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The Science and Medicine of Multiple Sclerosis

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. MS Neurotherapy Basics.

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The Science and Medicine of Multiple Sclerosis

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  1. 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

  2. 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

  3. 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)

  4. MS Neurotherapy: WHEN? Disease activity level All early MS is active (no remissions/ burnout) Damage process (macroscopic/ microscopic) often occult Benign MS <5% 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

  5. 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

  6. CIS/ First Attack High Risk MS Abnormal MRI silent lesion(s) suggestive for MS No better diagnosis Above criteria identity first relapse MS

  7. 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

  8. MS Neurotherapy: WHY? Most (>95%) untreated MS patients develop disability Physical, cognitive, vocational Ongoing accumulating macroscopic and microscopic injury Accelerated CNS tissue volume loss Permanent damage involved

  9. 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

  10. 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)

  11. MS Neurotherapy: HOW? First/ second line DMTs based on risk benefit ratio First line: GA, IFNβs; similar clinical efficacy; no short or long term safety issues Second line: Natalizumab, mitoxantrone; safety issues involve PML, cardiomyopathy/ treatment related leukemia

  12. MS Neurotherapy: HOW? Critical compliance issue Education and training (realistic expectations, management of side effects) Support services Open communications Treatment of depression

  13. MS Neurotherapy: HOW? Continued monitoring Regular assessments Evaluation for relapses, sustained worsening, MRI activity Breakthrough disease activity evaluation, for suboptimal response/ treatment failure

  14. Nova Scotia MS Cohort* 1980 to 2004 data (treatment era 1988-2004) Three populations Relapsing MS (N=390) SPMS (N=200) Relapsing onset MS (N=590) Pretreatment annual EDSS increases were 0.10, 0.31, 0.16 Treatment significantly lessened EDSS annual worsening (relative size effect- 112%, 21%, 105%) Neurology 2007;69:1498

  15. Italian MS Cohort* N=1,504 relapsing MS patients 1,103 on IFNβ 401 untreated Followed up to 7 years Propensity score inverse weighting used to evaluate Transition to SPMS EDSS 4 and 6 Ann Neurol 2007;61:300

  16. 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 2007;61:300

  17. IFNß-1a im Long-term Follow-up 8 Year Analysis Time to EDSS ≥ 6.0 22% ▼ 31% ▼ Rudick et al. MS 11:626, 2005

  18. ASSURANCE 15-year long-term follow-up of pivotal IM IFNβ1a relapsing trial (MSCRG) Involved 2-year completers Open label, retrospective, patient reported N=136 (of 172) participated 46% currently on IM IFNβ1a (median duration 13.3 years)

  19. ASSURANCE Those on IM IFNβ1a showed ↓ Mean EDSS change (2.3 vs. 3.3, p=0.011) ↓ EDSS 4 (64% vs. 83%, p=0.06) ↓ EDSS 6 (32% vs. 62%, p=0.008) ↓ EDSS 7 (9% vs. 33%, p=0.008) Better physical score on SF36 (p<0.0001), greater independence (p=0.0019; p=0.031)

  20. PRISMS Long Term Follow-up* 8-year follow-up of PRISMS SC IFNβ1a pivotal relapsing trial 382 of 560 subjects (68.2%) evaluated 275 (72%) still receiving IFNβ1a 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 2006;67:944

  21. IFNß-1a sq Long-term Follow-up 8 Year Analysis Time to Accumulated Disability % Free of 3 month Sustained EDSS Progression Kappos et al. Neurology 67:944, 2006

  22. 16 Year Follow-Up Pivotal Study (n=372) IFNβ-1b 250 µg 124 56 LTF IFNβ-1b 50 µg 125 52 Patients under regular medical care - no trial Placebo 123 58 1988 1990 1993 2005 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

  23. 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.

  24. 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 (<2) 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

  25. GA 10-Year Follow-up Prospective follow-up from pivotal relapsing trial N=108 remained in study; N=124 withdrew (N=50 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 >80%; ARR ~ 0.2

  26. 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

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