Download - ECTRIM Highlights 17 November 2012
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Treatment highlights from ECTRIMS 2012
Gavin Giovannoni
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Phase III TOWER study (teriflunomide) Kappos L, et al.
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0.501
0.389
0.319
0
0.1
0.2
0.3
0.4
0.5
0.6
Placebo(n = 388)
Teriflunomide7 mg
(n = 407)
Teriflunomide14 mg
(n = 370)
TOWER: annualized relapse rate
(primary endpoint)
RRR, relative risk reduction a Adjusted annualized relapse rate derived using a Poisson regression model with robust error variance Intent-to-treat population. Median duration of exposure: 581 days (placebo), 556 days (teriflunomide 7 mg) and 588 days (teriflunomide 14 mg). Kappa L, et al. ECTRIMS 2012. Oral presentation 153.
An
nu
ali
zed
rela
pse r
ate
a
RRR: 22.3%
P = 0.0183
RRR: 36.3%
P = 0.0001
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Phase II MS-STAT trial (high-dose simvastatin) Chataway J, et al.
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• Then repeat and screening scans are registered using a 12dof affine registration
– Linear transformation (rotation, translation, scaling and shear) to spatially align repeat scan to the
baseline scan
• This registration step allows for the automatic quantification of longitudinal changes with
the BSI (Boundary Shift Integral)
Freeborough PA & Fox NC. EEE Trans Med Imaging 1997; 16:623–9.
Segmentation
Whole brain segmentation in Native Space
3D rendered image
Whole brain volumes generated
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MS-STAT: BBSI change in whole brain volume
(primary outcome)
BBSI, brain boundary shift integral a Adjusting for minimisation variables and MRI site Chataway J, et al. ECTRIMS 2012. Oral presentation 38a.
Mean (SD)
placebo
Mean (SD)
simvastatin
Difference in
means
(95% CI)a
P value
Change in WBV
(%/year)
0.589 (0.528) 0.298
(0.562)
–0.254
(–0.423 to –0.085)
0.003
Number of patients
evaluated
64 66
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MS-STAT: change in whole brain volume
Chataway J, et al. ECTRIMS 2012. Oral presentation 38a.
Ch
an
ge W
BV
%/y
ear
Mean Individual values
3
2
1
0
–2
–1
0 to 12 months 12 to 25 months 0 to 25 months
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MS-STAT secondary outcomes: disability
Model adjusting for minimisation variables and baseline Chataway J, et al. ECTRIMS 2012. Oral presentation 38a.
Outcome Mean (SD) placebo
Mean (SD) simvastatin
Difference in means (95% CI)
EDSS (score 0 to 10)
6.35 (0.83) 5.93 (1.11) –0.254 (–0.464 to –0.069)
MSIS total (score 29 to 116)
76.1 (16.3) 70.1 (15.6) –4.78 (–9.39 to –0.02)
MSIS physical (score 20 to 80)
56.3 (11.8) 51.7 (11.4) –3.73 (–7.18 to –0.28)
MSIS psychological (score 9 to 36)
19.8 (6.0) 18.3 (5.8) –1.09 (–2.83 to 0.84)
MSFC Z score -1.21 (2.59) -0.78 (2.06) 0.289 (–0.333 to 0.961)
MSFC walk (speed ft/s)
1.55 (1.19) 1.83 (1.61) 0.085 (–0.249 to 0.533)
MSFC peg test (1/s)
0.030 (0.014) 0.033 (0.010) 0.002 (–0.001 to 0.004)
MSFC PASAT (score 0 to 60)
35.2 (18.0) 38.3 (15.4) 4.45 (–0.11 to 8.84)
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Variable Placebo (n = 70) Simvastatin (n = 70)
Total cholesterol (mmol/l) 5.64 (0.88) 5.51 (1.07)
EDSS (score 0 to 10)
– Median (range)
– Mean (SD)
6 (4 to 7)
5.87 (0.78)
6 (4 to 6.5)
5.75 (0.84)
MSIS total (score 29 to 116) 70.0 (14.5) 70.2 (14.0)
MSIS physical (score 20 to 80) 51.2 (10.4) 51.4 (10.6)
MSIS psychological (score 9 to 36) 18.8 (5.7) 18.9 (5.2)
MSFC Z score -0.29 (1.48) -0.03 (0.92)
MSFC walk (speed ft/s) 1.50 (0.87) 1.67 (0.91)
MSFC peg test (speed 1/s) 0.033 (0.010) 0.034 (0.009)
MSFC PASAT (score 0 to 60) 33.7 (16.1) 34.8 (13.8)
Participant characteristics
Values are mean (standard deviation) unless otherwise stated Chataway J, et al. ECTRIMS 2012. Oral presentation 38a.
