New Insights intoCurrent MS Treatment

NMSS 20th Annual Research Symposium

Robert Shin, MDMaryland 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

MS treatment 1995

• Betaseron

MS treatment 2000

• Betaseron• Avonex• Copaxone

MS treatment 2005

• Betaseron• Avonex• Copaxone• Rebif• Novantrone• Tysabri

MS relapse rates

0

1

2

3

Betaseron Avonex Copaxone Rebif Tysabri* SENTINEL

placebodrug

-34%

-18%

-29%

-33%

-66% -54%

Current MS treatment

• Long-term efficacy• Safety/Tolerability• Early treatment• Head-to-head comparisons

Long-term efficacy

Long-term efficacy

• Ideally demonstrated by long term, controlled, comparative trials

• Such studies are impractical and possibly unethical

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

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

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

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

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%

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)

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%

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?

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

Safety/Tolerability

Safety issues: beta interferon• Depression/suicidal ideation• Leukopenia/thrombocytopenia• Liver enzyme elevation/hepatic injury• Thyroid dysfunction

• Pregnancy category C

Safety issues: beta interferon

• CBC and liver panel• Thyroid function tests

• Monitor for depression

Safety issues: glatiramer acetate

• Pregnancy category B

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%

Conclusions

• Beta interferon and glatiramer are generally well-tolerated

Early treatment

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!

MS treatments

• Reduce relapse rate• Reduce disability• Reduce new/active MRI lesions

• Earlier treatment is better!

Clinically Isolated Syndrome (CIS)

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

• Optic neuritis• Brainstem syndrome• Spinal cord syndrome

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

Question

• Can MS treatments benefit patients with CIS?

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*

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

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

Head-to-head comparisons

Need for direct comparison

• Different studies should not be compared to each other

• Different inclusion/exclusion criteria• Different outcome measures• Different populations

MS relapse rates

0

1

2

3

Betaseron Avonex Copaxone Rebif Tysabri* SENTINEL

placebodrug

-34%

-18%

-29%

-33%

-66% -54%

Beta interferons

• Betaseron (beta interferon 1b)• Avonex (beta interferon 1a)• Rebif (beta interferon 1a)

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)

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

Interferon vs glatiramer?

• Rebif vs Copaxone

• Almost 800 patients randomized• Followed for 96 weeks

• No significant difference*

Interferon vs glatiramer?

• CombiRX– Copaxone + Avonex– Copaxone + placebo– Avonex + placebo

• Is Copaxone + Avonex superior to either drug alone?

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

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