optimizing neurotherapy for multiple sclerosis and parkinsons disease applying science, expert...

Optimizing Neurotherapy Optimizing Neurotherapy forfor

Multiple Sclerosis Multiple Sclerosis andand Parkinson’s DiseaseParkinson’s Disease

Applying Science, Expert Analysis, Guidelines, and Applying Science, Expert Analysis, Guidelines, and Landmark Trials to the Front Lines Patient CareLandmark Trials to the Front Lines Patient Care

New Frontiers New Frontiers and and Landmark Practice AdvancesLandmark Practice Advances

Program ChairmanProgram ChairmanC. Warren Olanow M.D., FRCPCC. Warren Olanow M.D., FRCPC

Henry P. and Georgette Goldschmidt Professor and Henry P. and Georgette Goldschmidt Professor and Chairman Emeritus, Department of Neurology Chairman Emeritus, Department of Neurology

Professor, Department of NeuroscienceProfessor, Department of NeuroscienceDirector, Robert and John M. Bendheim Parkinson’s Disease CenterDirector, Robert and John M. Bendheim Parkinson’s Disease Center

Mount Sinai School of MedicineMount Sinai School of Medicine

CME-certified symposium CME-certified symposium jointly jointly sponsored by the University of sponsored by the University of Massachusetts Medical School Massachusetts Medical School and CMEducation Resources, and CMEducation Resources, LLCLLC

Commercial Support: Commercial Support: Sponsored Sponsored by an independent educational by an independent educational grant from Teva Neuroscience, grant from Teva Neuroscience, Inc.Inc.

Faculty disclosures: Faculty disclosures: Listed in Listed in program syllabusprogram syllabus

Welcome and Program Overview Welcome and Program Overview

Program FacultyProgram Faculty

Program ChairmanProgram ChairmanC. Warren Olanow M.D., FRCPCC. Warren Olanow M.D., FRCPCHenry P. and Georgette Goldschmidt Henry P. and Georgette Goldschmidt Professor and Chairman Emeritus, Professor and Chairman Emeritus, Department of Neurology Department of Neurology Professor, Department of Professor, Department of NeuroscienceNeuroscienceDirector, Robert and John M. Director, Robert and John M. Bendheim Bendheim Parkinson’s Disease CenterParkinson’s Disease CenterMount Sinai School of MedicineMount Sinai School of Medicine

Douglas R. Jeffery, MD, PhDDouglas R. Jeffery, MD, PhDAssociate ProfessorAssociate ProfessorDepartment of NeurologyDepartment of NeurologyWake Forest University Baptist Wake Forest University Baptist Medical Medical CenterCenterWinston-Salem, NCWinston-Salem, NC

Howard L. Zwibel, MDHoward L. Zwibel, MDFounding Medical Director, EmeritusFounding Medical Director, EmeritusNeuroscience ConsultantsNeuroscience ConsultantsComprehensive Multiple Sclerosis Comprehensive Multiple Sclerosis Center in affiliation with the National Center in affiliation with the National Multiple Sclerosis Center Coral Multiple Sclerosis Center Coral Gables, FloridaGables, FloridaBaptist Health Doctors Hospital MS Baptist Health Doctors Hospital MS CenterCenterCoral Gables, FLCoral Gables, FL

Parkinson’s Disease Parkinson’s Disease andand Multiple SclerosisMultiple Sclerosis

Two Diseases in Need of a Neuroprotective Two Diseases in Need of a Neuroprotective TherapyTherapy






► Two important neurological disordersTwo important neurological disorders● Primarily affect older individuals (PD) Primarily affect older individuals (PD) ● Primarily affect younger individuals (MSPrimarily affect younger individuals (MS))

► Both have surrogate imaging markersBoth have surrogate imaging markers● FD-PET (PD)FD-PET (PD)● MRI (MS)MRI (MS)

► Treatments are available for both Treatments are available for both diseasesdiseases● Benefit symptoms (PD)Benefit symptoms (PD)● Reduce relapse rate (MS)Reduce relapse rate (MS)

Parkinson’s Disease and Multiple SclerosisParkinson’s Disease and Multiple Sclerosis

► Both result in unacceptable disability Both result in unacceptable disability for many patients despite available for many patients despite available treatmentstreatments

► Disease-modifying or neuroprotective Disease-modifying or neuroprotective therapies are urgent prioritiestherapies are urgent priorities

► Both offer many candidate disease-Both offer many candidate disease-modifying agents based on laboratory modifying agents based on laboratory workwork


► Development of a disease modifying Development of a disease modifying therapy in each condition would be therapy in each condition would be enhanced by:enhanced by:● Insight into the precise cause of the Insight into the precise cause of the

diseasedisease● Better animal modelsBetter animal models● Better clinical trial designs with Better clinical trial designs with

endpoints reflecting the underlying endpoints reflecting the underlying disease processdisease process

► Advances in these areas will be Advances in these areas will be reviewed in the current sessionreviewed in the current session


Attempts to Obtain Attempts to Obtain Neuroprotection for Parkinson’s Neuroprotection for Parkinson’s

DiseaseDisease






Current Therapies for PDCurrent Therapies for PD

► Primarily dopaminergicPrimarily dopaminergic

► Highly effective for the classic motor Highly effective for the classic motor featuresfeatures● Tremor, rigidity, bradykinesiaTremor, rigidity, bradykinesia

► Do not satisfactorily control non-Do not satisfactorily control non-dopaminergic featuresdopaminergic features● Gait dysfunction, freezing, postural Gait dysfunction, freezing, postural

instability, falling, autonomic dysfunction, instability, falling, autonomic dysfunction, mood disorders, sensory problems, mood disorders, sensory problems, cognitive impairment, dementiacognitive impairment, dementia

► Do not stop disease progressionDo not stop disease progression

The Sydney Long Term PD StudyThe Sydney Long Term PD Study

► 149 PD patients were entered149 PD patients were entered

► 52 survivors after 15 years52 survivors after 15 years

► None were still employedNone were still employed

► 40% were in a nursing home 40% were in a nursing home

► 95% had levodopa-induced dyskinesia and 95% had levodopa-induced dyskinesia and wearing offwearing off

► Non-dopaminergic features (falling, Non-dopaminergic features (falling, dementia) were the primary cause of dementia) were the primary cause of disability and of nursing home placementdisability and of nursing home placement

Neuroprotective (Disease-Neuroprotective (Disease-Modifying) Therapy For PDModifying) Therapy For PD

A treatment intervention that A treatment intervention that slows, stops or reverses disease slows, stops or reverses disease

progressionprogression

Neuroprotective Trials in PDNeuroprotective Trials in PDNegative StudiesNegative Studies

AgentAgent MechanismMechanism EndpointEndpoint

Vitamin EVitamin E Anti-oxidantAnti-oxidant Time to L-dopaTime to L-dopa

RiluzoleRiluzole Anti-glutamateAnti-glutamate Time to L-dopaTime to L-dopa

MinocyclineMinocycline Anti-InflammatoryAnti-Inflammatory ΔΔ UPDRS UPDRS

ImunophilinImunophilin TrophicTrophic Time to L-dopaTime to L-dopa

GDNF/NeurturinGDNF/Neurturin Trophic factorsTrophic factors ΔΔ UPDRS UPDRS

TCH346TCH346 Anti-apoptoticAnti-apoptotic Time to L-dopaTime to L-dopa

CEP1347CEP1347 Anti-apoptoticAnti-apoptotic Time to L-dopaTime to L-dopa

DA Cell TransplantDA Cell Transplant Cell replacementCell replacement ΔΔ UPDRS/QOLUPDRS/QOL

Obstacles to Finding a Neuroprotective Obstacles to Finding a Neuroprotective Therapy for PDTherapy for PD

► We do not know the precise etiology or We do not know the precise etiology or pathogenesis of PD—we don’t know pathogenesis of PD—we don’t know what to targetwhat to target

► We do not have a reliable animal model We do not have a reliable animal model that is progressive and reflects the that is progressive and reflects the etiopathogeneis of PDetiopathogeneis of PD

► We do not have a good method for We do not have a good method for determining the optimal dose to use in a determining the optimal dose to use in a clinical trialclinical trial

Neuroprotective Trials in PDNeuroprotective Trials in PDPositive StudiesPositive Studies

AgentAgent MechanismMechanism EndpointEndpoint

Selegiline (DATATOP)Selegiline (DATATOP) Anti-apoptoticAnti-apoptotic Time to L-dopaTime to L-dopa

Selegiline (SINDEPAR)Selegiline (SINDEPAR) Anti-apoptoticAnti-apoptotic Wash OutWash Out

Co-Q10Co-Q10 Bio-energeticBio-energetic ΔΔ UPDRS UPDRS

CreatineCreatine Bio-energeticBio-energetic ΔΔ UPDRS UPDRS

RopiniroleRopinirole Anti-apoptoticAnti-apoptotic ΒΒ-CIT-SPECT-CIT-SPECT

PramipexolePramipexole Anti-apoptoticAnti-apoptotic F-DOPA PETF-DOPA PET

Obstacles to Finding a Neuroprotective Obstacles to Finding a Neuroprotective Therapy for PDTherapy for PD

► We do not know the precise etiology or We do not know the precise etiology or pathogenesis of PD –we don’t know what pathogenesis of PD –we don’t know what to targetto target

► We do not have a reliable animal model We do not have a reliable animal model that is progressive and reflects the that is progressive and reflects the etiopathogeneis of PDetiopathogeneis of PD

► We do not have a good method for We do not have a good method for determining the optimal dose to use in a determining the optimal dose to use in a clinical trialclinical trial

► We do not have a clinical trial design that We do not have a clinical trial design that can reliably detect a disease-modifying can reliably detect a disease-modifying agentagent

Trial Designs for Neuroprotection in PDTrial Designs for Neuroprotection in PD

► Time to a milestone of disease progressionTime to a milestone of disease progression► Washout design (change from untreated Washout design (change from untreated

baseline to final visit performed after drug baseline to final visit performed after drug washout)washout)

► Change from baseline to final visit in Change from baseline to final visit in UPDRS scoreUPDRS score

► Neuroimaging of surrogate biomarker of Neuroimaging of surrogate biomarker of dopaminergic functiondopaminergic function

Delayed Start DesignDelayed Start Design

PlaceboPlacebo

Early StartEarly StartInterventionIntervention

Period IPeriod I

Early StartEarly Start

PlaceboPlacebo

SymptomaticSymptomaticEffectEffect

Delayed Start Delayed Start InterventionIntervention

Early StartEarly StartInterventionIntervention

Period IPeriod I Period IIPeriod II


DelayedDelayed StartStart


PlaceboPlacebo

PossiblePossibleDisease ModifyingDisease Modifying

Effect Effect

Delayed Start Delayed Start InterventionIntervention

Early studyEarly studyInterventionIntervention

Period IPeriod I Period IIPeriod II


DelayedDelayed StartStart


Delayed Start Study Delayed Start Study Principal Statistical AnalysesPrincipal Statistical Analyses

Delayed Start (Placebo-Rasagiline)

Early Start (Rasagiline-Rasagiline)Adapted from Olanow et al. Mov Disord. 2008.

Week7212 36 48 54 60 6624 42

Mea

n U

PDRS

cha

nge

from

bas

elin

e

Wor

seni

ngIm

prov

emen

t

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)

Issues That Must Be Addressed in a Issues That Must Be Addressed in a Delayed-Start Study Delayed-Start Study

► Duration of period 1 and period 2Duration of period 1 and period 2● Long enough for protective effect to occurLong enough for protective effect to occur● Long enough for full symptomatic effect to Long enough for full symptomatic effect to

occuroccur● Not so long that patients withdrawNot so long that patients withdraw

► Drop outsDrop outs► Missing dataMissing data

● Need for sensitivity and imputation analysesNeed for sensitivity and imputation analyses

► Sufficient numbers of visits to permit slope Sufficient numbers of visits to permit slope analysis in period 1 and 2analysis in period 1 and 2

The ADAGIO StudyThe ADAGIO Study

ADAGIO Study DesignADAGIO Study Design

Olanow et al. Mov Disord. 2008Olanow et al. Mov Disord. 2008

36-week (9-month9-month) Double Blind Active-

Treatment Phase

0 24 54 60 66 724 36 48Week

36-week (9-month) Double Blind Placebo-

Controlled Phase

12 42

Placebo

1 mg/day

2 mg/day

1 mg/dayUntreated Untreated PD patientsPD patients

2 mg/day

ADAGIO – Baseline CharacteristicsADAGIO – Baseline Characteristics

Olanow et al. Mov Disord 2008Olanow et al. Mov Disord 2008

Patients randomised (n)Patients randomised (n) 1,1761,176

Male patients (n, %)Male patients (n, %) 718 (61.1%)718 (61.1%)

Age, years (mean, SD)Age, years (mean, SD) 62.2 (9.6)62.2 (9.6)

PD duration, months (mean, SD)PD duration, months (mean, SD) 4.5 (4.6)4.5 (4.6)

UPDRS-Total score (mean, SD)UPDRS-Total score (mean, SD)

MotorMotor

ADLADL

20.4 (8.5)20.4 (8.5)

14,2 (6.4)14,2 (6.4)

5.2 (2.8)5.2 (2.8)

Hoehn & Yahr score (mean, SD)Hoehn & Yahr score (mean, SD) 1.5 (0.5)1.5 (0.5)

Rasagiline 1mg: Early vs Delayed Rasagiline 1mg: Early vs Delayed StartStart

Olanow et al. NEJM; 2009Olanow et al. NEJM; 2009

Rasagiline 2mg: Early vs Delayed Rasagiline 2mg: Early vs Delayed StartStart

Olanow et al. NEJM; 2009Olanow et al. NEJM; 2009

The ADAGIO Study The ADAGIO Study Summary and ConclusionsSummary and Conclusions

► Rasagiline 1 mg/day met all 3 primary Rasagiline 1 mg/day met all 3 primary outcomes of the delayed start studyoutcomes of the delayed start study● Is this a false positive?Is this a false positive?

