1. Disease modifying drugs in MS Eva Havrdová Charles University, First Medical Faculty, Dpt. of Neurology Praha, Czech Republic

2. MS – what we want to treat autoimmune inflammation in the CNS driven by myelin antigens myelin disintegration axonal loss

3. Transsection of demyelinated axons by cytotoxic lymfocyte Wekerle et al. (2000)

4. Early diagnostics is the clue for early treatment MRI, cerebrospinal fluid, evoked potentials

5. cerebrospinal fluid: oligoclonal bands, plasma cells

6. What we CAN treat?  acute attacks (new or recurrent symptoms lasting > 24 hrs),  long term treatment to modify the natural course of the disease (to prevent inflammation and axonal loss) = moderate but only prevention of disease progression  symptomatic treatment in any disease stage to alleviate symptoms and improve QoL

7. We have NO drugs to treat neither axonal loss nor to prevent it untill now EXCEPT EARLY suppression of CNS inflammation

8. Treatment of acute attack

9. international consensus:  high-dose methylprednisolon (corticosteroids) 3-5g with prevention of side-effects (protection of gut, antiosteoporotic treatment, etc) Treatment of acute attack international consensus:  high-dose methylprednisolon (corticosteroids) 3-5g with prevention of side-effects (protection of gut, antiosteoporotic treatment, etc)

10. Treatment of acute attack

11. Is it meaningful to treat all attacks with steroids?

12. Influence of methylprednisolon on tissue integrity B-CEL: lesions followed before Gd enhancement (n=15) S-CEL: lesions treated with steroids (n=15)

13. Long term treatment with disease modifying drugs (DMDs)

14. permanent disability Axonal loss RR-MSSP-MS treatment effect (1) silent clinical t treatment effect (2) treatment effect (???)

15. international consensus = early treatment initiation to decrease relapse rate prevent disability progression international consensus = early treatment initiation to decrease relapse rate prevent disability progression When to introduce this treatment?  disease activity (2 attacks / 2 years)  remittent disease stage  disability not too severe (chronic progression starts somewhere around Kurtzke EDSS 4-5)  compliance is guaranteed

16. Long-term treatment to alter the natural course of MS: first line treatment  IFN-beta, glatiramer acetate second-line treatment  IVIG third-line treatment  azathioprin (older immunomodulators and immunosupressants) Long-term treatment to alter the natural course of MS: first line treatment  IFN-beta, glatiramer acetate second-line treatment  IVIG third-line treatment  azathioprin (older immunomodulators and immunosupressants)

17. * high dose treatment groups IFNß-1b* IFNß-MS Study (n=227) IFNß-1a MSCRG (n=172) Glatiramer Johnson et al. (n=215) IVIG AIMS (n=147) IFNß-1a* PRISMS (n=371) x axis: compared drugs: IFNB-1b=Betaferon, IFNB-1a=Avonex, IFNB-1a *=Rebif, Glatiramer= Copaxone, IVIG= intravenous immunoglobulins y axis: relapse rate = number of attacks per year

18. What to do when this treatment fails? (relapses, progression of disability, MRI activity) Therapy escalation (Rieckmann 2004, Toyka 2008)  natalizumab (Tysabri)  pulses of cytostatics (mitoxantron, cyclophosphamide)

19. Role for adhesion molecules (implications for MS therapy) Reduced Leukocyte Infiltration and Brain Inflammation Leukocyte Infiltration and Brain Inflammation

20. AFFIRM study: Relapse rate Primary Endpoint for Year 1 FDA per subject mean relapse rate at 2 years = 0.67 for placebo and 0.22 for natalizumab (67% reduction) P<0.0001 Placebo n=315 Natalizumab n=627 P<0.0001 0.78 0.68 0.73 0.27 0.20 0.24 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Over 1 Year1-2 YearsOver 2 Years Annualized Relapse Rate (95% CI) 66% 71% 68%

21. Mean No. of New or Enlarging T2 Lesions 0 2 4 6 8 10 12 6.1 1.2 4.9 0.7 11.0 1.9 P<0.0001 Placebo n=315 Natalizumab n=627 83% 80% 86% Year 0–1Year 1–2Year 0–2 No of new and enlarging T2 lesions P<0.0001

22. Number of Patients at Risk Placebo Natalizumab 315296283264248240229216208200 627601582567546525517503490478 Proportion With Sustained Progression Hazard Ratio (HR)=0.58 (95% CI: 0.43, 0.77) P=0.0002 Placebo 29% Natalizumab 17% 0.0 0.1 0.2 0.3 0.4 Weeks 01224364860728496108120 199 473 Sustained Disability Progression (Pre-specified Primary Endpoint)

23. The more effective the therapy is, the more risks you face

24. SENTINEL – study combining natalizumabu with Avonex After > 2 years of administration: 2 serious adverse events  Progressive multifocal leukoencephalopathy

25. Registration in EU: August 2006 strictly for monotherapy Safety measures: baseline MRI, normal lymphocyte count, no history of malignancy or severe immunosuppression, neurologists trained in PML diagnostics June 2008: 2 cases of PML in monotherapy in EU

26. Negotiations for reimbursement:  European Code of Good Practice  National societies of professionals  National patient organizations Help:  pharmacoeconomic data  scientific data on early treatment (what is lost is not regained),  placebo controlled randomized trials,  international guidelines (included in the Code)  PR strategies

27. Never ever give up hope !