2Multiple Sclerosis and Parkinson’s Disease New Frontiers andLandmark Practice AdvancesOptimizing Neurotherapy forMultiple Sclerosis andParkinson’s DiseaseApplying Science, Expert Analysis, Guidelines, andLandmark Trials to the Front Lines Patient CareProgram ChairmanC. 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
3Welcome 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
4Program Faculty Program Chairman C. Warren Olanow M.D., FRCPC Henry P. and Georgette GoldschmidtProfessor and Chairman Emeritus,Department of Neurology Professor, Department of Neuroscience Director, Robert and John M. BendheimParkinson’s Disease Center Mount Sinai School of MedicineDouglas R. Jeffery, MD, PhDAssociate ProfessorDepartment of NeurologyWake Forest University Baptist MedicalCenterWinston-Salem, NCHoward L. Zwibel, MDFounding Medical Director, EmeritusNeuroscience ConsultantsComprehensive Multiple SclerosisCenter in affiliation with the NationalMultiple Sclerosis Center CoralGables, FloridaBaptist Health Doctors Hospital MS CenterCoral Gables, FL
5Two Diseases in Need of a Neuroprotective Therapy New Frontiers andLandmark Practice AdvancesParkinson’s Disease andMultiple SclerosisTwo Diseases in Need of a Neuroprotective TherapyProgram ChairmanC. 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
6Parkinson’s Disease and Multiple Sclerosis Two important neurological disordersPrimarily affect older individuals (PD)Primarily affect younger individuals (MS)Both have surrogate imaging markersFD-PET (PD)MRI (MS)Treatments are available for both diseasesBenefit symptoms (PD)Reduce relapse rate (MS)
7Parkinson’s Disease and Multiple Sclerosis Both result in unacceptable disability for many patients despite available treatmentsDisease-modifying or neuroprotective therapies are urgent prioritiesBoth offer many candidate disease- modifying agents based on laboratory work
8Parkinson’s Disease and Multiple Sclerosis Development of a disease modifying therapy in each condition would be enhanced by:Insight into the precise cause of the diseaseBetter animal modelsBetter clinical trial designs with endpoints reflecting the underlying disease processAdvances in these areas will be reviewed in the current session
9Attempts to Obtain Neuroprotection for Parkinson’s Disease New Frontiers andLandmark Practice AdvancesAttempts to Obtain Neuroprotection for Parkinson’s DiseaseProgram ChairmanC. 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
10Current Therapies for PD Primarily dopaminergicHighly effective for the classic motor featuresTremor, rigidity, bradykinesiaDo not satisfactorily control non-dopaminergic featuresGait dysfunction, freezing, postural instability, falling, autonomic dysfunction, mood disorders, sensory problems, cognitive impairment, dementiaDo not stop disease progression
11The Sydney Long Term PD Study 149 PD patients were entered52 survivors after 15 yearsNone were still employed40% were in a nursing home95% had levodopa-induced dyskinesia and wearing offNon-dopaminergic features (falling, dementia) were the primary cause of disability and of nursing home placement
12Neuroprotective (Disease-Modifying) Therapy For PD A treatment intervention that slows, stops or reverses disease progression
13Neuroprotective Trials in PD Negative Studies AgentMechanismEndpointVitamin EAnti-oxidantTime to L-dopaRiluzoleAnti-glutamateMinocyclineAnti-InflammatoryΔ UPDRSImunophilinTrophicGDNF/NeurturinTrophic factorsTCH346Anti-apoptoticCEP1347DA Cell TransplantCell replacementΔ UPDRS/QOL
14Obstacles to Finding a Neuroprotective Therapy for PD We do not know the precise etiology or pathogenesis of PD—we don’t know what to targetWe do not have a reliable animal model that is progressive and reflects the etiopathogeneis of PDWe do not have a good method for determining the optimal dose to use in a clinical trial
15Neuroprotective Trials in PD Positive Studies AgentMechanismEndpointSelegiline (DATATOP)Anti-apoptoticTime to L-dopaSelegiline (SINDEPAR)Wash OutCo-Q10Bio-energeticΔ UPDRSCreatineRopiniroleΒ-CIT-SPECTPramipexoleF-DOPA PET
16Obstacles to Finding a Neuroprotective Therapy for PD We do not know the precise etiology or pathogenesis of PD –we don’t know what to targetWe do not have a reliable animal model that is progressive and reflects the etiopathogeneis of PDWe do not have a good method for determining the optimal dose to use in a clinical trialWe do not have a clinical trial design that can reliably detect a disease-modifying agent
17Trial Designs for Neuroprotection in PD Time to a milestone of disease progressionWashout design (change from untreated baseline to final visit performed after drug washout)Change from baseline to final visit in UPDRS scoreNeuroimaging of surrogate biomarker of dopaminergic function
18Delayed Start Design Period I Placebo Early Start Early Start Intervention
19Delayed Start Design Period I Period II Delayed Start Symptomatic EffectPlaceboEarly StartEarly StartInterventionDelayed StartIntervention
20Delayed Start Design Possible Period I Period II Disease Modifying EffectPeriod IPeriod IIDelayedStartPlaceboEarly StartEarly studyInterventionDelayed StartIntervention
21Delayed Start Study Principal Statistical Analyses I. Superiority of Early Start vs Placebo (UPDRS Slope weeks 12 – 36)IIII. Superiority of Early Start vs Delayed Start (UPDRS change from baseline to week 72)Mean UPDRS change from baselineWorseningImprovementIIIIII. 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 slopeThe 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 considerationsMixed 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.122436424854606672WeekDelayed Start (Placebo-Rasagiline)Early Start (Rasagiline-Rasagiline)Adapted from Olanow et al. Mov Disord
22Issues That Must Be Addressed in a Delayed-Start Study Duration of period 1 and period 2Long enough for protective effect to occurLong enough for full symptomatic effect to occurNot so long that patients withdrawDrop outsMissing dataNeed for sensitivity and imputation analysesSufficient numbers of visits to permit slope analysis in period 1 and 2
24ADAGIO Study Design Placebo 1 mg/day 2 mg/day Untreated PD patients Week4122436425460667248ADAGIO 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 center1 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 Phase36-week (9-month) Double Blind Active-Treatment PhaseOlanow et al. Mov Disord. 2008
25ADAGIO – Baseline Characteristics Patients randomised (n)1,176Male 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)MotorADL20.4 (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.1Overall, 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 ± 8.5.1With 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 200825
26Rasagiline 1mg: Early vs Delayed Start Olanow et al. NEJM; 2009
27Rasagiline 2mg: Early vs Delayed Start Olanow et al. NEJM; 2009
28The ADAGIO Study Summary and Conclusions Rasagiline 1 mg/day met all 3 primary outcomes of the delayed start studyIs this a false positive?Rasagiline 2 mg/day failed to meet all primary outcomes of the delayed start studyIs this a false negative?