► Rasagiline 2 mg/day failed to meet all Rasagiline 2 mg/day failed to meet all primary outcomes of the delayed start studyprimary outcomes of the delayed start study● Is this a false negative?Is this a false negative?

ADAGIO – Clinical Significance of ADAGIO – Clinical Significance of Positive Result with Rasagiline 1 mgPositive Result with Rasagiline 1 mg

► UPDRS difference of 1.7 unitsUPDRS difference of 1.7 units

► 38% reduction in rate of decline 38% reduction in rate of decline of UPDRS score of UPDRS score

► Reflects only 9 months of active Reflects only 9 months of active treatmenttreatment

ADAGIO TrialADAGIO TrialClinical SignificanceClinical Significance

► Delayed-start study designed to determine Delayed-start study designed to determine if a study intervention has benefits that if a study intervention has benefits that cannot be accounted for by symptomatic cannot be accounted for by symptomatic effects aloneeffects alone

► Long-term studies are required to assess Long-term studies are required to assess effect of drug on cumulative disabilityeffect of drug on cumulative disability● Extension studyExtension study● Long-term simple studyLong-term simple study● Endpoints that include measures of motor and Endpoints that include measures of motor and

non-motor function - UPDRS gait, cognitive non-motor function - UPDRS gait, cognitive function, and quality of lifefunction, and quality of life

The Evidence for First Line Therapy in MS The Evidence for First Line Therapy in MS with Immune-Modulating Agents (IMTs)with Immune-Modulating Agents (IMTs)

From Mechanisms to Therapy-Landmark Trials, Long-From Mechanisms to Therapy-Landmark Trials, Long-Term Safety Data, and Clinical ExperienceTerm Safety Data, and Clinical Experience

New Dimensions and New Dimensions and Landmark Practice AdvancesLandmark Practice Advances

Howard L. Zwibel, MDHoward L. Zwibel, MDFounding Medical Director, Emeritus | NeuroscienceFounding Medical Director, Emeritus | Neuroscience

Consultants | Comprehensive Multiple Sclerosis CenterConsultants | Comprehensive Multiple Sclerosis Centerin affiliation with the National Multiple Sclerosis Centerin affiliation with the National Multiple Sclerosis CenterCoral Gables, Florida | Baptist Health Doctors HospitalCoral Gables, Florida | Baptist Health Doctors Hospital

MS Center | Coral Gables, FLMS Center | Coral Gables, FL

The Evidence for First Line Therapy in MS The Evidence for First Line Therapy in MS with Immune-Modulating Agents (IMTs)with Immune-Modulating Agents (IMTs)

From Mechanisms to Therapy-Landmark Trials, Long-From Mechanisms to Therapy-Landmark Trials, Long-Term Safety Data, and Clinical ExperienceTerm Safety Data, and Clinical Experience


NOTE: Both trade and chemic names areNOTE: Both trade and chemic names areused in the presentation to establish clarity, and used in the presentation to establish clarity, and

because many trials use acronyms that employ the because many trials use acronyms that employ the brand name. The use of brand names should not be brand name. The use of brand names should not be

construed as endorsements for these products.construed as endorsements for these products.

MS: Immune DysfunctionMS: Immune Dysfunction

Proinflammatory immune cells

Proinflammatory cytokines

Antigen-presenting cell

Blood-brain barrier

1.1. Ziemssen T. Ziemssen T. J NeurolJ Neurol. 2005;252:V/38-V/45. . 2005;252:V/38-V/45. 2.2. Yong VW, et al. Yong VW, et al. Neurology. Neurology. 2007;68:S32-S37. 2007;68:S32-S37. 3. 3. Dhib-Dhib-Jalbut S. Jalbut S. Neurology. Neurology. 2007;68:S13-S21. 2007;68:S13-S21. 4.4. Tzartos JS, et al. Tzartos JS, et al. Am J Pathol.Am J Pathol. 2008;172:146-155. 2008;172:146-155.

T cells

Diagnosis of MSDiagnosis of MS

Based on Based on modifications modifications to to McDonald McDonald CriteriaCriteria

CSF = cerebrospinal fluid CSF = cerebrospinal fluid Polman CH, et al. Polman CH, et al. Ann NeurolAnn Neurol. 2005;58:840-846.. 2005;58:840-846.Compston A, Coles A. Compston A, Coles A. Lancet. Lancet. 2008;372:1502-2008;372:1502-1517. Figure 1.1517. Figure 1.

Differentiating MS Lesions Using MRIDifferentiating MS Lesions Using MRI

T2 T2

T1 Post-Gd T1 Post-Gd ContrastContrastActive InflammationActive Inflammation

T1 T1 PrecontrastPrecontrastBlack HolesBlack Holes

A B

C

T2 with T2 with FLAIRFLAIR

D

FLAIR = Fluid Attenuated Inversion RecoverySlide courtesy of JS Wolinsky.

Note:Note:Scans are not from Scans are not from the same patient.the same patient.

Clinically Isolated Syndrome (CIS)Clinically Isolated Syndrome (CIS)

► Clinical episode consistent with demyelination Clinical episode consistent with demyelination ● Characterized by MRI and lab dataCharacterized by MRI and lab data● Patient may or may not develop clinically definite MS Patient may or may not develop clinically definite MS

(CDMS)(CDMS)► Features of CIS suggestive of a first MS attack include:Features of CIS suggestive of a first MS attack include:

● Appropriate age; female genderAppropriate age; female gender● Abnormal brain MRIAbnormal brain MRI● Optic neuritisOptic neuritis

• Typically unilateral, retrobulbar, and painfulTypically unilateral, retrobulbar, and painful● Brainstem/cerebellar dysfunctionBrainstem/cerebellar dysfunction

• Most commonly ocular motor syndromes (INO, Most commonly ocular motor syndromes (INO, nystagmus), ataxia, dysarthria, sensory or motor signsnystagmus), ataxia, dysarthria, sensory or motor signs

● MyelitisMyelitis• Partial sensory more common than partial motorPartial sensory more common than partial motor• Bowel and bladder dysfunction commonBowel and bladder dysfunction common

INO: Internuclear ophthalmoparesisINO: Internuclear ophthalmoparesisFrohman, et al. Frohman, et al. NeurologyNeurology. 2003;61:602-611.. 2003;61:602-611.

National MS Society. Clinically isolated syndrome. National MS Society. Clinically isolated syndrome. http://www.nationalmssociety.org/about-multiple-http://www.nationalmssociety.org/about-multiple-sclerosis/diagnosing-ms/cis/index.aspx. sclerosis/diagnosing-ms/cis/index.aspx. Accessed 12/08.Accessed 12/08.

Clinically Isolated Syndrome (CIS)Clinically Isolated Syndrome (CIS)

► The challenge for physician is to determine the The challenge for physician is to determine the likelihood that person experiencing this type of likelihood that person experiencing this type of demyelinating event is going to experience a demyelinating event is going to experience a second demyelinating event in the future, thereby second demyelinating event in the future, thereby meeting the criteria for a definite diagnosis of MS. meeting the criteria for a definite diagnosis of MS.

► When the CIS is accompanied by MRI-detected When the CIS is accompanied by MRI-detected brain lesions consistent with those seen in MS, brain lesions consistent with those seen in MS, there is a high risk of a second neurologic event there is a high risk of a second neurologic event and diagnosis of clinically definite MS within and diagnosis of clinically definite MS within several years. several years.

► Individuals who experience CIS with no evidence Individuals who experience CIS with no evidence of MRI-detected lesions are at relatively low risk of of MRI-detected lesions are at relatively low risk of developing MS.developing MS.

Fisniku LK, et al. Fisniku LK, et al. Brain.Brain. 2008;131:808-817. 2008;131:808-817.

CIS: MRI Lesions at Baseline Associated with CIS: MRI Lesions at Baseline Associated with Development of CDMS Over Next 20 YearsDevelopment of CDMS Over Next 20 Years

21%

82% 85%81%

(n = 34) (n = 22) (n = 20) (n = 31)

CIS or First Demyelinating Event: CIS or First Demyelinating Event: Phase III, Placebo-Controlled StudiesPhase III, Placebo-Controlled Studies

AcronymAcronym Full nameFull name Primary Primary Endpoint(s)Endpoint(s) StatusStatus

PreCISePreCISe

Study to Evaluate the Effect of Early Study to Evaluate the Effect of Early Glatiramer Acetate (GA, CopaxoneGlatiramer Acetate (GA, Copaxone®®) ) Treatment in Delaying the Conversion to Treatment in Delaying the Conversion to CDMS of Subjects Presenting with a CISCDMS of Subjects Presenting with a CIS

Time to clinically Time to clinically definite MS (CDMS)definite MS (CDMS) CompletedCompleted

BENEFITBENEFIT BetaferonBetaferon®® (IFN (IFN-1b) in Newly Emerging MS -1b) in Newly Emerging MS for Initial Treatmentfor Initial Treatment

Time to CDMS Time to CDMS Time to McDonald MSTime to McDonald MS CompletedCompleted

CHAMPSCHAMPS Controlled High-Risk Subjects (IFNControlled High-Risk Subjects (IFN-1a) -1a) AvonexAvonex®® Multiple Sclerosis Prevention Study Multiple Sclerosis Prevention Study

Probability of Probability of developing CDMSdeveloping CDMS

Changes in MRIChanges in MRICompletedCompleted

ETOMSETOMS Early Treatment of MS Study (IFNEarly Treatment of MS Study (IFN-1a)-1a) Conversion to CDMSConversion to CDMS CompletedCompleted

REFLEXREFLEX RebifRebif®® (IFN (IFN-1a) FLEXible Dosing in Early -1a) FLEXible Dosing in Early MSMS

Time to conversion to Time to conversion to MS (McDonald criteria)MS (McDonald criteria)

OngoingOngoing

Trade names are included in this presentation to reduce confusion regarding medication formulations and in no way endorses 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.the use of the product with the trade name.Comi G, et al. Comi G, et al. LancetLancet. 2009;Published online 10/7/09, DOI:10.1016/50140-6736(09)61259-9.. 2009;Published online 10/7/09, DOI:10.1016/50140-6736(09)61259-9.Kappos L, et al. Kappos L, et al. Neurology.Neurology. 2006;67(7):1242-1249. 2006;67(7):1242-1249.Jacobs LD, et al. Jacobs LD, et al. N Engl J Med.N Engl J Med. 2000;343(13):898-904. 2000;343(13):898-904.Comi G, et al. Comi G, et al. LancetLancet. 2001;357:1576-1582. . 2001;357:1576-1582.

Completed CIS Clinical Trials: Completed CIS Clinical Trials: Demographics and Key ResultsDemographics and Key Results

ParameterParameter PreCISePreCISe(GA)(GA)

BENEFITBENEFIT(IFN(IFN-1b SC)-1b SC)

CHAMPSCHAMPS(IFN(IFN-1a IM)-1a IM)

ETOMS ETOMS (IFN(IFN-1a SC)-1a SC)

DurationDuration 3 yrs (stopped 3 yrs (stopped early)early) 2 yrs2 yrs 3 yrs (stopped 3 yrs (stopped

early)early) 2 yrs2 yrs

Patients (N)Patients (N) 481481 468468 383383 308308

Patient agePatient age 31 31 ± 7 yrs± 7 yrs 30 yrs30 yrs 33 33 ± 7 yrs± 7 yrs 28 28 ± 6 yrs± 6 yrs

EDSS (mean)EDSS (mean) NANA 1.51.5 NANA 1.17 1.17 ± 1.2± 1.2

% Reduction % Reduction in CDMS Risk in CDMS Risk 45% 45% 50%50% 44%44% 39%39%

PP-value-value 0.0005 < 0.0001 0.002 0.0470.047

NA = not availableNA = not availableEDSS= expanded disability status scoreEDSS= expanded disability status scoreComi G, et al. Comi G, et al. LancetLancet. 2009;Published online 10/7/09, DOI:10.1016/50140-6736(09)61259-9.. 2009;Published online 10/7/09, DOI:10.1016/50140-6736(09)61259-9.Kappos L, et al. Kappos L, et al. Neurology.Neurology. 2006;67(7):1242-1249. 2006;67(7):1242-1249.Jacobs LD, et al. Jacobs LD, et al. N Engl J Med.N Engl J Med. 2000;343(13):898-904. 2000;343(13):898-904.Comi G, et al. Comi G, et al. LancetLancet. 2001;357:1576-1582. . 2001;357:1576-1582.