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Variable Placebo (n = 70) Simvastatin (n = 70)
Total cholesterol (mmol/l) 5.64 (0.88) 5.51 (1.07)
EDSS (score 0 to 10)
– Median (range)
– Mean (SD)
6 (4 to 7)
5.87 (0.78)
6 (4 to 6.5)
5.75 (0.84)
MSIS total (score 29 to 116) 70.0 (14.5) 70.2 (14.0)
MSIS physical (score 20 to 80) 51.2 (10.4) 51.4 (10.6)
MSIS psychological (score 9 to 36) 18.8 (5.7) 18.9 (5.2)
MSFC Z score -0.29 (1.48) -0.03 (0.92)
MSFC walk (speed ft/s) 1.50 (0.87) 1.67 (0.91)
MSFC peg test (speed 1/s) 0.033 (0.010) 0.034 (0.009)
MSFC PASAT (score 0 to 60) 33.7 (16.1) 34.8 (13.8)
Participant characteristics
Values are mean (standard deviation) unless otherwise stated Chataway J, et al. ECTRIMS 2012. Oral presentation 38a.
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Variable Placebo (n = 70) Simvastatin (n = 70)
Total cholesterol (mmol/l) 5.64 (0.88) 5.51 (1.07)
EDSS (score 0 to 10)
– Median (range)
– Mean (SD)
6 (4 to 7)
5.87 (0.78)
6 (4 to 6.5)
5.75 (0.84)
MSIS total (score 29 to 116) 70.0 (14.5) 70.2 (14.0)
MSIS physical (score 20 to 80) 51.2 (10.4) 51.4 (10.6)
MSIS psychological (score 9 to 36) 18.8 (5.7) 18.9 (5.2)
MSFC Z score -0.29 (1.48) -0.03 (0.92)
MSFC walk (speed ft/s) 1.50 (0.87) 1.67 (0.91)
MSFC peg test (speed 1/s) 0.033 (0.010) 0.034 (0.009)
MSFC PASAT (score 0 to 60) 33.7 (16.1) 34.8 (13.8)
Participant characteristics
Values are mean (standard deviation) unless otherwise stated Chataway J, et al. ECTRIMS 2012. Oral presentation 38a.
EDSS
(score 0 to 10) 6.35 (0.83) 5.93 (1.11) –0.254 (–0.464 to –0.069)
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CUPID study (cannabis) Zajicek J, et al.
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• To assess the value of Δ9-THC in slowing progressive MS over
3 years
• To assess the safety of Δ9-THC over the long term
• To improve research methodology by using new, patient-orientated
methods
Zajicek J, et al. ECTRIMS 2012. Oral presentation 161X.
CUPID: aims
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CUPID: EDSS progression over 3 years
Zajicek J, et al. ECTRIMS 2012. Oral presentation 161X.
Treatment group
Placebo
Active
0.0
0.2
0.4
0.6
0.8
1.0
0 200 400 600 800 1000 1200
P (
ED
SS
pro
gre
ss
ion
)
Time to EDSS progression (days)
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CUPID: EDSS progression according to
baseline EDSS score
Zajicek J, et al. ECTRIMS 2012. Oral presentation 161X.
Baseline EDSS score
6.5
5 5.5
4.5 4
6
0.0
0.2
0.4
0.6
0.8
1.0
0 200 400 600 800 1000 1200
P (
ED
SS
pro
gre
ss
ion
)
Time to EDSS progression (days)
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Log rank test P = 0.01
CUPID: EDSS progression in patients with
baseline EDSS <6 (post-hoc analysis)
Zajicek J, et al. ECTRIMS 2012. Oral presentation 161X.
n = 110
0.0
0.2
0.4
0.6
0.8
1.0
0 200 400 600 800 1000 1200
P (
ED
SS
pro
gre
ss
ion
)
Time to EDSS progression (days)
Treatment group
Placebo
Active
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It is time to change the way we measure change:
demonstration, explanation, recommendation Hobart J, et al.
