Clinical Challenges of MSClinical Challenges of MSA State-of-the-Discipline Overview and Lessons A State-of-the-Discipline Overview and Lessons

Learned from Landmark Trials Focused on Learned from Landmark Trials Focused on Immune-Modulating AgentsImmune-Modulating Agents

Jerry S. Wolinsky, MDJerry S. Wolinsky, MDBartels Family and Opal C. RankinBartels Family and Opal C. Rankin

Professor of NeurologyProfessor of NeurologyUniversity of Texas Health Science CenterUniversity of Texas Health Science Center

at Houstonat Houston

o If relapse rates are truly falling, what should now If relapse rates are truly falling, what should now be regarded as a treatment effect? be regarded as a treatment effect?

o Why are relapse rates falling? Why are relapse rates falling? o What is the basis for phase shift? What is the basis for phase shift? o Can it be prevented?Can it be prevented?o Can it be treated? Can it be treated? o How can it be recognized?How can it be recognized?o What is primary progressive disease? What is primary progressive disease?

Major Challenges of MS TherapeuticsMajor Challenges of MS Therapeutics

Better Treatment Effects or Better Treatment Effects or Shifting DiseaseShifting Disease

1992 – 2001 2002 - 2008

Annualized Relapse Rates:Annualized Relapse Rates:Proportional Treatment EffectsProportional Treatment Effects

Annu

aliz

ed R

elap

se R

ate

Annu

aliz

ed R

elap

se R

ate 43.3% ▼43.3% ▼ 57% ▼57% ▼

o The two cladribine tablet treatment groups of the study, The two cladribine tablet treatment groups of the study, assessing different dose regimens, demonstrated a assessing different dose regimens, demonstrated a statistically significant reduction in the annualized rate of statistically significant reduction in the annualized rate of relapses compared to placebo.relapses compared to placebo.

o Patients from the lower total dose group experienced a 58% Patients from the lower total dose group experienced a 58% relative reduction in annualized relapse rates with respect relative reduction in annualized relapse rates with respect to placebo (0.14 versus 0.33 for the placebo group; to placebo (0.14 versus 0.33 for the placebo group; p<0.001). p<0.001).

o Patients from the higher total dose group experienced a Patients from the higher total dose group experienced a 55% relative reduction in annualized relapse rates with 55% relative reduction in annualized relapse rates with respect to placebo (0.15 versus 0.33; p<0.001).respect to placebo (0.15 versus 0.33; p<0.001).

Are we entering a even better placebo era?Are we entering a even better placebo era?

http://www.emdserono.com/cmg.emdserono_us/en/http://www.emdserono.com/cmg.emdserono_us/en/images/20090123_en_tcm115_34944.pdfimages/20090123_en_tcm115_34944.pdf

Sormani et al. Ann Neurol 64:428, 2008Sormani et al. Ann Neurol 64:428, 2008

Will Rogers Phenomena:Will Rogers Phenomena:The joke’s on usThe joke’s on us

o ““When the Okies left When the Okies left Oklahoma and moved to Oklahoma and moved to California, they raised California, they raised the average intelligence the average intelligence level in both states.”level in both states.”

o MRI replaced CT and MRI replaced CT and arguably CSF for arguably CSF for diagnostic supportdiagnostic support

o McDonald’s replaced McDonald’s replaced Poser and we are moving Poser and we are moving towards Swanton and RIStowards Swanton and RIS

Orton et al. Lancet Neurol 5:932, 2006Orton et al. Lancet Neurol 5:932, 2006

Gender Creep:Gender Creep:Importance for TherapeuticsImportance for Therapeutics

o No apparent change in sex No apparent change in sex ratio among PPMS – ratio among PPMS – remains near 1:1remains near 1:1

o If female predominance is If female predominance is evident for CIS through RR evident for CIS through RR and SPMS does this account and SPMS does this account for changing features of for changing features of recent clinical trial cohorts?recent clinical trial cohorts?

o Should it influence decisions Should it influence decisions to start therapy?to start therapy?