BENEFIT 5-Year Extension Data: BENEFIT 5-Year Extension Data: Early Versus Delayed IFNEarly Versus Delayed IFNββ-1b -1b

Kappos L, et al. Kappos L, et al. Lancet.Lancet. 2009; published online September 11, 2009 2009; published online September 11, 2009 DOI:1016/S1474-4422(09)70237-6DOI:1016/S1474-4422(09)70237-6

57%57%

46%46%

HR 0.63, 95% Cl 0.48–0.83; HR 0.63, 95% Cl 0.48–0.83; PP = 0.003 = 0.003

37%37%reduction in reduction in

risk of risk of developing developing

CDMSCDMS

CDMS = clinically definite multiple sclerosis

CHAMPIONS (CHAMPS Open-label CHAMPIONS (CHAMPS Open-label Extension): Early Versus Delayed IFNExtension): Early Versus Delayed IFNββ-1a-1a

Kinkel RP, et al. Presented at the 25th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), Düsseldorf, Germany, September 9-12, 2009. Poster # 446.

40% 40% reduction in reduction in

risk of risk of developing developing

CDMSCDMS

Incidence of CDMS by Treatment Group: 10-year extension dataIncidence of CDMS by Treatment Group: 10-year extension data

Delayed Treatment (n = 190)Delayed Treatment (n = 190)

Immediate 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 < 0.001

► ““Initiation of treatment with an interferon Initiation of treatment with an interferon beta medication or glatiramer acetate beta medication or glatiramer acetate should be considered as soon as possible should be considered as soon as possible following a definite diagnosis of MS with following a definite diagnosis of MS with active, relapsing disease, and may also be active, relapsing disease, and may also be considered for selected patients with a first considered for selected patients with a first attack who are at high risk of MS.”attack who are at high risk of MS.”

National Clinical Advisory Board of the National Multiple Sclerosis Society (2007). National Clinical Advisory Board of the National Multiple Sclerosis Society (2007). http://www.nationalmssociety.org/about-multiple-sclerosis/treatments/download.aspx?id=8. Accessed 01/14/09. http://www.nationalmssociety.org/about-multiple-sclerosis/treatments/download.aspx?id=8. Accessed 01/14/09.

SummarySummary

►Early treatment of CIS with DMTs (GA, Early treatment of CIS with DMTs (GA, IFNIFNββ formulations) delays progression to formulations) delays progression to CDMSCDMS

►Early treatment of CIS or MSEarly treatment of CIS or MS

• Reduces rate of relapsesReduces rate of relapses

• Delays the development of disability Delays the development of disability

• May reduce the overall cost of careMay reduce the overall cost of care

Chan A, et al. J Neuron. 2008;255(suppl 6):22-27.Chan A, et al. J Neuron. 2008;255(suppl 6):22-27.

Current MS TherapiesCurrent MS Therapies Immunosuppressants or Immunomodulators?Immunosuppressants or Immunomodulators?

► Generally considered to be Generally considered to be immunomodulatorsimmunomodulators

● Glatiramer acetate [GA] injectionGlatiramer acetate [GA] injection

● IFNIFNββ products products

● Natalizumab (?)Natalizumab (?)

► Uses of these immunomodulatorsUses of these immunomodulators

● GA and IFNGA and IFNββ products are first-line therapies products are first-line therapies for the for the

long-term treatment of CIS and RRMS long-term treatment of CIS and RRMS

● Natalizumab for patients who are unresponsive or Natalizumab for patients who are unresponsive or who cannot tolerate first-line DMTs, first-line use in who cannot tolerate first-line DMTs, first-line use in very active RRMSvery active RRMS

Glatiramer AcetateGlatiramer Acetate

► Dose: 20 mg sc daily (pre-filled Dose: 20 mg sc daily (pre-filled syringes)syringes)

► Pregnancy Category: BPregnancy Category: B

► Drug Interactions: None noted in clinical Drug Interactions: None noted in clinical trialstrials

► Laboratory monitoring: None neededLaboratory monitoring: None needed

► Adverse events: Injection site reaction, Adverse events: Injection site reaction, immediate post-injection reactionimmediate post-injection reaction

Presumed MOA of Glatiramer Acetate: Presumed MOA of Glatiramer Acetate: ImmunomodulationImmunomodulation

● Induces a population of Induces a population of regulatory T-cell types regulatory T-cell types (Th2,Treg)(Th2,Treg)

● Anti-inflammatory cytokines Anti-inflammatory cytokines and neurotrophic factors are and neurotrophic factors are releasedreleased

● May prevent nerve damage May prevent nerve damage and lead to remyelination*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.

Proinflammatoryimmune cells

Regulatory T-cell types


T cells

Proinflammatorycytokines

Anti-inflammatorycytokines

Neurotrophic factors

Blood-brain barrier

Weber MS, et al. Weber MS, et al. Neurotherapeutics. Neurotherapeutics. 2007;4:647-653. 2007;4:647-653. Aharoni R, et al. Aharoni R, et al. Proc Natl Acad Sci U S A. Proc Natl Acad Sci U S A. 2008;105:11358-2008;105:11358-11363.11363.

InterferonsInterferonsAvonexAvonex®®, Betaseron, Betaseron®®, Rebif, Rebif®®

► Doses: Doses: ● Avonex Avonex ®® : 30 mcg IM once weekly : 30 mcg IM once weekly ● Betaseron Betaseron ®® : 250 mcg SC every other day : 250 mcg SC every other day● Rebif Rebif ®® : 22 mcg, or 44 mcg, SC TIW : 22 mcg, or 44 mcg, SC TIW

► Pregnancy Category: CPregnancy Category: C► Drug Interactions: Possible with hepatically Drug Interactions: Possible with hepatically

active drugsactive drugs► Laboratory monitoring: CBC, LFT, thyroidLaboratory monitoring: CBC, LFT, thyroid► Adverse events: Flu-like symptoms, injection Adverse events: Flu-like symptoms, injection

site reaction, depression, hepatic injurysite reaction, depression, hepatic injury

Presumed MOA of IFNPresumed MOA of IFNββ: : ImmunomodulationImmunomodulation

● Reduces Reduces proinflammatory proinflammatory cytokine levels cytokine levels

● Reduces lymphocyte Reduces lymphocyte trafficking into the trafficking into the central nervous central nervous system (CNS) system (CNS)

Proinflamatoryimmune cells

Eliminatedimmune cell


Proinflammatorycytokines

T cells

Blood-brain barrier

BetaseronBetaseron®® prescribing information. Bayer HealthCare Pharmaceuticals Inc. prescribing information. Bayer HealthCare Pharmaceuticals Inc.

Monoclonal AntibodyMonoclonal AntibodyNatalizumabNatalizumab

► Dose: Dose: ● 300 mg iv infusion monthly300 mg iv infusion monthly

► Pregnancy Category: CPregnancy Category: C► Drug Interactions: Immunosuppressants, Drug Interactions: Immunosuppressants,

corticosteroidscorticosteroids► Safety Issues: Safety Issues:

● Progressive Multifocal Leukoencephalopathy Progressive Multifocal Leukoencephalopathy (PML)(PML)

● Hypersensitivity Reaction / NAbsHypersensitivity Reaction / NAbs● Melanoma / Other CancersMelanoma / Other Cancers● Liver InjuryLiver Injury● Reactivation of Latent VirusesReactivation of Latent Viruses

Presumed MOA of Natalizumab: Presumed MOA of Natalizumab: Reduction of Cell TraffickingReduction of Cell Trafficking

● Inhibits the Inhibits the αα4-4-mediated adhesion of mediated adhesion of leukocytes to vascular leukocytes to vascular cell adhesion molecule-cell adhesion molecule-11

● Strongly reduces Strongly reduces proinflammatory cell proinflammatory cell recruitment to the CNSrecruitment to the CNS

Proinflammatory immune cells

Proinflammatory cytokines

Antigen-presenting cells

T cellsBlood-brain barrier

TysabriTysabri®® (natalizumab) prescribing information. (natalizumab) prescribing information. Biogen Idec Inc.Biogen Idec Inc.

Head to Head Clinical TrialsHead to Head Clinical Trials

Head to Head Clinical StudiesHead to Head Clinical Studies

EVEVidenceidence ofof IInterferonnterferon DDose-ose-response: response: EEuropeanuropean NNorthorth

AmericanAmerican CComparativeomparative EEfficacyfficacy

(The EVIDENCE Trial)(The EVIDENCE Trial)

Results : Primary EndpointResults : Primary EndpointProportion Relapse Free at 64 WeeksProportion Relapse Free at 64 Weeks

% R

elap

se F

ree

P = 0.023P = 0.02356.3%

48.2%

Panitch H, et.al. Panitch H, et.al. J Neurol Sci.J Neurol Sci. 2005;239:67-74. 2005;239:67-74.

Results : Mean T2 Active Lesions at 64 WeeksResults : Mean T2 Active Lesions at 64 WeeksSecondary EndpointSecondary Endpoint

Me

an

T2

Le

sio

ns

P < 0.001

0.9

1.4

Panitch H, et.al. Panitch H, et.al. J Neurol Sci.J Neurol Sci. 2005;239:67-74. 2005;239:67-74.


REREbifbif®® vs. vs. GGlatiramer latiramer AAcetate cetate in in RRelapsing MS elapsing MS DDisease isease

(The REGARD Study) (The REGARD Study)

Phase IV Multicenter, Open Label, Randomized Study Phase IV Multicenter, Open Label, Randomized Study of Rebifof Rebif®® 44 44 µµg Administered Three Times Per Week g Administered Three Times Per Week

by Subcutaneous Injection Compared with by Subcutaneous Injection Compared with CopaxoneCopaxone®® 20 mg Administered Daily by 20 mg Administered Daily by

Subcutaneous Injection in the Treatment of RRMSSubcutaneous Injection in the Treatment of RRMS

Time to First Relapse Time to First Relapse (Primary Endpoint)(Primary Endpoint)

Su

rviv

al d

istr

ibu

tio

n f

un

ctio

nS

urv

ival

dis

trib

uti

on

fu

nct

ion

Time to first relapse (days)Time to first relapse (days)

Hazard ratio (95% CI):0.943 (0.74, 1.21)p = 0.643

GA

IFNβ-1a

672 days(96 weeks)

Adapted from an analyst report by Bernstein Research, October 15, 2007.Adapted from an analyst report by Bernstein Research, October 15, 2007.


BBetaseronetaseron EEfficacy fficacy YYielding ielding OOutcomesutcomes of aof a NNewew DDoseose

(The BEYOND Study)(The BEYOND Study)

Annualized Relapse Rate 1 Year Annualized Relapse Rate 1 Year Before and During TreatmentBefore and During Treatment

0

0.5

1.0

1.5

2.0

Before During

IFNβ-1b500 ugIFNβ-1b250 ugGA

-79% -78% -79%

*No significant differences

Comi G. Presented at: The European Charcot Foundation Symposium 2007; Nov 29 – Dec 1, 2007; Comi G. Presented at: The European Charcot Foundation Symposium 2007; Nov 29 – Dec 1, 2007; Fiuggi, Italy.Fiuggi, Italy.


BEBEtaserontaseron®® vs. vs. COCOpaxonepaxone®® in MS with Triple-Dose in MS with Triple-Dose

Gadolinium and 3-T Gadolinium and 3-T MMRI RI EEndpointsndpoints

(The BECOME Study)(The BECOME Study)

The BECOME StudyThe BECOME Study

► Study DesignStudy Design● Investigator-initiated study (single site)Investigator-initiated study (single site)● N = 75N = 75● RRMS (61) and CIS (14) patientsRRMS (61) and CIS (14) patients● Triple dose Gd with 40 min post-injection delayTriple dose Gd with 40 min post-injection delay● 3-Tesla MRI3-Tesla MRI

• ““This protocol is optimized to detect This protocol is optimized to detect enhancement…”enhancement…”

● Sponsored by Berlex/Schering AGSponsored by Berlex/Schering AG

► Primary Outcome MeasurePrimary Outcome Measure● The mean number of combined active lesions (CALs) per The mean number of combined active lesions (CALs) per

scanscan

• CALs were defined as Gd-enhancing lesions + CALs were defined as Gd-enhancing lesions + new T2/FLAIR lesions unassociated with new T2/FLAIR lesions unassociated with enhancementenhancement

Wolansky L, et al. Presented at: 22nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis; September 27-30, 2006; Madrid, Spain.

BECOME: SummaryBECOME: Summary

► Primary Outcome (CAL Count)Primary Outcome (CAL Count)● ““The primary outcome of the BECOME study The primary outcome of the BECOME study

demonstrates that IFNdemonstrates that IFNββ-1b and GA have similar efficacy -1b and GA have similar efficacy and onset of action for suppression of blood–brain barrier and onset of action for suppression of blood–brain barrier (BBB) breakdown in MS”(BBB) breakdown in MS”

► No significant differences on the following secondary No significant differences on the following secondary outcomesoutcomes● New enhancing lesionsNew enhancing lesions● Black Holes (acute hypointensities and persistent black Black Holes (acute hypointensities and persistent black

holes)holes)● Clinical: ARR, sustained disability progression, cognitive Clinical: ARR, sustained disability progression, cognitive

functionfunction

► It is difficult to generalize from one set of cohorts, It is difficult to generalize from one set of cohorts, however, the implication of the BECOME trial is that however, the implication of the BECOME trial is that “the superiority of IFN“the superiority of IFNββ-1b over GA for reducing the -1b over GA for reducing the incidence of active inflammation in MS may have been incidence of active inflammation in MS may have been overestimatedoverestimated””

Wolansky L, et al. Wolansky L, et al. Presented at: 23rd Congress of the European Committee for Treatment and Research in Multiple Presented at: 23rd Congress of the European Committee for Treatment and Research in Multiple Sclerosis; October 11-14, 2007; Prague, Czech Republic. Sclerosis; October 11-14, 2007; Prague, Czech Republic. Cheriyan J, et al. Presented at: 132nd Annual Meeting, American Cheriyan J, et al. Presented at: 132nd Annual Meeting, American Neurological Association; October 7-10, 2007; Washington, D.C. Cadavid D, et al. Neurological Association; October 7-10, 2007; Washington, D.C. Cadavid D, et al. Presented at: 23rd Congress of the Presented at: 23rd Congress of the European Committee for Treatment and Research in Multiple Sclerosis; October 11-14, 2007; Prague, Czech Republic.European Committee for Treatment and Research in Multiple Sclerosis; October 11-14, 2007; Prague, Czech Republic.