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1. Delayed Progression 2. Stabilised Progression
3. Improved Function 4. Recovered Function
What are your expectations of a therapy for
progressive MS?
www.ms-res.org
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What are your expectations of a therapy for
progressive MS?
www.ms-res.org
20%
44%
18%
18%
0% 10% 20% 30% 40% 50%
Slowed
Stable
Improvement
Recovery
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Phase IIa study (natalizumab) Romme Christensen J, et al.
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Phase 2A study: CSF markers of inflammation
(secondary endpoints)
Romme Christensen J, et al. ECTRIMS 2012. Oral presentation 170.
0
50
100
150
200
Baseline 60 weeksNatalizumab
SPMS
PPMS
NIND Mean
+/- 95% CI
p=0.02
CS
F C
XC
L13 p
g/m
l
0.0
0.5
1.0
1.5
Baseline 60 weeksNatalizumab
SPMS
PPMSp=0.06
CS
F M
MP
9 n
g/m
l
NIND Mean
(limit of detection)
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Phase2A study: change in CSF osteopontin
concentration (primary endpoint)
Romme Christensen J, et al. ECTRIMS 2012. Oral presentation 170.
0
100
200
300
400
500
600
700
800
Baseline 60 weeksNatalizumab
SPMS
PPMS
NIND Mean
+/- 95% CI
p=0.0004
CS
F O
ste
op
on
tin
ng
/ml
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Phase 2A study: CSF markers of axonal damage
and demyelination (secondary endpoints)
Romme Christensen J, et al. ECTRIMS 2012. Oral presentation 170.
0
500
1000
1500
2000
2500
Baseline 60 weeksNatalizumab
SPMS
PPMS
NIND Mean
+/- 95% CI
p=0.03
CS
F N
eu
rofi
lam
en
t ll
igh
t n
g/L
0.0
0.5
1.0
1.5
2.0
2.5
Baseline 60 weeksNatalizumab
SPMS
PPMSp=0.048
CS
F M
BP
ng
/ml
NIND Mean
+/- 95% CI
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Current dogma
immune activation innate and
adaptive responses BBB breakdown
oligodendrocyte toxicity & demyelination
Acute axonal transection and loss
“autoimmune endophenotype”
axonal plasticity &
remyelination
delayed neuroaxonal loss
and gliosis
Gd-enhancement
T2 & T1 lesions
brain & spinal cord atrophy
release of soluble markers
Clinical Attack
Disease Progression
Clinical Recovery
– biology
– clinical outcomes
– biomarkers
focal inflammation
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CARE-MS I trial (alemtuzumab) Cohen J, et al.
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• A significantly greater proportion of patients were disease-free with
alemtuzumab vs. IFN β-1a SC in CARE-MS I
a Defined as absence of relapse or SAD. b Defined as absence of clinical disease activity or MRI activity. Cohen J, et al. Lancet 2012; 31 Oct [Epub ahead of print].
CARE-MS I: proportion of patients free of
clinical disease and MRI activity at 24 months P
ati
en
ts (
%)
56
27
42
81 74
39
56
93
0
10
20
30
40
50
60
70
80
90
100
Clinical disease activity-freeᵃ
MS disease activity-freeᵇ
No new orenlarging
T2-hyperintenselesions
No Gd-enhancinglesions
IFN β-1a SC Alemtuzumab 12 mg/day
P < 0.0001
P < 0.0001
P = 0.0064
P = 0.04
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SELECT study (daclizumab) Giovannoni G, et al.
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SELECT: proportion of patients free of disease
activity at Week 52
CI, confidence interval; DAC HYP, daclizumab high-yield process; OR, odds ratio. Giovannoni G, et al. ECTRIMS 2012. P921.
11%
39%
0
5
10
15
20
25
30
35
40
45
Placebo(n = 196)
DAC HYP(n = 404)
Dis
ease
-acti
vit
y f
ree (
%)
P < 0.0001
OR: 6.18 (95% CI, 3.71–10.32)
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ALLEGRO and BRAVO studies (laquinimod) Comi G, et al.
