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Inflammation and Secondary Progressive MS: Inflammation and Secondary Progressive MS: Trials of Immunosuppression & Trials of Immunosuppression &

ImmunomodulatorsImmunomodulatorsRuth Whitham, MD Ruth Whitham, MD

James Bowen, MDJames Bowen, MD

VA MS Center of Excellence-WestVA MS Center of Excellence-West

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MS is an Inflammatory Disease

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The Pathogenesis of MS May Involve Both

Inflammation and Neurodegeneration

InflammationInflammation

NeurodegenerationNeurodegeneration

RRMSRRMS SPMSSPMS

+ Relapses - Relapses+ Relapses - Relapses

PPMSPPMS

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Martino et al. Lancet Neurology. 2002; 1(8): 499-509

Detrimental inflammation• Proinflammatory cytokines sustaining the recruitment of blood-borne macrophages (eg, interleukin 1α / β)

• Myelinotoxic cytokines (eg, TNF- α via (TNFR1)

• Macrophages stripping myelin lamella from axons thus blocking conduction

• Myelin Specific CD4+ (and CD8+) effector T cells with a Th1-like profile

• Complement-fixing antimyelin components antibodies

Protective inflammation• Proinflammatory cytokines favoring in situ apoptosis of infiltrating T cells (eg, interferon γ)

• Proinflammatory cytokines stimulating remyelination (eg, TNF-α via TNFR2)

•Macrophages phagocytosing myelin debris in situ

• Encephalitogenic CD4+ T cells producing neurotrophins (eg, brain-derived neurotrophic factor) and PGE2

• Antioligodendrocyte antibodies

Demyelination Remyelination

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IFN-Beta: Mechanisms of Action

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European StudyEuropean Study:: Betaferon N=718: 2 years Betaferon N=718: 2 years 8 MIU SQ QOD vs placebo8 MIU SQ QOD vs placebo

North American StudyNorth American Study:: Betaseron N=939: 3 years Betaseron N=939: 3 years 8 MIU SQ QOD vs 5 MIU/m8 MIU SQ QOD vs 5 MIU/m22 (9.6 MIU) vs placebo (9.6 MIU) vs placebo

SPECTRIMSSPECTRIMS:: Rebif N=618: 3 years Rebif N=618: 3 years 44 mcg vs 22 mcg tiw vs placebo44 mcg vs 22 mcg tiw vs placebo

IMPACTIMPACT:: Avonex N=436: 2 years Avonex N=436: 2 years 60 mcg IM weekly vs placebo60 mcg IM weekly vs placebo

Controlled Studies of -Interferons in SPMS

Lancet 1998; Neurology 2000; Neurology 2001; Neurology 2002Lancet 1998; Neurology 2000; Neurology 2001; Neurology 2002

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Baseline Subject Characteristics for the Four Interferon Studies

Mean age: 41-48 (European younger, Avonex older)Mean age: 41-48 (European younger, Avonex older)

MS Duration: 8-16 years (European shorter, Avonex MS Duration: 8-16 years (European shorter, Avonex longer)longer)

SPMS Duration: 2-4 years (European shorter)SPMS Duration: 2-4 years (European shorter)

% of patients with pre-study relapses: 40-70% % of patients with pre-study relapses: 40-70% (European higher)(European higher)

Entry EDSS: 5.1 – 5.4 (inclusion 3.0 (3.5) – 6.5)Entry EDSS: 5.1 – 5.4 (inclusion 3.0 (3.5) – 6.5)

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Primary Outcome Measures for the Four Studies

Time to Confirmed Progression by EDSSTime to Confirmed Progression by EDSS European Betaferon: Progression confirmed atEuropean Betaferon: Progression confirmed at 3 mo.3 mo. NA Betaseron: Progression confirmed at NA Betaseron: Progression confirmed at 6 mo.6 mo. SPECTRIMS Rebif: Progression confirmed at SPECTRIMS Rebif: Progression confirmed at 6 mo.6 mo.

