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Optimizing Neurotherapy for Multiple Sclerosis and Parkinsons Disease Applying Science, Expert Analysis, Guidelines, and Landmark Trials to the Front.

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Presentation on theme: "Optimizing Neurotherapy for Multiple Sclerosis and Parkinsons Disease Applying Science, Expert Analysis, Guidelines, and Landmark Trials to the Front."— Presentation transcript:

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2 Optimizing Neurotherapy for Multiple Sclerosis and Parkinsons Disease Applying Science, Expert Analysis, Guidelines, and Landmark Trials to the Front Lines Patient Care New Frontiers and Landmark Practice Advances 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 Parkinsons Disease Center Mount Sinai School of Medicine

3 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 Welcome and Program Overview

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

5 Parkinsons Disease and Multiple Sclerosis Two Diseases in Need of a Neuroprotective Therapy New Frontiers and Landmark Practice Advances 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 Parkinsons Disease Center Mount Sinai School of Medicine

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

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

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

9 Attempts to Obtain Neuroprotection for Parkinsons Disease New Frontiers and Landmark Practice Advances 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 Parkinsons Disease Center Mount Sinai School of Medicine

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

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

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

13 Neuroprotective Trials in PD Negative Studies AgentMechanismEndpoint Vitamin E Anti-oxidant Time to L-dopa RiluzoleAnti-glutamate MinocyclineAnti-Inflammatory Δ UPDRS ImunophilinTrophic Time to L-dopa GDNF/Neurturin Trophic factors Δ UPDRS TCH346Anti-apoptotic Time to L-dopa CEP1347Anti-apoptotic DA Cell Transplant Cell replacement Δ UPDRS/QOL

14 Obstacles to Finding a Neuroprotective Therapy for PD We do not know the precise etiology or pathogenesis of PDwe dont know what to target We do not know the precise etiology or pathogenesis of PDwe dont 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 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 good method for determining the optimal dose to use in a clinical trial

15 Neuroprotective Trials in PD Positive Studies AgentMechanismEndpoint Selegiline (DATATOP) Anti-apoptotic Time to L-dopa Selegiline (SINDEPAR) Anti-apoptotic Wash Out Co-Q10Bio-energetic Δ UPDRS CreatineBio-energetic RopiniroleAnti-apoptotic Β-CIT-SPECT PramipexoleAnti-apoptotic F-DOPA PET

16 Obstacles to Finding a Neuroprotective Therapy for PD We do not know the precise etiology or pathogenesis of PD –we dont know what to target We do not know the precise etiology or pathogenesis of PD –we dont 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 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 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 We do not have a clinical trial design that can reliably detect a disease-modifying agent

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

18 Delayed Start Design Placebo Early Start Intervention Period I Early Start

19 Placebo SymptomaticEffect Delayed Start Intervention Early Start Intervention Period I Period II Early Start Delayed Start Start Delayed Start Design

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

21 Delayed Start Study Principal Statistical Analyses Delayed Start (Placebo-Rasagiline) Early Start (Rasagiline-Rasagiline) Adapted from Olanow et al. Mov Disord Week Mean UPDRS change from baseline Worsening Improvement I I. Superiority of Early Start vs Placebo (UPDRS Slope weeks 12 – 36) III III. Non-Inferiority of Early Start vs Delayed Start (UPDRS slope weeks 48 – 72;) II II. Superiority of Early Start vs Delayed Start ( UPDRS change from baseline to week 72)

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

23 The ADAGIO Study

24 ADAGIO Study Design Olanow et al. Mov Disord month 36-week (9-month) Double Blind Active- Treatment Phase Week 36-week (9-month) Double Blind Placebo- Controlled Phase 1242 Placebo 1 mg/day 2 mg/day 1 mg/day Untreated PD patients 2 mg/day

25 ADAGIO – Baseline Characteristics Olanow et al. Mov Disord 2008 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 Motor ADL ADL 20.4 (8.5) 14,2 (6.4) 5.2 (2.8) Hoehn & Yahr score (mean, SD) 1.5 (0.5)

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

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

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

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

30 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 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 Long-term studies are required to assess effect of drug on cumulative disability Extension study Extension study Long-term simple study Long-term simple study Endpoints that include measures of motor and non- motor function - UPDRS gait, cognitive function, and quality of life Endpoints that include measures of motor and non- motor function - UPDRS gait, cognitive function, and quality of life

31 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 From Mechanisms to Therapy-Landmark Trials, Long- Term Safety Data, and Clinical Experience New Dimensions and Landmark Practice Advances 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

32 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 From Mechanisms to Therapy-Landmark Trials, Long- Term Safety Data, and Clinical Experience New Dimensions and Landmark Practice Advances 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.

