Defining the window of opportunity to treat ms
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Defining the window of opportunity to treat ms

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    Defining the window of opportunity to treat ms Defining the window of opportunity to treat ms Presentation Transcript

    • Defining the window of opportunity to treat MS? Gavin Giovannoni Barts and The London
    • Should multiple sclerosis be redefined as a dementia?
    • www.multiple-sclerosis-research.org
    • Definition of dementia Dementia is a loss of mental ability severe enough to interfere with normal activities of daily living, lasting more than six months, not present since birth, and not associated with a loss or alteration of consciousness. • Normal activities of daily living • Physical • Mental • Social • Occupational • Lasting more than six months • Not present since birth • Not associated with a loss or alteration of consciousness     
    • Social functioning Pfleger et al. Multiple Sclerosis 2010; 16(7) 878–882.
    • Occupational functioning Pfleger et al. Multiple Sclerosis 2010; 16(1) 121–126.
    • At what level of physical disability does unemployment occur? Kobelt et al. Neurol Neurosurg Psychiatry 2006;77:918–926.
    • 57% 7% -20% 0% 20% 40% 60% CISers n = 40 Feuillet et al. Mult Scler. 2007. Healthy Controls n = 30 p < 0.0001 Deficits were found mainly in memory, speed of information processing, attention and executive functioning. MSers failing ≥ 2 cognitive tests Cognition in early multiple sclerosis
    • Definition of dementia Dementia is a loss of mental ability severe enough to interfere with normal activities of daily living, lasting more than six months, not present since birth, and not associated with a loss or alteration of consciousness. • Normal activities of daily living • Physical • Mental • Social • Occupational • Lasting more than six months • Not present since birth • Not associated with a loss or alteration of consciousness        “Multiple sclerosis is therefore a dementia.”
    • What is the pathological substrate of MS dementia?
    • 11,000 to 1 Trapp, et al. NEJM 1998;338:278-85
    • Control Multiple sclerosis
    • Brain atrophy occurs across all stages of the disease De Stefano, et al. Neurology 2010 n= 963 MSers
    • Laquinimod: Percent of brain volume change from baseline to month 24 %ChangeFromBaseline -1.2 -0.4 -1.6 -0.8 Placebo (n = 1006) Laquinimod 0.6 mg (n = 984) 0 -1.188 -0.834 POOLED 30% P<0.0001 Vollmer T et al. Presented at 64th American Academy of Neurology Annual meeting, New Orleans 2012 Session S01.007
    • BRAVO: reduced rate of brain volume loss *Adjusted for baseline characteristics. Reference: 1. Vollmer T et al. Presented at: 5th Joint Triennial Congress of the European and Americas Committee for Treatment and Research in Multiple Sclerosis; October 19-22, 2011; Amsterdam, Netherlands. Abstract 148. Mult Scler. 2011;17:S507. 16 27.5% Reduction P<0.0001 -1.4 -1.2 -1 -0.8 -0.6 -0.4 -0.2 0 -27.4% Improvement P<0.0001 LAQUINIMOD 0.6mg PLACEBO -1.14% -0.83% Percent Brain Volume Change* (Months 0-24) -1.25% AVONEX® 30mcg +9% Deterioration P=0.14
    • Fingolimod has an early and sustained effect on the rate of brain atrophy compared with placebo and IFNb-1a IM FREEDOMS, 2 years Fingolimod 0.5 mg (n = 356) Placebo (n = 329) *** * ** 60 12 24 Time (months) 0 -0.4 -0.8 -1.2 -1.6 -2.0 −38% vs placebo p<0.001 ChangeinmeanBVfrom baseline(%) TRANSFORMS, 1 year 0 12 Time (months) 0.0 -0.4 -0.6 -1.0 IFNb-1a IM (n = 359) Fingolimod 0.5 mg (n = 368) −40% vs IFNb-1a IM p<0.001 ***-0.2 -0.8 ChangeinmeanBVfrom baseline(%) ITT population with evaluable MRI images. Note: n numbers for FREEDOMS data reflect the number of patients with available data at 24 months. *p<0.05; **p<0.01; ***p<0.001 vs comparator; p-values are for comparisons over Months 0-6, Months 0-12, Months 0-24 BV, brain volume; ITT, intent-to-treat. Gilenya™ Prescribing Information 19 April 2012. Reproduced with permission. Kappos L et al. N Engl J Med 2010; 362: 387-401, and Cohen JA et al. N Engl J Med 2010; 362: 402-415. Copyright © 2011 Massachusetts Medical Society. All rights reserved
    • Defining the window of opportunity to treat MS?
    • Coles et al. J Neurol. 2006 Jan;253(1):98-108. Post-inflammatory neurodegeneration
    • 21-year long-term follow-up of IFNb-1b study time from study randomization to death Early treatment (3 years) with IFNb-1b was associated with a 47% reduction in the risk of dying over 21 years compared with initial placebo treatment Goodin et al Neurology. 2012 Apr 24;78(17):1315-22. At risk: IFNB-1b 250 µg Placebo 124 123 124 120 121 117 118 109 104 88 HR=0.532 (95% CI: 0.314–0.902) 46.8% reduction in hazard ratio Log rank, P=0.0173 IFNB-1b 250 µg Placebo 65% 70% 75% 80% 85% 90% 95% 100% 0 2 4 6 8 10 12 14 16 18 20 22 Proportionofpatientswhoarestillalive Time (Years)
    • Theoretical model: treat early and effectively Natural course of disease Later intervention Later treatment Treatment at diagnosis Intervention at diagnosis Time Disease Onset Disability
    • Defining your treatment strategy?
    • survival analysis “hit hard and early ” MS is an autoimmune disease hypothesis 15-20 year experiment What is your treatment philosophy? maintenance-escalation vs. induction
    • Can you name me any diseases that you don’t treat early?
    • Time is Brain Conclusion
    • Definition of dementia Dementia is a loss of mental ability severe enough to interfere with normal activities of daily living, lasting more than six months, not present since birth, and not associated with a loss or alteration of consciousness. • Normal activities of daily living • Physical • Mental • Social • Occupational • Lasting more than six months • Not present since birth • Not associated with a loss or alteration of consciousness        “Multiple sclerosis is therefore a preventable dementia.”