New Multiple Sclerosis Diagnostic Criteria CLINICAL ATTACKS OBJECTIVEADDITIONAL REQUIREMENTS 2 or more None; clinical evidence will suffice 2 or more1Dissemination

New Multiple Sclerosis Diagnostic Criteria

CLINICAL ATTACKS

OBJECTIVE ADDITIONAL REQUIREMENTS

2 or more 2 or more None; clinical evidence will suffice

2 or more 1 Dissemination in space by MRI, or, positive CSF and 2 or more MRI lesions c/w MS or

second clinical attack at a different site

1 2 or more Dissemination in time by second MRI or, second clinical attack

1 1 Dissemination in space by MRI, OR positive CSF and 2 or more MRI lesions AND

Dissemination in time by by MRI or second clinical attack

0 1 Positive CSF AND

dissemination in space by MRI evidence of 9 or more T2 lesions,

Or 2 or more cord lesions, or 4-8 brain lesions and 1 cord lesion, or positive VEP with 4-8 MRI lesions or, positive VEP, 1 cord lesion and <4 brain lesions

AND dissemination in time by MRI

Axons are Transected in MS Plaques

Trapp BD, et al. N Engl J Med. 1998;338:278-285.

SMI-32 (non-phosphorylated neurofilament) -demyelinated axons and swellings MBP intact axons

Natural History Of MSNatural History Of MSClinical and MRI MeasuresClinical and MRI Measures

Measures of brain volumeMeasures of brain volume

Relapses and impairmentRelapses and impairment

TimeTime

Hartung HP et al. The Lancet 2002;360:2018-2025.

MRI Total T2 Lesion AreaMRI Total T2 Lesion Area

MRI activityMRI activity

RelapsingRelapsingPreclinicalPreclinical ProgressiveProgressive

Time from onset of MS (years)

Per

cent

of

patie

nts

Actuarial analysis of disability: percentage of patients not having reached DSS 6: difference between the groups significant (P<0.0001).

5040302010

20

0

0

40

60

80

100

Early Relapses Affect Long-term DisabilityEarly Relapses Affect Long-term Disability

Low (0-1 attacks in 2 years)

Intermediate (2-4 attacks in 2 years)

High (> 5 in 2 years)

Weinshenker BG, et al. Brain. 1989;112:1422.

Presence of MRI Lesions Predict Development Presence of MRI Lesions Predict Development of MSof MS

0

10

20

30

40

50

60

0 1 2 3 4 5

Year

% C

D M

S

16% No lesions*

37% 1-2 lesions*

51% > 3 lesions*

ONTT: Optic Neuritis Treatment TrialONTT: Optic Neuritis Treatment Trial*Number of lesions present at baseline*Number of lesions present at baselineThe exact relationship between MRI findings and the clinical status of patients is unknownThe exact relationship between MRI findings and the clinical status of patients is unknownArch Neurol 1993 Aug;50(8):841-6Arch Neurol 1993 Aug;50(8):841-6

PRISMS 4 TrialPRISMS 4 Trial: Transient : Transient Effect of Effect of NAbs With NAbs With Rebif 44 mcg tiw SC on RRebif 44 mcg tiw SC on Relapse Counts? elapse Counts?

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

Prest

udy0-

6m

6-12

m

12-1

8m

18-2

4m

24-3

0m

30-3

6m

36-4

2m

42-4

8m

# of

Rel

apse

s#

of R

elap

ses

Average years 1-4: NAb+ vs NAb- p = 0.3164Average years 1-4: NAb+ vs NAb- p = 0.3164

NAb + (n=35)NAb + (n=35)

NAb NAb −− (n=147) (n=147)

PRISMS Study Group. Neurology. 2001;56:1628–1636.

