARD 2007 REGARD 2007 BEYOND 2007 BEYOND 2007 BECOME 2007 BECOME 2007

Long Term IMT Data

Long-term Study Design in RRMS
Copaxone® (glatiramer acetate injection)20,21 N=251 in original pivotal trial; 19 placebo patients of 251 in pivotal trial did not enter open-label extension, and 1 patient received 1 dose of COPAXONE® and never returned for evaluation. Therefore, 231 patients were included in the mITT analysis. The Ongoing cohort included 108 patients at 10 years and 100 patients at 15 years. Avonex® (IFNβ-1a)9,23 Avonex®: N=301; 158 Avonex®, 143 placebo; subset (85 Avonex®, 87 placebo) followed for 2 years. 15-year retrospective follow-up: n=116; 15-year follow-up consisted of a questionnaire at year 15. Betaseron® (IFNβ-1b)24,25 Betaseron®: N=372; 125 Betaseron® 1.6 MIU, 124 Betaseron® 8 MIU, 123 placebo. 16-year retrospective follow-up: n=328 identified patients (35 of these were deceased but included in the study as identified patients). LTFU data were obtained in an observational study consisting of a single-visit assessment or report at 16 years. At LTFU, 182/260 patients were not taking Betaseron®. Rebif® (IFNβ-1a)26 N=560; 184 Rebif® 44 mcg, 189 Rebif® 22 mcg, 187 placebo; at end of year 2, 172 placebo patients randomized to 22 mcg (n=84) or 44 mcg (n=87); and double-blind study was continued to year 4. LTFU data were obtained in an observational study consisting of a single-visit assessment 7-8 years after enrollment. Tysabri® (natalizumab)27 N=942; Tysabri® 300 mg (n=627) or placebo (n=315). Up to 15 years 2 yrs 15 years 5 yrs 16 years 4 yrs 7-8 years 3 yrs Key Prospective study design Retrospective follow-up 9. Jacobs LD, et al. Ann Neurol. 1996;39: Ford C, et al. WCTRIMS Abstract P Ford CC, et al. Mult Scler. 2006;12: 23. Bermel RA, et al. WCTRIMS Abstract P IFNβ Study Group. Neurology. 1995;45: Ebers G, et al. AAN P 26. Kappos L, et al. Neurology. 2006;67: O’Connor PW, et al. AAN P

Pivotal Trial and Extension-Phase Study Design
2008 15-year analysis for Ongoing cohort Mean disease duration: 22 years EDSS assessment Ongoing 6-month assessments 3 6 9 12 15 18 21 24 27 30 33 36 glatiramer acetate injection Ongoing (n=100) 13.6 years mITT†‡ (n=232) 8.6 years placebo Withdrawn total (n=132) The 2-year pivotal trial of COPAXONE® (glatiramer acetate injection) was followed by an ongoing open-label extension phase. In the ongoing open-label study, patients were evaluated for neurologic status by EDSS every 6 months and examined within 7 days of suspected relapse. Mean disease duration for the Ongoing cohort was 8.4 years at study entry, translating to about 22 years at most recent follow-up For the extension phase, all patients who received at least 1 dose of COPAXONE® since study inception were included in the modified intent-to-treat (mITT) analysis. One patient in this cohort withdrew before an on-treatment neurologic evaluation; therefore, the efficacy-evaluable mITT cohort comprised 231 patients The Ongoing cohort included 108 patients 10 years into the open-label extension phase. At the 15-year follow-up, there were 100 patients remaining in the study after up to 15 years on therapy (mean 13.6 years) 50 patients who had withdrawn from the study were evaluated at an LTFU visit approximately 10 years after initiating COPAXONE®. The Withdrawn with no LTFU cohort (n=74) included patients who had withdrawn from the study and could not be reached or declined LTFU NOTE: No further EDSS assessments were undertaken after the 10-year evaluation of the Withdrawn cohort. Thus, no data on the Withdrawn cohort are available at the 15-year follow-up. 4.8 years Double-blind, placebo-controlled phase Open-label extension phase 35* 60 120+ 180 Months *Due to staggered enrollment, the duration of the trial was 35 months in order to obtain 2-year results for all participants. The mean time on treatment was 30 months. †19 placebo patients of 251 in original pivotal trial chose not to enter open-label extension. ‡1 patient in the Withdrawn without long-term follow-up (LTFU) cohort withdrew before an on-treatment neurologic evaluation; therefore, 231 patients were included in the efficacy evaluable modified intent-to-treat (mITT) cohort. 29. Johnson KP, et al. Neurology. 1995;45: Ford C, et al. WCTRIMS Abstract P Ford CC, et al. Mult Scler. 2006;12: Johnson KP, et al. Neurology. 1998;50:

Yearly Relapse Rate While on GA
0.25 0.5 0.75 1 1.25 Mean Relapse Rate Here is the baseline annualized relapse rate of all patients when they entered the study. Then you can see the relapse rate for all patients on GA each consecutive year. Note that during the first year the yearly relapse rates of patients taking GA declined approximately 50% to By treatment year 4, patients were having the equivalent of one relapse every 4 years. And by the end here it was down to about 1 every 5 years. That is an 80% drop in relapse rate. Now the reason that the values in years 10, 11, and 12 are depicted in a different color is because these are patients who started on GA from the beginning, and the patients who started on placebo have not yet reached this time point. ___ Data comes from Figure 2 page 315 of Ford, et al. Multiple Sclerosis 2006;12: Values in years 10, 11, and 12 are depicted in a different font to indicate that they are calculated from patients who have reached the 10-12th year of GA therapy because they started GA during the placebo controlled randomized trial. At the time of the datalock (Nov. 2003), the patients who had received placebo during the placebo controlled trial had not reached years of GA therapy. The number of patients assessed per year are as follows: baseline, n=232; year 1, n=231; year 2, n=208; year 3, n=196; year 4, n=175; year 5 n=163; year 6, n=149; year 7, n=143; year 8, n=138; year 9, n=125; year 10, n=64; year 11, n=57; year 12, n=51 * Year † # of pts†: *ARR in the 2 years before GA start †After year 9, mITT data included only those of patients randomized to GA in the double-blind phase of the study. Crossovers from placebo group had not yet received GA Ford CC, et al. Mult Scler. 2006;12:

Demonstrated Long-term Benefits
EDSS levels at 15-year follow-up 100 80 60 Patients (%) 38% 40 18% After an average of 22 years with RRMS and a mean of 14 years of COPAXONE® (glatiramer acetate injection) therapy, the majority of patients still in the study had not reached EDSS 4, 6, or 8 20 3% EDSS of 4 or higher EDSS of 6 or higher EDSS of 8 or higher After an average of 22 years with RRMS and a mean of 14 years of COPAXONE® (glatiramer acetate injection) therapy, the majority of patients still in the study had not reached EDSS 4, 6, or 8 The labeling for COPAXONE® does not include an indication for slowing progression of disability. Ford C, et al. WCTRIMS Abstract P44.

ASSURANCE 15-year long-term follow-up of pivotal IM IFNβ1a relapsing trial (MSCRG) Involved 2-year completers Open label, retrospective, patient reported N=136 (of 172) participated 46% currently on IM IFNβ1a (median duration 13.3 years) Rudick et al. MS 11:626, 2005

ASSURANCE Those on IM IFNβ1a showed
↓ Mean EDSS change (2.3 vs. 3.3, p=0.011) ↓ EDSS 4 (64% vs. 83%, p=0.06) ↓ EDSS 6 (32% vs. 62%, p=0.008) ↓ EDSS 7 (9% vs. 33%, p=0.008) Better physical score on SF36 (p<0.0001), greater independence (p=0.0019; p=0.031) Rudick et al. MS 11:626, 2005

Patients under regular medical care - no trial
16 Year Follow-Up Pivotal Study (n=372) IFNβ-1b 250 µg 124 56 IFNβ-1b 50 µg 125 52 Patients under regular medical care - no trial LTF Placebo 123 58 1988 1990 1993 2005 Cross-sectional investigation of: - clinical outcomes (disability, relapse rate) - imaging (brain and spinal MRI) - cognition and mood - QoL, resource use - lab parameter including NAb's and PgX Goodin et al., Multiple Sclerosis; 2008: 14 (Suppl 1), P52 72

16-Year LTF: Patient Disposition in the Intent-to-Treat Population
7.2% 4.8% 16.3% 10.5% Deceased Not found Alive 13.6% 11.4% 84.7% 79.2% 72.4% Proportion of Patients Placebo n = 123 INFB-1b 50 µg n = 125 IFNB-1b 250 µg n = 124 Ebers G. Presented at ECTRIMS 2006, Madrid, Spain. 73

16-Year LTF: Other Findings
The most important predictors for better long-term outcomes from the IFNB-1b 16-year LTF study were Low EDSS (<2) at study entry High exposure to IFNB-1b The risk of any negative outcome* was reduced by 60% with high compared to low exposure Safety and tolerability No new or unexpected side effects Flu-like symptoms , injection site reactions and NAbs continued at a low level *EDSS 6; SPMS; EDSS 6/SPMS, Wheelchair Goodin et al. Multiple Sclerosis; 2008: 14 (Suppl 1), P52 74

PRISMS Long Term Follow-up
8-year follow-up of PRISMS SC IFNβ1a pivotal relapsing trial 382 of 560 subjects (68.2%) evaluated 275 (72%) still receiving IFNβ1a Subjects initially randomized to 44mcg showed best EDSS, relapse rate, T2 burden of disease at 8 years -no brain atrophy difference 19.7% progressed to SPMS Neurology 2006;67:944

Natalizumab Monotherapy Trial: ARR
0.81† 0.73‡ 68% reduction* 68% reduction* 0.26† 0.23‡ Natalizumab Monotherapy Trial: ARR At 1 year, the preplanned interim analysis showed that natalizumab reduced the ARR to 0.26 relapse per year, compared with 0.81 relapse per year in the placebo group (P<0.001).1 The 1-year final analysis showed an ARR of 0.27 for the natalizumab group and 0.78 for the placebo group (65% reduction; P<0.001).1 The 2-year final analysis showed an ARR of 0.23 for the natalizumab group and 0.73 for the placebo group.1 The 68% relative reduction in the ARR with natalizumab was maintained at 2 years (P<0.001).1 1. Polman CH, O’Connor PW, Havrdova E, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006;354: *P<0.001. †Preplanned interim analysis. ‡Final analysis. Polman CH et al. N Engl J Med. 2006;354:

Natalizumab Monotherapy Trial: Time to Sustained Progression
Placebo Natalizumab P<0.001. Natalizumab Monotherapy Trial: Time to Sustained Progression Sustained progression of disability over 2 years was less likely with natalizumab vs placebo. The cumulative probability of progression (Kaplan-Meier analysis) was 17% in the natalizumab group and 29% in the placebo group (hazard ratio, 0.58; 95% CI, ; P<0.001).1 This represents a relative 42% decrease in the risk of sustained progression of disability with natalizumab.1 1. Polman CH, O’Connor PW, Havrdova E, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006;354: Adapted with permission from Polman CH et al. N Engl J Med. 2006;354:

Natalizumab: AFFIRM Gd-Enhancing Lesions
P<0.001 between groups for all time intervals. 92% Natalizumab: AFFIRM Gd-Enhancing Lesions Natalizumab decreased Gd-enhancing lesions by 92% compared with placebo (means years 1 and 2, 0.2 vs 2.4, respectively; P<0.001) across years 1 and 2, a 92% relative reduction.1 1. Miller DH, Soon D, Fernando KT, et al. MRI outcomes in a placebo-controlled trial of natalizumab in relapsing MS. Neurology. 2007;68: 92% 92% Miller DH et al. Neurology. 2007;68:

Natalizumab: AFFIRM T2 Lesions
P<0.0001 83% Natalizumab: AFFIRM T2 Lesions In a 2-year, placebo-controlled trial, the monoclonal antibody natalizumab decreased new or enlarging T2 lesions by 83% compared with placebo (means, 11.0 vs 1.9, respectively; P<0.001).1 1. Miller DH, Soon D, Fernando KT, et al. MRI outcomes in a placebo-controlled trial of natalizumab in relapsing MS. Neurology. 2007;68: Miller DH et al. Neurology. 2007;68:

Summary GA and interferons
Efficacy data documented from initial event to long-term GA long-term data is prospective Interferon data long-term is retrospective No long-term safety signalling with GA or interferons Natalizumab Efficacy data short term Safety signalling for development of PML 80

New Dimensions and Landmark Practice Advances The Evolution of Chemotherapeutic Agents in the Treatment of Multiple Sclerosis Douglas R. Jeffery, MD, PhD Associate Professor Department of Neurology Wake Forest University Baptist Medical Center Winston-Salem, NC

“Chemotherapeutic” Nonspecific cytotoxic agents that kill cells via a mechanism that involves impairment of cell division Usually mediated by an effect on DNA or RNA synthesis Through this mechanism such agents kill T-cells, B-cells, and macrophages thus impairing an immune response against a wide variety of stimuli Immunosuppressive agents that also increase the risk of infection through the nonspecific suppression of immune function

The Search for a Treatment
Early on there were no treatments for MS Other disciplines (rheumatology) adopted the use of chemotherapeutic agents to treat autoimmune diseases MS thought by many to be autoimmune in nature Investigators in the MS field considered the use of these agents Early study designs were flawed and some doubted the effectiveness of these agents

Benefits vs. Risk of Chemotherapuetuc Agents
Chemotherapies are nonspecific immunosuppressive agents Many have well known and very serious side effects Immunosuppression Infection Hepatoxicity Secondary malignancy In the absence of other effective treatments the benefits outweighed the risks in those with worsening disability

Agents that have Been Studied in MS
Azathioprine Methotrexate Cyclophosphamide Mycophenylate Mitoxantrone Cladribine Cyclosporine

Azathioprine Earliest studies date back to 1971
Small poorly controlled trials suggested a modest effect on relapses Later controlled trials confirmed an effect on relapse rate but not disability progression Cochrane meta analysis suggested an effect on relapse rate Odds ratio of remaining relapse free on azathioprine was 1.51 at yr 1, 2.04 at yr 2, and 1.97 at yr 3 Yudkin et. al. 1991

Azathioprine Used widely in Europe prior to the introduction of IFNβs
Less popular in the modern era of immunomodulatory therapy Studied and used widely as a combination therapy in those with a suboptimal response to IFNβs and galtiramer acatete (GLAT) Use as a monotherapy felt to be suboptimal given potential for longterm toxicity

Azathioprine in Multiple Sclerosis
354 patients randomized to azathioprine vs. placebo Double blinded, 3 yr duration At 3 yrs mean EDSS decreased 0.80 in the placebo and 0.62 in the treated group At 3yrs the placebo group had an average of 2,5 relapse while the azathioprine group had an average of 2.2 relapses (ns) Results showed a very small benefit Could not be recommended for most patients with MS Lancet. 1988; 23:

Effect of Azathioprine on MRI Metrics
14 patients with at least three gd(+) lesions within 6 months Azathioprine dosed up to 3mg/kg daily depending on lymphocyte counts Evaluation for six months before treatment and six months of treatment Reduction of greater than 50% observed in 12 of 14 patients Reduction of greater than 50% or more in new T2 lesions Azathioprine reduced new MS brain lesions Massacesi, et. al. 2005

Toxicity of Azathioprine
Bone marrow suppression Leukopenia Lymphopenia Thrombocytopenia Increased risk of infection Hepatotoxicity Malignancy risk increased with duration of exposure Solid organ tumors, myelodysplastic syndromes, epitheliomas, skin cancer La Mantia 2007, Confravreux 1996

Cyclophosphamide Early studies suggested a possible effect in secondarily progressive MS and rapidly progressive MS Conflicting results of several trials led to controversy as to whether it was effective at all Some believed it was highly effective and others felt it to be ineffective and dangerous Both were right. It depended on whether the extent of the inflammatory process present Hauser et. al Weiner et. al. 1993

Northeast Cooperative MS Treatment Group
Randomized Standard vs modified induction Induction only vs induction + maintenance IV CTX (700 mg/m2) bimonthly Induction IV CTX (600 mg/m2) days 1, 2, 4, 6, 8 IV ACTH for 14 days Maintenance Weiner et. al. 1993

Percentage Stable/Improved on DSS
NE Cooperative Study Percentage Stable/Improved on DSS Months on Study 6 12 18 24 30 36 Induct (20) 75% 56% 46% 24% 17% 15% Boosters (127) 71% 55% 48% 38% 27% 20% P value 0.76 0.71 0.61 0.04 0.14

Months on Study, with Maintenance
NE Cooperative Study Months on Study, with Maintenance 6 12 18 24 30 36 Younger (<41) 81% 62% 57% 42% 40% 28% Older (>41) 60% 47% 34% 14% 21% P value 0.02 0.13 0.10 0.18 0.01 0.05

Cytoxan Factors effecting response to therapy Younger age
Rapidly progressive course Relapses in the year before therapy <2yrs in the progressive phase Enhancing lesions on T1+Gd

Canadian Cooperative Trial
CP-MS EDSS and increase >1.0 step prior 1 year Randomized IVCTX + prednisone 55 PlEx + POCTX + prednisone 57 Sham PlEx + placebo po meds 56 Blinded examining neurologist Lancet 337:441, 1991

