Managing Relapsing Remitting MS Risks & benefits of emerging therapies. Dr Mike Boggild The Walton Centre

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1 Managing Relapsing Remitting MS Risks & benefits of emerging therapies Dr Mike Boggild The Walton Centre

2 MS: Facts and figures Affects 1 in 800 in the UK Commonest cause of acquired neurological disability in young adults Approximately three times as common in women Increasing in women, why? Auto-immune disorder, no systemic manifestations Age range 10-60, peak at Natural history 30 years+, little impact on life expectancy for the majority

3 Risks vs benefits: entering the new era of MS therapeutics MS risk.. 50% out of work 5 years from diagnosis 30-40% require mobility aid 15 years from onset 40-50% will require wheelchair 90% will develop progressive neurological disability (Emerging) therapy risk 0.1% PML: Natalizumab 0.25% late leukaemia: Mitoxantrone

4 Disease evolution in MS Inflammation (relapses) Anti-inflammatory agents Axonal injury/demyelination (persistent relapse related disability) Axonal degeneration (progression) Repair strategies???? Neuro-protection?

5 MS spectrum Asymptomatic Definite MS Malignant MS Single episode demyelination Of uncertain prognosis

6 Markers of poor prognosis Relapses Frequent early Severe Motor (ataxia/weakness) Disability Early (within 5 years from onset) MRI 10 or more lesions

7 Predicting prognosis Miss NA, Age 30 3 relapses in 2 years from onset Motor involvement in attacks Minor residual disability (EDSS 1.5) at 2 years What is her risk (untreated) of needing a stick at 10 years (and a wheelchair by age 45-50)? 50)? 90%

8 Very active MS Relapsing remitting disease Frequent disabling relapses At presentation On 1 st line therapy Accumulating disability from relapses High MRI lesion load

9 Treatment should. Maximise recovery (from relapses) Optimum use of steroids Plasma exchange Rapidly suppress further disease activity (clinical/mri MRI) Prevent (delay) progressive disability Be safe.. Risks vs benefits

10 MS: first-line therapies Beta-interferon interferon s 10 years clinical experience Modest effect RRMS (30% relapse reduction) Limited disability data Time to onset 3 months? Glatiramer Acetate 8 years clinical experience Modest effect.. (30%..) Time to onset 6-99 months?

11 MS: Emerging therapies Natalizumab CAMPATH-1H Mitoxantrone

12 Natalizumab (Tysabri) Adhesion molecule blocker Monoclonal antibody Subject of largest clinical trials in MS to date AFFIRM, SENTINEL European licence July 2006 Currently under review by NICE Given by monthly IV infusion 15,000/annum (+infusion costs)

13 Natalizumab: 68% Reduction in Annualized Relapse Rate Placebo n= TYSABRI n=627 Annualized Relapse Rate (95% CI) P< % P< % 0.67 P< % 0.0 Years 0-2 Year 0-1 Year 1-2 Polman C, et al. Presented at the 57 th Annual Meeting of the American Academy of Neurology, April 12, AFFIRM Study

14 Natalizumab Relapses Reduced by 68% Onset of action within 12 weeks Disability 42% reduced risk of disability progession Safety Very well tolerated (patients felt well ) But. 3 cases of PML (in 3000)

15 /22 2 treatments 4 have had 3 treatments months after 2 nd treatment CAMPATH-1H: compassionate use 2 Relapses per 3 month epoch % reduction in relapse rate after Campath-1H Before treatment 2.21 relapses/ patient / year After treatment 10 investigator-confirmed episodes, 0.19 relapses/ patient / year (p<0.0001). Campath-1H treatments Months before and after Campath-1H Correct to 1 June 2004

16 Change in disability after Campath-1H. A) Annual change in disability from baseline after treatment in the secondary progressive cohort Change in EDSS from baseline B) Three-monthly change in disability from baseline after treatment in the relapsingremitting cohort Change in EDSS from baseline Years after Campath-1H Months after Campath-1H Correct to 1 June 2004

17 CAMPATH-1H Relapses 90% reduction (in aggressive MS) 75% reduction vs Interferon (Rebif( 44) Onset -?immediate Disability No long-term data yet (2007) Safety Rebound auto-immunity (thyroid/itp) Risks of long-term lymphopenia Cost: 500/annum (+monitoring)

18 Mitoxantrone Cytotoxic immunosuppressant (chemotherapy) Monthly infusions Cost ~ 500/annum (+monitoring) Relapses 70-90% reduction (Edan( Edan: : very active MS) Disability >50% reduction in progression (MIMS) Safety Cumulative cardiotoxicity (max years) Late Leukaemia (1 in 400)

19 The challenge is to use emerging, more effective, anti-inflammatory therapies to maximum benefit for our patients whilst minimising risk CAMPATH-1H Natalizumab Mitoxantrone

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21 Karen A, Age 24 Travel consultant May 02 L sensory/motor, diplopia IVMP July 02 Imbalance, diplopia, off legs Bed bound, spastic quad, vomiting INO, R facial palsy, NG fed IVMP (x2), long oral tail Mitoxantrone Aug 02 June 03 Total dose: 90mg (20 x3, 10 x3) GA from April 03 Overlap 4 months June 06 No further events, EDSS 0

22 Sequential Mitox/GA in very active RRMS

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24 UNKEMPT study (Mx Mx/GA vs Rebif 44) Inclusion criteria (enriching for high risk ) Disease duration <5 years EDSS relapses in last 2 years And 3 of 2 or more relapses in first 2 years from onset Residual disability from early attacks (EDSS >1.5) Motor features (pyramidal/ataxia) in early attacks 10 or more lesions on MR brain Primary outcomes Sustained EDSS progression MSIS-29 Secondary outcomes ARR 10 UK centres Including Sheffield! Currently randomising

25 In summary.. Tysabri (Natalizumab) 68% relapse reduction Sustained to 2 years Well tolerated Long-term risks uncertain (1:1000 PML?) CAMPATH 90% relapse reduction, annual treatment Auto-immunity, long-term? Mitoxantrone 90% relapse reduction Possibly sustained with GA Risk of serious adverse effect 1%?

26 Risks worth taking? Yes if if. Early aggressive anti-inflammatory inflammatory treatment prevents late disease progression/disability Currently a leap of faith We can identify poor prognosis MS with reasonable confidence before substantial residual disability Time is ripe for a paradigm shift in MS management