Progression - what to do ?
Dr Ben Turner
Acronyms used in this talk:
RRMS = Relapsing Remitting MS
SPMS = Secondary Progressive MS
PPMS = Primary Progressive MS
CIS= Clinically Isolated Syndrome
GD = gadolinium enhancing lesions
T2 lesions = T2 lesions on MRI scans
SAD = Sustained accumulation of disability
PPMS
increasing disability
SPMS
increasing disability
increasing disability
increasing disability
increasing disability
RRMS
increasing disability
(A)
time
(B)
time
time
(C)
(D)
time
(E)
time
(F)
time
Treatments focus on early stage of inflammation
3
© Novartis Pharma
•RRMS: relapsing remitting multiple sclerosis; SPMS: secondary progressive multiple sclerosis
•Barten LJ et al Drug Des Devel Ther 2010;4:343-66
MUL12-E002
Date of preparation November 2012
Demyelination and Axonal Degeneration in MS
Waxman S. NEJM 338, 5, 323
The Evolution of MS
Pre-clinical
RRMS
CIS
SPMS
First clinical
event
Clinical
Threshold
Total lesion load
MRI Activity
Number of lesions
20-year follow-up Results: Serial median T2 Lesion Load (cm3)
Median T2 lesion volume (cm3) over time for patient groups
SPMS
60
Numbers of patients
RRMS
T2Lesion Volume
CIS
40
11
13
14
17
20
33
20
26
26
0
27
0
28
25
18
15
30
21
5
10
14
20
Year
Estimated rate of lesion growth in SPMS = 2.89 cm3/year
Estimated rate of lesion growth in RRMS = 0.80 cm3/year (p<0.001)
Fisniku LK et al. Unpublished
European Charcot Foundation Satellite Symposium, ECTRIMS, Prague 11/10/2007
Is the rate of progression the same
for all patients ?
Subgroup 1
Subgroup 2
Subgroup 3
7
6
DSS Score
5
4
3
2
1
0
0
5
10
15
20
25
Time from MS clinical onset (years)
30
35
Control
Multiple sclerosis
Brain atrophy occurs across all stages
n= 963 pwMS
De Stefano, et al. Neurology 2010
interferon
alemtuzumab
Therapeutic Lag
Tur et al. Interferon Beta-1b for the Treatment of Primary Progressive Multiple Sclerosis:
Five-Year Clinical Trial Follow-up. Arch Neurol. 2011 Nov;68(11):1421-7.
MS-STAT trial - High dose oral Simvastatin in
Secondary Progressive Multiple Sclerosis in
whole brain volume (%/year)
Mean (SD)
placebo
Mean (SD)
simvastatin
Difference in means
(95% CI)*
p-value
Change WBV (%/year)
0.589
(0.528)
0.298
(0.562)
-0.254
(-0.423 to -0.085)
0.003
Number patients evaluated
64
66
*Adjusting for minimisation variables and MRI site
Kapoor, et al. Lancet 2010
The Asynchronous Progressive MS hypothesis
Diagnosis of Progressive MS
Therapeutic window 1
Therapeutic window 2
Therapeutic window 3
Therapeutic window 4
Bladder
Motor system to legs
Cerebellar or balance systems
Sensory
Therapeutic window 5
Upper limbs
Therapeutic window 6
Cognition
Therapeutic window 7
Therapeutic window 8, etc….
Vision
Etc.
Effective DMTs could still target the remaining windows
of therapeutic opportunity for individual neurological
systems
PPMS
RIS
RRMS
CIS
R-SPMS
SPMS
Disease Severity
Inflammation
Neuroaxonal loss
Subclinical
disease
Brain volume loss
1st clinical
attack
Relapses
1st MRI
lesion
MRI Events
Time (Years)
PPMS: Fingolimod, Ocrelizumab, Laquinimod
SPMS: Natalizumab, Siponimod, DMF
CIS: PHENYTOIN
RRMS:
Multiple Studies
Early SPMS: PROXIMUS
oxcarbazepine
Late SPMS: SMART STUDY
ibudilast, amiloride, riluzole
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
Thank You
Ben Turner