Randomized, placebo-controlled Clin-def, CP MS EDSS Worsening on EDSS >1.0 steps prior 12M Non-blinded monitoring neurologist Blinded examining neurologist Lancet 337:441, 1991

CTX group (n=55) IV CTX 1 gm QOD until WBC<4.5 up to 9 gm Prednisone 40 mg qD x 10 then taper over 6 d PlEx group (n=57) PlEx qW for 20 wk PO CTX mg/kg/d for 22 wk Prednisone 20 mg QOD Placebo group (n=56) Sham PlEx, PO CTX placebo, Prednisone placebo Lancet 337:441, 1991

Canadian Cooperative Trial Results
No significant differences in: Rate of failure (increase in EDSS >1.0 sustained for 6 months) Proportions improved, stable, worse at each visit up to 36 months Mean change in EDSS Lancet 337:441, 1991

Proportion of treatment failures CTX 35% PlEx 32% Plac 29% Mean time to treatment failure (months) CTX PlEx Plac Lancet 337:441, 1991

M12 vs. baseline Improved Stable Worse IVCTX 3 (6%) 38 (79%) 7 (15%) PIEx 4 (8%) 39 (81%) 5 (10%) Placebo 1 (2%) 35 (73%) 12 (25%) CTX vs placebo p=0.295 Lancet 337:441, 1991

M24 vs. baseline Improved Stable Worse IVCTX 2 (6%) 13 (42%) 16 (52%) PIEx 1 (3%) 25 (81%) 5 (16%) Placebo 20 (67%) 10 (33%) CTX vs placebo p=0.088 Lancet 337:441, 1991

M36 vs. baseline Improved Stable Worse IVCTX 2 (4%) 24 (44%) 28 (52%) PIEx 1 (2%) 34 (59%) 22 (39%) Placebo 32 (59%) 21 (39%) CTX vs placebo p=0.290 Lancet 337:441, 1991

Kaiser Study CP-MS (EDSS 3.0-8.0)
Increased EDSS or AI >1 step prior 1 year Randomized IV CTX 22 Placebo 20 Single-blind Likosky WH et al. JNNP 54:1055, 1991

EDSS Stable or Improved*
Kaiser Study Results EDSS Stable or Improved* CTX Placebo 12 Months 14/22 (64%) 14/20 (70%) 24 Months 9/19 (47%) 9/17 (53%) * based on EDSS change of >1.0 step Likosky WH et al. JNNP 54:1055, 1991

Kaiser Study Results Mean DEDSS Placebo-CTX (95% CI) Month CTX Placebo
0 to 12 0.50 0.53 0.03 (-0.60 to 0.65) 0 to 18 0.38 0.73 0.35 (-0.40 to 1.10) 0 to 24 0.58 0.97 0.39 (-0.45 to 1.23) Likosky WH et al. JNNP 54:1055, 1991

Spectrum of Disease Activity
Early inflammatory process with frequent relapse and “apparent” progression may appear “progressive” Usually accompanied by numerous enhancing lesions and rapidly increasing T2 lesion burden Late stage secondary progression related to a poorly understood degenerative process Infrequent enhancing lesions and little evidence of progression on MRI These forms of disease differ in their response to treatment

Secondary-progressive
Natural History of MS Betaseron® (interferon beta-1b): Trials in Secondary-Progressive Multiple Sclerosis Measures of brain volume Secondary-progressive Relapses and impairment MRI burden of disease MRI activity Preclinical Relapsing-remitting The natural history of MS is represented schematically in this diagram. Based on the current knowledge and understanding of MS, this diagram correlates brain volume, relapses, MRI lesion burden, and MRI activity over the course of the disease. The RR stage of MS is characterized by MRI brain activity sometimes accompanied by relapses and a slow accumulation of impairment between relapses. MRI activity may already be present before any manifestation of clinical signs. As the patient “transitions” into the SP phase of the disease, several changes occur: (1) brain volume decreases and continues to decrease although not necessarily at a steady rate; (2) relapses occur early on and then diminish while impairment increases steadily; (3) MRI lesion burden increases; and (4) MRI activity slowly declines. This sequence of events suggests that SP MS patients are not a homogeneous population. Unlike the RR population, SP patients have a broader spectrum of disease characteristics. The ovals represent the “substages” within the SP phase of the disease. The oval to the left encompasses SP patients who have more inflammatory disease as determined by MRI disease activity and clinical relapses. The oval to the right encompasses SP patients who have passed the active, inflammatory stage and experience fewer relapses. The overlap represents those that cannot be readily distinguished as in the “earlier” or “later” phase of SP MS. Given this information and the results of the trials of Betaseron (interferon beta-1b) in SP MS, we now have a greater insight into the nature of SP MS. As a result, it may now be important to carefully explore the implications of the spectrum of SP disease in clinical trial design and treatment. Time

Reconciliation of Early Studies on the Use of Cyclophosphamide and Mitoxantrone in MS
Many early studies probably included patients with very active inflammation that led to the appearance of progressive disease The reality was that the dynamics of disease in these patients was characterized by active inflammation The Canadian cooperative trial and the Kaiser trial probably included a greater proportion of patients with primary progressive MS and true secondary progression CPM was effective in those with an active inflammatory component but not in those with slowly progressive degeneration observed in true secondary progression

Cyclophosphamide Potential Adverse Effects
Acute: Chronic: Nausea / malaise Infertility Alopecia Pulmonary fibrosis Hemorrhagic cystitis Myocarditis Myelosuppression Malignancy Infection

Mitoxantrone An anthracenedione related to dauxorubicin with potent immunosuppressive effects Intercalates DNA and blocks the synthesis of RNA Inhibits topoisomerase Potent effects on B-cell and T-cell function Inhibits both passive and active EAE

