The Science and Medicine of Multiple Sclerosis

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The Science and Medicine of Multiple Sclerosis
When, Why and How of Multiple Sclerosis
Neurotherapy
P.K. Coyle, MD Professor and Acting
Chair Department of Neurology Director, MS
Comprehensive Care Center SUNY at Stony
Brook Stony Brook, NY
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MS Neurotherapy Basics

• Wellness program
• Diet, exercise, sleep, weight, alcohol/ tobacco
• Health maintenance
• Vitamin D and B12, bone density, blood pressure,
  lipids, glucose, breast/prostate/ colon screening
• Optimized symptomatic management
• Disease modifying therapies (DMTs)
• most patients eligible, no absolute
  contraindications

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MS Neurotherapy WHEN?

• Considerations
• Clinical subtype
• Disease activity level
• Disease timepoint/ duration
• Clinical subtype
• All relapsing forms of MS
• Progressive MS has no proven DMTs (?GA anti-CD
  20 FTY 720 MBP analog)

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MS Neurotherapy WHEN?

• Disease activity level
• All early MS is active (no remissions/ burnout)
• Damage process (macroscopic/ microscopic) often
  occult
• Benign MS lt5
• Disease timepoint/ duration
• Definite relapsing MS
• Clinically isolated syndrome (CIS)/ first attack-
  high risk MS
• Radiologically isolated syndrome (RIS)
• Multiple positive phase III trials in relapsing
  MS and CIS

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CIS/ First Attack High Risk MS

• Appropriate age
• 15 to 45/50 years
• Suggestive clinical syndrome
• Monocular optic neuritis
• Incomplete transverse myelitis
• Isolated brainstem/ cerebellar syndrome
• Multifocal CNS syndrome
• Paroxysmal attacks

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CIS/ First Attack High Risk MS

• Abnormal MRI
• silent lesion(s) suggestive for MS
• No better diagnosis
• Above criteria identity first relapse MS

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RIS

• Routine MRI is abnormal and suggestive for MS
• No prior history consistent with MS
• Issue involves presymptomatic MS vs. asymptomatic
  MS vs. not MS
• No accepted management protocol

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MS Neurotherapy WHY?

• Most (gt95) untreated MS patients develop
  disability
• Physical, cognitive, vocational
• Ongoing accumulating macroscopic and microscopic
  injury
• Accelerated CNS tissue volume loss
• Permanent damage involved

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MS Neurotherapy WHY?

• DMTs decrease this injury/ disability process
• Starting DMT immediately, esp in functionally
  intact patients, gives better long term outcomes
• First line DMTs are safe and well tolerated
• This approach (aggressive early therapy) endorsed
  for other organ-specific immune mediated disorders

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MS Neurotherapy HOW?

• DMT choice based on
• Disease features (subtype, duration, prognostic
  profile, clinical/ MRI features)
• Drug features (efficacy, tolerability, dosing/
  administration, convenience, risk/ benefit ratio,
  screening, cost)
• Patient characteristics (comorbidity, lifestyle,
  expectations, pregnancy concerns)

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MS Neurotherapy HOW?

• First/ second line DMTs based on risk benefit
  ratio
• First line GA, IFNßs similar clinical efficacy
  no short or long term safety issues
• Second line Natalizumab, mitoxantrone safety
  issues involve PML, cardiomyopathy/ treatment
  related leukemia

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MS Neurotherapy HOW?

• Critical compliance issue
• Education and training (realistic expectations,
  management of side effects)
• Support services
• Open communications
• Treatment of depression

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MS Neurotherapy HOW?

• Continued monitoring
• Regular assessments
• Evaluation for relapses, sustained worsening, MRI
  activity
• Breakthrough disease activity evaluation, for
  suboptimal response/ treatment failure

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Nova Scotia MS Cohort

• 1980 to 2004 data (treatment era 1988-2004)
• Three populations
• Relapsing MS (N390)
• SPMS (N200)
• Relapsing onset MS (N590)
• Pretreatment annual EDSS increases were 0.10,
  0.31, 0.16
• Treatment significantly lessened EDSS annual
  worsening (relative size effect- 112, 21, 105)

Neurology 2007691498
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Italian MS Cohort

• N1,504 relapsing MS patients
• 1,103 on IFNß
• 401 untreated
• Followed up to 7 years
• Propensity score inverse weighting used to
  evaluate
• Transition to SPMS
• EDSS 4 and 6

Ann Neurol 200761300
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Italian MS Cohort

• Treated group significantly less likely to reach
  disability markers
• After 7 years SPMS in 8 vs. 20.2
• EDSS 4 in 20.5 vs. 28 EDSS 6 in 7.7 vs. 12.4
• Conclusion DMT slows disability progression in
  relapsing MS