33 MS: Immune Dysfunction Proinflammatory immune cells Proinflammatory cytokines Antigen-presenting cell Blood-brain barrier 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: T cells

34 Diagnosis of MS Based on modifications to McDonald Criteria CSF = cerebrospinal fluid Polman CH, et al. Ann Neurol. 2005;58: Compston A, Coles A. Lancet. 2008;372: Figure 1.

35 Differentiating MS Lesions Using MRI T2 T1 Post-Gd Contrast Active Inflammation T1 Precontrast Black Holes AB C T2 with FLAIR D FLAIR = Fluid Attenuated Inversion Recovery Slide courtesy of JS Wolinsky. Note: Scans are not from the same patient.

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

37 National MS Society. Clinically isolated syndrome. sclerosis/diagnosing-ms/cis/index.aspx. Accessed 12/08. 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. 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. 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. Individuals who experience CIS with no evidence of MRI- detected lesions are at relatively low risk of developing MS.

38 Fisniku LK, et al. Brain. 2008;131: CIS: MRI Lesions at Baseline Associated with Development of CDMS Over Next 20 Years 21% 82% 85% 81% (n = 34)(n = 22)(n = 20)(n = 31)

39 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 ® (IFN -1b) in Newly Emerging MS for Initial Treatment Time to CDMS Time to McDonald MS Completed CHAMPS Controlled High-Risk Subjects (IFN -1a) Avonex ® Multiple Sclerosis Prevention Study Probability of developing CDMS Changes in MRI Completed ETOMS Early Treatment of MS Study (IFN -1a) Conversion to CDMS Completed REFLEX Rebif ® (IFN -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:

40 Completed CIS Clinical Trials: Demographics and Key Results ParameterPreCISe(GA)BENEFIT (IFN -1b SC) CHAMPS (IFN -1a IM) ETOMS (IFN -1a SC) Duration 3 yrs (stopped early) 2 yrs 3 yrs (stopped early) 2 yrs Patients (N) Patient age 31 ± 7 yrs 30 yrs 33 ± 7 yrs 28 ± 6 yrs EDSS (mean) NA1.5NA 1.17 ± 1.2 % Reduction in CDMS Risk 45%50%44%39% P-value < 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:

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

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

43 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. 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.

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

45 Chan A, et al. J Neuron. 2008;255(suppl 6): Current MS Therapies Immunosuppressants or Immunomodulators? Generally considered to be immunomodulators Generally considered to be immunomodulators Glatiramer acetate [GA] injection Glatiramer acetate [GA] injection IFNβ products IFNβ products Natalizumab (?) Natalizumab (?) Uses of these immunomodulators Uses of these immunomodulators GA and IFNβ products are first-line therapies for the long-term treatment of CIS and RRMS 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 Natalizumab for patients who are unresponsive or who cannot tolerate first-line DMTs, first-line use in very active RRMS

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

47 Presumed MOA of Glatiramer Acetate: Immunomodulation Induces a population of regulatory T-cell types (Th2,Treg) Induces a population of regulatory T-cell types (Th2,Treg) Anti-inflammatory cytokines and neurotrophic factors are released Anti-inflammatory cytokines and neurotrophic factors are released May prevent nerve damage and lead to remyelination* 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 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. Proinflammatory immune cells Regulatory T-cell types Antigen-presenting cell T cells Proinflammatory cytokines Anti-inflammatory cytokines Neurotrophic factors Blood-brain barrier Weber MS, et al. Neurotherapeutics. 2007;4: Aharoni R, et al. Proc Natl Acad Sci U S A. 2008;105:

48 Interferons Avonex ®, Betaseron ®, Rebif ® Doses: Doses: Avonex ® : 30 mcg IM once weekly Avonex ® : 30 mcg IM once weekly Betaseron ® : 250 mcg SC every other day Betaseron ® : 250 mcg SC every other day Rebif ® : 22 mcg, or 44 mcg, SC TIW Rebif ® : 22 mcg, or 44 mcg, SC TIW Pregnancy Category: C Pregnancy Category: C Drug Interactions: Possible with hepatically active drugs Drug Interactions: Possible with hepatically active drugs Laboratory monitoring: CBC, LFT, thyroid Laboratory monitoring: CBC, LFT, thyroid Adverse events: Flu-like symptoms, injection site reaction, depression, hepatic injury Adverse events: Flu-like symptoms, injection site reaction, depression, hepatic injury

49 Presumed MOA of IFN β : Immunomodulation Reduces proinflammatory cytokine levels Reduces proinflammatory cytokine levels Reduces lymphocyte trafficking into the central nervous system (CNS) Reduces lymphocyte trafficking into the central nervous system (CNS) Proinflamatory immune cells Eliminated immune cell Antigen-presenting cell Proinflammatory cytokines T cells Blood-brain barrier Betaseron ® prescribing information. Bayer HealthCare Pharmaceuticals Inc.

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

51 Presumed MOA of Natalizumab: Reduction of Cell Trafficking Inhibits the α4-mediated adhesion of leukocytes to vascular cell adhesion molecule-1 Inhibits the α4-mediated adhesion of leukocytes to vascular cell adhesion molecule-1 Strongly reduces proinflammatory cell recruitment to the CNS Strongly reduces proinflammatory cell recruitment to the CNS Proinflammatory immune cells Proinflammatory cytokines Antigen-presenting cells T cells Blood-brain barrier Tysabri ® (natalizumab) prescribing information. Biogen Idec Inc. Tysabri ® (natalizumab) prescribing information. Biogen Idec Inc.

52 Head to Head Clinical Trials

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

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

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

56 Head to Head Clinical Studies 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

57 Time to First Relapse (Primary Endpoint) Survival distribution function Time to first relapse (days) Hazard ratio (95% CI): (0.74, 1.21) p = GA IFNβ-1a 672 days (96 weeks) Adapted from an analyst report by Bernstein Research, October 15, 2007.

58 Head to Head Clinical Studies Betaseron Efficacy Yielding Outcomes of a New Dose (The BEYOND Study)

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

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

61 The BECOME Study Study Design Study Design Investigator-initiated study (single site) Investigator-initiated study (single site) N = 75 N = 75 RRMS (61) and CIS (14) patients RRMS (61) and CIS (14) patients Triple dose Gd with 40 min post-injection delay Triple dose Gd with 40 min post-injection delay 3-Tesla MRI 3-Tesla MRI This protocol is optimized to detect enhancement… This protocol is optimized to detect enhancement… Sponsored by Berlex/Schering AG Sponsored by Berlex/Schering AG Primary Outcome Measure Primary Outcome Measure The mean number of combined active lesions (CALs) per scan The mean number of combined active lesions (CALs) per scan CALs were defined as Gd-enhancing lesions + new T2/FLAIR lesions unassociated with enhancement CALs were defined as Gd-enhancing lesions + new T2/FLAIR lesions unassociated with enhancement 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.

62 BECOME: Summary Primary Outcome (CAL Count) 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 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 No significant differences on the following secondary outcomes New enhancing lesions New enhancing lesions Black Holes (acute hypointensities and persistent black holes) Black Holes (acute hypointensities and persistent black holes) Clinical: ARR, sustained disability progression, cognitive function 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 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.

63 Trends Across Clinical Trials: % Reduction in ARR – ~2 Years % Reduction in ARR vs Baseline Johnson1995Jacobs1996 IFNβ-1b study group,1993PRISMS-21998Kappos ECTRIMS 2006, NEJM 2006 Polman2006REGARD2007REGARD2007BEYOND2007BEYOND2007BECOME2007BECOME GAAvonexBetaseronRebif 44FTY720TysabriGARebif 44GABetaseronGABetaseron

64 Trends Across Clinical Trials: Annualized Relapse Rate – ~2 Years Johnson1995Polman2006REGARD2007REGARD2007BECOME2007BECOME2007Kappos ECTRIMS 2006 Jacobs1996 IFNB-1b study group,1993PRISMS-21998BEYOND2007BEYOND2007 Annualized Relapse Rate – 2-yrs

