New Insights into Current MS Treatment

1. New Insights intoCurrent MS Treatment NMSS 20th Annual Research Symposium Robert Shin, MD Maryland Center for MS

2. 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*

3. MS treatment 1990

4. MS treatment 1995 • Betaseron

5. MS treatment 2000 • Betaseron • Avonex • Copaxone

6. MS treatment 2005 • Betaseron • Avonex • Copaxone • Rebif • Novantrone • Tysabri

9. MS relapse rates -33% -29% -34% -18% -66% -54%

10. Current MS treatment • Long-term efficacy • Safety/Tolerability • Early treatment • Head-to-head comparisons

11. Long-term efficacy

12. Long-term efficacy • Ideally demonstrated by long term, controlled, comparative trials • Such studies are impractical and possibly unethical

13. 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

14. 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

15. 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

16. 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

17. 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%

18. 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)

19. 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%

20. 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?

21. 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

22. Safety/Tolerability

23. Safety issues: beta interferon • Depression/suicidal ideation • Leukopenia/thrombocytopenia • Liver enzyme elevation/hepatic injury • Thyroid dysfunction • Pregnancy category C

24. Safety issues: beta interferon • CBC and liver panel • Thyroid function tests • Monitor for depression

25. Safety issues: glatiramer acetate • Pregnancy category B

26. 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%

27. Conclusions • Beta interferon and glatiramer are generally well-tolerated

28. Early treatment

29. 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!

30. MS treatments • Reduce relapse rate • Reduce disability • Reduce new/active MRI lesions • Earlier treatment is better!

31. Clinically Isolated Syndrome (CIS) • A single episode of neurologic dysfunction caused by a single demyelinating lesion • Optic neuritis • Brainstem syndrome • Spinal cord syndrome

32. 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

33. Question • Can MS treatments benefit patients with CIS?

34. 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*

35. 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

36. 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

37. Head-to-head comparisons

38. Need for direct comparison • Different studies should not be compared to each other • Different inclusion/exclusion criteria • Different outcome measures • Different populations

39. MS relapse rates -33% -29% -34% -18% -66% -54%

40. Beta interferons • Betaseron (beta interferon 1b) • Avonex (beta interferon 1a) • Rebif (beta interferon 1a)

41. 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)

42. 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

43. Interferon vs glatiramer? • Rebif vs Copaxone • Almost 800 patients randomized • Followed for 96 weeks • No significant difference*

44. Interferon vs glatiramer? • CombiRX • Copaxone + Avonex • Copaxone + placebo • Avonex + placebo • Is Copaxone + Avonex superior to either drug alone?

45. 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

46. 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