Clinical Trials of Mitoxantrone in MS
Early trials produced slightly conflicting results and employed dose regimens that differed considerably This may have been due to the patient populations studied What emerged was a marked reduction in relapse rate and a reduction in enhancing lesion frequency Suggesting that MITX might be useful in rapidly progressive forms of MS characterized by active inflammatory disease

Methylprednisolone and Mitoxantrone in MS (MP+M): Trial Design
Triage M -2 M -1 M 0 M 1 M 2 M 3 M 4 M 5 M 6 Randomized Treatment Mitoxantrone 20 mg/mo IV + Methylprednisolone 1 g/mo IV

MP+M: Lower Incidence of New MRI Lesions
Percentage of Patients Developing New Gd-Enhancing Lesions 100 MP (N = 21) MP+M (N = 21) *P = .009 †P = .030 ‡P = .033 §P = .001 * 80 † ‡ 60 Patients (%) 40 86% Reduction 20 -1 1 2 3 4 5 6 Months Edan et al

MP+M: Slower Progression of Neurologic Disability
Confirmed EDSS 1-Point Variation* Between Patient Inclusion and End of Study P<.01 (N = 12) (N = 12) Patients (%) (N = 8) (N = 6) (N = 3) (N = 1) *EDSS changes from and from were considered equivalent to 1-point change. The 1-point variation was measured for 2 months running at the end of the study. Edan et al

Mitoxantrone and IVMP in RPMS Relapse Assessment
Mito + IVMP P-value Baseline annualized relapse rate 2.9 3.1 NS On study annualized relapse rate 3.0 0.7 0.003 Patients free of relapses on study 7 (33%) 14 (67%) 0.031 Edan G et al. J Neurol Neurosurg Psychiatry. 1997;62:

MP+M: Conclusions Addition of mitoxantrone to methylprednisolone significantly Reduced new MRI lesions Slowed the progression of neurologic disability Reduced relapse rate Edan et al

Mitoxantrone in Multiple Sclerosis (MIMS): Study Design
2-year, double-blind, multicenter, placebo controlled 194 patients, years, EDSS 3-6 Treatment arms Mitoxantrone 5 mg/m2, IV, q3mo Mitoxantrone 12 mg/m2, IV, q3mo Placebo

MIMS Design Placebo Mitoxantrone 5 mg/m2 Mitoxantrone 12 mg/m2 R A N D
Z E Mitoxantrone 5 mg/m2 Mitoxantrone 12 mg/m2 Rx every 3 months x 24 months Follow up at Month 36 Hartung, H.P. et al. The Lancet v

MIMS Study Inclusion and Exclusion Criteria
Inclusion Criteria Exclusion Criteria Age 18 to 55 Definite MS (Poser’s criteria) Secondary progressive or remitting progressive MS (worsening RRMS) EDSS progression 1 point in preceding 18 months Baseline EDSS from Benign or primary progressive MS Relapse or treatment with corticosteroids in preceding 8 weeks Prior treatment with NOVANTRONE® Immunosuppressive therapy in preceding 9 months Cardiac risk factors Major medical illness Hartung, H.P. et al. The Lancet v

MIMS Baseline Demographics* (1)
Placebo (n=64) Mitox 5 Mitox 12 (n=60) Male/Female (%) 52/48 39/61 53/47 Mean age (years) 40 Type of MS Remittent progressive (%) 45 58 47 Secondary progressive (%) 55 42 53 * No significant differences between the 3 groups Hartung, H.P. et al. The Lancet v

Mitoxantrone Efficacy at 2 Years: Primary Efficacy Variables
Placebo (n=64) Mitoxantrone 12 mg/m2 (n=60) P-value Mitoxantrone 12 mg/m2 vs. Placebo Multivariate primary efficacy criterion <0.0001 EDSS change (mean) 0.23 -0.13 0.0194 Mean no. of treated relapses 1.20 0.40 0.0002 Time to first treated relapse (median months) 14.2 NR 0.0004 SNS change (mean) 0.77 -1.07 0.0269 NR=not reached within 24 months. Hartung, H.P. et al. The Lancet v

Mean Change in EDSS Changes in EDSS (m24 - Baseline) p = 0.0194 †
† Placebo vs. Mitoxantrone 12 mg/m2 Hartung, H.P. et al. The Lancet v

EDSS >1.0 Point Deterioration from Baseline
% of patients (N=5) † Placebo vs. Mitoxantrone 12 mg/m2 Hartung, H.P. et al. The Lancet v

Time to First Treated Relapse
Placebo Mitox 12 1.00 0.75 Mitox 12mg not reached 0.50 Placebo =14.19 m. 0.25 p=0.0004† 0.00 3 6 9 12 15 18 21 24 Months † Placebo vs. Mitoxantrone 12 mg/m2 Hartung, H.P. et al. The Lancet v

MIMS: Patients With New Gd-Enhancing Lesions (N = 110)
19% (N = 7) P = .02 at Month 24 Placebo Mitoxantrone 12 mg/m2 16% (N = 5) 12% (N = 4) Patients (%) (N = 0) 0% Month

Mean Change in Number of T2-Weighted Lesions at 24 Months
Significantly Reduced the Change in the Number of T2-Weighted Lesions vs Placebo Mean Change in Number of T2-Weighted Lesions at 24 Months 85% reduction Mitoxantrone 12 mg/m2 (n=28) Placebo (n=32)

Potential Adverse Effects of Mitoxantrone
Acute Alopecia Myelosupression Infection Nausea/vomiting Malaise Discoloration of sclera Arrhythmia Chronic Cardiac toxicity Malignancy Amenorrhea Infertility Fetal malformation

Mitoxantrone Approved by the FDA for worsening RR MS, SP MS with relapse, and PR MS Recognized as a rescue therapy More dangerous than A,B,C,R Useful in those failing conventional therapy or with aggressive disease from the outset

The “Evolution” Much has changed since the advent of mitoxantrone
Our understanding of the disease process and the importance of the inflammatory process has grown substantially Not much has changed regarding the profiles of the chemotherapeutic agents used and being developed Cladribine is a perfect example