29ADAGIO – Clinical Significance of Positive Result with Rasagiline 1 mg UPDRS difference of 1.7 units38% reduction in rate of decline of UPDRS scoreReflects only 9 months of active treatment
30ADAGIO Trial Clinical Significance Delayed-start study designed to determine if a study intervention has benefits that cannot be accounted for by symptomatic effects aloneLong-term studies are required to assess effect of drug on cumulative disabilityExtension studyLong-term simple studyEndpoints that include measures of motor and non-motor function - UPDRS gait, cognitive function, and quality of life
31New Dimensions andLandmark Practice AdvancesThe Evidence for First Line Therapy in MS with Immune-Modulating Agents (IMTs)From Mechanisms to Therapy-Landmark Trials, Long-Term Safety Data, and Clinical ExperienceHoward L. Zwibel, MDFounding Medical Director, Emeritus | NeuroscienceConsultants | Comprehensive Multiple Sclerosis Centerin affiliation with the National Multiple Sclerosis CenterCoral Gables, Florida | Baptist Health Doctors HospitalMS Center | Coral Gables, FL
32New Dimensions andLandmark Practice AdvancesThe Evidence for First Line Therapy in MS with Immune-Modulating Agents (IMTs)From Mechanisms to Therapy-Landmark Trials, Long-Term Safety Data, and Clinical ExperienceNOTE: Both trade and chemic names areused 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.
33MS: Immune Dysfunction Proinflammatory immune cellsProinflammatory cytokinesAntigen-presenting cellBlood-brain barrierT cellsThe 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 disabilityAn 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 death1. 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:
34Based on modifications to McDonald Criteria Diagnosis of MSBased on modifications toMcDonald CriteriaModified 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 fluidPolman CH, et al. Ann Neurol. 2005;58:Compston A, Coles A. Lancet. 2008;372: Figure 1.
35Differentiating MS Lesions Using MRI Note:Scans are not from the same patient.DABT2 with FLAIRT2CT1 PrecontrastBlack HolesDifferentiating MS Lesions Using MRIThese 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.ReferencesImages 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 ContrastActive InflammationFLAIR = Fluid Attenuated Inversion RecoverySlide courtesy of JS Wolinsky.35
36Clinically Isolated Syndrome (CIS) Clinical episode consistent with demyelinationCharacterized by MRI and lab dataPatient may or may not develop clinically definite MS (CDMS)Features of CIS suggestive of a first MS attack include:Appropriate age; female genderAbnormal brain MRIOptic neuritisTypically unilateral, retrobulbar, and painfulBrainstem/cerebellar dysfunctionMost commonly ocular motor syndromes (INO, nystagmus), ataxia, dysarthria, sensory or motor signsMyelitisPartial sensory more common than partial motorBowel and bladder dysfunction commonINO: Internuclear ophthalmoparesisFrohman, et al. Neurology. 2003;61:36
37Clinically 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
38CIS: 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.Reference1. 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
39CIS or First Demyelinating Event: Phase III, Placebo-Controlled Studies AcronymFull namePrimary Endpoint(s)StatusPreCISeStudy to Evaluate the Effect of Early Glatiramer Acetate (GA, Copaxone®) Treatment in Delaying the Conversion to CDMS of Subjects Presenting with a CISTime to clinically definite MS (CDMS)CompletedBENEFITBetaferon® (IFNb-1b) in Newly Emerging MS for Initial TreatmentTime to CDMSTime to McDonald MSCHAMPSControlled High-Risk Subjects (IFNb-1a) Avonex® Multiple Sclerosis Prevention StudyProbability of developing CDMSChanges in MRIETOMSEarly Treatment of MS Study (IFNb-1a)Conversion to CDMSREFLEXRebif® (IFNb-1a) FLEXible Dosing in Early MSTime to conversion to MS (McDonald criteria)OngoingTrade 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:
40Completed CIS Clinical Trials: Demographics and Key Results ParameterPreCISe(GA)BENEFIT(IFNb-1b SC)CHAMPS(IFNb-1a IM)ETOMS(IFNb-1a SC)Duration3 yrs (stopped early)2 yrsPatients (N)481468383308Patient age31 ± 7 yrs30 yrs33 ± 7 yrs28 ± 6 yrsEDSS (mean)NA1.51.17 ± 1.2% Reductionin CDMS Risk45%50%44%39%P-value0.0005<0.0020.047NA = not availableEDSS= expanded disability status scoreComi 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:
41BENEFIT 5-Year Extension Data: Early Versus Delayed IFNβ-1b 57%37% reduction in risk of developing CDMS46%CDMS = clinically definite multiple sclerosisHR 0.63, 95% Cl 0.48–0.83; P = 0.003Kappos L, et al. Lancet. 2009; published online September 11, 2009 DOI:1016/S (09)
42CHAMPIONS (CHAMPS Open-label Extension): Early Versus Delayed IFNβ-1a Incidence of CDMS by Treatment Group: 10-year extension dataDelayed Treatment (n = 190)40% reduction in risk of developing CDMSImmediate Treatment (n = 193)Univariate HR (95% CI) = 0.64 (0.47–0.86), P = 0.003Adjusted HR (95% CI) = 0.60 (0.44–0.81), P < 0.001Kinkel 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.