Trends Across Clinical Trials:Trends Across Clinical Trials:% Reduction in ARR – ~2 Years% Reduction in ARR – ~2 Years

% R

edu

ctio

n i

n A

RR

vs

Bas

elin

e%

Red

uct

ion

in

AR

R v

s B

asel

ine

JohnsonJohnson19951995

JacobsJacobs19961996

IFNIFNββ-1b study-1b studygroup,1993group,1993

PRISMS-2PRISMS-219981998

KapposKapposECTRIMS 2006,ECTRIMS 2006,

NEJM 2006NEJM 2006

PolmanPolman20062006

REGARDREGARD20072007


BEYONDBEYOND20072007


BECOMEBECOME20072007


59

4451

42

7985

71 69

79 7884 86

0

20

40

60

80

100

GA Avonex Betaseron Rebif 44 FTY720 Tysabri GA Rebif 44 GA Betaseron GA Betaseron

Trends Across Clinical Trials:Trends Across Clinical Trials:Annualized Relapse Rate – ~2 YearsAnnualized Relapse Rate – ~2 Years

0.59

0.67

0.840.87

0.200.23

0.29 0.300.34 0.35

0.320.28

0.00

0.20

0.40

0.60

0.80

1.00

GA Avonex Betaseron Rebif 44 FTY720 Tysabri GA Rebif 44 GA Betaseron GA Betaseron

JohnsonJohnson19951995

PolmanPolman20062006





KapposKapposECTRIMS 2006ECTRIMS 2006

JacobsJacobs19961996

IFNB-1b studyIFNB-1b studygroup,1993group,1993

PRISMS-2PRISMS-219981998



Ann

ualiz

ed R

elap

se R

ate

– 2-

yrs

Ann

ualiz

ed R

elap

se R

ate

– 2-

yrs

Long Term IMT DataLong Term IMT Data

Long-term Study Design in RRMSLong-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

16years

4 yrs

7-8 years

3yrs Key

Prospective study design

Retrospective follow-up

9.9. Jacobs LDJacobs LD, et al., et al. Ann Neurol. Ann Neurol. 1996;39:285-294. 1996;39:285-294. 20.20. Ford C, et al. WCTRIMS 2008. Abstract P44. Ford C, et al. WCTRIMS 2008. Abstract P44. 21.21. Ford CC, et al. Ford CC, et al. Mult Scler. Mult Scler. 2006;12:309-320. 2006;12:309-320. 23. 23. Bermel RA, et al. WCTRIMS 2008.Bermel RA, et al. WCTRIMS 2008. Abstract P14.Abstract P14. 24. 24. IFNIFNββ Study Group. Study Group. Neurology. Neurology. 1995;45:1277-1285. 1995;45:1277-1285. 25. 25. Ebers G, et al. AAN 2006. Ebers G, et al. AAN 2006. P01.079. P01.079. 26. 26. Kappos L, et al. Kappos L, et al. Neurology. Neurology. 2006;67:944-953. 2006;67:944-953. 27.27. O’Connor PW, et al. AAN 2007. O’Connor PW, et al. AAN 2007. P06.082.P06.082.

Pivotal Trial and Extension-Phase Pivotal Trial and Extension-Phase Study DesignStudy Design

Months

3 6 9 12 15 18 21 24 27 30 33 36

Withdrawn total (n=132)

180

Double-blind,placebo-controlled phase

0 35* 60

glatiramer acetate glatiramer acetate injectioninjection

placeboplacebo

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

120+

29. Johnson KP, et al. Neurology. 1995;45:1268-1276. 51. Ford C, et al. WCTRIMS 2008. Abstract P44. 52. Ford CC, et al. Mult Scler. 2006;12:309-320. 56. Johnson KP, et al. Neurology. 1998;50:701-708.

*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.

2008• 15-year analysis for Ongoing cohort• Mean disease duration: 22 years

# of pts# of pts††: 232 231 208 196 175 163 149 143 138 125 64 57 51: 232 231 208 196 175 163 149 143 138 125 64 57 51

* 1 * 1 2 2 3 4 5 6 7 8 9 10 11 12 3 4 5 6 7 8 9 10 11 12

Mea

n R

elap

se R

ate

Mea

n R

elap

se R

ate

*ARR in the 2 years before GA start *ARR in the 2 years before GA start ††AAfter year 9, mITT data included only those of patients randomized to GA in the double-blind phase of the study. Crossovers from fter 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 placebo group had not yet received GA

Yearly Relapse Rate While on GAYearly Relapse Rate While on GA

YearYear††

00

0.250.25

0.50.5

0.750.75

11

1.251.25

Ford CC, et al. Ford CC, et al. Mult SclerMult Scler. 2006;12:309-320.. 2006;12:309-320.

Demonstrated Long-term BenefitsDemonstrated Long-term BenefitsP

atie

nts

(%)

EDSS levels at 15-year follow-up

0

20

40

60

80

100

EDSS of 8 or higher

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 2008. Abstract P44.

ASSURANCEASSURANCE

► 15-year long-term follow-up of pivotal IM 15-year long-term follow-up of pivotal IM IFNIFNββ1a relapsing trial (MSCRG)1a relapsing trial (MSCRG)● Involved 2-year completersInvolved 2-year completers● Open label, retrospective, patient Open label, retrospective, patient

reportedreported

► N=136 (of 172) participatedN=136 (of 172) participated

► 46% currently on IM IFN46% currently on IM IFNββ1a (median 1a (median duration 13.3 years)duration 13.3 years)

Rudick et al. MS 11:626, 2005

ASSURANCEASSURANCE

► Those on IM IFNThose on IM IFNββ1a showed1a 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), Better physical score on SF36 (p<0.0001),

greater independence (p=0.0019; p=0.031)greater independence (p=0.0019; p=0.031)

Rudick et al. MS 11:626, 2005

124124

125125

123123

5252

5858

5656IFNIFNββ-1b 250 µg-1b 250 µg

IFNIFNββ-1b 50 µg-1b 50 µg

PlaceboPlacebo

19881988 19931993

Pivotal Study (n=372)Pivotal Study (n=372)

LTFLTF

20052005

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

19901990

16 Year Follow-Up16 Year Follow-Up

Goodin et al., Goodin et al., Multiple SclerosisMultiple Sclerosis; 2008: 14 (Suppl 1), P52; 2008: 14 (Suppl 1), P52

PlaceboPlacebon = 123n = 123

INFINFBB-1b-1b50 µg50 µg

n = 125n = 125

IFNB-1b IFNB-1b 250 µg250 µgn = 124n = 124

16-Year LTF: 16-Year LTF: Patient Disposition Patient Disposition in the Intent-to-Treat Populationin the Intent-to-Treat Population

DeceasedDeceased

Not foundNot found

AliveAlive

Pro

port

ion

of P

atie

nts

Pro

port

ion

of P

atie

nts

72.4%72.4%

16.3%16.3%7.2%7.2% 4.8%4.8%

10.5%10.5%13.6%13.6%

11.4%11.4% 84.7%84.7%79.2%79.2%

Ebers G. Presented at ECTRIMS 2006, Madrid, Spain.Ebers G. Presented at ECTRIMS 2006, Madrid, Spain.

16-Year LTF: Other Findings16-Year LTF: Other Findings

► The most important predictors for better long-term The most important predictors for better long-term outcomes from the IFNB-1b 16-year LTF study wereoutcomes 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% The risk of any negative outcome* was reduced by 60% with high compared to low exposurewith high compared to low exposure

► Safety and tolerabilitySafety and tolerability● No new or unexpected side effectsNo new or unexpected side effects● Flu-like symptoms , injection site reactions and NAbs Flu-like symptoms , injection site reactions and NAbs

continued at a low levelcontinued at a low level

**EDSS 6; SPMS; EDSS 6/SPMS, WheelchairEDSS 6; SPMS; EDSS 6/SPMS, Wheelchair

Goodin et al. Goodin et al. Multiple SclerosisMultiple Sclerosis; 2008: 14 (Suppl 1), P52; 2008: 14 (Suppl 1), P52

PRISMS Long Term Follow-upPRISMS Long Term Follow-up

► 8-year follow-up of PRISMS SC IFN8-year follow-up of PRISMS SC IFNββ1a 1a pivotal relapsing trialpivotal relapsing trial

► 382 of 560 subjects (68.2%) evaluated382 of 560 subjects (68.2%) evaluated● 275 (72%) still receiving IFN275 (72%) still receiving IFNββ1a 1a ● Subjects initially randomized to 44mcg showed Subjects initially randomized to 44mcg showed

best EDSS, relapse rate, T2 burden of disease at best EDSS, relapse rate, T2 burden of disease at 8 years8 years-no brain atrophy difference-no brain atrophy difference

► 19.7% progressed to SPMS19.7% progressed to SPMS

Neurology 2006;67:944Neurology 2006;67:944

Natalizumab Monotherapy Trial: ARRNatalizumab Monotherapy Trial: ARR

Polman CH et al. Polman CH et al. N Engl J MedN Engl J Med. 2006;354:899-910. . 2006;354:899-910.

68% reduction*68% reduction*68% reduction*68% reduction*

0.81†

0.26†

0.73‡

0.23‡

*P<0.001.†Preplanned interim analysis.‡Final analysis.

0

0.1

0.2

0.3

0.4

0 12 24 36 48 60 72 84 96 108 120

Weeks

Pro

po

rtio

n o

f P

ati

en

ts w

ith

Su

sta

ine

d

Pro

gre

ss

ion

of

Dis

ab

ility

Natalizumab Monotherapy Trial:Natalizumab Monotherapy Trial:Time to Sustained ProgressionTime to Sustained Progression

Adapted with permission from Polman CH et al. Adapted with permission from Polman CH et al. N Engl J MedN Engl J Med. 2006;354:899-910.. 2006;354:899-910.

Placebo

Natalizumab

P<0.001.

Natalizumab: Natalizumab: AFFIRM Gd-Enhancing LesionAFFIRM Gd-Enhancing Lesionss

P<0.001 between groups for all time intervals.

Miller DH et al. Miller DH et al. NeurologyNeurology. 2007;68:1390-1401.. 2007;68:1390-1401.

92% 92%

92%

Miller DH et al. Neurology. 2007;68:1390-1401.

Natalizumab: AFFIRM T2 LesionsNatalizumab: AFFIRM T2 Lesions

P<0.0001

83%

SummarySummary

GA and interferonsGA and interferons► Efficacy data documented from initial event to long-Efficacy data documented from initial event to long-

termterm► GA long-term data is prospectiveGA long-term data is prospective► Interferon data long-term is retrospectiveInterferon data long-term is retrospective► No long-term safety signalling with GA or interferonsNo long-term safety signalling with GA or interferons

Natalizumab Natalizumab ► Efficacy data short termEfficacy data short term► Safety signalling for development of PMLSafety signalling for development of PML

The Evolution of The Evolution of Chemotherapeutic Agents in Chemotherapeutic Agents in

the Treatment of Multiple the Treatment of Multiple SclerosisSclerosis

Douglas R. Jeffery, MD, PhDDouglas R. Jeffery, MD, PhDAssociate ProfessorAssociate Professor

Department of NeurologyDepartment of NeurologyWake Forest University Baptist Medical CenterWake Forest University Baptist Medical Center

Winston-Salem, NCWinston-Salem, NC


““Chemotherapeutic” Chemotherapeutic”

► Nonspecific cytotoxic agents that kill cells Nonspecific cytotoxic agents that kill cells via a mechanism that involves impairment via a mechanism that involves impairment of cell divisionof cell division

► Usually mediated by an effect on DNA or Usually mediated by an effect on DNA or RNA synthesisRNA synthesis

► Through this mechanism such agents kill T-Through this mechanism such agents kill T-cells, B-cells, and macrophages thus cells, B-cells, and macrophages thus impairing an immune response against a impairing an immune response against a wide variety of stimuliwide variety of stimuli

► Immunosuppressive agents that also Immunosuppressive agents that also increase the risk of infection through the increase the risk of infection through the nonspecific suppression of immune nonspecific suppression of immune functionfunction

The Search for a TreatmentThe Search for a Treatment

► Early on there were no treatments for MSEarly on there were no treatments for MS► Other disciplines (rheumatology) adopted Other disciplines (rheumatology) adopted

the use of chemotherapeutic agents to the use of chemotherapeutic agents to treat autoimmune diseasestreat autoimmune diseases

► MS thought by many to be autoimmune in MS thought by many to be autoimmune in naturenature

► Investigators in the MS field considered Investigators in the MS field considered the use of these agentsthe use of these agents

► Early study designs were flawed and some Early study designs were flawed and some doubted the effectiveness of these agentsdoubted the effectiveness of these agents

Benefits vs. Risk of Benefits vs. Risk of Chemotherapuetuc AgentsChemotherapuetuc Agents

