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New Insights into Current MS Treatment NMSS 20th Annual Research Symposium Robert Shin, MD Maryland Center for MS Impact of MS Leading non-traumatic cause of disability in young adults 250,000 to 350,000 affected in US* National cost of nearly $10 billion per year* MS treatment 1990

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New insights into current ms treatment l.jpg

New Insights intoCurrent MS Treatment

NMSS 20th Annual Research Symposium

Robert Shin, MD

Maryland Center for MS


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Impact of MS

  • Leading non-traumatic cause of disability in young adults

  • 250,000 to 350,000 affected in US*

  • National cost of nearly $10 billion per year*




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MS treatment 2000

  • Betaseron

  • Avonex

  • Copaxone


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MS treatment 2005

  • Betaseron

  • Avonex

  • Copaxone

  • Rebif

  • Novantrone

  • Tysabri


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MS relapse rates

-33%

-29%

-34%

-18%

-66%

-54%


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Current MS treatment

  • Long-term efficacy

  • Safety/Tolerability

  • Early treatment

  • Head-to-head comparisons



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Long-term efficacy

  • Ideally demonstrated by long term, controlled, comparative trials

  • Such studies are impractical and possibly unethical


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Extension studies

  • PRISMS-4 (Rebif)

    • 7 to 8 years

    • Relapse rate 1.02 (crossover) vs 0.72 (44mcg)

    • Disability progression delayed by 18 months

  • CHAMPS/CHAMPIONS (Avonex)

    • 5 years (extended to 10 years)

    • 44% reduction in CDMS at 1.5 years

    • 43% reduction in CDMS at 5 years


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Long-term follow up

  • Copaxone at 10 years

    • 108 on Copaxone therapy

    • 47 patients withdrew but were followed

    • 77 patients lost to follow up

    • 92% still walking without assistance


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Long-term follow up

  • Copaxone at 26* years

    • 46 followed

    • 28 patients withdrew

    • Average follow-up 10.5 years

    • 26.7% required assistance to walk


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Long-term follow up

  • Betaseron at 16 years

    • Identified 331/372 original patients

    • 51% (treated) vs 45% (placebo) ambulatory

    • 95% (treated) vs 83% (placebo) alive


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Long-term follow up

  • Avonex at 8 years

    • 160 patients, at least 2 years of Avonex

    • Sustained disability at 6 months predicted disability at 8 years

    • 67% required assistance vs 24%


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Neutralizing antibodies

  • Protein or peptide based therapies may lead to the production of antibodies

  • When antibodies block the biologic effect of the protein/peptide they are referred to as “neutralizing antibodies” (NAbs)


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NAbs to beta interferon

  • Betaseron (beta interferon 1b)

    • 28% to 47%

  • Rebif (beta interferon 1a)

    • 13% to 24%

  • Avonex (beta interferon 1a)

    • 2% to 6%


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NAbs to beta interferon

  • Typically appear within 3 to 18 months of initiation of treatment

  • Reduction in efficacy may be delayed

    • Increased relapses

    • Increased MRI disease burden

  • NAbs may disappear over time?


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Conclusions

  • Both beta interferon and glatiramer may be effective even after 5 to 15 years of treatment

  • Neutralizing antibodies may appear in a minority of patients taking beta interferon



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Safety issues: beta interferon

  • Depression/suicidal ideation

  • Leukopenia/thrombocytopenia

  • Liver enzyme elevation/hepatic injury

  • Thyroid dysfunction

  • Pregnancy category C


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Safety issues: beta interferon

  • CBC and liver panel

  • Thyroid function tests

  • Monitor for depression


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Safety issues: glatiramer acetate

  • Pregnancy category B


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Rebif new formulation (RNF)

  • Human serum albumin-free

  • Fetal bovine serum-free

  • Reduced injection site reactions

    • 30.8% vs 85.8%

  • Increase in flu-like side effects

    • 71% vs 48%


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Conclusions

  • Beta interferon and glatiramer are generally well-tolerated



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Damage occurs early in MS

  • Loss of N-acetylaspartate (NAA)

  • Diffusion tensor imaging (DTI) changes

  • White and gray matter magnetization transfer ratio (MTR) abnormalities

  • Cerebral atrophy

  • Time is brain!


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MS treatments

  • Reduce relapse rate

  • Reduce disability

  • Reduce new/active MRI lesions

  • Earlier treatment is better!


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Clinically Isolated Syndrome (CIS)

  • A single episode of neurologic dysfunction caused by a single demyelinating lesion

  • Optic neuritis

  • Brainstem syndrome

  • Spinal cord syndrome


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CIS and MRI

  • Patients with CIS are at increased risk to develop MS in the future

  • An abnormal MRI is associated with a greatly increased risk to develop MS in the future


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Question

  • Can MS treatments benefit patients with CIS?


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MS medications for CIS

  • ETOMS (Early Treatment of MS)

  • CHAMPS (Controlled High-risk Avonex MS Prevention Study)

  • BENEFIT (Betaseron in Newly Emerging MS For Initial Treatment)

  • PreCISe*


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MS medications for CIS

  • Randomized controlled trials consistently show fewer relapses among CIS patients treated with DMT

  • Avonex and Betaseron now carry FDA indications for treatment of CIS


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Conclusions

  • Early treatment of MS is preferable to a delay in treatment

  • CIS may be the first occurrence of MS

  • MS treatments can be considered in CIS



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Need for direct comparison

  • Different studies should not be compared to each other

  • Different inclusion/exclusion criteria

  • Different outcome measures

  • Different populations


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MS relapse rates

-33%

-29%

-34%

-18%

-66%

-54%


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Beta interferons

  • Betaseron (beta interferon 1b)

  • Avonex (beta interferon 1a)

  • Rebif (beta interferon 1a)


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INCOMIN

  • Beta interferon

    • Betaseron vs Avonex

  • 188 patients followed for 2 years

  • Betaseron 42% more likely to be relapse-free

    • 51% (Betaseron) vs 36% (Avonex)

  • Betaseon more likely to be free of MRI activity

    • 55% (Betaseron) vs 26% (Avonex)


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EVIDENCE

  • Beta interferon 1a

    • 44 mcg tiw (Rebif) vs 30 mcg weekly (Avonex)

  • 677 patients followed for 48 weeks

  • 27% fewer relapses in Rebif group

  • One third reduction in MRI activity


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Interferon vs glatiramer?

  • Rebif vs Copaxone

  • Almost 800 patients randomized

  • Followed for 96 weeks

  • No significant difference*


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Interferon vs glatiramer?

  • CombiRX

    • Copaxone + Avonex

    • Copaxone + placebo

    • Avonex + placebo

  • Is Copaxone + Avonex superior to either drug alone?


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Conclusions

  • Higher dose, higher frequence beta interferon appears to be more effective than lower dose interferon

  • We do not know whether beta interferon or glatiramer acetate is more effective


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Summary

  • There have been great advances in treating MS over the past 15 years

  • Clinical research has been crucial in helping us better understand and refine MS treatment


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