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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 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
% 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
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)
***
* **
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
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
Pro
po
rtio
n o
f p
ati
en
ts w
ho
are
sti
ll a
live
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
Dis
abili
ty
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.”