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.”National Clinical Advisory Board of the National Multiple Sclerosis Society (2007). Accessed 01/14/09.
44SummaryEarly treatment of CIS with DMTs (GA, IFNβ formulations) delays progression to CDMSEarly treatment of CIS or MSReduces rate of relapsesDelays the development of disabilityMay reduce the overall cost of care
45Current MS Therapies Immunosuppressants or Immunomodulators? Generally considered to be immunomodulatorsGlatiramer acetate [GA] injectionIFNβ productsNatalizumab (?)Uses of these immunomodulatorsGA and IFNβ products are first-line therapies for the long-term treatment of CIS and RRMSNatalizumab for patients who are unresponsive or who cannot tolerate first-line DMTs, first-line use in very active RRMSIt 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.
47Presumed MOA of Glatiramer Acetate: Immunomodulation Proinflammatory immune cellsProinflammatory cytokinesAnti-inflammatory cytokinesRegulatory T-cell typesAntigen-presenting cellNeurotrophic factorsT cellsBlood-brain barrierInduces a population of regulatory T-cell types (Th2,Treg)Anti-inflammatory cytokines and neurotrophic factors are releasedMay 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 MST 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:*
48Interferons Avonex®, Betaseron®, Rebif® Doses:Avonex ® : 30 mcg IM once weeklyBetaseron ® : 250 mcg SC every other dayRebif ® : 22 mcg, or 44 mcg, SC TIWPregnancy Category: CDrug Interactions: Possible with hepatically active drugsLaboratory monitoring: CBC, LFT, thyroidAdverse events: Flu-like symptoms, injection site reaction, depression, hepatic injuryMay be beneficial to address IFN-statin drug-drug interaction from AAN 2007 (Dhawan & Birnbaum).
49Presumed MOA of IFNβ: Immunomodulation Proinflamatory immune cellsProinflammatory cytokinesEliminated immune cellT cellsAntigen-presenting cellBlood-brain barrierReduces proinflammatory cytokine levelsReduces 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 BBBIt is not known what role these effects play in the observed clinical activity of IFNβ in MSBetaseron® prescribing information. Bayer HealthCare Pharmaceuticals Inc.
50Monoclonal Antibody Natalizumab Dose:300 mg iv infusion monthlyPregnancy Category: CDrug Interactions: Immunosuppressants, corticosteroidsSafety Issues:Progressive Multifocal Leukoencephalopathy (PML)Hypersensitivity Reaction / NAbsMelanoma / Other CancersLiver InjuryReactivation of Latent Viruses
51Presumed MOA of Natalizumab: Reduction of Cell Trafficking Proinflammatory immune cellsProinflammatory cytokinesAntigen-presenting cellsBlood-brain barrierT cellsInhibits the α4-mediated adhesion of leukocytes to vascular cell adhesion molecule-1Strongly reduces proinflammatory cell recruitment to the CNSNatalizumab 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 cellsThus, natalizumab helps prevent proinflammatory cells from being recruited to the CNSIt is not known if these effects play an important role in the observed clinical activity of natalizumab in MSTysabri® (natalizumab) prescribing information. Biogen Idec Inc.
55Results : Mean T2 Active Lesions at 64 Weeks Secondary Endpoint 1.4P < 0.0010.9Mean T2 LesionsPanitch H, et.al. J Neurol Sci. 2005;239:67-74.
56Head 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
57Time to First Relapse (Primary Endpoint) 672 days (96 weeks)IFNβ-1aHazard ratio (95% CI): (0.74, 1.21) p = 0.643GASurvival distribution function460/736 planned patients (63%) were expected to have 1 relapse258/764 patients (34%) experienced 1 relapseTime to first relapse (days)Adapted from an analyst report by Bernstein Research, October 15, 2007.57
58Head to Head Clinical Studies Betaseron Efficacy Yielding Outcomes of a New Dose(The BEYOND Study)Friday, 12 October 2007Immunomodulation 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 500mcg and 250 mcg interferon beta-1bS. 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 theBEYOND ProgrammeBackgound: Data suggest that doses of interferon beta-1b (IFNB-1b; Betaferon®/ Betaseron®) higher than thecurrently approved, 250 mcg every other day (eod) may provide greater efficacy in treating patients with relapsingremitting multiple sclerosis (RRMS) without compromising tolerability or safety.Objective: The BEYOND (Betaferon®/ Betaseron® Efficacy Yielding Outcomes of a New Dose) programme wasestablished to assess the safety, tolerability and efficacy of 500 mcg IFNB-1b eod. This programme consists of asmall-scale first phase (pilot study) and a larger scale second phase (phase IIIb trial). The extension of the first phaseof the programme is reported here.Methods: The first phase was a double-blind, randomised, parallel group, multicentre pilot study comparing IFNB-1b500 mcg and 250 mcg eod in patients with RRMS; the 500 mcg dose was shown to be well tolerated and safe overthe 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 wasunblinded at Week 10 of the extension study and the 61 remaining patients chose their therapeutic dose: 22 chosethe 250 mcg dose and 39 chose the 500 mcg dose. After 3 years of follow-up, 42 patients are still participating: 12 inthe 250 mcg group and 30 in the 500 mcg group returned for the follow-up visit. After 3-years, no relevant changefrom baseline in alanine aminotransferase (ALT) or aspartate aminotransferse (AST) levels was observed in any ofthe 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 theapproved 250 mcg dose over a 3-year period. The second phase of the BEYOND programme is currentlyinvestigating the efficacy and safety of the 500 mcg dose of IFNB-1b in a larger number of patients to confirm theconclusions of this pilot study.Disclosure:The BEYOND Pilot study is financially supported by Bayer Schering Pharma AG
59Annualized Relapse Rate 1 Year Before and During Treatment 0.51.01.52.0BeforeDuringIFNβ-1b500 ug250 ugGA-79%-78%*No significant differencesComi G. Presented at: The European Charcot Foundation Symposium 2007; Nov 29 – Dec 1, 2007; Fiuggi, Italy.