MSFC Change from Baseline to Month 24MSFC Change from Baseline to Month 24 IMPACT AvonexIMPACT Avonex

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Primary Outcome Results for the Four Studies

Primary Outcome AchievedPrimary Outcome Achieved European Betaferon: 9-12 mo. delay in time to progression by EDSSEuropean Betaferon: 9-12 mo. delay in time to progression by EDSS

IMPACT Avonex: Decrease in MSFC from baseline to month 24 IMPACT Avonex: Decrease in MSFC from baseline to month 24

reduced by 40%; driven by 9HPT (No benefit on EDSS)reduced by 40%; driven by 9HPT (No benefit on EDSS)

Primary Outcome Not AchievedPrimary Outcome Not Achieved NA Betaseron and SPECTRIMS RebifNA Betaseron and SPECTRIMS Rebif

No difference from placebo in time to progression by EDSS No difference from placebo in time to progression by EDSS

Gender Effect Only in Rebif StudyGender Effect Only in Rebif Study Females showed delay in time to progression by EDSS at both Females showed delay in time to progression by EDSS at both

doses compared to placebodoses compared to placebo

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Secondary Outcomes Similar in the Four Interferon Studies

Benefit for Relapse MeasuresBenefit for Relapse Measures Reduced relapse rate and severityReduced relapse rate and severity

Reduced number of subjects relapsing Reduced number of subjects relapsing

Increased time to first relapseIncreased time to first relapse

Reduced steroids & hospitalizationsReduced steroids & hospitalizations

Benefit for MRI MeasuresBenefit for MRI Measures Reduced Gd enhancementReduced Gd enhancement

Reduced cumulative number of new or enlarging T2 lesions Reduced cumulative number of new or enlarging T2 lesions

Reduced cumulative T2 lesion volumeReduced cumulative T2 lesion volume

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12 mg/m2 (N = 60) vs 5 mg/m2 (N = 12 mg/m2 (N = 60) vs 5 mg/m2 (N = 64) vs Placebo (N = 64)64) vs Placebo (N = 64)

EDSS 3-6, RRMS or SPMS, with EDSS EDSS 3-6, RRMS or SPMS, with EDSS decrease by at least 1 point/18 mos.decrease by at least 1 point/18 mos.

Composite outcome (EDSS, AI, Std Composite outcome (EDSS, AI, Std Neuro exam, Time to 1Neuro exam, Time to 1stst steroids, Time steroids, Time to 1to 1stst attack) positive p = 0.0001 attack) positive p = 0.0001

Mitoxantrone in SPMS

Hartung HP, et al. Lancet 2002;360:2018-25

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Mitoxantrone in SPMS

ESSS worse by ESSS worse by ≤ 1 = 25 vs 8% (-≤ 1 = 25 vs 8% (-64%, p = 0.013)64%, p = 0.013)

Relapses 1.15 vs 0.42/yr (yr 1, p = Relapses 1.15 vs 0.42/yr (yr 1, p = 0.0001)0.0001)

Relapses 0.85 vs 0.27/yr (yr 2, p = Relapses 0.85 vs 0.27/yr (yr 2, p = 0.0001)0.0001)

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Mitoxantrone in SPMS

Effects sustained for 3 years (1 Effects sustained for 3 years (1 yr post Tx) only for Std Neuro yr post Tx) only for Std Neuro Exam.Exam.

Mean EDSS 4.45 (early)Mean EDSS 4.45 (early) 94/188 had SPMS94/188 had SPMS

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Glatiramer in SPMS

106 (76 SPMS) progressive course 106 (76 SPMS) progressive course EDSS = 2-6.5EDSS = 2-6.5

Glatiramer 15mg sq qd vs placeboGlatiramer 15mg sq qd vs placebo Trends for all outcome measures, but Trends for all outcome measures, but

not statistically significant.not statistically significant. Little change in placebo groups.Little change in placebo groups.

Bornstein MB, et al. 1982;11:317-319.

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Methotrexate

60 chronic progressive MS, EDSS 3-6.560 chronic progressive MS, EDSS 3-6.5 MTX 7.5/wk vs placebo X 2 years.MTX 7.5/wk vs placebo X 2 years. Treatment failureTreatment failure

EDSS worseEDSS worse AI worseAI worse Box/Block test worse by Box/Block test worse by ≤ 20%≤ 20% 9HP worse 9HP worse by by ≤ 20%≤ 20%

Goodkin DE, et al. Ann Neurol 1995;37:30-40

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Methotrexate

Sustained treatment failure seen in Sustained treatment failure seen in 51.6% of MTX vs 82.8% of placebo51.6% of MTX vs 82.8% of placebo

9HP (p = 0.007)9HP (p = 0.007) BBT (p = 0.068)BBT (p = 0.068) EDSS (p = 0.205)EDSS (p = 0.205) AI (p = ns)AI (p = ns)

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Cyclophosphamide in SPMS

490 pts (362 SPMS) decline 1 point 490 pts (362 SPMS) decline 1 point on EDSS/1 yr.on EDSS/1 yr.