Annu

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Annu

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Gender Effect on Annualized Relapse Rates:Gender Effect on Annualized Relapse Rates:Meta-analysis RRMSMeta-analysis RRMS

Wolinsky et al. J Neurol Sci (in review)Wolinsky et al. J Neurol Sci (in review)

Gender Effect on Progression:Gender Effect on Progression:Meta-analysis RRMS of Confirmed Accumulated DisabilityMeta-analysis RRMS of Confirmed Accumulated Disability

Prop

ortio

n of

with

≥1

poin

t inc

reas

e Pr

opor

tion

of w

ith ≥

1 po

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ncre

ase

in E

DSS

sus

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ed fo

r 3 m

onth

s in

ED

SS s

usta

ined

for 3

mon

ths

Both males and females benefited Both males and females benefited

Females Odds Ratio 0.58, 95% CI 0.33-1.00Females Odds Ratio 0.58, 95% CI 0.33-1.00

Males Odds Ratio 0.62, 95% CI 0.29-1.32Males Odds Ratio 0.62, 95% CI 0.29-1.32

Wolinsky et al. J Neurol Sci (in review)Wolinsky et al. J Neurol Sci (in review)

Cum

ulati

ve P

ropo

rtion

of

Cum

ulati

ve P

ropo

rtion

of

Pati

ents

Pro

gres

sing

Pati

ents

Pro

gres

sing

MonthsMonths

Female Patients on Study Drug, N/ Population at Risk, N; (% ITT)PBO: 151/151 (100%) 121/122 (81%) 93/97 (64%) 16/23 (15%)

Male Patients on Study Drug, N/ Population at Risk, N; (% ITT)PBO: 163/163 (100%) 118/122 (75%) 82/88 (54%) 14/23 (14%)

Gender Effect on Progression:Gender Effect on Progression:Post Hoc Sensitivity Analyses PPMS TrialPost Hoc Sensitivity Analyses PPMS Trial

Wolinsky et al. J Neurol Sci (in review)Wolinsky et al. J Neurol Sci (in review)

Phase ShiftPhase ShiftMore of the Same or an More of the Same or an

Alternative ProcessAlternative Process

Laboratory-based biomarkers of Drug ActivityLaboratory-based biomarkers of Drug ActivityGadolinium EnhancementsGadolinium EnhancementsUnique Active LesionsUnique Active LesionsEarly Detected Laboratory-based Adverse EventsEarly Detected Laboratory-based Adverse EventsIncreased Lesion VolumeIncreased Lesion VolumeRelapsesRelapsesCommon Clinical Adverse EventsCommon Clinical Adverse EventsT1 hypointense Lesion ResolutionT1 hypointense Lesion ResolutionAccumulated DisabilityAccumulated DisabilityEvolution of AtrophyEvolution of AtrophyRare Clinical Adverse EventsRare Clinical Adverse EventsPhase shift reductionPhase shift reduction

Frequency of MS Clinical Trial EndpointsFrequency of MS Clinical Trial Endpoints

Deceasing Event Frequency

Course of Relapsing MSCourse of Relapsing MSO

ccur

renc

e, E

xten

t, or

Sev

erity

Occ

urre

nce,

Ext

ent,

or S

ever

ity

TimeTime

SPMSSPMS

Inflammatory PhaseInflammatory Phase

Matrix Destructive PhaseMatrix Destructive Phase

Early RREarly RR

SubclinicalSubclinicalCICISS

atrophyatrophy

disabilitydisability

GdGd

Late RRLate RR

T2 burdenT2 burden

black holesblack holes

Effects of glatiramer acetate on disease activity:Effects of glatiramer acetate on disease activity:Effects on an Early Phase ShiftEffects on an Early Phase Shift

Prop

ortio

n Co

nver

ting

Prop

ortio

n Co

nver

ting

from

‘CIS

’ to

‘CD

MS’

from

‘CIS

’ to

‘CD

MS’

Comi et al. AAN, 2008Comi et al. AAN, 2008

GAGA

PBOPBO

Hazard Ratio = 0.55 [CI 0.40, 0.77]Hazard Ratio = 0.55 [CI 0.40, 0.77]p = 0.0005 p = 0.0005

Havrdova et al. Lancet Neurol 8:254, Havrdova et al. Lancet Neurol 8:254, 20092009

Effects of natalizumab on disease activity:Effects of natalizumab on disease activity:Effects on Phase Shift?Effects on Phase Shift?

Havrdova et al. Lancet Neurol 8:254, Havrdova et al. Lancet Neurol 8:254, 20092009

Effects of natalizumab on disease activity:Effects of natalizumab on disease activity:Effects on Phase Shift?Effects on Phase Shift?

What is PPMS?What is PPMS?Different Course - SorryDifferent Course - Sorry