65 Long Term IMT Data

66 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: Bermel RA, et al. WCTRIMS Abstract P IFNβ Study Group. Neurology. 1995;45: Ebers G, et al. AAN P Kappos L, et al. Neurology. 2006;67: OConnor PW, et al. AAN P

67 Pivotal Trial and Extension-Phase Study Design Months Withdrawn total (n=132) 180 Double-blind, placebo-controlled phase 035*60 glatiramer acetate injection placebo EDSS assessment Ongoing (n=100) mITT (n=232) 8.6 years 13.6 years Ongoing 6-month assessments Open-label extension phase 4.8 years 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: *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 year analysis for Ongoing cohort Mean disease duration: 22 years

68 # of pts : * * Mean Relapse Rate *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 Yearly Relapse Rate While on GA Year Ford CC, et al. Mult Scler. 2006;12:

69 Demonstrated Long-term Benefits Patients (%) EDSS levels at 15-year follow-up EDSS of 8 or higher 3%3% EDSS of 6 or higher 18 % EDSS of 4 or higher 38 % 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.

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

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

72 IFNβ-1b 250 µg IFNβ-1b 50 µg Placebo Pivotal Study (n=372) LTF 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 Patients under regular medical care - no trial Year Follow-Up Goodin et al., Multiple Sclerosis; 2008: 14 (Suppl 1), P52

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

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

75 PRISMS Long Term Follow-up 8-year follow-up of PRISMS SC IFNβ1a pivotal relapsing trial 8-year follow-up of PRISMS SC IFNβ1a pivotal relapsing trial 382 of 560 subjects (68.2%) evaluated 382 of 560 subjects (68.2%) evaluated 275 (72%) still receiving IFNβ1a 275 (72%) still receiving IFNβ1a Subjects initially randomized to 44mcg showed best EDSS, relapse rate, T2 burden of disease at 8 years 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 19.7% progressed to SPMS Neurology 2006;67:944

76 Natalizumab Monotherapy Trial: ARR Polman CH et al. N Engl J Med. 2006;354: % reduction* *P< Preplanned interim analysis. Final analysis.

77 Natalizumab Monotherapy Trial: Time to Sustained Progression Adapted with permission from Polman CH et al. N Engl J Med. 2006;354: Placebo Natalizumab P<0.001.

78 Natalizumab: AFFIRM Gd-Enhancing Lesion s P<0.001 between groups for all time intervals. Miller DH et al. Neurology. 2007;68: %

79 Miller DH et al. Neurology. 2007;68: Natalizumab: AFFIRM T2 Lesions P< %

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

81 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 New Dimensions and Landmark Practice Advances

82 Chemotherapeutic Nonspecific cytotoxic agents that kill cells via a mechanism that involves impairment of cell division 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 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 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 Immunosuppressive agents that also increase the risk of infection through the nonspecific suppression of immune function

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

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

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

86 Azathioprine Earliest studies date back to 1971 Earliest studies date back to 1971 Small poorly controlled trials suggested a modest effect on relapses Small poorly controlled trials suggested a modest effect on relapses Later controlled trials confirmed an effect on relapse rate but not disability progression Later controlled trials confirmed an effect on relapse rate but not disability progression Cochrane meta analysis suggested an effect on relapse rate 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 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

87 Azathioprine Used widely in Europe prior to the introduction of IFNβs Used widely in Europe prior to the introduction of IFNβs Less popular in the modern era of immunomodulatory therapy 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) 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 Use as a monotherapy felt to be suboptimal given potential for longterm toxicity

88 Azathioprine in Multiple Sclerosis 354 patients randomized to azathioprine vs. placebo 354 patients randomized to azathioprine vs. placebo Double blinded, 3 yr duration Double blinded, 3 yr duration At 3 yrs mean EDSS decreased 0.80 in the placebo and 0.62 in the treated group 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) 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 Results showed a very small benefit Could not be recommended for most patients with MS Could not be recommended for most patients with MS Lancet. 1988; 23:

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

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

91 Cyclophosphamide Early studies suggested a possible effect in secondarily progressive MS and rapidly progressive MS 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 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 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 Both were right. It depended on whether the extent of the inflammatory process present Hauser et. al. Weiner et. al. 1993

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

93 NE Cooperative Study Percentage Stable/Improved on DSS Months on Study Induct (20) 75%56%46%24%17%15% Boosters (127) 71%55%48%38%27%20% P value

94 NE Cooperative Study Months on Study, with Maintenance Younger (<41) 81%62%57%42%40%28% Older (>41) 60%47%40%34%14%21% P value

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

96 Canadian Cooperative Trial CP-MS CP-MS EDSS and increase >1.0 step prior 1 year EDSS and increase >1.0 step prior 1 year Randomized Randomized IVCTX + prednisone55 IVCTX + prednisone55 PlEx + POCTX + prednisone57 PlEx + POCTX + prednisone57 Sham PlEx + placebo po meds56 Sham PlEx + placebo po meds56 Blinded examining neurologist Blinded examining neurologist Lancet 337:441, 1991

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

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

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

100 Proportion of treatment failures Proportion of treatment failures CTX35% CTX35% PlEx32% PlEx32% Plac29% Plac29% Mean time to treatment failure (months) Mean time to treatment failure (months) CTX CTX PlEx PlEx Plac Plac Canadian Cooperative Trial Results Lancet 337:441, 1991

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

102 Canadian Cooperative Trial Results CTX vs placebo p=0.088 M24 vs. baseline ImprovedStableWorse IVCTX 2 (6%) 13 (42%) 16 (52%) PIEx 1 (3%) 25 (81%) 5 (16%) Placebo0 20 (67%) 10 (33%) Lancet 337:441, 1991

103 Canadian Cooperative Trial Results CTX vs placebo p=0.290 M36 vs. baseline ImprovedStableWorse IVCTX 2 (4%) 24 (44%) 28 (52%) PIEx 1 (2%) 34 (59%) 22 (39%) Placebo 1 (2%) 32 (59%) 21 (39%) Lancet 337:441, 1991

104 Kaiser Study CP-MS (EDSS ) CP-MS (EDSS ) Increased EDSS or AI >1 step prior 1 year Increased EDSS or AI >1 step prior 1 year Randomized Randomized IV CTX22 IV CTX22 Placebo20 Placebo20 Single-blind Single-blind Likosky WH et al. JNNP 54:1055, 1991

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

106 Kaiser Study Results Mean EDSS Placebo- CTX (95% CI) MonthCTXPlacebo 0 to (-0.60 to 0.65) 0 to (-0.40 to 1.10) 0 to (-0.45 to 1.23) Likosky WH et al. JNNP 54:1055, 1991

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

108 Relapsing-remitting Secondary-progressive Preclinical Time Natural History of MS Measures of brain volume Relapses and impairment MRI burden of disease MRI activity

109 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 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 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 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 CPM was effective in those with an active inflammatory component but not in those with slowly progressive degeneration observed in true secondary progression

110 Cyclophosphamide Potential Adverse Effects Acute:Chronic: Nausea / malaiseInfertility AlopeciaPulmonary fibrosis Hemorrhagic cystitisMyocarditis MyelosuppressionMalignancy Infection

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

112 Clinical Trials of Mitoxantrone in MS Early trials produced slightly conflicting results and employed dose regimens that differed considerably Early trials produced slightly conflicting results and employed dose regimens that differed considerably This may have been due to the patient populations studied 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 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 Suggesting that MITX might be useful in rapidly progressive forms of MS characterized by active inflammatory disease

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

114 Edan et al MP+M: Lower Incidence of New MRI Lesions Percentage of Patients Developing New Gd-Enhancing Lesions MP (N = 21) MP+M (N = 21) Patients (%) Months * § 86% Reduction *P =.009 P =.030 P =.033 § P =.001

115 MP+M: Slower Progression of Neurologic Disability Patients(%) (N = 12) (N = 8) (N = 6) (N = 3) (N = 1) (N = 12) Confirmed EDSS 1-Point Variation* Between Patient Inclusion and End of Study *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 P<.01