► Chemotherapies are nonspecific Chemotherapies are nonspecific immunosuppressive agentsimmunosuppressive agents

► Many have well known and very serious Many have well known and very serious side effectsside effects● ImmunosuppressionImmunosuppression● InfectionInfection● HepatoxicityHepatoxicity● Secondary malignancySecondary malignancy

► In the absence of other effective In the absence of other effective treatments the benefits outweighed the treatments the benefits outweighed the risks in those with worsening disabilityrisks in those with worsening disability

Agents that have Been Studied in MSAgents that have Been Studied in MS

► AzathioprineAzathioprine► MethotrexateMethotrexate► CyclophosphamideCyclophosphamide► MycophenylateMycophenylate► MitoxantroneMitoxantrone► CladribineCladribine► CyclosporineCyclosporine

AzathioprineAzathioprine

► Earliest studies date back to 1971Earliest studies date back to 1971► Small poorly controlled trials suggested a Small poorly controlled trials suggested a

modest effect on relapsesmodest effect on relapses► Later controlled trials confirmed an effect on Later controlled trials confirmed an effect on

relapse rate but not disability progressionrelapse rate but not disability progression► Cochrane meta analysis suggested an effect Cochrane meta analysis suggested an effect

on relapse rateon relapse rate► Odds ratio of remaining relapse free on Odds ratio of remaining relapse free on

azathioprine was 1.51 at yr 1, 2.04 at yr 2, azathioprine was 1.51 at yr 1, 2.04 at yr 2, and 1.97 at yr 3and 1.97 at yr 3

Yudkin et. al. 1991Yudkin et. al. 1991

AzathioprineAzathioprine

► Used widely in Europe prior to the Used widely in Europe prior to the introduction of IFNintroduction of IFNββss

► Less popular in the modern era of Less popular in the modern era of immunomodulatory therapyimmunomodulatory therapy

► Studied and used widely as a combination Studied and used widely as a combination therapy in those with a suboptimal therapy in those with a suboptimal response to IFNresponse to IFNββs and galtiramer acatete s and galtiramer acatete (GLAT)(GLAT)

► Use as a monotherapy felt to be suboptimal Use as a monotherapy felt to be suboptimal given potential for longterm toxicitygiven potential for longterm toxicity

Azathioprine in Multiple SclerosisAzathioprine in Multiple Sclerosis

► 354 patients randomized to azathioprine vs. 354 patients randomized to azathioprine vs. placeboplacebo

► Double blinded, 3 yr durationDouble blinded, 3 yr duration► At 3 yrs mean EDSS decreased 0.80 in the At 3 yrs mean EDSS decreased 0.80 in the

placebo and 0.62 in the treated groupplacebo and 0.62 in the treated group► At 3yrs the placebo group had an average of At 3yrs the placebo group had an average of

2,5 relapse while the azathioprine group had 2,5 relapse while the azathioprine group had an average of 2.2 relapses (ns)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 Could not be recommended for most patients

with MSwith MSLancet. 1988; 23:179-183Lancet. 1988; 23:179-183

Effect of Azathioprine on MRI Metrics Effect of Azathioprine on MRI Metrics

► 14 patients with at least three gd(+) lesions within 14 patients with at least three gd(+) lesions within 6 months6 months

► Azathioprine dosed up to 3mg/kg daily depending Azathioprine dosed up to 3mg/kg daily depending on lymphocyte countson lymphocyte counts

► Evaluation for six months before treatment and six Evaluation for six months before treatment and six months of treatmentmonths of treatment

► Reduction of greater than 50% observed in 12 of 14 Reduction of greater than 50% observed in 12 of 14 patientspatients

► Reduction of greater than 50% or more in new T2 Reduction of greater than 50% or more in new T2 lesionslesions

► Azathioprine reduced new MS brain lesionsAzathioprine reduced new MS brain lesions

Massacesi, et. al. 2005Massacesi, et. al. 2005

Toxicity of AzathioprineToxicity of Azathioprine

► Bone marrow suppression Bone marrow suppression ● LeukopeniaLeukopenia● LymphopeniaLymphopenia● ThrombocytopeniaThrombocytopenia

► Increased risk of infectionIncreased risk of infection► HepatotoxicityHepatotoxicity► Malignancy risk increased with duration of Malignancy risk increased with duration of

exposureexposure● Solid organ tumors, myelodysplastic Solid organ tumors, myelodysplastic

syndromes, epitheliomas, skin cancersyndromes, epitheliomas, skin cancer

La Mantia 2007, Confravreux 1996La Mantia 2007, Confravreux 1996

CyclophosphamideCyclophosphamide

► Early studies suggested a possible effect in Early studies suggested a possible effect in secondarily progressive MS and rapidly secondarily progressive MS and rapidly progressive MSprogressive MS

► Conflicting results of several trials led to Conflicting results of several trials led to controversy as to whether it was effective controversy as to whether it was effective at allat all

► Some believed it was highly effective and Some believed it was highly effective and others felt it to be ineffective and others felt it to be ineffective and dangerousdangerous

► Both were right. It depended on whether Both were right. It depended on whether the extent of the inflammatory process the extent of the inflammatory process present present

Hauser et. al. Weiner et. al. 1993 Hauser et. al. Weiner et. al. 1993

Northeast Cooperative MS Treatment Northeast Cooperative MS Treatment GroupGroup

► RandomizedRandomized● Standard vs modified inductionStandard vs modified induction● Induction only vs induction + Induction only vs induction +

maintenancemaintenanceIV CTX (700 mg/mIV CTX (700 mg/m22) bimonthly) bimonthly

► InductionInduction● IV CTX (600 mg/mIV CTX (600 mg/m22) days 1, 2, 4, 6, 8) days 1, 2, 4, 6, 8● IV ACTH for 14 daysIV ACTH for 14 days

► MaintenanceMaintenance● IV CTX (700 mg/mIV CTX (700 mg/m22) bimonthly) bimonthly

Weiner et. al. 1993Weiner et. al. 1993

NE NE CooperativeCooperative Study Study

Percentage Stable/Improved on DSSPercentage Stable/Improved on DSS

Months on StudyMonths on Study

66 1212 1818 2424 3030 3636

Induct (20)Induct (20) 75%75% 56%56% 46%46% 24%24% 17%17% 15%15%

Boosters (127)Boosters (127) 71%71% 55%55% 48%48% 38%38% 27%27% 20%20%

P valueP value 0.760.76 0.710.71 0.610.61 0.040.04 0.040.04 0.140.14

NE Cooperative StudyNE Cooperative Study

Months on Study, with MaintenanceMonths on Study, with Maintenance

66 1212 1818 2424 3030 3636

Younger (<41)Younger (<41) 81%81% 62%62% 57%57% 42%42% 40%40% 28%28%

Older (>41)Older (>41) 60%60% 47%47% 40%40% 34%34% 14%14% 21%21%

P valueP value 0.020.02 0.130.13 0.100.10 0.180.18 0.010.01 0.050.05

CytoxanCytoxan

► Factors effecting response to Factors effecting response to therapytherapy● Younger ageYounger age● Rapidly progressive courseRapidly progressive course● Relapses in the year before Relapses in the year before

therapytherapy● <2yrs in the progressive phase<2yrs in the progressive phase● Enhancing lesions on T1+GdEnhancing lesions on T1+Gd

Canadian Cooperative TrialCanadian Cooperative Trial

► CP-MSCP-MS► EDSS 4.0-6.5 and increase EDSS 4.0-6.5 and increase >>1.0 step 1.0 step

prior 1 yearprior 1 year► RandomizedRandomized

● IVCTX + prednisoneIVCTX + prednisone 5555● PlEx + POCTX + prednisonePlEx + POCTX + prednisone 5757● Sham PlEx + placebo po medsSham PlEx + placebo po meds 5656

► Blinded examining neurologistBlinded examining neurologist

Lancet 337:441, 1991Lancet 337:441, 1991


► Randomized, placebo-controlledRandomized, placebo-controlled

► Clin-def, CP MSClin-def, CP MS

► EDSS 4.0-6.5EDSS 4.0-6.5

► Worsening on EDSS Worsening on EDSS >>1.0 steps prior 1.0 steps prior 12M12M

► Non-blinded monitoring neurologistNon-blinded monitoring neurologist

► Blinded examining neurologistBlinded examining neurologist

Lancet 337:441, 1991Lancet 337:441, 1991


► CTX group (n=55)CTX group (n=55)● IV CTX 1 gm QOD until WBC<4.5 up to 9 IV CTX 1 gm QOD until WBC<4.5 up to 9

gmgm● Prednisone 40 mg qD x 10 then taper over Prednisone 40 mg qD x 10 then taper over

6 d6 d

► PlEx group (n=57)PlEx group (n=57)● PlEx qW for 20 wkPlEx qW for 20 wk● PO CTX 1.5-2.0 mg/kg/d for 22 wkPO CTX 1.5-2.0 mg/kg/d for 22 wk● Prednisone 20 mg QODPrednisone 20 mg QOD

► Placebo group (n=56)Placebo group (n=56)● Sham PlEx, PO CTX placebo, Prednisone Sham PlEx, PO CTX placebo, Prednisone

placeboplaceboLancet 337:441, 1991Lancet 337:441, 1991

Canadian Cooperative TrialCanadian Cooperative TrialResultsResults

No significant differences in:No significant differences in:

► Rate of failure (increase in EDSS Rate of failure (increase in EDSS >>1.0 sustained for 6 months)1.0 sustained for 6 months)

► Proportions improved, stable, worse Proportions improved, stable, worse at each visit up to 36 monthsat each visit up to 36 months

► Mean change in EDSSMean change in EDSS

Lancet 337:441, 1991Lancet 337:441, 1991

► Proportion of treatment failuresProportion of treatment failures● CTXCTX 35%35%● PlExPlEx 32%32%● PlacPlac 29%29%

► Mean time to treatment failure Mean time to treatment failure (months)(months)● CTXCTX 24.8 24.8 ++ 7.6 7.6● PlExPlEx 29.3 29.3 ++ 10.9 10.9● PlacPlac 20.6 20.6 ++ 9.5 9.5


Lancet 337:441, 1991Lancet 337:441, 1991

CTX vs placebo p=0.295CTX vs placebo p=0.295


M12 M12 vs. baselinevs. baseline

ImprovedImproved StableStable WorseWorse

IVCTXIVCTX 3 (6%)3 (6%) 38 (79%)38 (79%) 7 (15%)7 (15%)

PIExPIEx 4 (8%)4 (8%) 39 (81%)39 (81%) 5 (10%)5 (10%)

PlaceboPlacebo 1 (2%)1 (2%) 35 (73%)35 (73%) 12 (25%)12 (25%)

Lancet 337:441, 1991Lancet 337:441, 1991



M24M24 vs. baseline vs. baseline


IVCTXIVCTX 2 (6%)2 (6%) 13 (42%)13 (42%) 16 (52%)16 (52%)

PIExPIEx 1 (3%)1 (3%) 25 (81%)25 (81%) 5 (16%)5 (16%)

PlaceboPlacebo 00 20 (67%)20 (67%) 10 (33%)10 (33%)

Lancet 337:441, 1991Lancet 337:441, 1991



M36M36 vs. baseline vs. baseline


IVCTXIVCTX 2 (4%)2 (4%) 24 (44%)24 (44%) 28 (52%)28 (52%)

PIExPIEx 1 (2%)1 (2%) 34 (59%)34 (59%) 22 (39%)22 (39%)

PlaceboPlacebo 1 (2%)1 (2%) 32 (59%)32 (59%) 21 (39%)21 (39%)

Lancet 337:441, 1991Lancet 337:441, 1991

Kaiser StudyKaiser Study

► CP-MS (EDSS 3.0-8.0)CP-MS (EDSS 3.0-8.0)► Increased EDSS or AI Increased EDSS or AI >>1 step 1 step

prior 1 yearprior 1 year► RandomizedRandomized

● IV CTXIV CTX 2222● PlaceboPlacebo 2020

► Single-blindSingle-blind

Likosky WH et al. JNNP 54:1055, 1991Likosky WH et al. JNNP 54:1055, 1991

Kaiser StudyKaiser StudyResultsResults

* based on EDSS change of * based on EDSS change of >>1.0 step1.0 step

EDSS Stable or Improved*EDSS Stable or Improved*

CTXCTX PlaceboPlacebo

12 Months12 Months 14/22 (64%)14/22 (64%) 14/20 (70%)14/20 (70%)

24 Months24 Months 9/19 (47%)9/19 (47%) 9/17 (53%)9/17 (53%)


Kaiser StudyKaiser StudyResultsResults

Mean Mean EDSSEDSSPlacebo-Placebo-CTX CTX

(95% CI)(95% CI)MonthMonth CTXCTX PlaceboPlacebo

0 to 120 to 12 0.500.50 0.530.53 0.03 (-0.60 to 0.03 (-0.60 to 0.65)0.65)

0 to 180 to 18 0.380.38 0.730.73 0.35 (-0.40 to 0.35 (-0.40 to 1.10)1.10)

0 to 240 to 24 0.580.58 0.970.97 0.39 (-0.45 to 0.39 (-0.45 to 1.23)1.23)


Spectrum of Disease ActivitySpectrum of Disease Activity

► Early inflammatory process with frequent Early inflammatory process with frequent relapse and “apparent” progression may relapse and “apparent” progression may appear “progressive”appear “progressive”

