1. CMSC, June 2004 Inflammation and Secondary Progressive MS: Trials of Immunosuppression & Immunomodulators Ruth Whitham, MD James Bowen, MD VA MS Center of Excellence-West

2. CMSC, June 2004 MS is an Inflammatory Disease

3. CMSC, June 2004 The Pathogenesis of MS May Involve Both Inflammation and NeurodegenerationInflammation Neurodegeneration Neurodegeneration RRMS SPMS SPMS + Relapses - Relapses PPMS

4. CMSC, June 2004 Martino et al. Lancet Neurology. 2002; 1(8): 499-509 Detrimental inflammation Proinflammatory cytokines sustaining the recruitment of blood-borne macrophages (eg, interleukin 1α / β) Myelinotoxic cytokines (eg, TNF- α via (TNFR1) Macrophages stripping myelin lamella from axons thus blocking conduction Myelin Specific CD4+ (and CD8+) effector T cells with a Th1-like profile Complement-fixing antimyelin components antibodies Protective inflammation Proinflammatory cytokines favoring in situ apoptosis of infiltrating T cells (eg, interferon γ) Proinflammatory cytokines stimulating remyelination (eg, TNF-α via TNFR2) Macrophages phagocytosing myelin debris in situ Encephalitogenic CD4+ T cells producing neurotrophins (eg, brain-derived neurotrophic factor) and PGE2 Antioligodendrocyte antibodies DemyelinationRemyelination

5. CMSC, June 2004 IFN-Beta: Mechanisms of Action

6. CMSC, June 2004 European Study: Betaferon N=718: 2 years  8 MIU SQ QOD vs placebo North American Study: Betaseron N=939: 3 years  8 MIU SQ QOD vs 5 MIU/m 2 (9.6 MIU) vs placebo SPECTRIMS: Rebif N=618: 3 years  44 mcg vs 22 mcg tiw vs placebo IMPACT: Avonex N=436: 2 years  60 mcg IM weekly vs placebo Controlled Studies of  -Interferons in SPMS Lancet 1998; Neurology 2000; Neurology 2001; Neurology 2002

7. CMSC, June 2004 Baseline Subject Characteristics for the Four Interferon Studies  Mean age: 41-48 (European younger, Avonex older)  MS Duration: 8-16 years (European shorter, Avonex longer)  SPMS Duration: 2-4 years (European shorter)  % of patients with pre-study relapses: 40-70% (European higher)  Entry EDSS: 5.1 – 5.4 (inclusion 3.0 (3.5) – 6.5)

8. CMSC, June 2004 Primary Outcome Measures for the Four Studies Time to Confirmed Progression by EDSS  European Betaferon: Progression confirmed at 3 mo.  NA Betaseron: Progression confirmed at 6 mo.  SPECTRIMS Rebif: Progression confirmed at 6 mo. MSFC Change from Baseline to Month 24  IMPACT Avonex

9. CMSC, June 2004 Primary Outcome Results for the Four Studies Primary Outcome Achieved  European Betaferon: 9-12 mo. delay in time to progression by EDSS  IMPACT Avonex: Decrease in MSFC from baseline to month 24 reduced by 40%; driven by 9HPT (No benefit on EDSS) Primary Outcome Not Achieved  NA Betaseron and SPECTRIMS Rebif  No difference from placebo in time to progression by EDSS Gender Effect Only in Rebif Study  Females showed delay in time to progression by EDSS at both doses compared to placebo

10. CMSC, June 2004 Secondary Outcomes Similar in the Four Interferon Studies Benefit for Relapse Measures  Reduced relapse rate and severity  Reduced number of subjects relapsing  Increased time to first relapse  Reduced steroids & hospitalizations Benefit for MRI Measures  Reduced Gd enhancement  Reduced cumulative number of new or enlarging T2 lesions  Reduced cumulative T2 lesion volume

11. CMSC, June 2004

12. 12 mg/m2 (N = 60) vs 5 mg/m2 (N = 64) vs Placebo (N = 64) 12 mg/m2 (N = 60) vs 5 mg/m2 (N = 64) vs Placebo (N = 64) EDSS 3-6, RRMS or SPMS, with EDSS decrease by at least 1 point/18 mos. EDSS 3-6, RRMS or SPMS, with EDSS decrease by at least 1 point/18 mos. Composite outcome (EDSS, AI, Std Neuro exam, Time to 1 st steroids, Time to 1 st attack) positive p = 0.0001 Composite outcome (EDSS, AI, Std Neuro exam, Time to 1 st steroids, Time to 1 st attack) positive p = 0.0001 Mitoxantrone in SPMS Hartung HP, et al. Lancet 2002;360:2018-25

13. CMSC, June 2004 Mitoxantrone in SPMS ESSS worse by ≤ 1 = 25 vs 8% (-64%, p = 0.013) ESSS worse by ≤ 1 = 25 vs 8% (-64%, p = 0.013) Relapses 1.15 vs 0.42/yr (yr 1, p = 0.0001) Relapses 1.15 vs 0.42/yr (yr 1, p = 0.0001) Relapses 0.85 vs 0.27/yr (yr 2, p = 0.0001) Relapses 0.85 vs 0.27/yr (yr 2, p = 0.0001)

14. CMSC, June 2004 Mitoxantrone in SPMS Effects sustained for 3 years (1 yr post Tx) only for Std Neuro Exam. Effects sustained for 3 years (1 yr post Tx) only for Std Neuro Exam. Mean EDSS 4.45 (early) Mean EDSS 4.45 (early) 94/188 had SPMS 94/188 had SPMS

15. CMSC, June 2004 Glatiramer in SPMS 106 (76 SPMS) progressive course EDSS = 2-6.5 106 (76 SPMS) progressive course EDSS = 2-6.5 Glatiramer 15mg sq qd vs placebo Glatiramer 15mg sq qd vs placebo Trends for all outcome measures, but not statistically significant. Trends for all outcome measures, but not statistically significant. Little change in placebo groups. Little change in placebo groups. Bornstein MB, et al. 1982;11:317-319.