60Head to Head Clinical Studies BEtaseron® vs. COpaxone® in MS with Triple-Dose Gadolinium and 3-T MRI Endpoints(The BECOME Study)
61The BECOME Study “This protocol is optimized to detect enhancement…” Study DesignInvestigator-initiated study (single site)N = 75RRMS (61) and CIS (14) patientsTriple dose Gd with 40 min post-injection delay3-Tesla MRI“This protocol is optimized to detect enhancement…”Sponsored by Berlex/Schering AGPrimary Outcome MeasureThe mean number of combined active lesions (CALs) per scanCALs were defined as Gd-enhancing lesions + new T2/FLAIR lesions unassociated with enhancementPatients 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 RRMSUsing 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 MRIThis 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.
62BECOME: 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 outcomesNew enhancing lesionsBlack Holes (acute hypointensities and persistent black holes)Clinical: ARR, sustained disability progression, cognitive functionIt 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.
63Trends Across Clinical Trials: % Reduction in ARR – ~2 Years 594451427985716978848620406080100GAAvonexBetaseronRebif 44FTY720Tysabri% Reduction in ARR vs BaselineThis 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 baselineGA ARR: 2.9 relapses in prior 2 yrs at baseline; 2.9/2 = 1.45 ARR at baselineAvonex 2-yr ARR: used the ‘all pts’ valueBetaseron ARR: 3.4 relapses in prior 2 yrs at baseline; 3.4/2 = 1.70 ARR at baselineRebif 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-yrsFTY720: 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 graphReduction 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 posterREFERENCES: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.Johnson1995Jacobs1996IFNβ-1b studygroup,1993PRISMS-21998KapposECTRIMS 2006, NEJM 2006Polman2006REGARD2007REGARD2007BEYOND2007BEYOND2007BECOME2007BECOME2007
64Trends Across Clinical Trials: Annualized Relapse Rate – ~2 Years Annualized Relapse Rate – 2-yrsAvonex 2-yr ARR: used the ‘all pts’ valueRebif 44 ARR 2-yr: at 2 yrs; 1.73/2 = 0.87 ARR at 2-yrsBECOME: used ‘confirmed relapse’ ARR value from Cadavid ECTRIMS 2007 poster for this graphREFERENCES: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.Johnson1995Jacobs1996IFNB-1b studygroup,1993PRISMS-21998KapposECTRIMS 2006Polman2006REGARD2007REGARD2007BEYOND2007BEYOND2007BECOME2007BECOME2007
66Long-term Study Design in RRMS Copaxone® (glatiramer acetate injection)20,21N=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)9,23Avonex®: 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)24,25Betaseron®: 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)26N=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)27N=942; Tysabri® 300 mg (n=627) or placebo (n=315).Up to 15 years2 yrs15 years5 yrs16 years4 yrs7-8 years3 yrsKeyProspective study designRetrospective follow-up9. 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 P26. Kappos L, et al. Neurology. 2006;67: O’Connor PW, et al. AAN P
67Pivotal Trial and Extension-Phase Study Design 200815-year analysis for Ongoing cohortMean disease duration: 22 yearsEDSS assessmentOngoing 6-month assessments369121518212427303336glatiramer acetate injectionOngoing (n=100)13.6 yearsmITT†‡(n=232)8.6 yearsplaceboWithdrawn 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-upFor 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 patientsThe 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 LTFUNOTE: 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 yearsDouble-blind,placebo-controlled phaseOpen-label extension phase35*60120+180Months*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:
68Yearly Relapse Rate While on GA 0.250.50.7511.25Mean Relapse RateHere 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 GAFord CC, et al. Mult Scler. 2006;12:
69Demonstrated Long-term Benefits EDSS levels at 15-year follow-up1008060Patients (%)38%4018%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 8203%EDSS of 4 or higherEDSS of 6 or higherEDSS of 8 or higherAfter 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 8The labeling for COPAXONE® does not include an indication for slowing progression of disability.Ford C, et al. WCTRIMS Abstract P44.
