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Disease modifying drugs in MS Eva Havrdová Charles University, First Medical Faculty,

Disease modifying drugs in MS Eva Havrdová Charles University, First Medical Faculty, Dpt. of Neurology Praha, Czech Republic. MS – what we want to treat autoimmune inflammation in the CNS driven by myelin antigens myelin disintegration axonal loss.

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Disease modifying drugs in MS Eva Havrdová Charles University, First Medical Faculty,

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  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. Treatment of acute attack internationalconsensus:  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. silent clinical RR-MS SP-MS permanent disability Axonal loss treatment effect (2) treatment effect (1) treatment effect (???) t

  15. 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)

  17. IFNß-1b* IFNß-MS Study (n=227) IFNß-1a MSCRG (n=172) IFNß-1a* PRISMS (n=371) Glatiramer Johnson et al. (n=215) IVIG AIMS (n=147) * high dose treatment groups 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. Leukocyte Chemoattractant signal a4b1 (VLA-4) Blood Vessel Lumen Endothelial Cells Tissue VCAM-1 Leukocyte Chemoattractant Signal a4b1 (VLA-4) Blood Vessel Lumen Endothelial Cells Tissue VCAM-1 Role for adhesion molecules(implications for MS therapy) Leukocyte Infiltration and Brain Inflammation Reduced Leukocyte Infiltration and Brain Inflammation

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

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

  22. Sustained Disability Progression(Pre-specified Primary Endpoint) 0.4 Hazard Ratio (HR)=0.58 (95% CI: 0.43, 0.77) P=0.0002 Placebo 29% 0.3 0.2 Proportion With Sustained Progression Natalizumab 17% 0.1 0.0 0 12 24 36 48 60 72 84 96 108 120 Weeks Number of Patients at Risk Placebo 315 296 283 264 248 240 229 216 208 200 199 Natalizumab 627 601 582 567 546 525 517 503 490 478 473

  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 !

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