16. CMSC, June 2004 Methotrexate 60 chronic progressive MS, EDSS 3-6.5 60 chronic progressive MS, EDSS 3-6.5 MTX 7.5/wk vs placebo X 2 years. MTX 7.5/wk vs placebo X 2 years. Treatment failure Treatment failure  EDSS worse  AI worse  Box/Block test worse by ≤ 20%  9HP worse by ≤ 20% Goodkin DE, et al. Ann Neurol 1995;37:30-40

17. CMSC, June 2004 Methotrexate Sustained treatment failure seen in 51.6% of MTX vs 82.8% of placebo Sustained treatment failure seen in 51.6% of MTX vs 82.8% of placebo 9HP (p = 0.007) 9HP (p = 0.007) BBT (p = 0.068) BBT (p = 0.068) EDSS (p = 0.205) EDSS (p = 0.205) AI (p = ns) AI (p = ns)

18. CMSC, June 2004 Cyclophosphamide in SPMS 490 pts (362 SPMS) decline 1 point on EDSS/1 yr. 490 pts (362 SPMS) decline 1 point on EDSS/1 yr. 476 (348 SPMS) Rx with CYC 700 mg/m2/mo + MP 1gm X 1 year. 476 (348 SPMS) Rx with CYC 700 mg/m2/mo + MP 1gm X 1 year. Endpoint: Compare relapse rate in year prior to Rx to year of Rx. Endpoint: Compare relapse rate in year prior to Rx to year of Rx. Zephir H. J Neurol Sci. 2004;218:73-77.

19. CMSC, June 2004 Cyclophosphamide in SPMS 0.81 relapse/yr before 0.81 relapse/yr before 0.12 relapse/yr during first 6 months 0.12 relapse/yr during first 6 months 0.14 relapse/yr during first 12 months 0.14 relapse/yr during first 12 months 78.6% stable or improved EDSS at 12 mos. 78.6% stable or improved EDSS at 12 mos. However, retrospective, open label, not controlled However, retrospective, open label, not controlled Zephir H. J Neurol Sci. 2004;218:73-77.

20. CMSC, June 2004 Methylprednisolone 108 SPMS 108 SPMS 500 vs 10 mg qd X3d methylprednisolone + 11 day oral taper q 8 wks X 2 years. 500 vs 10 mg qd X3d methylprednisolone + 11 day oral taper q 8 wks X 2 years. Sustained worsening on composite outcome measure (EDSS, AI, BBT, 9HP) 38.9% vs 53.7% (p = 0.18) Sustained worsening on composite outcome measure (EDSS, AI, BBT, 9HP) 38.9% vs 53.7% (p = 0.18) Goodkin DE, et al. Neurology 1998;51:239-45.

21. CMSC, June 2004 Methylprednisolone Low Dose High Dose P = 0.04 Goodkin DE, et al. Neurology 1998;51:239-45.

22. CMSC, June 2004 Natalizumab 213: 71 placebo, 68 3mg/kg, 74 6 mg/kg 213: 71 placebo, 68 3mg/kg, 74 6 mg/kg Monthly MRI X 6 months Monthly MRI X 6 months SPMS 26 (37%), 21 (31%), 22 (30%) SPMS 26 (37%), 21 (31%), 22 (30%) New enhancing lesions New enhancing lesions  5.4 placebo  1.0 nat 3mg/kg (p = 0.005)  2.0 nat 6 mg/kg (p = 0.08)

23. CMSC, June 2004 Other Treatments Azathioprine Azathioprine Cladribine Cladribine Plasma Exchange Plasma Exchange IVIG IVIG Total Lymphoid Irradiation Total Lymphoid Irradiation High Dose Immunotherapy (SCT) High Dose Immunotherapy (SCT)

24. CMSC, June 2004 Difficulties with SPMS Studies Is all or part of SPMS a non-inflammatory disease? Is all or part of SPMS a non-inflammatory disease? Is SPMS one disease? Is SPMS one disease? Studies have insufficient power. Studies have insufficient power. Measurements of disability are insensitive to change (unchanging placebo groups) Measurements of disability are insensitive to change (unchanging placebo groups) Are measured changes clinically significant? Are measured changes clinically significant?

25. CMSC, June 2004 Currently available DMT’s and immunosuppressants probably primarily target inflammation Currently available DMT’s and immunosuppressants probably primarily target inflammation SPMS may be more likely to respond to currently available treatments if onset of progression is recent, there is a relapsing component, and MRI scan shows active disease SPMS may be more likely to respond to currently available treatments if onset of progression is recent, there is a relapsing component, and MRI scan shows active disease Effects of currently available DMT’s are more pronounced on relapse measures and MRI measures than on disease progression Effects of currently available DMT’s are more pronounced on relapse measures and MRI measures than on disease progression Effects on disease progression are modest Effects on disease progression are modest There may be unintended negative consequences of suppressing inflammation in SPMS There may be unintended negative consequences of suppressing inflammation in SPMS Conclusions