Defining the window of opportunity to treat ms
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Transcript of Defining the window of opportunity to treat ms
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Defining the window of opportunity to treat MS?
Gavin Giovannoni
Barts and The London
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Should multiple sclerosis be redefined as a dementia?
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www.multiple-sclerosis-research.org
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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
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Social functioning
Pfleger et al. Multiple Sclerosis 2010; 16(7) 878–882.
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Occupational functioning
Pfleger et al. Multiple Sclerosis 2010; 16(1) 121–126.
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At what level of physical disability does unemployment occur?
Kobelt et al. Neurol Neurosurg Psychiatry 2006;77:918–926.
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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
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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.”
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What is the pathological substrate of MS dementia?
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11,000 to 1
Trapp, et al. NEJM 1998;338:278-85
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Control Multiple sclerosis
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Brain atrophy occurs across all stages of the disease
De Stefano, et al. Neurology 2010
n= 963 MSers
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Laquinimod: Percent of brain volume
change from baseline to month 24
% C
ha
ng
e F
rom
Ba
se
line
-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
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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
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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)
***
* **
6 0 12 24
Time (months)
0
-0.4
-0.8
-1.2
-1.6
-2.0
−38%
vs placebo p<0.001
Ch
ange
in m
ean
BV
fro
m
bas
elin
e (%
)
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
Ch
ange
in m
ean
BV
fro
m
bas
elin
e (%
)
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
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Defining the window of opportunity to treat MS?
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Coles et al. J Neurol. 2006 Jan;253(1):98-108.
Post-inflammatory neurodegeneration
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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
Pro
po
rtio
n o
f p
ati
en
ts w
ho
are
sti
ll a
live
Time (Years)
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Theoretical model: treat early and effectively
Natural course of disease
Later intervention
Later treatment
Treatment at diagnosis Intervention
at diagnosis
Time Disease Onset
Dis
abili
ty
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Defining your treatment strategy?
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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
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Can you name me any diseases that you don’t treat early?
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Time is Brain
Conclusion
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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.”