70ASSURANCE15-year long-term follow-up of pivotal IM IFNβ1a relapsing trial (MSCRG)Involved 2-year completersOpen label, retrospective, patient reportedN=136 (of 172) participated46% currently on IM IFNβ1a (median duration 13.3 years)Rudick et al. MS 11:626, 2005
71ASSURANCE 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
72Patients under regular medical care - no trial 16 Year Follow-UpPivotal Study (n=372)IFNβ-1b 250 µg12456IFNβ-1b 50 µg12552Patients under regular medical care - no trialLTFPlacebo123581988199019932005Cross-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 PgXGoodin et al., Multiple Sclerosis; 2008: 14 (Suppl 1), P5272
7316-Year LTF: Patient Disposition in the Intent-to-Treat Population 7.2%4.8%16.3%10.5%DeceasedNot foundAlive13.6%11.4%84.7%79.2%72.4%Proportion of PatientsPlacebon = 123INFB-1b50 µgn = 125IFNB-1b250 µgn = 124Ebers G. Presented at ECTRIMS 2006, Madrid, Spain.73
7416-Year LTF: Other Findings The most important predictors for better long-term outcomes from the IFNB-1b 16-year LTF study wereLow EDSS (<2) at study entryHigh exposure to IFNB-1bThe risk of any negative outcome* was reduced by 60% with high compared to low exposureSafety and tolerabilityNo new or unexpected side effectsFlu-like symptoms , injection site reactions and NAbs continued at a low level*EDSS 6; SPMS; EDSS 6/SPMS, WheelchairGoodin et al. Multiple Sclerosis; 2008: 14 (Suppl 1), P5274
75PRISMS Long Term Follow-up 8-year follow-up of PRISMS SC IFNβ1a pivotal relapsing trial382 of 560 subjects (68.2%) evaluated275 (72%) still receiving IFNβ1aSubjects initially randomized to 44mcg showed best EDSS, relapse rate, T2 burden of disease at 8 years-no brain atrophy difference19.7% progressed to SPMSNeurology 2006;67:944
76Natalizumab Monotherapy Trial: ARR 0.81†0.73‡68% reduction*68% reduction*0.26†0.23‡Natalizumab Monotherapy Trial: ARRAt 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).11. 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:
77Natalizumab Monotherapy Trial: Time to Sustained Progression PlaceboNatalizumabP<0.001.Natalizumab Monotherapy Trial: Time to Sustained ProgressionSustained 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.11. 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:
78Natalizumab: AFFIRM Gd-Enhancing Lesions P<0.001 between groups for all time intervals.92%Natalizumab: AFFIRM Gd-Enhancing LesionsNatalizumab 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.11. 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:
79Natalizumab: AFFIRM T2 Lesions P<0.000183%Natalizumab: AFFIRM T2 LesionsIn 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).11. 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:
80Summary GA and interferons Efficacy data documented from initial event to long-termGA long-term data is prospectiveInterferon data long-term is retrospectiveNo long-term safety signalling with GA or interferonsNatalizumabEfficacy data short termSafety signalling for development of PML80
81New Dimensions andLandmark Practice AdvancesThe Evolution of Chemotherapeutic Agents in the Treatment of Multiple SclerosisDouglas R. Jeffery, MD, PhDAssociate ProfessorDepartment of NeurologyWake Forest University Baptist Medical CenterWinston-Salem, NC
82“Chemotherapeutic”Nonspecific cytotoxic agents that kill cells via a mechanism that involves impairment of cell divisionUsually mediated by an effect on DNA or RNA synthesisThrough this mechanism such agents kill T-cells, B-cells, and macrophages thus impairing an immune response against a wide variety of stimuliImmunosuppressive agents that also increase the risk of infection through the nonspecific suppression of immune function
83The Search for a Treatment Early on there were no treatments for MSOther disciplines (rheumatology) adopted the use of chemotherapeutic agents to treat autoimmune diseasesMS thought by many to be autoimmune in natureInvestigators in the MS field considered the use of these agentsEarly study designs were flawed and some doubted the effectiveness of these agents
84Benefits vs. Risk of Chemotherapuetuc Agents Chemotherapies are nonspecific immunosuppressive agentsMany have well known and very serious side effectsImmunosuppressionInfectionHepatoxicitySecondary malignancyIn the absence of other effective treatments the benefits outweighed the risks in those with worsening disability
85Agents that have Been Studied in MS AzathioprineMethotrexateCyclophosphamideMycophenylateMitoxantroneCladribineCyclosporine
86Azathioprine Earliest studies date back to 1971 Small poorly controlled trials suggested a modest effect on relapsesLater controlled trials confirmed an effect on relapse rate but not disability progressionCochrane meta analysis suggested an effect on relapse rateOdds ratio of remaining relapse free on azathioprine was 1.51 at yr 1, 2.04 at yr 2, and 1.97 at yr 3Yudkin et. al. 1991
87Azathioprine Used widely in Europe prior to the introduction of IFNβs Less popular in the modern era of immunomodulatory therapyStudied 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
88Azathioprine in Multiple Sclerosis 354 patients randomized to azathioprine vs. placeboDouble blinded, 3 yr durationAt 3 yrs mean EDSS decreased 0.80 in the placebo and 0.62 in the treated groupAt 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 benefitCould not be recommended for most patients with MSLancet. 1988; 23:
89Effect of Azathioprine on MRI Metrics 14 patients with at least three gd(+) lesions within 6 monthsAzathioprine dosed up to 3mg/kg daily depending on lymphocyte countsEvaluation for six months before treatment and six months of treatmentReduction of greater than 50% observed in 12 of 14 patientsReduction of greater than 50% or more in new T2 lesionsAzathioprine reduced new MS brain lesionsMassacesi, et. al. 2005
90Toxicity of Azathioprine Bone marrow suppressionLeukopeniaLymphopeniaThrombocytopeniaIncreased risk of infectionHepatotoxicityMalignancy risk increased with duration of exposureSolid organ tumors, myelodysplastic syndromes, epitheliomas, skin cancerLa Mantia 2007, Confravreux 1996