116 Mitoxantrone and IVMP in RPMS Relapse Assessment Edan G et al. J Neurol Neurosurg Psychiatry. 1997;62: IVMP(n=21) Mito + IVMP (n=21)P-value Baseline annualized relapse rate NS On study annualized relapse rate Patients free of relapses on study 7 (33%) 14 (67%) 0.031

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

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

119 MIMS Design Rx every 3 months x 24 months Follow up at Month 36 Placebo Mitoxantrone 5 mg/m 2 Mitoxantrone 12 mg/m 2 RANDOMIZE Hartung, H.P. et al. The Lancet v

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

121 MIMS Baseline Demographics* (1) * No significant differences between the 3 groups Hartung, H.P. et al. The Lancet v Placebo(n=64) Mitox 5 (n=64) Mitox 12 (n=60) Male/Female (%) 52/4839/6153/47 Mean age (years) Type of MS Remittent progressive (%) Remittent progressive (%) Secondary progressive (%) Secondary progressive (%)554253

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

123 Mean Change in EDSS Mean Change in EDSS Changes in EDSS (m24 - Baseline) Placebo vs. Mitoxantrone 12 mg/m 2 p = Hartung, H.P. et al. The Lancet v

124 EDSS >1.0 Point Deterioration from Baseline % of patients Placebo vs. Mitoxantrone 12 mg/m 2 p = (N=5) (N=16) Hartung, H.P. et al. The Lancet v

125 Time to First Treated Relapse PlaceboMitox p= Months Placebo vs. Mitoxantrone 12 mg/m 2 Placebo =14.19 m. Mitox 12mg not reached Hartung, H.P. et al. The Lancet v

126 MIMS: Patients With New Gd-Enhancing Lesions (N = 110) P =.02 at Month 24 Patients (%) Placebo Mitoxantrone 12 mg/m 2 Month 12% (N = 4) 19% (N = 7) 0% 16% (N = 5) (N = 0)

127 Significantly Reduced the Change in the Number of T2-Weighted Lesions vs Placebo Mean Change in Number of T2-Weighted Lesions at 24 Months Placebo(n=32)Mitoxantrone 12 mg/m 2 (n=28) 85% reduction

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

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

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

131 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

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

133 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.

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

135 57.6% reduction (P < 0.001) Placebo (n = 437) Cladribine 3.5 mg/kg (n = 433) Cladribine 5.25 mg/kg (n = 456) Annualized relapse rate 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, % reduction (P < 0.001) Primary Outcome Reduction in Relapse Rates (ITT)

136 Secondary Outcome Reduction in Disability Progression (ITT) 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, Proportion with 3-month confirmed EDSS progression (%) 33%31% Relativereduction Number of patients at risk: Placebo 3.5 mg/kg 5.25 mg/kg Placebo Cladribine 3.5 mg/kg 0.67 (0.48, 0.93); P = Cladribine 5.25 mg/kg 0.69 (0.49, 0.96); P = Hazard ratio vs placebo (95% CI)*

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

138 Patients with AE (%) Placebo (n = 435) Cladribine 3.5 mg/kg (n = 430) Cladribine 5.25 mg/kg (n = 454) Cladribine overall (n = 884 ) Any treatment-emergent AE AEs leading to discontinuation AEs leading to withdrawal Serious AEs Deaths* (n = 2) (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 Secondary Outcome Safety Overview Giovannoni G et al. Presented at American Academy of Neurology 61st Annual Meeting; Seattle, USA; April 30, 2009.

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

140 Cladribine: Effect after 3-5 years on Naïve (CD45RA+) and Memory (CD45RO+) - CD4+ Tcells Raspadori D, et al. Leukemia. 1999;13: 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

