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

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

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

cerebrospinal fluid: oligoclonal bands, plasma cells

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

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

Treatment of acute attack

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)

Treatment of acute attack

Is it meaningful to treat all attacks with steroids?

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

Long term treatment with disease modifying drugs (DMDs)

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

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

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)

* 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

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)

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

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< Placebo n=315 Natalizumab n=627 P< Over 1 Year1-2 YearsOver 2 Years Annualized Relapse Rate (95% CI) 66% 71% 68%

Mean No. of New or Enlarging T2 Lesions P< 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

Number of Patients at Risk Placebo Natalizumab Proportion With Sustained Progression Hazard Ratio (HR)=0.58 (95% CI: 0.43, 0.77) P= Placebo 29% Natalizumab 17% Weeks Sustained Disability Progression (Pre-specified Primary Endpoint)

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

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

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

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

Never ever give up hope !