► Usually accompanied by numerous Usually accompanied by numerous enhancing lesions and rapidly increasing enhancing lesions and rapidly increasing T2 lesion burdenT2 lesion burden

► Late stage secondary progression related Late stage secondary progression related to a poorly understood degenerative to a poorly understood degenerative process process

► Infrequent enhancing lesions and little Infrequent enhancing lesions and little evidence of progression on MRI evidence of progression on MRI

► These forms of disease differ in their These forms of disease differ in their response to treatmentresponse to treatment

Relapsing-remittingRelapsing-remitting

Secondary-progressiveSecondary-progressive

PreclinicalPreclinical

TimeTime

Natural History of MSNatural History of MS

Measures of brain volumeMeasures of brain volumeRelapses and impairmentRelapses and impairmentMRI burden of diseaseMRI burden of diseaseMRI activityMRI activity

Reconciliation of Early Studies on the Use of Reconciliation of Early Studies on the Use of Cyclophosphamide and Mitoxantrone in MSCyclophosphamide and Mitoxantrone in MS

► Many early studies probably included patients Many early studies probably included patients with very active inflammation that led to the with very active inflammation that led to the appearance of progressive disease appearance of progressive disease

► The reality was that the dynamics of disease in The reality was that the dynamics of disease in these patients was characterized by active these patients was characterized by active inflammation inflammation

► The Canadian cooperative trial and the Kaiser trial The Canadian cooperative trial and the Kaiser trial probably included a greater proportion of patients probably included a greater proportion of patients with primary progressive MS and true secondary with primary progressive MS and true secondary progressionprogression

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

CyclophosphamideCyclophosphamidePotential Adverse EffectsPotential Adverse Effects

Acute:Acute: Chronic:Chronic:

Nausea / malaiseNausea / malaise InfertilityInfertility

AlopeciaAlopecia Pulmonary Pulmonary fibrosisfibrosis

Hemorrhagic cystitisHemorrhagic cystitis MyocarditisMyocarditis

MyelosuppressionMyelosuppression MalignancyMalignancy

InfectionInfection

MitoxantroneMitoxantrone

► An anthracenedione related to An anthracenedione related to dauxorubicin with potent dauxorubicin with potent immunosuppressive effects immunosuppressive effects

► Intercalates DNA and blocks the Intercalates DNA and blocks the synthesis of RNAsynthesis of RNA

► Inhibits topoisomeraseInhibits topoisomerase

► Potent effects on B-cell and T-cell Potent effects on B-cell and T-cell functionfunction

► Inhibits both passive and active EAEInhibits both passive and active EAE

Clinical Trials of Mitoxantrone in MSClinical Trials of Mitoxantrone in MS

► Early trials produced slightly conflicting Early trials produced slightly conflicting results and employed dose regimens that results and employed dose regimens that differed considerablydiffered considerably

► This may have been due to the patient This may have been due to the patient populations studiedpopulations studied

► What emerged was a marked reduction in What emerged was a marked reduction in relapse rate and a reduction in enhancing relapse rate and a reduction in enhancing lesion frequencylesion frequency

► Suggesting that MITX might be useful in Suggesting that MITX might be useful in rapidly progressive forms of MS rapidly progressive forms of MS characterized by active inflammatory characterized by active inflammatory disease disease

Methylprednisolone and Mitoxantrone in Methylprednisolone and Mitoxantrone in MS (MP+M): Trial DesignMS (MP+M): Trial Design

TriageTriage

M -2M -2 M -1M -1 M 0M 0

M 1M 1 M 2M 2 M 3M 3 M 4M 4 M 5M 5 M 6M 6

M 1M 1 M 2M 2 M 3M 3 M 4M 4 M 5M 5 M 6M 6

Randomized TreatmentRandomized Treatment

Mitoxantrone 20 mg/mo IV +Mitoxantrone 20 mg/mo IV +Methylprednisolone 1 g/mo IVMethylprednisolone 1 g/mo IV

Methylprednisolone 1 g/mo IVMethylprednisolone 1 g/mo IV

Edan et al. 1997.

MP+M: Lower Incidence of MP+M: Lower Incidence of New MRI LesionsNew MRI Lesions

Percentage of Patients Developing New Gd-Enhancing LesionsPercentage of Patients Developing New Gd-Enhancing Lesions

MP (N = 21)

MP+M (N = 21)

0

20

40

60

80

100

Pat

ien

ts (

%)

-1 0 1 2 3 654Months

*

†‡ §

86%Reduction

*P = .009†P = .030‡P = .033§P = .001

MP+M: Slower Progression of MP+M: Slower Progression of Neurologic DisabilityNeurologic Disability

Pat

ient

sP

atie

nts

(%)

(%)

(N = 12)

(N = 8)

(N = 6)

(N = 3)

(N = 1)

(N = 12)

Confirmed EDSS 1-Point Variation* Between Confirmed EDSS 1-Point Variation* Between Patient Inclusion and End of StudyPatient Inclusion and End of Study

*EDSS changes from 6.0-6.5 and from 6.5-7.0 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. 1997.

P<.01

Mitoxantrone and IVMP in RPMS Mitoxantrone and IVMP in RPMS Relapse AssessmentRelapse Assessment

Edan G et al. J Neurol Neurosurg Psychiatry. 1997;62:112-118.

IVMPIVMP

(n=21)(n=21)

Mito + Mito + IVMPIVMP

(n=21)(n=21)P-valueP-value

Baseline annualized Baseline annualized relapse raterelapse rate 2.92.9 3.13.1 NSNS

On study annualized On study annualized relapse raterelapse rate 3.03.0 0.70.7 0.0030.003

Patients free of relapses Patients free of relapses on studyon study 7 (33%)7 (33%) 14 (67%)14 (67%) 0.0310.031

MP+M: ConclusionsMP+M: Conclusions

► Addition of mitoxantrone to Addition of mitoxantrone to methylprednisolone significantlymethylprednisolone significantly

● Reduced new MRI lesionsReduced new MRI lesions● Slowed the progression of neurologic disabilitySlowed the progression of neurologic disability● Reduced relapse rateReduced relapse rate

Edan et al. 1997.

Mitoxantrone in Multiple Sclerosis Mitoxantrone in Multiple Sclerosis (MIMS): Study Design(MIMS): Study Design

► 2-year, double-blind, multicenter, placebo 2-year, double-blind, multicenter, placebo controlledcontrolled

► 194 patients, 18-55 years, EDSS 3-6 194 patients, 18-55 years, EDSS 3-6

► Treatment armsTreatment arms● Mitoxantrone 5 mg/mMitoxantrone 5 mg/m22, IV, q3mo, IV, q3mo● Mitoxantrone 12 mg/mMitoxantrone 12 mg/m22, IV, q3mo, IV, q3mo● PlaceboPlacebo

MIMS DesignMIMS Design

Rx every 3 months x 24 monthsFollow up at Month 36

PlaceboPlacebo

Mitoxantrone 5 mg/mMitoxantrone 5 mg/m22

Mitoxantrone 12 mg/mMitoxantrone 12 mg/m22

RRAANNDDOOMMIIZZEE

Hartung, H.P. et al. The Lancet 2002. v360 2018-2025

MIMS StudyMIMS StudyInclusion and Exclusion CriteriaInclusion and Exclusion Criteria

► Age 18 to 55Age 18 to 55► Definite MS (Poser’s Definite MS (Poser’s

criteria)criteria)► Secondary progressive Secondary progressive

or remitting progressive or remitting progressive MSMS(worsening RRMS)(worsening RRMS)

► EDSS progression EDSS progression 1 point in preceding 1 point in preceding 18 months18 months

► Baseline EDSS from Baseline EDSS from 3.0-6.03.0-6.0

► Benign or primary Benign or primary progressive MSprogressive MS

► Relapse or treatment Relapse or treatment with corticosteroids in with corticosteroids in precedingpreceding8 weeks8 weeks

► Prior treatment with Prior treatment with NOVANTRONENOVANTRONE®®

► Immunosuppressive Immunosuppressive therapytherapyin preceding 9 monthsin preceding 9 months

► Cardiac risk factorsCardiac risk factors► Major medical illnessMajor medical illness

Inclusion CriteriaInclusion Criteria Exclusion CriteriaExclusion Criteria

Hartung, H.P. et al. The Lancet 2002. v360 2018-2025

MIMS Baseline Demographics* (1)MIMS Baseline Demographics* (1)

* No significant differences between the 3 * No significant differences between the 3 groupsgroups

Hartung, H.P. et al. The Lancet 2002. v360 2018-2025Hartung, H.P. et al. The Lancet 2002. v360 2018-2025

PlaceboPlacebo(n=64)(n=64)

Mitox 5Mitox 5(n=64)(n=64)

Mitox 12Mitox 12(n=60)(n=60)

Male/Female (%)Male/Female (%) 52/4852/48 39/6139/61 53/4753/47

Mean age (years)Mean age (years) 4040 4040 4040

Type of MSType of MS

Remittent progressive (%)Remittent progressive (%) 4545 5858 4747

Secondary progressive (%)Secondary progressive (%) 5555 4242 5353

Mitoxantrone Efficacy at 2 Years: Mitoxantrone Efficacy at 2 Years: Primary Efficacy VariablesPrimary Efficacy Variables

NR=not reached within 24 months.NR=not reached within 24 months.

Placebo Placebo (n=64)(n=64)

Mitoxantrone Mitoxantrone 12 mg/m12 mg/m22

(n=60)(n=60)

P-value P-value Mitoxantrone Mitoxantrone 12 mg/m12 mg/m22 vs. vs.

PlaceboPlacebo

Multivariate primary efficacy Multivariate primary efficacy criterioncriterion <0.0001<0.0001

EDSS change (mean)EDSS change (mean) 0.230.23 -0.13-0.13 0.01940.0194

Mean no. of treated relapsesMean no. of treated relapses 1.201.20 0.400.40 0.00020.0002

Time to first treated relapse Time to first treated relapse (median months)(median months) 14.214.2 NRNR 0.00040.0004

SNS change (mean)SNS change (mean) 0.770.77 -1.07-1.07 0.02690.0269


Mean Change in EDSSMean Change in EDSSC

ha

nge

s in

ED

SS

Ch

ang

es

in E

DS

S(m

24 -

Ba

selin

e)

(m24

- B

ase

line

)

† Placebo vs. Mitoxantrone 12 mg/m2

p = 0.0194 †


EDSS >1.0 Point Deterioration EDSS >1.0 Point Deterioration from Baselinefrom Baseline

% o

f p

ati

en

ts

† Placebo vs. Mitoxantrone 12 mg/m2

p = 0.036 †

(N=5)

(N=16)


Time to First Treated RelapseTime to First Treated Relapse

Placebo Mitox 12

0.00

0.25

0.50

0.75

1.00

0 3 6 9 12 15 18 21 24

p=0.0004†

MonthsMonths† Placebo vs. Mitoxantrone 12 mg/m2

Placebo =14.19 m.

Mitox 12mg not reached


MIMS: Patients WithMIMS: Patients WithNew Gd-Enhancing Lesions New Gd-Enhancing Lesions (N = 110)(N = 110)

P = .02 at Month 24

Pat

ient

s (%

)P

atie

nts

(%)

PlaceboMitoxantrone 12 mg/m2

MonthMonth

12%12%(N = 4)(N = 4)

19%19%(N = 7)(N = 7)

0%

16% 16% (N = 5)(N = 5)

(N = 0)

Significantly Reduced the Change in the Significantly Reduced the Change in the Number of T2-Weighted Lesions vs Number of T2-Weighted Lesions vs

PlaceboPlacebo

Mean Change inMean Change inNumber ofNumber of

T2-Weighted T2-Weighted Lesions at 24 Lesions at 24

MonthsMonths

PlaceboPlacebo(n=32)(n=32)

MitoxantroneMitoxantrone12 mg/m12 mg/m22

(n=28)(n=28)

85%reduction

Potential Adverse Effects of Potential Adverse Effects of MitoxantroneMitoxantrone

► AcuteAcute● AlopeciaAlopecia● MyelosupressionMyelosupression● InfectionInfection● Nausea/vomitingNausea/vomiting● MalaiseMalaise● Discoloration of Discoloration of

sclera sclera ● ArrhythmiaArrhythmia

► ChronicChronic● Cardiac toxicityCardiac toxicity● MalignancyMalignancy● AmenorrheaAmenorrhea● InfertilityInfertility● Fetal malformationFetal malformation

MitoxantroneMitoxantrone

► Approved by the FDA for worsening Approved by the FDA for worsening RR MS, SP MS with relapse, and PR RR MS, SP MS with relapse, and PR MSMS

► Recognized as a rescue therapyRecognized as a rescue therapy

► More dangerous than A,B,C,RMore dangerous than A,B,C,R

► Useful in those failing conventional Useful in those failing conventional therapy or with aggressive disease therapy or with aggressive disease from the outsetfrom the outset

The “Evolution”The “Evolution”

► Much has changed since the advent of Much has changed since the advent of mitoxantronemitoxantrone

► Our understanding of the disease process Our understanding of the disease process and the importance of the inflammatory and the importance of the inflammatory process has grown substantiallyprocess has grown substantially

► Not much has changed regarding the Not much has changed regarding the profiles of the chemotherapeutic agents profiles of the chemotherapeutic agents used and being developedused and being developed

► Cladribine is a perfect example Cladribine is a perfect example

CladrbineCladrbine

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

BackgroundBackground

► Approved by FDA for:Approved by FDA for:● Hairy cells leukemiaHairy cells leukemia● Malignant lymphomaMalignant lymphoma

► A few phase 1 and 2 studies have A few phase 1 and 2 studies have been conducted in MS with been conducted in MS with cladribine iv or s/c.cladribine iv or s/c.

