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MS treatment and preservation of end-organ damage in MS
Gavin Giovannoni
Barts and The London
.
Thomas Blizard Curling 1811 – 1888
• Assistant-surgeon to The Royal London Hospital in 1883 and full surgeon in 1849
• President of the Royal College of Surgeons
• Seminal work on tetanus, winning the Jacksonian prize for his work
• Famous for his skill in treating diseases of the testes and rectum
ESRF end-stage renal failure
Does the brain fail in MS?
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
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
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Bra
in V
olu
me
(m
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Age (years)
Brain atrophy curves
Lower limit of normal
Average
Upper limit of normal
Hypothetical treatment effects
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Bra
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olu
me
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Age (years)
Brain atrophy curves
MS lower limit
MS Average
MS Upper limit
-5%
-30%
Hypothetical treatment effects
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.
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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
-1.0%
-0.8%
-0.6%
-0.4%
-0.2%
0.0% Years 0-2
-0.82%
-0.80%
P=0.822†
Placebo (N=315) Natalizumab (N=627)
Year 0-1* Year 1-2
-0.40%
-0.56%
-0.43%
-0.24%
P=0.004†
P=0.002†
†Difference between treatments; ‡Change from baseline; Miller DH et al. Neurology 2007;68:1390-1401.
AFFIRM Study: natalizumab and brain atrophy
Mea
n (
SE
) p
erc
en
tag
e c
ha
ng
e i
n B
PF
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-30%
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Bra
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olu
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L)
Age (years)
Brain atrophy curves
MS Average
Hypothetical treatment effects
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-20%
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Bra
in V
olu
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Age (years)
Brain atrophy curves
late treatment
Hypothetical treatment effects
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Bra
in V
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me
(m
L)
Age (years)
Brain atrophy curves
-5%
-18%
early treatment
late treatment
Hypothetical treatment effects
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Bra
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olu
me
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Age (years)
Brain atrophy curves
-5% -11%
early very
highly-effective
treatment
late very
highly-effective
treatment
-15%
Hypothetical treatment effects
Treatment Effect on Disability Strongly Predicted by Effect on T2 Lesion Volume and Brain Atrophy, Combined
Meta-analysis of treatment effect on EDSS worsening (y) vs effects on
MRI lesions and brain atrophy, individually or combined, in 13 placebo-
controlled RRMS trials (13,500 patients)
Sormani MP et al. Ann Neurol. 2014;75:43-49.
Defining the window of opportunity to treat MS?
Coles et al. J Neurol. 2006 Jan;253(1):98-108.
Post-inflammatory neurodegeneration
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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
liv
e
Time (Years)
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
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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
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.”
Stigmatizing
Stigmatizing
Brain Health
Active tablet
Placebo tablet
Year 1 Year 2 Year 3
600 MSers
300 MSers
300 MSers
Petzold et al. J Neurol Neurosurg Psychiatry. 2005 Feb;76(2):206-11.
Spinal fluid neurofilament levels
Axonal damage in relapsing MS is markedly reduced by natalizumab
Gunnarsson et al. Ann Neurol 2010; Epub.
=
Recruitment Trial Data analysis
6 months
6 months 60 MSers
6 months
LP1 LP2 LP3
30 MSers active tablet
30 MSers placebo tablet
2 years
6 months
600 MSers for 7 years 60 MSers for 2 years
3 LPs = 10x as many trials in a ⅓ of the time
13%
66%
21%
n = 127
MRI Events
1st clinical attack
Time (Years)
Subclinical disease
Inflammation
Brain volume loss
Neuroaxonal loss
Dis
eas
e S
eve
rity
SPMS RRMS
1st MRI lesion
Relapses
CIS RIS R-SPMS
RIS = radiologically isolated syndrome; CIS = clinically isolated syndrome, RRMS = relapsing-remitting MS; R-SPMS = relapsing secondary progressive MS; SPMS = secondary progressive MS; PPMS = primary progressive MS
SPMS: Natalizumab, Siponimod
Late SPMS: SMART STUDY ibudilast, amiloride, riluzole
Early SPMS: PROXIMUS oxcarbazepine
CIS: PHENYTOIN RRMS: ? DE-FLAMES STUDY
PPMS
PPMS: Fingolimod, Ocrelizumab, Laquinimod
MRI Events
1st clinical attack
Time (Years)
Subclinical disease
Inflammation
Brain volume loss
Neuroaxonal loss
Dis
eas
e S
eve
rity
SPMS RRMS
1st MRI lesion
Relapses
CIS RIS R-SPMS
RIS = radiologically isolated syndrome; CIS = clinically isolated syndrome, RRMS = relapsing-remitting MS; R-SPMS = relapsing secondary progressive MS; SPMS = secondary progressive MS; PPMS = primary progressive MS
SPMS: Natalizumab, Siponimod
Late SPMS: SMART STUDY ibudilast, amiloride, riluzole
Early SPMS: PROXIMUS oxcarbazepine
CIS: PHENYTOIN RRMS: ? DE-FLAMES STUDY
PPMS
PPMS: Fingolimod, Ocrelizumab, Laquinimod
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