Cladrbine Synthetic purine analogue product (adenosine analogue)
Deoxycytidine kinase (phosphorylation) Affect cellular metabolism, induce DNA damage and apoptosis in dividing and non dividing cells Reduction of CD4 and CD8 T cells, B cells but also other immune cells such as neutrophils and monocytes

Background Approved by FDA for:
Hairy cells leukemia Malignant lymphoma A few phase 1 and 2 studies have been conducted in MS with cladribine iv or s/c. Pregnancy category D

The FDA has a categorization of drug risks to the fetus that runs from: "Category A" (safest) to "Category X" (known danger--do not use!) Category A Controlled studies in women fail to demonstrate a risk to the fetus in the first trimester (and there is no evidence of a risk in later trimesters), and the possibility of fetal harm appears remote. Category B Either animal-reproduction studies have not demonstrated a fetal risk but there are no controlled studies in pregnant women, or animal-reproduction studies have shown an adverse effect (other than a decrease in fertility) that was not confirmed in controlled studies in women in the first trimester (and there is no evidence of a risk in later trimesters). Category C Either studies in animals have revealed adverse effects on the fetus (teratogenic or embryocidal or other) and there are no controlled studies in women, or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the fetus. Category D There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective). Category X Studies in animals or human beings have demonstrated fetal abnormalities, or there is evidence of fetal risk based on human experience or both, and the risk of the use of the drug in pregnant women clearly outweighs any possible benefit. The drug is contraindicated in women who are or may become pregnant.

CLARITY - Treatment Regimen
Annual short-course treatment Each course = 1–2 tablets (10 mg) daily for 4 or 5 consecutive days per month Courses given for 2 or 4 consecutive months in Year 1 and for 2 consecutive months in Year 2 First 48 weeks Second 48 weeks X X X X X X Placebo •• •• 1326 randomized (1:1:1) X X Screening Placebo course Cladribine course X Cladribine tables: 4 courses, total dose 3.5 mg/kg • •• •• •• Cladribine tables: 6 courses, total dose 5.25 mg/kg Giovannoni G et al. Presented at American Academy of Neurology 61st Annual Meeting; Seattle, USA; April 30, 2009. 134

Primary Outcome Reduction in Relapse Rates (ITT)
54.5% reduction (P < 0.001) 57.6% reduction (P < 0.001) 0.33 Annualized relapse rate 0.15 0.14 Placebo (n = 437) Cladribine 3.5 mg/kg (n = 433) Cladribine 5.25 mg/kg (n = 456) ITT = intent-to-treat population; error bars indicate upper limit of 95% confidence interval. Giovannoni G et al. Presented at American Academy of Neurology 61st Annual Meeting; Seattle, USA; April 30, 2009. 135

Secondary Outcome Reduction in Disability Progression (ITT)
Hazard ratio vs placebo (95% CI)* Placebo Cladribine 3.5 mg/kg (0.48, 0.93); P = 0.018 Cladribine 5.25 mg/kg (0.49, 0.96); P = 0.026 33% 31% Proportion with 3-month confirmed EDSS progression (%) Relative reduction Number of patients at risk: Placebo 3.5 mg/kg 5.25 mg/kg 437 433 456 424 447 399 407 425 373 389 404 355 379 388 333 364 375 315 355 363 304 347 350 304 347 350 Time to sustained change for  3 months in EDSS of  1 point (or  1.5 point if baseline EDSS was 0, or  0.5 point if baseline EDSS was 5); CI = confidence interval; *Cox proportional hazards model. Giovannoni G et al. Presented at American Academy of Neurology 61st Annual Meeting; Seattle, USA; April 30, 2009. 136

Secondary Outcome Improvement in MRI Parameters (ITT)
Placebo Cladribine 3.5 mg/kg Cladribine 5.25 mg/kg –87.9%* –76.9%* –77.9%* 2.00 –86.8%* –73.4%* –74.6%* 1.50 *P < 0.001 *P < 0.001 *P < 0.001 Mean ± SE lesions/patient/scan 1.00 0.50 T1 Gd+ lesions Active T2 lesions Combined unique lesions SE = standard error. Giovannoni G et al. Presented at American Academy of Neurology 61st Annual Meeting; Seattle, USA; April 30, 2009. 137

Secondary Outcome Safety Overview
Patients with AE (%) Placebo (n = 435) Cladribine mg/kg (n = 430) Cladribine mg/kg (n = 454) Cladribine overall (n = 884) Any treatment-emergent AE AEs leading to discontinuation AEs leading to withdrawal Serious AEs Deaths* 73.3 2.1 1.1 6.4 0.5 (n = 2) 80.7 3.5 1.2 8.4 83.9 7.9 2.0 9.0 (n = 2) 82.4 5.8 1.6 8.7 0.4 (n = 2) *Placebo: hemorrhagic cerebrovascular accident, suicide; cladribine 3.5 mg/kg: acute myocardial infarction, pancreatic carcinoma; cladribine 5.25 mg/kg: drowning, pancytopenia/pneumonia then cardiorespiratory arrest. AEs = adverse events Giovannoni G et al. Presented at American Academy of Neurology 61st Annual Meeting; Seattle, USA; April 30, 2009. 138

Cladribine Depletion of Lymphocyte Subpopulations in Phase 3 Trial in SPMS and PPMS CD4+ (helper T cells) CD8+ (cytotoxic T cells) CD19+ (B cells) CD19+/CD56+ (natural killer cells) Placebo Cladribine 0.7 mg/kg Cladribine 2.1 mg/kg Guarnaccia JB, et al. Presented at: WCTRIMS; September 17-20, 2008; Montreal, Canada. [P55].