► Pregnancy category DPregnancy category D

The FDA has a categorization of drug risks to the fetus that runs from: "Category A" (safest) to "Category X" (known danger--do not use!)

Category A

Controlled studies in women fail to demonstrate a risk to the fetus in the first trimester (and there is no evidence of a risk in later trimesters), and the possibility of fetal harm appears remote.

Category B

Either animal-reproduction studies have not demonstrated a fetal risk but there are no controlled studies in pregnant women, or animal-reproduction studies have shown an adverse effect (other than a decrease in fertility) that was not confirmed in controlled studies in women in the first trimester (and there is no evidence of a risk in later trimesters).

Category C

Either studies in animals have revealed adverse effects on the fetus (teratogenic or embryocidal or other) and there are no controlled studies in women, or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the fetus.

Category D

There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).

Category X

Studies in animals or human beings have demonstrated fetal abnormalities, or there is evidence of fetal risk based on human experience or both, and the risk of the use of the drug in pregnant women clearly outweighs any possible benefit. The drug is contraindicated in women who are or may become pregnant.

CLARITY - Treatment RegimenCLARITY - Treatment Regimen

ScreeningScreening1326 1326

randomizedrandomized(1:1:1)(1:1:1)

► Annual short-course treatmentAnnual short-course treatment● Each course = 1–2 tablets (10 mg) daily for 4 or 5 consecutive Each course = 1–2 tablets (10 mg) daily for 4 or 5 consecutive

days per monthdays per month● Courses given for 2 or 4 consecutive months in Year 1 and Courses given for 2 or 4 consecutive months in Year 1 and

for 2 consecutive months in Year 2for 2 consecutive months in Year 2

First 48 weeks Second 48 weeksX X X X

X 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; Giovannoni G et al. Presented at American Academy of Neurology 61st Annual Meeting; Seattle, USA; April 30, 2009. April 30, 2009.

Placebocourse

Cladribinecourse

0

0.1

0.2

0.3

0.457.6% reduction

(P < 0.001)

PlaceboPlacebo(n = 437)(n = 437)

CladribineCladribine3.5 mg/kg3.5 mg/kg(n = 433)(n = 433)


Ann

ualiz

ed r

elap

se r

ate

Ann

ualiz

ed r

elap

se r

ate

0.140.14 0.150.15

0.330.33

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.

54.5% reduction (P < 0.001)

Primary Outcome Primary Outcome Reduction in Relapse Rates (ITT)Reduction in Relapse Rates (ITT)

Secondary Outcome Secondary Outcome Reduction in Disability Progression (ITT)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, 2009.

Pro

port

ion

with

3-m

onth

Pro

port

ion

with

3-m

onth

conf

irmed

ED

SS

pro

gres

sion

(%

)co

nfirm

ed E

DS

S p

rogr

essi

on (

%)

33%33% 31%31%

RelativeRelativereductionreduction

Number of patients at risk:Placebo3.5 mg/kg5.25 mg/kg

437433456

424424447

399407425

373389404

355379388

333364375

315355363

304347350

304347350

Placebo

Cladribine 3.5 mg/kg 0.67 (0.48, 0.93); P = 0.018

Cladribine 5.25 mg/kg 0.69 (0.49, 0.96); P = 0.026

Hazard ratio vs placebo (95% CI)*

–73.4%*–86.8%*

–87.9%*

–74.6%*

–76.9%* –77.9%*

Secondary Outcome Secondary Outcome Improvement in MRI Parameters (ITT)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, 2009.

2.00

1.50

1.00

0.50

0

Mea

n ±

SE

lesi

on

s/p

atie

nt/

scan

T1 Gd+ lesions

Active T2lesions

Combined unique lesions

Placebo Cladribine 3.5 mg/kg Cladribine 5.25 mg/kg

*P < 0.001 *P < 0.001 *P < 0.001

0.91

1.43

1.72

0.120.38 0.43

0.11 0.33 0.38

Patients with AE (%)Patients with AE (%)PlaceboPlacebo(n = 435)(n = 435)

CladribineCladribine3.5 mg/kg3.5 mg/kg

(n = 430)(n = 430)

CladribineCladribine5.25 mg/kg5.25 mg/kg

(n = 454)(n = 454)

CladribineCladribineoveralloverall

(n = 884(n = 884))

Any treatment-emergent AEAny treatment-emergent AE

AEs leading to discontinuationAEs leading to discontinuation

AEs leading to withdrawalAEs leading to withdrawal

Serious AEsSerious AEs

Deaths*Deaths*

73.373.3

2.12.1

1.11.1

6.46.4

0.50.5(n = 2)(n = 2)

80.780.7

3.53.5

1.21.2

8.48.4

0.50.5(n = 2)(n = 2)

83.983.9

7.97.9

2.02.0

9.09.0

0.4 0.4 (n = 2)(n = 2)

82.482.4

5.85.8

1.61.6

8.78.7

0.40.4(n = 2)(n = 2)

*Placebo: hemorrhagic cerebrovascular accident, suicide; cladribine 3.5 mg/kg: acute myocardial *Placebo: hemorrhagic cerebrovascular accident, suicide; cladribine 3.5 mg/kg: acute myocardial infarction, pancreatic carcinoma; cladribine 5.25 mg/kg: drowning, pancytopenia/pneumonia then infarction, pancreatic carcinoma; cladribine 5.25 mg/kg: drowning, pancytopenia/pneumonia then cardiorespiratory arrest. cardiorespiratory arrest.

AEs = adverse eventsAEs = adverse events

Secondary Outcome Secondary Outcome Safety OverviewSafety Overview

Giovannoni G et al. Presented at American Academy of Neurology 61st Annual Meeting; Giovannoni G et al. Presented at American Academy of Neurology 61st Annual Meeting; Seattle, USA; April 30, 2009. Seattle, USA; April 30, 2009.

CD4+ (helper T cells)

CD8+ (cytotoxic T cells)

CD19+ (B cells)

CD19+/CD56+ (natural killer cells)

CladribineCladribine

Guarnaccia JB, et al. Presented at: WCTRIMS; September 17-20, 2008; Montreal, Canada. [P55].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 Depletion of Lymphocyte Subpopulations in Phase 3 Trial in SPMS and PPMSand PPMS

Cladribine: Effect after 3-5 years on Naïve Cladribine: Effect after 3-5 years on Naïve (CD45RA+) and Memory (CD45RO+) - CD4+ (CD45RA+) and Memory (CD45RO+) - CD4+

Tcells Tcells

Raspadori D, et al. Raspadori D, et al. LeukemiaLeukemia. 1999;13:1254-1257.. 1999;13:1254-1257.

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

Laboratory Laboratory testtest StatisticsStatistics

Cladribine 5.25 Cladribine 5.25 mg/kg (n=454)mg/kg (n=454)

n (%)n (%)

Cladribine 3.5 Cladribine 3.5 mg/kg (n=430)mg/kg (n=430)

n (%)n (%)

Placebo Placebo (n=435)(n=435)n (%)n (%)

HaemoglobinHaemoglobin Mean duration (SD) (weeks)Mean duration (SD) (weeks)

Median duration (weeks)Median duration (weeks)

Min;Max duration (weeks)Min;Max duration (weeks)

0 0 (1 total)(1 total) 3 3 (5 total)(5 total)17.5 (6.8)17.5 (6.8)

18.118.1

10.4;24.010.4;24.0

2 2 (3 total)(3 total)13.0 (8.3)13.0 (8.3)

13.013.0

7.1;18.97.1;18.9

WBCWBC Mean duration (SD) (weeks)Mean duration (SD) (weeks)



8 8 (10 total)(10 total)11.8 (10.3)11.8 (10.3)

9.09.0

1.4;29.11.4;29.1

6 6 (6 total)(6 total)3.7 (1.9)3.7 (1.9)

3.43.4

1.6;6.01.6;6.0

2 2 (2 total)(2 total)2.8 (0.9)2.8 (0.9)

2.82.8

2.1;3.42.1;3.4

NeutrophilsNeutrophils Mean duration (SD) (weeks)Mean duration (SD) (weeks)



17 17 (17 total)(17 total)8.1 (9.6)8.1 (9.6)

5.95.9

1.1;42.11.1;42.1

12 12 (12 total)(12 total)5.2 (3.8)5.2 (3.8)

4.94.9

1.0;12.11.0;12.1

17 17 (18 total)(18 total)4.8 (3.1)4.8 (3.1)

4.34.3

1.1;12.11.1;12.1

LymphocyteLymphocyte Mean duration (SD) (weeks)Mean duration (SD) (weeks)



108 108 (203 total)(203 total)29.4 (20.8)29.4 (20.8)

24.124.1

2.9;88.02.9;88.0

52 52 (110 total)(110 total)25.4 (19.8)25.4 (19.8)

23.423.4

0.9;92.70.9;92.7

2 2 (2 total)(2 total)4.6 (0.6)4.6 (0.6)

4.64.6

4.1;5.04.1;5.0

Subject with Resolved Grade 3 and 4 ToxicitySubject with Resolved Grade 3 and 4 ToxicityHematology (resolved = returning to Grade 1 or Hematology (resolved = returning to Grade 1 or

0)0)► App. 50% of Grade 3 and 4 lymphopenia resolved on study; median duration ~ App. 50% of Grade 3 and 4 lymphopenia resolved on study; median duration ~

24 wks24 wks► Almost all other Grade 3 and 4 toxicities resolved on studyAlmost 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.

Adverse Events of Special InterestAdverse Events of Special InterestHerpes ZosterHerpes Zoster

► Herpes zoster was reported more frequently with cladribine Herpes zoster was reported more frequently with cladribine tablets than placebotablets than placebo

● 20 patients had 21 zoster events in the cladribine tablets groups20 patients had 21 zoster events in the cladribine tablets groups

● All 21 cases were self-limiting and dermatomalAll 21 cases were self-limiting and dermatomal

Preferred term, Preferred term, n (%) patients n (%) patients

PlaceboPlacebo (n=435)(n=435)

Cladribine Cladribine 3.5 mg/kg3.5 mg/kg (n=430)(n=430)

Cladribine Cladribine 5.25 mg/kg5.25 mg/kg

(n=454)(n=454)


(n=884)(n=884)

Herpes zoster Herpes zoster 0 0 8 (1.9) 8 (1.9) 11 (2.4) 11 (2.4) 19 (2.1)19 (2.1)

Herpes zoster oticus Herpes zoster oticus 00 00 1 (0.2) 1 (0.2) 1 (0.1)1 (0.1)

Varicella Varicella 1 (0.2)1 (0.2) 1 (0.2) 1 (0.2) 1 (0.2) 1 (0.2) 2 (0.2)2 (0.2)

S. Cook, et al. Presented at ECTRIMS 25th Annual Meeting; Dusseldorf, Germany; September 11, 2009. S. Cook, et al. Presented at ECTRIMS 25th Annual Meeting; Dusseldorf, Germany; September 11, 2009.

Adverse Events of Special Interest Adverse Events of Special Interest MalignanciesMalignancies

Preferred term, % (n)Preferred term, % (n) PlaceboPlacebo(n = 435)(n = 435)




(n = 884)(n = 884)

During studyDuring study

Cervix carcinoma Stage 0Cervix carcinoma Stage 0

Malignant melanomaMalignant melanoma

Ovarian cancerOvarian cancer

Pancreatic cancer, Pancreatic cancer, metastaticmetastatic

During post-study surveillance During post-study surveillance

ChoriocarcinomaChoriocarcinoma

00

00

00

00

00

00

0.2 (1)0.2 (1)

0.2 (1)0.2 (1)

0.2 (1)0.2 (1)

00

0.2 (1)0.2 (1)

00

00

00

0.2 (1)0.2 (1)

0.1 (1)0.1 (1)

0.1 (1)0.1 (1)

0.1 (1)0.1 (1)

0.1 (1)0.1 (1)

0.1 (1)0.1 (1)

Giovannoni G et al. Presented at American Academy of Neurology 61st Annual Meeting; Seattle, USA; April 30, 2009.

CladribineCladribine

Cladribine SummaryCladribine Summary

► Efficacy is comparable to high dose IFNEfficacy is comparable to high dose IFN► Toxicity is considerableToxicity is considerable

● Risk of malignancyRisk of malignancy● Long-term immunosuppressionLong-term immunosuppression● Increased risk of herpes infectionsIncreased risk of herpes infections● InfertilityInfertility● Fetal malformationFetal malformation● Graft vs. hostGraft vs. host

► How long can it be used with CD-4 counts How long can it be used with CD-4 counts markedly reducedmarkedly reduced

► What do you do if patients are worsening?What do you do if patients are worsening?

Evolution?Evolution?