91CyclophosphamideEarly studies suggested a possible effect in secondarily progressive MS and rapidly progressive MSConflicting results of several trials led to controversy as to whether it was effective at allSome believed it was highly effective and others felt it to be ineffective and dangerousBoth were right. It depended on whether the extent of the inflammatory process presentHauser et. al Weiner et. al. 1993
92Northeast Cooperative MS Treatment Group RandomizedStandard vs modified inductionInduction only vs induction + maintenanceIV CTX (700 mg/m2) bimonthlyInductionIV CTX (600 mg/m2) days 1, 2, 4, 6, 8IV ACTH for 14 daysMaintenanceWeiner et. al. 1993
93Percentage Stable/Improved on DSS NE Cooperative StudyPercentage Stable/Improved on DSSMonths on Study61218243036Induct (20)75%56%46%24%17%15%Boosters (127)71%55%48%38%27%20%P value0.760.710.610.040.14
94Months on Study, with Maintenance NE Cooperative StudyMonths on Study, with Maintenance61218243036Younger (<41)81%62%57%42%40%28%Older (>41)60%47%34%14%21%P value0.020.130.100.180.010.05
95Cytoxan Factors effecting response to therapy Younger age Rapidly progressive courseRelapses in the year before therapy<2yrs in the progressive phaseEnhancing lesions on T1+Gd
98Canadian Cooperative Trial CTX group (n=55)IV CTX 1 gm QOD until WBC<4.5 up to 9 gmPrednisone 40 mg qD x 10 then taper over 6 dPlEx group (n=57)PlEx qW for 20 wkPO CTX mg/kg/d for 22 wkPrednisone 20 mg QODPlacebo group (n=56)Sham PlEx, PO CTX placebo, Prednisone placeboLancet 337:441, 1991
99Canadian 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 monthsMean change in EDSSLancet 337:441, 1991
100Canadian Cooperative Trial Results Proportion of treatment failuresCTX 35%PlEx 32%Plac 29%Mean time to treatment failure (months)CTXPlExPlacLancet 337:441, 1991
102Canadian Cooperative Trial Results M24 vs. baselineImprovedStableWorseIVCTX2 (6%)13 (42%)16 (52%)PIEx1 (3%)25 (81%)5 (16%)Placebo20 (67%)10 (33%)CTX vs placebo p=0.088Lancet 337:441, 1991
103Canadian Cooperative Trial Results M36 vs. baselineImprovedStableWorseIVCTX2 (4%)24 (44%)28 (52%)PIEx1 (2%)34 (59%)22 (39%)Placebo32 (59%)21 (39%)CTX vs placebo p=0.290Lancet 337:441, 1991
104Kaiser Study CP-MS (EDSS 3.0-8.0) Increased EDSS or AI >1 step prior 1 yearRandomizedIV CTX 22Placebo 20Single-blindLikosky WH et al. JNNP 54:1055, 1991
105EDSS Stable or Improved* Kaiser Study ResultsEDSS Stable or Improved*CTXPlacebo12 Months14/22 (64%)14/20 (70%)24 Months9/19 (47%)9/17 (53%)* based on EDSS change of >1.0 stepLikosky WH et al. JNNP 54:1055, 1991
106Kaiser Study Results Mean DEDSS Placebo-CTX (95% CI) Month CTX Placebo 0 to 120.500.530.03 (-0.60 to 0.65)0 to 180.380.730.35 (-0.40 to 1.10)0 to 240.580.970.39 (-0.45 to 1.23)Likosky WH et al. JNNP 54:1055, 1991
107Spectrum 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 burdenLate stage secondary progression related to a poorly understood degenerative processInfrequent enhancing lesions and little evidence of progression on MRIThese forms of disease differ in their response to treatment
108Secondary-progressive Natural History of MSBetaseron® (interferon beta-1b): Trials in Secondary-Progressive Multiple SclerosisMeasures of brain volumeSecondary-progressiveRelapses and impairmentMRI burden of diseaseMRI activityPreclinicalRelapsing-remittingThe 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
109Reconciliation 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 diseaseThe reality was that the dynamics of disease in these patients was characterized by active inflammationThe Canadian cooperative trial and the Kaiser trial probably included a greater proportion of patients with primary progressive MS and true secondary progressionCPM was effective in those with an active inflammatory component but not in those with slowly progressive degeneration observed in true secondary progression
111MitoxantroneAn anthracenedione related to dauxorubicin with potent immunosuppressive effectsIntercalates DNA and blocks the synthesis of RNAInhibits topoisomerasePotent effects on B-cell and T-cell functionInhibits both passive and active EAE
112Clinical Trials of Mitoxantrone in MS Early trials produced slightly conflicting results and employed dose regimens that differed considerablyThis may have been due to the patient populations studiedWhat emerged was a marked reduction in relapse rate and a reduction in enhancing lesion frequencySuggesting that MITX might be useful in rapidly progressive forms of MS characterized by active inflammatory disease
113Methylprednisolone and Mitoxantrone in MS (MP+M): Trial Design TriageM -2M -1M 0M 1M 2M 3M 4M 5M 6Randomized TreatmentMitoxantrone 20 mg/mo IV +Methylprednisolone 1 g/mo IV
114MP+M: Lower Incidence of New MRI Lesions Percentage of Patients Developing New Gd-Enhancing Lesions100MP (N = 21)MP+M (N = 21)*P = .009†P = .030‡P = .033§P = .001*80†‡60Patients (%)4086%Reduction20-1123456MonthsEdan et al
115MP+M: Slower Progression of Neurologic Disability Confirmed EDSS 1-Point Variation* BetweenPatient Inclusion and End of StudyP<.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
116Mitoxantrone and IVMP in RPMS Relapse Assessment Mito + IVMPP-valueBaseline annualized relapse rate2.93.1NSOn study annualized relapse rate3.00.70.003Patients free of relapses on study7 (33%)14 (67%)0.031Edan G et al. J Neurol Neurosurg Psychiatry. 1997;62:
117MP+M: ConclusionsAddition of mitoxantrone to methylprednisolone significantlyReduced new MRI lesionsSlowed the progression of neurologic disabilityReduced relapse rateEdan et al
118Mitoxantrone in Multiple Sclerosis (MIMS): Study Design 2-year, double-blind, multicenter, placebo controlled194 patients, years, EDSS 3-6Treatment armsMitoxantrone 5 mg/m2, IV, q3moMitoxantrone 12 mg/m2, IV, q3moPlacebo
119MIMS Design Placebo Mitoxantrone 5 mg/m2 Mitoxantrone 12 mg/m2 R A N D ZEMitoxantrone 5 mg/m2Mitoxantrone 12 mg/m2Rx every 3 months x 24 monthsFollow up at Month 36Hartung, H.P. et al. The Lancet v