Cladribine: Effect after 3-5 years on Naïve (CD45RA+) and Memory (CD45RO+) - CD4+ Tcells
Hairy Cell Leukemia patients were treated with Cladribine (1 mg/kg c.i. for 7 days) At 3-5 years post dose, there was a decrease in CD4+/CD45RA+ cells while CD4+CD45RO+ cells slightly increased These findings may suggest that CD4+/CD45RA+ cells are more sensitive than CD4+/CD45RO+ to the toxic effect of cladribine FC JG Raspadori D, et al. Leukemia. 1999;13:

Subject with Resolved Grade 3 and 4 Toxicity Hematology (resolved = returning to Grade 1 or 0)
App. 50% of Grade 3 and 4 lymphopenia resolved on study; median duration ~ 24 wks Almost all other Grade 3 and 4 toxicities resolved on study Laboratory test Statistics Cladribine 5.25 mg/kg (n=454) n (%) Cladribine 3.5 mg/kg (n=430) Placebo (n=435) Haemoglobin Mean duration (SD) (weeks) Median duration (weeks) Min;Max duration (weeks) 0 (1 total) 3 (5 total) 17.5 (6.8) 18.1 10.4;24.0 2 (3 total) 13.0 (8.3) 13.0 7.1;18.9 WBC 8 (10 total) 11.8 (10.3) 9.0 1.4;29.1 6 (6 total) 3.7 (1.9) 3.4 1.6;6.0 2 (2 total) 2.8 (0.9) 2.8 2.1;3.4 Neutrophils 17 (17 total) 8.1 (9.6) 5.9 1.1;42.1 12 (12 total) 5.2 (3.8) 4.9 1.0;12.1 17 (18 total) 4.8 (3.1) 4.3 1.1;12.1 Lymphocyte 108 (203 total) 29.4 (20.8) 24.1 2.9;88.0 52 (110 total) 25.4 (19.8) 23.4 0.9;92.7 4.6 (0.6) 4.6 4.1;5.0 PS. Sorenson, et al. Presented at ECTRIMS 25th Annual Meeting; Dusseldorf, Germany; September 10, 2009; Poster 472.

Adverse Events of Special Interest Herpes Zoster
Preferred term, n (%) patients Placebo (n=435) Cladribine 3.5 mg/kg (n=430) Cladribine mg/kg (n=454) Cladribine overall (n=884) Herpes zoster 8 (1.9) 11 (2.4) 19 (2.1) Herpes zoster oticus 1 (0.2) 1 (0.1) Varicella 1 (0.2) 2 (0.2) Severity grades as follows: mg/kg group: mild=7, moderate=5, severe=1 (oticus), serious*= mg/kg group: mild=2, moderate=5, severe=1, serious*=1 *so classified because they resulted in hospitalisation RELATIONSHIP BETWEEN LYMPHOCYTE COUNTS AND ZOSTER Herpes zoster, herpes zoster neurological and herpes zoster oticus infections developed in 17, 2 and 1 patients, respectively (8 in the 3.5 mg/kg group and 12 in the 5.25 mg/kg group). In the 3.5 mg/kg group, 5 out of the 8 patients (62.5%) experienced grade 3 or 4 lymphopenia at any time during the study, and 5 out of the 12 (41.7%) in the 5.25 mg/kg group did likewise. Herpes zoster infections therefore developed in 3.18% of cladribine tablet treated patients experiencing grade 3 or 4 lymphopenia at anytime during study compared with development in 1.75% of cladribine tablet treated patients that did not experience grade 3 or 4 lymphopenia during the study. Serial lymphocyte measurements reveal that in 70% of patients that developed zoster infection, lymphocyte counts were grade 2 or above at the approximate time of infection (lymphocyte counts were within grade 0, 1, 2 and 3 for 3, 3, 8 and 6 patients respectively). Herpes zoster was reported more frequently with cladribine tablets than placebo 20 patients had 21 zoster events in the cladribine tablets groups All 21 cases were self-limiting and dermatomal S. Cook, et al. Presented at ECTRIMS 25th Annual Meeting; Dusseldorf, Germany; September 11, 2009. 142

Adverse Events of Special Interest Malignancies
Preferred term, % (n) Placebo (n = 435) Cladribine mg/kg (n = 430) Cladribine mg/kg (n = 454) Cladribine overall (n = 884) During study Cervix carcinoma Stage 0 Malignant melanoma Ovarian cancer Pancreatic cancer, metastatic During post-study surveillance Choriocarcinoma 0.2 (1) 0.1 (1) Giovannoni G et al. Presented at American Academy of Neurology 61st Annual Meeting; Seattle, USA; April 30, 2009.

Cladribine FC JG

Cladribine Summary Efficacy is comparable to high dose IFN
Toxicity is considerable Risk of malignancy Long-term immunosuppression Increased risk of herpes infections Infertility Fetal malformation Graft vs. host How long can it be used with CD-4 counts markedly reduced What do you do if patients are worsening?

Evolution? There has been no evolution!
Chemotherapeutic agents remain nonselective, broad spectrum cytotoxic agents that suppress the immune system in a nonspecific fashion They all have considerable risk of adverse events that include secondary malignancy, infection, infertility, fetal malformation, and other end organ toxicity Newer monoclonal antibodies and other innovative therapies appear equally or more effective and have manageable risk

Challenging Cases in the
Case Studies Challenging Cases in the Management of Multiple Sclerosis and Parkinson’s Disease

Multiple Sclerosis Case #1
24-year-old female with diplopia on looking to the right for a day or two – Austin ophthalmologist found nothing unusual Back in Houston another ophthalmologist called it ‘some type of optic nerve inflammation’ and gave her 5 days of oral steroids 2 weeks into symptoms seen by a pro who noted skew deviation, marked asymmetric nystagmus with torsion and jerk greater to the right, no INO, no APD and normal VERs to go with complaints of vertical diplopia and oscillopsia

UPIN 4804 06/06/08

4 days later continued double vision on looking to the right Extensive past history uncovered only one week of nausea and vomiting about 4 months ago attributed to food poisoning Nystagmus to right gaze of greater amplitude in adducting eye with incomplete abduction of right eye, remaining exam normal CSF with 10 lymphocytes, IgG index 1.15 and 3 OCBs Intravenous methylprednisolone course started

UPIN 4804 07/02/08

Multiple Sclerosis Case #1 The Issues
The subject was born and raised outside of the reach of the Scandinavian gene pool - is this NMO, and how unusual is this? When you have CIS and can’t diagnose more than suspect MS by McDonald’s or Swanton’s, do you just treat, use Frohman? When asked about the familial risk of MS in the company of the patients twin sister, what is the best course?

