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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 liv...
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 wer...
Definition of dementia
Dementia is a loss of mental ability severe enough to interfere with normal
activities of daily liv...
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 = ...
BRAVO: reduced rate of brain volume loss
*Adjusted for baseline characteristics.
Reference: 1. Vollmer T et al. Presented ...
Fingolimod has an early and sustained effect on the rate
of brain atrophy compared with placebo and IFNb-1a IM
FREEDOMS, 2...
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...
Theoretical model: treat early and effectively
Natural course
of disease
Later
intervention
Later
treatment
Treatment
at d...
Defining your
treatment strategy?
survival analysis
“hit hard and early ”
MS is an autoimmune
disease hypothesis
15-20 year
experiment
What is your treatmen...
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 liv...
Defining the window of opportunity to treat ms
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Transcript of "Defining the window of opportunity to treat ms"

  1. 1. Defining the window of opportunity to treat MS? Gavin Giovannoni Barts and The London
  2. 2. Should multiple sclerosis be redefined as a dementia?
  3. 3. www.multiple-sclerosis-research.org
  4. 4. 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     
  5. 5. Social functioning Pfleger et al. Multiple Sclerosis 2010; 16(7) 878–882.
  6. 6. Occupational functioning Pfleger et al. Multiple Sclerosis 2010; 16(1) 121–126.
  7. 7. At what level of physical disability does unemployment occur? Kobelt et al. Neurol Neurosurg Psychiatry 2006;77:918–926.
  8. 8. 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
  9. 9. 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.”
  10. 10. What is the pathological substrate of MS dementia?
  11. 11. 11,000 to 1 Trapp, et al. NEJM 1998;338:278-85
  12. 12. Control Multiple sclerosis
  13. 13. Brain atrophy occurs across all stages of the disease De Stefano, et al. Neurology 2010 n= 963 MSers
  14. 14. 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
  15. 15. 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
  16. 16. 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
  17. 17. Defining the window of opportunity to treat MS?
  18. 18. Coles et al. J Neurol. 2006 Jan;253(1):98-108. Post-inflammatory neurodegeneration
  19. 19. 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)
  20. 20. Theoretical model: treat early and effectively Natural course of disease Later intervention Later treatment Treatment at diagnosis Intervention at diagnosis Time Disease Onset Disability
  21. 21. Defining your treatment strategy?
  22. 22. 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
  23. 23. Can you name me any diseases that you don’t treat early?
  24. 24. Time is Brain Conclusion
  25. 25. 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.”
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