120MIMS Study Inclusion and Exclusion Criteria Inclusion CriteriaExclusion CriteriaAge 18 to 55Definite MS (Poser’s criteria)Secondary progressive or remitting progressive MS (worsening RRMS)EDSS progression 1 point in preceding 18 monthsBaseline EDSS fromBenign or primary progressive MSRelapse or treatment with corticosteroids in preceding 8 weeksPrior treatment with NOVANTRONE®Immunosuppressive therapy in preceding 9 monthsCardiac risk factorsMajor medical illnessHartung, H.P. et al. The Lancet v
121MIMS Baseline Demographics* (1) Placebo(n=64)Mitox 5Mitox 12(n=60)Male/Female (%)52/4839/6153/47Mean age (years)40Type of MSRemittent progressive (%)455847Secondary progressive (%)554253* No significant differences between the 3 groupsHartung, H.P. et al. The Lancet v
122Mitoxantrone Efficacy at 2 Years: Primary Efficacy Variables Placebo (n=64)Mitoxantrone 12 mg/m2 (n=60)P-value Mitoxantrone 12 mg/m2 vs. PlaceboMultivariate primary efficacy criterion<0.0001EDSS change (mean)0.23-0.130.0194Mean no. of treated relapses1.200.400.0002Time to first treated relapse (median months)14.2NR0.0004SNS change (mean)0.77-1.070.0269NR=not reached within 24 months.Hartung, H.P. et al. The Lancet v
123Mean Change in EDSS Changes in EDSS (m24 - Baseline) p = 0.0194 † † Placebo vs. Mitoxantrone 12 mg/m2Hartung, H.P. et al. The Lancet v
124EDSS >1.0 Point Deterioration from Baseline % of patients(N=5)† Placebo vs. Mitoxantrone 12 mg/m2Hartung, H.P. et al. The Lancet v
125Time to First Treated Relapse PlaceboMitox 121.000.75Mitox 12mg not reached0.50Placebo =14.19 m.0.25p=0.0004†0.003691215182124Months† Placebo vs. Mitoxantrone 12 mg/m2Hartung, H.P. et al. The Lancet v
126MIMS: Patients With New Gd-Enhancing Lesions (N = 110) 19%(N = 7)P = .02 at Month 24PlaceboMitoxantrone 12 mg/m216%(N = 5)12%(N = 4)Patients (%)(N = 0)0%Month
127Mean Change in Number of T2-Weighted Lesions at 24 Months Significantly Reduced the Change in the Number of T2-Weighted Lesions vs PlaceboMean Change in Number of T2-Weighted Lesions at 24 Months85% reductionMitoxantrone12 mg/m2(n=28)Placebo(n=32)
128Potential Adverse Effects of Mitoxantrone AcuteAlopeciaMyelosupressionInfectionNausea/vomitingMalaiseDiscoloration of scleraArrhythmiaChronicCardiac toxicityMalignancyAmenorrheaInfertilityFetal malformation
129MitoxantroneApproved by the FDA for worsening RR MS, SP MS with relapse, and PR MSRecognized as a rescue therapyMore dangerous than A,B,C,RUseful in those failing conventional therapy or with aggressive disease from the outset
130The “Evolution” Much has changed since the advent of mitoxantrone Our understanding of the disease process and the importance of the inflammatory process has grown substantiallyNot much has changed regarding the profiles of the chemotherapeutic agents used and being developedCladribine is a perfect example
131Cladrbine Synthetic purine analogue product (adenosine analogue) Deoxycytidine kinase (phosphorylation)Affect cellular metabolism, induce DNA damage and apoptosis in dividing and non dividing cellsReduction of CD4 and CD8 T cells, B cells but also other immune cells such as neutrophils and monocytes
132Background Approved by FDA for: Hairy cells leukemiaMalignant lymphomaA few phase 1 and 2 studies have been conducted in MS with cladribine iv or s/c.Pregnancy category D
133The 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 AControlled 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 BEither 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 CEither 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 DThere 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 XStudies 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.
134CLARITY - Treatment Regimen Annual short-course treatmentEach course = 1–2 tablets (10 mg) daily for 4 or 5 consecutive days per monthCourses given for 2 or 4 consecutive months in Year 1 and for 2 consecutive months in Year 2First 48 weeksSecond 48 weeksX X X XX XPlacebo••••1326 randomized (1:1:1)X XScreeningPlacebo courseCladribine courseXCladribine tables: 4 courses, total dose 3.5 mg/kg•••••••Cladribine tables: 6 courses, total dose 5.25 mg/kgGiovannoni G et al. Presented at American Academy of Neurology 61st Annual Meeting; Seattle, USA; April 30, 2009.134
135Primary Outcome Reduction in Relapse Rates (ITT) 54.5% reduction (P < 0.001)57.6% reduction (P < 0.001)0.33Annualized relapse rate0.150.14Placebo (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
136Secondary Outcome Reduction in Disability Progression (ITT) Hazard ratio vs placebo (95% CI)*PlaceboCladribine 3.5 mg/kg (0.48, 0.93); P = 0.018Cladribine 5.25 mg/kg (0.49, 0.96); P = 0.02633%31%Proportion with 3-month confirmed EDSS progression (%)RelativereductionNumber of patients at risk:Placebo 3.5 mg/kg5.25 mg/kg437433456424447399407425373389404355379388333364375315355363304347350304347350Time 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
137Secondary 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 < 0.001Mean ± SE lesions/patient/scan1.000.50T1 Gd+ lesionsActive T2 lesionsCombined unique lesionsSE = standard error. Giovannoni G et al. Presented at American Academy of Neurology 61st Annual Meeting; Seattle, USA; April 30, 2009.137
138Secondary 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 AEAEs leading to discontinuationAEs leading to withdrawalSerious AEsDeaths*184.108.40.206.40.5 (n = 2)220.127.116.11.483.97.92.09.0(n = 2)18.104.22.168.70.4 (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 eventsGiovannoni G et al. Presented at American Academy of Neurology 61st Annual Meeting; Seattle, USA; April 30, 2009.138
139CladribineDepletion of Lymphocyte Subpopulations in Phase 3 Trial in SPMS and PPMSCD4+ (helper T cells)CD8+ (cytotoxic T cells)CD19+ (B cells)CD19+/CD56+ (natural killer cells)PlaceboCladribine 0.7 mg/kgCladribine 2.1 mg/kgGuarnaccia JB, et al. Presented at: WCTRIMS; September 17-20, 2008; Montreal, Canada. [P55].