141 Laboratory test Statistics Cladribine 5.25 mg/kg (n=454) n (%) Cladribine 3.5 mg/kg (n=430) n (%) Placebo (n=435) n (%) Haemoglobin Mean duration (SD) (weeks) Median duration (weeks) Min;Max duration (weeks) 0 (1 total) 3 (5 total) 17.5 (6.8) ; (3 total) 13.0 (8.3) ;18.9 WBC Mean duration (SD) (weeks) Median duration (weeks) Min;Max duration (weeks) 8 (10 total) 11.8 (10.3) ; (6 total) 3.7 (1.9) ;6.0 2 (2 total) 2.8 (0.9) ;3.4 Neutrophils Mean duration (SD) (weeks) Median duration (weeks) Min;Max duration (weeks) 17 (17 total) 8.1 (9.6) ; (12 total) 5.2 (3.8) ; (18 total) 4.8 (3.1) ;12.1 Lymphocyte Mean duration (SD) (weeks) Median duration (weeks) Min;Max duration (weeks) 108 (203 total) 29.4 (20.8) ; (110 total) 25.4 (19.8) ; (2 total) 4.6 (0.6) ;5.0 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 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 Almost all other Grade 3 and 4 toxicities resolved on study PS. Sorenson, et al. Presented at ECTRIMS 25th Annual Meeting; Dusseldorf, Germany; September 10, 2009; Poster 472.

142 Adverse Events of Special Interest Herpes Zoster Herpes zoster was reported more frequently with cladribine tablets than placebo Herpes zoster was reported more frequently with cladribine tablets than placebo 20 patients had 21 zoster events in the cladribine tablets groups 20 patients had 21 zoster events in the cladribine tablets groups All 21 cases were self-limiting and dermatomal All 21 cases were self-limiting and dermatomal Preferred term, n (%) patients Preferred term, n (%) patientsPlacebo (n=435) (n=435) Cladribine 3.5 mg/kg (n=430) (n=430) Cladribine 5.25 mg/kg (n=454) Cladribine overall (n=884) (n=884) Herpes zoster 08 (1.9) 11 (2.4) 19 (2.1) Herpes zoster oticus 0 01 (0.2) 1 (0.1) Varicella1 (0.2)1 (0.2) 1 (0.2) 1 (0.2) 2 (0.2) S. Cook, et al. Presented at ECTRIMS 25th Annual Meeting; Dusseldorf, Germany; September 11, S. Cook, et al. Presented at ECTRIMS 25th Annual Meeting; Dusseldorf, Germany; September 11, 2009.

143 Adverse Events of Special Interest Malignancies Preferred term, % (n) Placebo (n = 435) Cladribine 3.5 mg/kg (n = 430) Cladribine 5.25 mg/kg (n = 454) Cladribine overall (n = 884) During study During study Cervix carcinoma Stage 0 Cervix carcinoma Stage 0 Malignant melanoma Malignant melanoma Ovarian cancer Ovarian cancer Pancreatic cancer, metastatic Pancreatic cancer, metastatic During post-study surveillance During post-study surveillance Choriocarcinoma Choriocarcinoma (1) (1) Giovannoni G et al. Presented at American Academy of Neurology 61st Annual Meeting; Seattle, USA; April 30, 2009.

144 Cladribine

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

146 Evolution? There has been no evolution! There has been no evolution! Chemotherapeutic agents remain nonselective, broad spectrum cytotoxic agents that suppress the immune system in a nonspecific fashion 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 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 Newer monoclonal antibodies and other innovative therapies appear equally or more effective and have manageable risk

147 Challenging Cases in the Management of Multiple Sclerosis and Parkinsons Disease Case Studies

148 24-year-old female with diplopia on looking to the right for a day or two – Austin ophthalmologist found nothing unusual 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 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 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 Multiple Sclerosis Case #1

149 UPIN /06/08

150 UPIN /06/08

151 4 days later continued double vision on looking to the right 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 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 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 CSF with 10 lymphocytes, IgG index 1.15 and 3 OCBs Intravenous methylprednisolone course started Intravenous methylprednisolone course started Multiple Sclerosis Case #1

152 UPIN /02/08

153 UPIN /02/08

154 The subject was born and raised outside of the reach of the Scandinavian gene pool - is this NMO, and how unusual is this?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 cant diagnose more than suspect MS by McDonalds or Swantons, do you just treat, use Frohman?When you have CIS and cant diagnose more than suspect MS by McDonalds or Swantons, 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?When asked about the familial risk of MS in the company of the patients twin sister, what is the best course? Multiple Sclerosis Case #1 The Issues

155 30-year-old Caucasian female presented initially with right optic neuritis. 30-year-old Caucasian female presented initially with right optic neuritis. Vision improved after high dose intravenous methylprednisolone treatment 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. 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. No disease modifying therapy was started at that time. Multiple Sclerosis Case #2