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Pooled analysis of ALLEGRO and BRAVO
Phase III trials: annualized relapse rate
a AAR analysis was a baseline adjusted Quasi-likelihood Poisson regression analysis, including baseline EDSS score, log of prior 2 year relapse rate + 1 and country or geographic region as covariates Vollmer T, et al. AAN 2012. S01.007.
21% reduction
in annualized
relapse rates
(P = 0.0005)
0.38
0.3
0
0.1
0.2
0.3
0.4
Placebo Laquinimod
Ad
juste
d A
AR
a
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0%
5%
10%
15%
20%
Day 0 Day 100 Day 200 Day 300 Day 400 Day 500 Day 600 Day 700
Pooled analysis of ALLEGRO and BRAVO: risk
for 3-month confirmed disability progression
Vollmer T, et al. AAN 2012. S01.007.
Hazard ratio = 0.658
P = 0.0017
% o
f p
ati
en
ts w
ith
co
nfi
rme
d
pro
gre
ss
ion
at
3 m
on
ths
Laquinimod 0.6 mg (n = 984)
Placebo (n = 1006)
34.2%
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Pooled analysis of ALLEGRO and BRAVO: risk
for 6-month confirmed disability progression
Vollmer T, et al. AAN 2012. S01.007.
Hazard ratio = 0.54
P = 0 .0001
Laquinimod 0.6 mg (n = 984)
Placebo (n = 1006)
% o
f p
ati
en
ts w
ith
co
nfi
rme
d
pro
gre
ss
ion
at
6 m
on
ths
0%
5%
10%
15%
20%
Day 0 Day 100 Day 200 Day 300 Day 400 Day 500 Day 600 Day 700
46%
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ALLEGRO: confirmed disability progression
for patients completing 1 year in OLE
OLE, open-label extension Comi G, et al. ECTRIMS 2012. P156.
0%
5%
10%
15%
20%
25%
30%
Days 0 Days 150 Days 300 Days 450 Days 600 Days 750 Days 900 Days 1050
Delayed Start Early Start
Pati
en
ts (
%)
Time to progression (days)
Delayed start n = 363 346 337 321 316 308 298 293
Early start n = 372 365 362 358 347 337 337 330
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Pooled analysis of ALLEGRO and BRAVO: brain
volume change from baseline to 24 months
Vollmer T, et al. AAN 2012. S01.007.
Ch
an
ge f
rom
baselin
e (
%)
Laquinimod 0.6 mg (n = 984)
Placebo (n = 1006)
–1.188
–0.834
–1.6
–1.2
–0.8
–0.4
0.0
30% P < 0.0001
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BRAVO: brain volume change from baseline to
24 monthsa
–1.14%
–0.82%
–1.24%
–1.4
–1.2
–1.0
–0.8
–0.6
–0.4
–0.2
0.0
Laquinimod
0.6 mg
Placebo IFN β-1a IM
30 mcg
a Adjusted for baseline characteristics. Vollmer T, et al. ECTRIMS 2011. Oral presentation 148.
Ch
an
ge f
rom
baselin
e (
%)
–27.4%
improvement
P < 0.0001 +9%
deterioration
P = 0.14
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FREEDOMS: overview of placebo-controlled data
a Log-rank test comparing the survival distributions between treatment groups. b Cox proportional hazard model adjusted for treatment, country, baseline EDSS and age. Significant change in the rate of brain atrophy vs placebo. Rank ANCOVA adjusted for treatment group, country and baseline normalized brain volume. Kappos L et al. N Engl J Med 2010; 362:387–401.