140Cladribine: 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 increasedThese findings may suggest that CD4+/CD45RA+ cells are more sensitive than CD4+/CD45RO+ to the toxic effect of cladribineFC JGRaspadori D, et al. Leukemia. 1999;13:
141Subject 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 wksAlmost all other Grade 3 and 4 toxicities resolved on studyLaboratory testStatisticsCladribine 5.25 mg/kg (n=454)n (%)Cladribine 3.5 mg/kg (n=430)Placebo (n=435)HaemoglobinMean duration (SD) (weeks)Median duration (weeks)Min;Max duration (weeks)0 (1 total)3 (5 total)17.5 (6.8)18.110.4;24.02 (3 total)13.0 (8.3)13.07.1;18.9WBC8 (10 total)11.8 (10.3)9.01.4;29.16 (6 total)3.7 (1.9)3.41.6;6.02 (2 total)2.8 (0.9)2.82.1;3.4Neutrophils17 (17 total)8.1 (9.6)5.91.1;42.112 (12 total)5.2 (3.8)4.91.0;12.117 (18 total)4.8 (3.1)4.31.1;12.1Lymphocyte108 (203 total)29.4 (20.8)24.12.9;88.052 (110 total)25.4 (19.8)23.40.9;92.74.6 (0.6)4.64.1;5.0PS. Sorenson, et al. Presented at ECTRIMS 25th Annual Meeting; Dusseldorf, Germany; September 10, 2009; Poster 472.
142Adverse Events of Special Interest Herpes Zoster Preferred term, n (%) patientsPlacebo(n=435)Cladribine 3.5 mg/kg(n=430)Cladribine mg/kg(n=454)Cladribine overall(n=884)Herpes zoster8 (1.9) 11 (2.4) 19 (2.1)Herpes zoster oticus1 (0.2) 1 (0.1)Varicella1 (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 hospitalisationRELATIONSHIP BETWEEN LYMPHOCYTE COUNTS AND ZOSTERHerpes 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 placebo20 patients had 21 zoster events in the cladribine tablets groupsAll 21 cases were self-limiting and dermatomalS. Cook, et al. Presented at ECTRIMS 25th Annual Meeting; Dusseldorf, Germany; September 11, 2009.142
143Adverse 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 studyCervix carcinoma Stage 0Malignant melanomaOvarian cancerPancreatic cancer, metastaticDuring post-study surveillanceChoriocarcinoma0.2 (1)0.1 (1)Giovannoni G et al. Presented at American Academy of Neurology 61st Annual Meeting; Seattle, USA; April 30, 2009.
145Cladribine Summary Efficacy is comparable to high dose IFN Toxicity is considerableRisk of malignancyLong-term immunosuppressionIncreased risk of herpes infectionsInfertilityFetal malformationGraft vs. hostHow long can it be used with CD-4 counts markedly reducedWhat do you do if patients are worsening?
146Evolution? There has been no evolution! Chemotherapeutic agents remain nonselective, broad spectrum cytotoxic agents that suppress the immune system in a nonspecific fashionThey all have considerable risk of adverse events that include secondary malignancy, infection, infertility, fetal malformation, and other end organ toxicityNewer monoclonal antibodies and other innovative therapies appear equally or more effective and have manageable risk
147Challenging Cases in the Case StudiesChallenging Cases in theManagement of Multiple Sclerosis and Parkinson’s Disease
148Multiple Sclerosis Case #1 24-year-old female with diplopia on looking to the right for a day or two – Austin ophthalmologist found nothing unusualBack in Houston another ophthalmologist called it ‘some type of optic nerve inflammation’ and gave her 5 days of oral steroids2 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
151Multiple Sclerosis Case #1 4 days later continued double vision on looking to the rightExtensive past history uncovered only one week of nausea and vomiting about 4 months ago attributed to food poisoningNystagmus to right gaze of greater amplitude in adducting eye with incomplete abduction of right eye, remaining exam normalCSF with 10 lymphocytes, IgG index 1.15 and 3 OCBsIntravenous methylprednisolone course started
154Multiple 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?
155Multiple Sclerosis Case #2 30-year-old Caucasian female presented initially with right optic neuritis.Vision improved after high dose intravenous methylprednisolone treatmentT2-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.
156Multiple Sclerosis Case #2 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 therapyResidual numbness in the feet and bladder control difficulties.
157Multiple Sclerosis Case #2 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.
158Multiple Sclerosis Case #2 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.
159Multiple Sclerosis Case #2 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.
160Multiple Sclerosis Case #3 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.
161Is 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?
162Multiple Sclerosis Case #4 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.
164Parkinson’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.
165Parkinson’s Disease Case #1 Family History: No family history of Parkinson’s diseaseMedical History/Medications: Wife noticed that for the past three years the patient moves about during sleep. No current medicationsExamination: 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
166Parkinson’s Disease Case #2 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.
167Parkinson’s Disease Case #2 Family History: Father died with Parkinson Disease and a cousin diagnosed with Parkinson’s disease 2 years ago is responding well to levodopaMedical History/Medications: No significant medical or surgical history. No current medicationsExamination: 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 normalDecision making: Patient diagnosed with Parkinson’s disease with some disability and he wishes to start treatment.
168Parkinson’s Disease Case #3 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.
169Parkinson’s Disease Case #3 Family History: no relatives with PDMedical History: No significant medical or surgical historyMedications: Amitriptyline 50 mg. q.h.s for depression in addition to carbidopa-levodopaDecision making: treatment of motor fluctuations, non-motor features of PD
170Parkinson’s Disease Case #4 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.
171Parkinson’s Disease Case #4 Family History: 87-year-old sister diagnosed with Alzheimer’s disease and Parkinson’s diseaseMedical History: Mild stroke 3 years ago; has minimal residual effects of right-sided weakness.Medications: She takes 1 aspirin daily in addition to carbidopa-levodopaDecision making: management of advanced PD motor and non-motor features