156 1 year later- numbness and weakness of both legs, urinary hesitancy, and increasing gait difficulties over several days. 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 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 years. MRI brain- one new periventricular white matter lesion without enhancement in comparison to last years. Motor symptoms improved with high dose corticosteroid therapy Motor symptoms improved with high dose corticosteroid therapy Residual numbness in the feet and bladder control difficulties. Residual numbness in the feet and bladder control difficulties. Multiple Sclerosis Case #2

157 Given diagnosis of MS and therapy with once weekly IM interferon beta was begun. 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. 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. 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. Disease modifying therapy was changed to a high dose subcutaneous interferon beta. Multiple Sclerosis Case #2

158 Over the next year, she had no new symptoms and there were no new lesions seen on a repeat MRI scan. 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. After several months she complained of balance difficulties, memory difficulties, and an increase in fatigue. MRI scan showed additional Gd+ enhancing lesions. MRI scan showed additional Gd+ enhancing lesions. A test for neutralizing antibody against interferon beta (NAb) revealed a titer greater than 1:100. A test for neutralizing antibody against interferon beta (NAb) revealed a titer greater than 1:100. Multiple Sclerosis Case #2

159 The same interferon treatment was continued but after several months she complained of ongoing problems with memory. 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. Several new enhancing lesions were again found on MRI. A repeat NAb titer was unchanged. Multiple Sclerosis Case #2

160 Student nurse falls hitting head on concrete when obese patient she is transporting begins to fall off litter. MRI shows pineal cyst. 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. 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. Three yearly follow-ups show no new MRI lesions, no symptoms and no neurologic abnormalities. Multiple Sclerosis Case #3

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

162 32-year-old healthy female post-doc researcher who participated in an MRI study as a volunteer. 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. 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. No neurological symptoms except rare migraine headaches and no signs on her neurological exam. Multiple Sclerosis Case #4

163 Multiple Sclerosis Case #3 Research Brain MRI

164 Parkinsons 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. 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. 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.

165 Family History: No family history of Parkinsons disease Family History: No family history of Parkinsons disease Medical History/Medications: Wife noticed that for the past three years the patient moves about during sleep. No current medications 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. 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 Decision making: Making the diagnosis of PD; early non-motor features of PD; when to initiate therapy Parkinsons Disease Case #1

166 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. 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. Complains of fatigue, lack of motivation and disinterest. He tends to fall asleep easily during the day. Parkinsons Disease Case #2

167 Family History: Father died with Parkinson Disease and a cousin diagnosed with Parkinsons disease 2 years ago is responding well to levodopa Family History: Father died with Parkinson Disease and a cousin diagnosed with Parkinsons disease 2 years ago is responding well to levodopa Medical History/Medications: No significant medical or surgical history. No current medications 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 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 Parkinsons disease with some disability and he wishes to start treatment. Decision making: Patient diagnosed with Parkinsons disease with some disability and he wishes to start treatment. Parkinsons Disease Case #2

168 68-year-old woman with a 4-year history of Parkinsons 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. 68-year-old woman with a 4-year history of Parkinsons 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. 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. Parkinsons Disease Case #3

169 Family History: no relatives with PD Family History: no relatives with PD Medical History: No significant medical or surgical history Medical History: No significant medical or surgical history Medications: Amitriptyline 50 mg. q.h.s for depression in addition to carbidopa- levodopa 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 Decision making: treatment of motor fluctuations, non-motor features of PD Parkinsons Disease Case #3

170 82-year-old woman has a history of Parkinsons disease for 12 years. She presented with shuffling gait, masked facies, postural instability, and a pill- rolling tremor of the right hand. 82-year-old woman has a history of Parkinsons 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. 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. Parkinsons Disease Case #4

171 Family History: 87-year-old sister diagnosed with Alzheimers disease and Parkinsons disease Family History: 87-year-old sister diagnosed with Alzheimers disease and Parkinsons disease Medical History: Mild stroke 3 years ago; has minimal residual effects of right-sided weakness. 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 Medications: She takes 1 aspirin daily in addition to carbidopa-levodopa Decision making: management of advanced PD motor and non-motor features Decision making: management of advanced PD motor and non-motor features Parkinsons Disease Case #4


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