Ann Neurol 200761300
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IFNß-1a im Long-term Follow-up 8 Year Analysis
Time to EDSS 6.0
Rudick et al. MS 11626, 2005
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ASSURANCE

• 15-year long-term follow-up of pivotal IM IFNß1a
  relapsing trial (MSCRG)
• Involved 2-year completers
• Open label, retrospective, patient reported
• N136 (of 172) participated
• 46 currently on IM IFNß1a (median duration 13.3
  years)

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ASSURANCE

• Those on IM IFNß1a showed
• ? Mean EDSS change (2.3 vs. 3.3, p0.011)
• ? EDSS 4 (64 vs. 83, p0.06)
• ? EDSS 6 (32 vs. 62, p0.008)
• ? EDSS 7 (9 vs. 33, p0.008)
• Better physical score on SF36 (plt0.0001), greater
  independence (p0.0019 p0.031)

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PRISMS Long Term Follow-up

• 8-year follow-up of PRISMS SC IFNß1a pivotal
  relapsing trial
• 382 of 560 subjects (68.2) evaluated
• 275 (72) still receiving IFNß1a
• Subjects initially randomized to 44mcg showed
  best EDSS, relapse rate, T2 burden of disease at
  8 years
• -no brain atrophy difference
• 19.7 progressed to SPMS
• Neurology 200667944

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IFNß-1a sq Long-term Follow-up 8 Year Analysis
Time to Accumulated Disability
Free of 3 month Sustained EDSS Progression
44 µg 22µg Late Rx All
N at Risk 134 138 134 396
Reached EDSS 4.0 23.9 28.9 27.6 26.8
Time to 20th tile 5.8 yr 4.6 yr 3.5 yr 4.8 yr
19.7 of all subjects in LTFU developed SPMS (12 months of 1.0 EDSS change without relapse) 19.7 of all subjects in LTFU developed SPMS (12 months of 1.0 EDSS change without relapse) 19.7 of all subjects in LTFU developed SPMS (12 months of 1.0 EDSS change without relapse) 19.7 of all subjects in LTFU developed SPMS (12 months of 1.0 EDSS change without relapse) 19.7 of all subjects in LTFU developed SPMS (12 months of 1.0 EDSS change without relapse)
Kappos et al. Neurology 67944, 2006
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16 Year Follow-Up
Pivotal Study (n372)
IFNß-1b 250 µg
124
56
LTF
IFNß-1b 50 µg
125
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Patients under regular medical care - no trial
123
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Placebo
1988
1993
2005
1990
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
Goodin et al., Early treatment with interferon
beta-1b associated with improved long-term
outcome in multiple sclerosis. Multiple
Sclerosis 2008 14 (Suppl 1), P52
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16-Year LTF Patient Disposition in the
Intent-to-Treat Population
4.8
7.2
16.3
10.5
Deceased Not found Alive
13.6
11.4
84.7
79.2
72.4
Proportion of Patients
Placebo n 123
INFB-1b 50 µg n 125
IFNB-1b 250 µg n 124
Ebers G. Presented at ECTRIMS 2006, Madrid, Spain.
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16-Year LTF Other findings

• The most important predictors for better
  long-term outcomes from the IFNB-1b 16-year LTF
  study were
• Low EDSS (lt2) at study entry
• High exposure to IFNB-1b
• The risk of any negative outcome was reduced by
  60 with high compared to low exposure
• Safety and tolerability
• No new or unexpected side effects
• Flu-like symptoms , injection site reactions and
  NAbs continued at a low level
• EDSS 6 SPMS EDSS 6/SPMS, Wheelchair

Goodin et al., Early treatment with interferon
beta-1b associated with improved long-term
outcome in multiple sclerosis. Multiple
Sclerosis 2008 14 (Suppl 1), P52
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GA 10-Year Follow-up

• Prospective follow-up from pivotal relapsing
  trial
• N108 remained in study N124 withdrew (N50
  returned for LTFU)
• EDSS ? by 0.50 1.65 in ongoing cohort vs. 2.24
  1.86 in withdrawn cohort
• -EDSS stable or improved in 62 vs. 28
• -EDSS 4 (24.8 vs 68)
• -EDSS 6 (1 vs 10)
• Relapse reduction gt80 ARR 0.2

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Summary

• There is strong justification for treating
  relapsing forms of MS (including first attack)
• - Increasing rationale for the earlier the
  better
• There is accumulating data to support that
  treatment is changing MS natural history
• Accumulating long term follow-up studies all
  support early treatment
• Therapy is optimized by tailoring DMD choice,
  providing support services, and ongoing follow-up
• This modern treatment era is changing the face of
  MS