The clinical utility of measuring NAb in an individual on IFN- therapy is uncertain

PRISMS Trial ConclusionsPRISMS Trial Conclusions

• Rebif efficacy is sustained over 4 years as measured by:

– MRI– Relapses– Disability

• 44 mcg TIW yields greater efficacy than 22 mcg TIW• Patients treated at a high dose early have better outcomes • With respect to NAbs, treatment decisions are best made on

clinical grounds– By year 4: 7/8 patients are NAb-free

• Side effects are generally mild and manageable


Summary Efficacy at Week 24 and Week 48Summary Efficacy at Week 24 and Week 48 Week 24 Week 48

p-value Relative improvement

p-value Relative improvement

Odds Ratio - relapsing 0.0005 47% 0.009 33%

Hazard ratio, time to relapse

0.001 37% 0.003

30%

Relapse rate 0.025 26% 0.093 16%

CU active

<0.001

48%

T2 lesions <0.001 50% <0.001 36%

T2 active scans <0.001 45% <0.001 38%

T2 inactive patients <0.001 39% <0.001 40%

Neurology.Neurology. 2002;59:1496-1506 2002;59:1496-1506

The exact relationship between MRI findings and the clinical status of patients is unknown

Rebif vs. Avonex

Rebif vs. Avonex

Natural History Of MSNatural History Of MSClinical and MRI MeasuresClinical and MRI Measures

Measures of brain volumeMeasures of brain volume

Relapses and impairmentRelapses and impairment

TimeTime

Hartung HP et al. The Lancet 2002;360:2018-2025.

MRI Total T2 Lesion AreaMRI Total T2 Lesion Area

MRI activityMRI activity

RelapsingRelapsingPreclinicalPreclinical ProgressiveProgressive

PRISMS Trial ConclusionsPRISMS Trial Conclusions

• Rebif efficacy is sustained over 4 years as measured by:

– MRI– Relapses– Disability

• 44 mcg TIW yields greater efficacy than 22 mcg TIW• Patients treated at a high dose early have better outcomes • With respect to NAbs, treatment decisions are best made on

clinical grounds– By year 4: 7/8 patients are NAb-free

• Side effects are generally mild and manageable


EVIDENCE 48 Week Trial: ConclusionsEVIDENCE 48 Week Trial: Conclusions

• Treatment regimen (dose and frequency) has significant and sustained impact on efficacy of IFN-1a in RRMS at 48 weeks

• The positive treatment effects seen with Rebif 44 g tiw SC vs. Avonex 30 mcg qw IM at 24 weeks were sustained up to 48 weeks

– Proportion of relapse-free patients– MRI activity

• Efficacy was not achieved at the expense of safety– Despite differences in adverse events, discontinuation

rate for adverse events was comparable (Avonex-4.2%, Rebif – 4.7%)

– NAb status had no effect on relapse rate at 48 weeksThe exact relationship between MRI findings and the clinical status of patients is unknown.The clinical utility of measuring NAbs in an individual on The clinical utility of measuring NAbs in an individual on IFN in uncertain.Neurology. 2002;59:1496-1506Neurology. 2002;59:1496-1506

PULSED PULSED METHYLPREDNISOLONEMETHYLPREDNISOLONE

CharacteristicsCharacteristics Pulsed MP, Pulsed MP, n=39n=39

Control, Control, n=42n=42

PP Value Value

Sex, M/F, n Sex, M/F, n (%)(%) 12 (30)/27 12 (30)/27 (69)(69)

14(33)/14(33)/28(66)28(66)

NSNS

RR, Av (SD)RR, Av (SD) 0.6 (0.7)0.6 (0.7) 0.6 (0.3)0.6 (0.3) NSNS

EDSS, av/(SD)EDSS, av/(SD) 1.7 (1.4)1.01.7 (1.4)1.0 3.4 (2.0) 3.03.4 (2.0) 3.0 <.0001<.0001

T2, mL, av (SD)T2, mL, av (SD) 21.4 21.4 (25.4)/0.6(25.4)/0.6

27.8(36.4)/127.8(36.4)/1 NSNS

T1,mL, av, (SD)T1,mL, av, (SD) 2.7(3.7)/02.7(3.7)/0 6.7(5.3)/06.7(5.3)/0 <.0001<.0001

Brain vol mL, Brain vol mL, (SD)(SD)

1,257.4 (64.3)1,257.4 (64.3) 1,188.9 1,188.9 (139.9)(139.9)

0.0030.003

Real Power. Real Performance.