476 (348 SPMS) Rx with CYC 700 476 (348 SPMS) Rx with CYC 700 mg/m2/mo + MP 1gm X 1 year.mg/m2/mo + MP 1gm X 1 year.

Endpoint: Compare relapse rate in Endpoint: Compare relapse rate in year prior to Rx to year of Rx.year prior to Rx to year of Rx.

Zephir H. J Neurol Sci. 2004;218:73-77.

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Cyclophosphamide in SPMS

0.81 relapse/yr before0.81 relapse/yr before 0.12 relapse/yr during first 6 months0.12 relapse/yr during first 6 months 0.14 relapse/yr during first 12 months0.14 relapse/yr during first 12 months

78.6% stable or improved EDSS at 12 78.6% stable or improved EDSS at 12 mos.mos.

However, retrospective, open label, not However, retrospective, open label, not controlledcontrolledZephir H. J Neurol Sci. 2004;218:73-77.

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Methylprednisolone

108 SPMS108 SPMS 500 vs 10 mg qd X3d 500 vs 10 mg qd X3d

methylprednisolone + 11 day oral methylprednisolone + 11 day oral taper q 8 wks X 2 years.taper q 8 wks X 2 years.

Sustained worsening on composite Sustained worsening on composite outcome measure (EDSS, AI, BBT, outcome measure (EDSS, AI, BBT, 9HP)9HP)38.9% vs 53.7% (p = 0.18)38.9% vs 53.7% (p = 0.18)

Goodkin DE, et al. Neurology 1998;51:239-45.

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Methylprednisolone

Low Dose

High Dose

P = 0.04

Goodkin DE, et al. Neurology 1998;51:239-45.

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Natalizumab

213: 71 placebo, 68 3mg/kg, 74 6 213: 71 placebo, 68 3mg/kg, 74 6 mg/kgmg/kg

Monthly MRI X 6 monthsMonthly MRI X 6 months SPMS 26 (37%), 21 (31%), 22 (30%)SPMS 26 (37%), 21 (31%), 22 (30%) New enhancing lesionsNew enhancing lesions

5.4 placebo5.4 placebo 1.0 nat 3mg/kg (p = 0.005)1.0 nat 3mg/kg (p = 0.005) 2.0 nat 6 mg/kg (p = 0.08)2.0 nat 6 mg/kg (p = 0.08)

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Other Treatments

AzathioprineAzathioprine CladribineCladribine Plasma ExchangePlasma Exchange IVIGIVIG Total Lymphoid IrradiationTotal Lymphoid Irradiation High Dose Immunotherapy (SCT)High Dose Immunotherapy (SCT)

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Difficulties with SPMS Studies

Is all or part of SPMS a non-Is all or part of SPMS a non-inflammatory disease?inflammatory disease?

Is SPMS one disease?Is SPMS one disease? Studies have insufficient power.Studies have insufficient power. Measurements of disability are Measurements of disability are

insensitive to change (unchanging insensitive to change (unchanging placebo groups)placebo groups)

Are measured changes clinically Are measured changes clinically significant?significant?

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Currently available DMT’s and Currently available DMT’s and immunosuppressants probably primarily immunosuppressants probably primarily target inflammationtarget inflammation

SPMS may be more likely to respond to SPMS may be more likely to respond to currently available treatments if onset of currently available treatments if onset of progression is recent, there is a relapsing progression is recent, there is a relapsing component, and MRI scan shows active component, and MRI scan shows active diseasedisease

Effects of currently available DMT’s are more Effects of currently available DMT’s are more pronounced on relapse measures and MRI pronounced on relapse measures and MRI measures than on disease progressionmeasures than on disease progression

Effects on disease progression are modestEffects on disease progression are modest

There may be unintended negative There may be unintended negative consequences of suppressing inflammation in consequences of suppressing inflammation in SPMSSPMS

Conclusions