30-year-old Caucasian female presented initially with right optic neuritis. Vision improved after high dose intravenous methylprednisolone treatment T2-weighted MRI brain scan showed 2 areas of abnormal signal in the periventricular and subcortical white matter. No disease modifying therapy was started at that time.

1 year later- numbness and weakness of both legs, urinary hesitancy, and increasing gait difficulties over several days. MRI cord -increased T2 signal at C8 with a corresponding area of Gd enhancement on T1. MRI brain- one new periventricular white matter lesion without enhancement in comparison to last year’s. Motor symptoms improved with high dose corticosteroid therapy Residual numbness in the feet and bladder control difficulties.

Given diagnosis of MS and therapy with once weekly IM interferon beta was begun. 6 months later she complained of markedly increased fatigue and “fuzzy thinking.” Brain MRI scan revealed several new T2 lesions in both cerebral hemispheres and several new enhancing lesions around the corpus callosum. Disease modifying therapy was changed to a high dose subcutaneous interferon beta.

Over the next year, she had no new symptoms and there were no new lesions seen on a repeat MRI scan. After several months she complained of balance difficulties, memory difficulties, and an increase in fatigue. MRI scan showed additional Gd+ enhancing lesions. A test for neutralizing antibody against interferon beta (NAb) revealed a titer greater than 1:100.

The same interferon treatment was continued but after several months she complained of ongoing problems with memory. Several new enhancing lesions were again found on MRI. A repeat NAb titer was unchanged.

Student nurse falls hitting head on concrete when obese patient she is transporting begins to fall off litter. MRI shows pineal cyst. 18 months later, follow-up MRI shows unchanged cyst but single periventricular non- enhancing white matter lesion. Three yearly follow-ups show no new MRI lesions, no symptoms and no neurologic abnormalities.

Is it Multiple Sclerosis?
While hiking with physician husband on hot afternoon, she notes numbness in left foot. Spinal cord MRI shows enhancing lesion at T17. Is it MS? Treatment recommendations?

32-year-old healthy female post-doc researcher who participated in an MRI study as a volunteer. Subject has no family history of MS or immune-mediated diseases. No personal past medical history. No neurological symptoms except rare migraine headaches and no signs on her neurological exam.

Research Brain MRI

Parkinson’s Disease Case #1
A 56-year-old male in good health presents with slight, intermittent rest tremor of the left (non-dominant) hand. Tremor worse with stress and when he walks. Wife has noticed decreased arm swing on the left. He notes some stiffness on the left side and some constipation. He states that symptoms are only minimally bothersome and not interfering with job or home life. The couple is troubled that the condition will become apparent to coworkers and interfere with career.

Family History: No family history of Parkinson’s disease Medical History/Medications: Wife noticed that for the past three years the patient moves about during sleep. No current medications Examination: Reveals normal mental status and eye movements. He has slight bradykinesia on repetitive alternating movements in the left hand and a slight rest tremor is noted. Decision making: Making the diagnosis of PD; early non-motor features of PD; when to initiate therapy

58-year-old male in good health presents with resting tremor of the right (dominant) hand and difficulty with simple tasks such as brushing teeth and combing hair. He works as a desk clerk and has noticed significant problems with writing. Also has trouble buttoning and at times has trouble cutting food. Complains of fatigue, lack of motivation and disinterest. He tends to fall asleep easily during the day.

Family History: Father died with Parkinson Disease and a cousin diagnosed with Parkinson’s disease 2 years ago is responding well to levodopa Medical History/Medications: No significant medical or surgical history. No current medications Examination: Bilateral bradykinesia and asymmetric rest tremor right greater than left. Gait is slow but there is no problem turning. Pull Test is negative. Rest of the examination is normal Decision making: Patient diagnosed with Parkinson’s disease with some disability and he wishes to start treatment.

68-year-old woman with a 4-year history of Parkinson’s disease. She initially presented with asymmetric tremor involving the left hand. Subsequently, she progressed to have tremor both sides and significant slowness bilaterally. Was started on levodopa 3 years ago. Currently takes carbidopa-levodopa 25/100 one tablet 4 times per day. She is experiencing return of tremor and slowness and sweating and abdominal pain as the medication is wearing off. During off periods, and in the early morning hours and she has painful dystonia of the left foot. She has abnormal movements while the medication is working.

Family History: no relatives with PD Medical History: No significant medical or surgical history Medications: Amitriptyline 50 mg. q.h.s for depression in addition to carbidopa-levodopa Decision making: treatment of motor fluctuations, non-motor features of PD

82-year-old woman has a history of Parkinson’s disease for 12 years. She presented with shuffling gait, masked facies, postural instability, and a pill-rolling tremor of the right hand. Initially responded well to carbidopa-levodopa. Then she developed mild wearing off and dyskinesia. Over the past two years she has been experiencing visual hallucinations, paranoia, and vivid dreams. She has become more forgetful and gets lost easily around familiar places. She falls frequently.

Family History: 87-year-old sister diagnosed with Alzheimer’s disease and Parkinson’s disease Medical History: Mild stroke 3 years ago; has minimal residual effects of right-sided weakness. Medications: She takes 1 aspirin daily in addition to carbidopa-levodopa Decision making: management of advanced PD motor and non-motor features

Multiple Sclerosis and Parkinson’s Disease

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