31

Evaluating Efficacy—MRI MRI Measures and Meanings

• Gd-enhanced T1-weighted lesions indicate24

— Leakage of the BBB

— Acute inflammation

*Quality of life as measured by sexual dysfunction, overall mental health, and limitations due to physical and emotional dysfunction.

Clinical Correlations

Disability Relapses QOL* Fatigue Cognition

Weak24 Moderate24,25 No26 No27 No published reports


32


• T2-weighted lesions indicate24

— Edema

— Moderate demyelination

— Gliosis

— Axonal loss

*Quality of life as measured by sexual dysfunction, overall mental health, and limitations due to physical and emotional dysfunction.

Clinical Correlation


Weak24 No28 Moderate26 No29 No30,31


33


• Black hole lesions (or T1 hypointense lesions) indicate24,30

— Significant demyelination

— Severe tissue damage

— Gliosis

— Axonal loss

Acute vs Chronic T1 Lesions

• T1-weighted lesion persists over 6-month period defined as a chronic T1 lesion, or black holeClinical Correlation


Strong32 No33 Strong26 No published reports

Strong34


34

Considerations in Long-term Treatment COPAXONE®: Long-term Relapse Rate Reduction

• Over the long term (2 years), studies demonstrate a reduction in relapses

— 29% reduction in relapse rate vs placebo at 2 years in first pivotal trial1

• COPAXONE® 1.19 vs placebo 1.68 (P=0.055)

— 75% reduction in relapse rate vs placebo at 2 years in second pivotal trial2

• COPAXONE® 0.60 vs placebo 2.40 (P=0.005) n=50; 25 COPAXONE®, 25 placebo

Double-blind, randomized, placebo-controlled, multicenter study of glatiramer acetate in relapsing-remitting multiple sclerosis patients (n=251; 125 COPAXONE®, 126 placebo).


35

Considerations in Long-term Treatment

IFNs and Neutralizing Antibodies (NAbs)

NAbs may compromise efficacy*

• Higher relapse rates35-38

• More Gd-enhancing lesions36

• More T2 active lesions37

• More BOD† accumulation37

*Based on a comparison of NAb+ vs NAb- patients.† BOD=Burden of disease, defined as the summed cross-sectional area of lesions in T2 scans, analyzed as a percent change from baseline.


36

Considerations in Long-term Treatment

IFNs and Neutralizing Antibodies (NAbs)

Long-term Effects

NAbs in patients (n=167) administered IFN-44 g 3x/wk compared with NAb- patients included37

• 62% increase in relapse rate at years 3 and 4 (P=0.002)

• 366% increase in T2 active lesions over 4 years (P<0.001)

• 26% relative increase in BOD* over 4 years (P<0.001)

COPAXONE® IS NOT ASSOCIATED WITH NAbs IN CLINICAL TRIALS39

*BOD=Burden of disease, defined as the summed cross-sectional area of lesions in T2 scans, analyzed as a percent change from baseline.


37

Considerations in Long-term Treatment COPAXONE®: Tolerability

• COPAXONE® is not associated with the following14:

• Well tolerated over 8 years1-3

COPAXONE® is indicated for the reduction of relapses in relapsing-remitting multiple sclerosis.

Most common adverse effects in controlled trials were injection site reactions, vasodilatation, chest pain, asthenia, infection, pain, nausea, arthralgia, anxiety, and hypertonia.

About 10% of patients experienced an immediate postinjection reaction (flushing, chest pain, palpitations, anxiety, dyspnea, throat constriction, and urticaria). The symptoms were transient and self-limited, and did not require specific treatment.

Transient chest pain was noted in 21% of COPAXONE patients (vs 11% placebo); no long-term sequelae.