► There has been no evolution!There has been no evolution!► Chemotherapeutic agents remain Chemotherapeutic agents remain

nonselective, broad spectrum cytotoxic nonselective, broad spectrum cytotoxic agents that suppress the immune system in agents that suppress the immune system in a nonspecific fashiona nonspecific fashion

► They all have considerable risk of adverse They all have considerable risk of adverse events that include secondary malignancy, events that include secondary malignancy, infection, infertility, fetal malformation, and infection, infertility, fetal malformation, and other end organ toxicityother end organ toxicity

► Newer monoclonal antibodies and other Newer monoclonal antibodies and other innovative therapies appear equally or more innovative therapies appear equally or more effective and have manageable risk effective and have manageable risk

Challenging Cases Challenging Cases in the in the Management Management ofof Multiple Sclerosis Multiple Sclerosis

andand Parkinson’s Disease Parkinson’s Disease

Case StudiesCase Studies

► 24-year-old female with diplopia on looking 24-year-old female with diplopia on looking to the right for a day or two – Austin to the right for a day or two – Austin ophthalmologist found nothing unusual ophthalmologist found nothing unusual

► Back in Houston another ophthalmologist Back in Houston another ophthalmologist called it ‘some type of optic nerve called it ‘some type of optic nerve inflammation’ and gave her 5 days of oral inflammation’ and gave her 5 days of oral steroidssteroids

► 2 weeks into symptoms seen by a pro who 2 weeks into symptoms seen by a pro who noted skew deviation, marked asymmetric noted skew deviation, marked asymmetric nystagmus with torsion and jerk greater to nystagmus with torsion and jerk greater to the right, no INO, no APD and normal VERs the right, no INO, no APD and normal VERs to go with complaints of vertical diplopia to go with complaints of vertical diplopia and oscillopsia and oscillopsia

Multiple Sclerosis Case #1Multiple Sclerosis Case #1

UPIN 480406/06/08

► 4 days later continued double vision on 4 days later continued double vision on looking to the rightlooking to the right

► Extensive past history uncovered only one Extensive past history uncovered only one week of nausea and vomiting about 4 week of nausea and vomiting about 4 months ago attributed to food poisoningmonths ago attributed to food poisoning

► Nystagmus to right gaze of greater Nystagmus to right gaze of greater amplitude in adducting eye with incomplete amplitude in adducting eye with incomplete abduction of right eye, remaining exam abduction of right eye, remaining exam normalnormal

► CSF with 10 lymphocytes, IgG index 1.15 CSF with 10 lymphocytes, IgG index 1.15 and 3 OCBsand 3 OCBs

► Intravenous methylprednisolone course Intravenous methylprednisolone course startedstarted


UPIN 480407/02/08

► The subject was born and raised outside of the The subject was born and raised outside of the reach of the Scandinavian gene pool - is this reach of the Scandinavian gene pool - is this NMO, and how unusual is this?NMO, and how unusual is this?

► When you have CIS and can’t diagnose more When you have CIS and can’t diagnose more than suspect MS by McDonald’s or Swanton’s, than suspect MS by McDonald’s or Swanton’s, do you just treat, use Frohman?do you just treat, use Frohman?

► When asked about the familial risk of MS in the When asked about the familial risk of MS in the company of the patients twin sister, what is the company of the patients twin sister, what is the best course? best course?

Multiple Sclerosis Case #1Multiple Sclerosis Case #1The IssuesThe Issues

► 30-year-old Caucasian female presented 30-year-old Caucasian female presented initially with right optic neuritis. initially with right optic neuritis.

► Vision improved after high dose intravenous Vision improved after high dose intravenous methylprednisolone treatment methylprednisolone treatment

► T2-weighted MRI brain scan showed 2 areas T2-weighted MRI brain scan showed 2 areas of abnormal signal in the periventricular and of abnormal signal in the periventricular and subcortical white matter.subcortical white matter.

► No disease modifying therapy was started at No disease modifying therapy was started at that time. that time.


► 1 year later- numbness and weakness of both legs, 1 year later- numbness and weakness of both legs, urinary hesitancy, and increasing gait difficulties urinary hesitancy, and increasing gait difficulties over several days. over several days.

► MRI cord -increased T2 signal at C8 with a MRI cord -increased T2 signal at C8 with a corresponding area of Gd enhancement on T1. corresponding area of Gd enhancement on T1.

► MRI brain- one new periventricular white matter MRI brain- one new periventricular white matter lesion without enhancement in comparison to last lesion without enhancement in comparison to last year’s. year’s.

► Motor symptoms improved with high dose Motor symptoms improved with high dose corticosteroid therapycorticosteroid therapy

► Residual numbness in the feet and bladder control Residual numbness in the feet and bladder control difficulties. difficulties.


► Given diagnosis of MS and therapy with once Given diagnosis of MS and therapy with once weekly IM interferon beta was begun.weekly IM interferon beta was begun.

► 6 months later she complained of markedly 6 months later she complained of markedly increased fatigue and “fuzzy thinking.” increased fatigue and “fuzzy thinking.”

► Brain MRI scan revealed several new T2 lesions Brain MRI scan revealed several new T2 lesions in both cerebral hemispheres and several new in both cerebral hemispheres and several new enhancing lesions around the corpus callosum. enhancing lesions around the corpus callosum.

► Disease modifying therapy was changed to a Disease modifying therapy was changed to a high dose subcutaneous interferon beta. high dose subcutaneous interferon beta.


► Over the next year, she had no new Over the next year, she had no new symptoms and there were no new lesions symptoms and there were no new lesions seen on a repeat MRI scan.seen on a repeat MRI scan.

► After several months she complained of After several months she complained of balance difficulties, memory difficulties, and balance difficulties, memory difficulties, and an increase in fatigue.an increase in fatigue.

► MRI scan showed additional Gd+ enhancing MRI scan showed additional Gd+ enhancing lesions. lesions.

► A test for neutralizing antibody against A test for neutralizing antibody against interferon beta (NAb) revealed a titer interferon beta (NAb) revealed a titer greater than 1:100. greater than 1:100.


► The same interferon treatment was The same interferon treatment was continued but after several months she continued but after several months she complained of ongoing problems with complained of ongoing problems with memory. memory.

► Several new enhancing lesions were again Several new enhancing lesions were again found on MRI. A repeat NAb titer was found on MRI. A repeat NAb titer was unchanged.unchanged.


► Student nurse falls hitting head on Student nurse falls hitting head on concrete when obese patient she is concrete when obese patient she is transporting begins to fall off litter. MRI transporting begins to fall off litter. MRI shows pineal cyst.shows pineal cyst.

► 18 months later, follow-up MRI shows 18 months later, follow-up MRI shows unchanged cyst but single unchanged cyst but single periventricular non-enhancing white periventricular non-enhancing white matter lesion.matter lesion.

► Three yearly follow-ups show no new MRI Three yearly follow-ups show no new MRI lesions, no symptoms and no neurologic lesions, no symptoms and no neurologic abnormalities.abnormalities.


► While hiking with physician husband on While hiking with physician husband on hot afternoon, she notes numbness in hot afternoon, she notes numbness in left foot.left foot.

► Spinal cord MRI shows enhancing lesion Spinal cord MRI shows enhancing lesion at T17.at T17.

► Is it MS?Is it MS?

► Treatment recommendations?Treatment recommendations?

Is it Multiple Sclerosis?Is it Multiple Sclerosis?

► 32-year-old healthy female post-doc 32-year-old healthy female post-doc researcher who participated in an MRI researcher who participated in an MRI study as a volunteer.study as a volunteer.

► Subject has no family history of MS or Subject has no family history of MS or immune-mediated diseases. No immune-mediated diseases. No personal past medical history.personal past medical history.

► No neurological symptoms except rare No neurological symptoms except rare migraine headaches and no signs on migraine headaches and no signs on her neurological exam.her neurological exam.


Multiple Sclerosis Case #3Multiple Sclerosis Case #3Research Brain MRIResearch Brain MRI

Parkinson’s Disease Case #1Parkinson’s Disease Case #1

► A 56-year-old male in good health presents A 56-year-old male in good health presents with slight, intermittent rest tremor of the with slight, intermittent rest tremor of the left (non-dominant) hand. Tremor worse left (non-dominant) hand. Tremor worse with stress and when he walks. Wife has with stress and when he walks. Wife has noticed decreased arm swing on the left.noticed decreased arm swing on the left.

► He notes some stiffness on the left side He notes some stiffness on the left side

and some constipation. He states that and some constipation. He states that symptoms are only minimally bothersome symptoms are only minimally bothersome and not interfering with job or home life. and not interfering with job or home life. The couple is troubled that the condition The couple is troubled that the condition will become apparent to coworkers and will become apparent to coworkers and interfere with career.interfere with career.

► Family History: Family History: No family history of No family history of Parkinson’s diseaseParkinson’s disease

► Medical History/Medications: Medical History/Medications: Wife noticed Wife noticed that for the past three years the patient that for the past three years the patient moves about during sleep.moves about during sleep.No current medicationsNo current medications

► Examination: Examination: RReveals normal mental status eveals normal mental status and eye movements. He has slight and eye movements. He has slight bradykinesia on repetitive alternating bradykinesia on repetitive alternating movements in the left hand and a slight rest movements in the left hand and a slight rest tremor is noted. tremor is noted.

► Decision making: Decision making: Making the diagnosis of PD; Making the diagnosis of PD; early non-motor features of PD; when to early non-motor features of PD; when to initiate therapyinitiate therapy


► 58-year-old male in good health presents 58-year-old male in good health presents with resting tremor of the right with resting tremor of the right (dominant) hand and difficulty with (dominant) hand and difficulty with simple tasks such as brushing teeth and simple tasks such as brushing teeth and combing hair. He works as a desk clerk combing hair. He works as a desk clerk and has noticed significant problems with and has noticed significant problems with writing. Also has trouble buttoning and at writing. Also has trouble buttoning and at times has trouble cutting food.times has trouble cutting food.

► Complains of fatigue, lack of motivation Complains of fatigue, lack of motivation and disinterest. He tends to fall asleep and disinterest. He tends to fall asleep easily during the day.easily during the day.


► Family History: Family History: Father died with Parkinson Father died with Parkinson Disease and a cousin diagnosed with Disease and a cousin diagnosed with Parkinson’s disease 2 years ago is Parkinson’s disease 2 years ago is responding well to levodoparesponding well to levodopa

► Medical History/Medications: Medical History/Medications: No significant No significant medical or surgical history. No current medical or surgical history. No current medicationsmedications

► Examination: Examination: Bilateral bradykinesia and Bilateral bradykinesia and asymmetric rest tremor right greater than asymmetric rest tremor right greater than left. Gait is slow but there is no problem left. Gait is slow but there is no problem turning. Pull Test is negative. Rest of the turning. Pull Test is negative. Rest of the examination is normalexamination is normal

► Decision makingDecision making:: Patient diagnosed with Patient diagnosed with Parkinson’s disease with some disability and Parkinson’s disease with some disability and he wishes to start treatment.he wishes to start treatment.


► 68-year-old woman with a 4-year history of 68-year-old woman with a 4-year history of Parkinson’s disease. She initially presented with Parkinson’s disease. She initially presented with asymmetric tremor involving the left hand. asymmetric tremor involving the left hand. Subsequently, she progressed to have tremor Subsequently, she progressed to have tremor both sides and significant slowness bilaterally. both sides and significant slowness bilaterally. Was started on levodopa 3 years ago.Was started on levodopa 3 years ago.

► Currently takes carbidopa-levodopa 25/100 one Currently takes carbidopa-levodopa 25/100 one tablet 4 times per day. She is experiencing tablet 4 times per day. She is experiencing return of tremor and slowness and sweating and return of tremor and slowness and sweating and abdominal pain as the medication is wearing off. abdominal pain as the medication is wearing off. During off periods, and in the early morning During off periods, and in the early morning hours and she has painful dystonia of the left hours and she has painful dystonia of the left foot. She has abnormal movements while the foot. She has abnormal movements while the medication is working. medication is working.


► Family History: Family History: no relatives with PDno relatives with PD

► Medical History: Medical History: No significant No significant medical or surgical history medical or surgical history

► Medications: Medications: Amitriptyline 50 mg. Amitriptyline 50 mg. q.h.s for depression in addition to q.h.s for depression in addition to carbidopa-levodopacarbidopa-levodopa

► Decision makingDecision making: treatment of motor : treatment of motor fluctuations, non-motor features of fluctuations, non-motor features of PDPD


► 82-year-old woman has a history of 82-year-old woman has a history of Parkinson’s disease for 12 years. She Parkinson’s disease for 12 years. She presented with shuffling gait, masked presented with shuffling gait, masked facies, postural instability, and a pill-rolling facies, postural instability, and a pill-rolling tremor of the right hand.tremor of the right hand.

► Initially responded well to carbidopa-Initially responded well to carbidopa-levodopa. Then she developed mild wearing levodopa. Then she developed mild wearing off and dyskinesia. Over the past two years off and dyskinesia. Over the past two years she has been experiencing visual she has been experiencing visual hallucinations, paranoia, and vivid dreams. hallucinations, paranoia, and vivid dreams. She has become more forgetful and gets She has become more forgetful and gets lost easily around familiar places. She falls lost easily around familiar places. She falls frequently.frequently.


► Family History: Family History: 87-year-old sister 87-year-old sister diagnosed with Alzheimer’s disease and diagnosed with Alzheimer’s disease and Parkinson’s diseaseParkinson’s disease

► Medical History: Medical History: Mild stroke 3 years ago; Mild stroke 3 years ago; has minimal residual effects of right-sided has minimal residual effects of right-sided weakness. weakness.

► MedicationsMedications: She takes 1 aspirin daily in : She takes 1 aspirin daily in addition to carbidopa-levodopaaddition to carbidopa-levodopa

► Decision making: Decision making: management of management of advanced PD motor and non-motor advanced PD motor and non-motor featuresfeatures


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