38

In Conclusion

COPAXONE®: Summary

Benefits For the Short Term

• Early reduction in both Gd enhancement and relapses1,2,20

• Favorable tolerability profile that allows patients to stay with therapy

Benefits For the Long Term

• Long-term reduction in relapses demonstrated in pivotal studies at 2 years1,2

• No evidence of NAbs from clinical trials that may interfere with efficacy39

• Long-term safety of COPAXONE® demonstrated over 8 years1-3

• Available in a Pre-Filled Syringe for increased patient convenience

IndicationIndication

Now approved for use in worsening MS:Now approved for use in worsening MS:

NOVANTRONENOVANTRONE®® is indicated for reducing is indicated for reducing neurologic disability and/or the frequency of neurologic disability and/or the frequency of clinical relapses in patients with secondary clinical relapses in patients with secondary progressive, progressive relapsing, progressive, progressive relapsing, and worsening relapsing-remitting MS. and worsening relapsing-remitting MS. NOVANTRONE is not indicated for primary NOVANTRONE is not indicated for primary progressive MS.progressive MS.

Before prescribingBefore prescribing NOVANTRONE, please review NOVANTRONE, please review important treatment considerations (included in this important treatment considerations (included in this presentation) and full prescribing information presentation) and full prescribing information available at www.novantrone.com or by calling available at www.novantrone.com or by calling 1-800-IMMUNEX1-800-IMMUNEX

Unfavorable Prognostic FactorsUnfavorable Prognostic Factors

High MRI lesion burden at first episodeHigh MRI lesion burden at first episode Moderate-to-severe disability at 5 yearsModerate-to-severe disability at 5 years Progressive clinical course from onsetProgressive clinical course from onset Male genderMale gender Late onset (age >40 years)Late onset (age >40 years) Two or more relapses in first yearTwo or more relapses in first year

The Burden of Worsening MSThe Burden of Worsening MS

Half of patients with relapsing-remitting MS Half of patients with relapsing-remitting MS convert to secondary progressive MS convert to secondary progressive MS withinwithin10 years of onset10 years of onset

Within 15 years of diagnosis, about 50% of Within 15 years of diagnosis, about 50% of patients with secondary progressive MS patients with secondary progressive MS require walking aids and 10% are require walking aids and 10% are wheelchair-boundwheelchair-bound

NOVANTRONENOVANTRONE®® Efficacy at 2 Years: Efficacy at 2 Years: Primary Efficacy VariablesPrimary Efficacy Variables

NR=not reached within 24 months.

p-value

NOVANTRONE NOVANTRONE Placebo 12 mg/m2 12 mg/m2

(n=64) (n=60)vs Placebo

Multivariate primary efficacy criterion

<0.0001

EDSS change (mean) 0.23 -0.13

0.0194

AI change (mean) 0.77 0.30

0.0306

Mean no. of treated relapses 1.20 0.40

0.0002

Time to first treated

relapse (median months) 14.2 NR

0.0004

SNS change (mean) 0.77 -1.07

0.0269

Conclusions: Clinical EfficacyConclusions: Clinical Efficacy

NOVANTRONENOVANTRONE®® significantly reduced neurologic significantly reduced neurologic disabilitydisability

Significantly reduced EDSS progressionSignificantly reduced EDSS progression

61% reduction in deterioration in Ambulatory Index61% reduction in deterioration in Ambulatory Index

NOVANTRONE significantly reduced relapse ratesNOVANTRONE significantly reduced relapse rates

Prolonged time to first treated relapseProlonged time to first treated relapse

67% reduction in the number of treated relapses67% reduction in the number of treated relapses

MSFC IN MTX+IFN1AMSFC IN MTX+IFN1A

• Methotrexate and Betainterferon Methotrexate and Betainterferon stabilize diseasestabilize disease

Azathioprine and Azathioprine and Betainterferon are better Betainterferon are better together than alonetogether than alone

Documents

New Multiple Sclerosis Diagnostic Criteria CLINICAL ATTACKS OBJECTIVEADDITIONAL REQUIREMENTS 2 or more None; clinical evidence will suffice 2 or more1Dissemination