0.4
0.18
0
0.1
0.2
0.3
0.4
Placebo
(n = 418)
Fingolimod0.5 mg
(n = 425)
54% relative
reduction
P < 0.001
Time to first progression (days)
Pa
tie
nts
wit
h E
DS
S
pro
gre
ss
ion
co
nfi
rme
d
aft
er
6 m
on
ths
(%
)
Significant reduction in risk of 6-month
confirmed disability progression
37% risk
reduction
30
25
20
15
10
5
0
0 90 180 270 360 450 540 630 720
19.0%
12.5%
Placebo Fingolimod 0.5 mg
(HR: 0.63; P = 0.012)a,b
FREEDOMS: 2-year results
Me
an
ch
an
ge
in
bra
in
vo
lum
e f
rom
bas
eli
ne (
%)a
Time (months)
–1.4
–1.2
–1.0
–0.8
–0.6
–0.4
–0.2
0
0 6 12 24
–1.31
–0.84
Placebo (n = 329)
Fingolimod 0.5 mg (n = 356)
P = 0.006
P = 0.03
P < 0.001
*
*
*
P = 0.001
38%
relative
reduction
An
nu
ali
ze
d r
ela
ps
e r
ate
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SELECTION trial (daclizumab HYP) Giovannoni G, et al.
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An
nu
ali
zed
rela
pse r
ate
SELECTION: annualized relapse rate during
years 1 and 2
Giovannoni G, et al. ECTRIMS 2012. Oral presentation 169.
0.434 (0.347, 0.544)
0.148 (0.096, 0.229)
0.165 (0.105, 0.260)
0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
0.4
0.45
0.5
Placebon = 163
DAC HYPn = 129
DAC HYPn = 1292
Year 2 Year 1 Year 1
Year 2 of DAC HYP
62% reduction vs.
SELECT pbo
Year 1 of DAC HYP
66% reduction vs.
SELECT pbo
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SELECTION: confirmed disability progression
over 2 years
Giovannoni G, et al. ECTRIMS 2012. Oral presentation 169.
Pro
po
rtio
n o
f p
ati
en
ts w
ith
co
nfi
rme
d
dis
ab
ilit
y p
rog
res
sio
n
Time on study (months)
DAC HYP after placebo
DAC HYP continues
Placebo
6%
0.3
0.2
0.1
0.0
0 3 6 9 12 15 18 21 24
DAC HYP Placebo
13%
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SELECTION: confirmed disability progression
over 2 years
Giovannoni G, et al. ECTRIMS 2012. Oral presentation 169.
Pro
po
rtio
n o
f p
ati
en
ts w
ith
co
nfi
rme
d
dis
ab
ilit
y p
rog
res
sio
n
Time on study (months)
DAC HYP after placebo
DAC HYP continues
Placebo
Placebo patients start
DAC HYP
DAC HYP 16%
6%
0.3
0.2
0.1
0.0
0 3 6 9 12 15 18 21 24
12% DAC HYP
DAC HYP Placebo
13%
50% risk reduction
(95% CI 12-71%; P=0.015)
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Confirmed 3-month disability progression after
initiation of DAC HYP
Giovannoni G, et al. ECTRIMS 2012. Oral presentation 169.
17 subjects
with progression
7 subjects
with progression Pati
en
ts w
ith
co
nfi
rmed
dis
ab
ilit
y
pro
gre
ss
ion
(%
)
10%
5%
0%
2%
4%
6%
8%
10%
12%
Placebon = 1632
DAC HYPn = 1632
Year 2 Year 1
Reduction = 50% P = 0.033
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SELECT trial (daclizumab HYP) Havrdova E, et al.
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SELECT: confirmed disability progression in patients
who did and did not experience a disabling relapse
Havrdova E, et al. ECTRIMS 2012. Oral presentation 949.
Pati
en
ts w
ith
3-m
on
th
co
nfi
rmed
dis
ab
ilit
y p
rog
ress
ion
(%
)
6%
2%
7%
4%
0
5
10
15
20
Placebo(n = 196)
DAC HYP(n = 404)
Disabling relapse
No disabling relapse
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Do these two examples suggest that relapses
are not related to disease progression?
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immune activation innate and
adaptive responses BBB breakdown
oligodendrocyte toxicity & demyelination
Acute axonal transection and loss
“autoimmune endophenotype”
axonal plasticity &
remyelination
delayed neuroaxonal loss
and gliosis
Gd-enhancement
T2 & T1 lesions
brain & spinal cord atrophy
release of soluble markers
Clinical Attack
Disease Progression
Clinical Recovery
– biology
– clinical outcomes
– biomarkers
focal inflammation
Is the current dogma wrong?
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immune activation innate and
adaptive responses BBB breakdown
oligodendrocyte toxicity & demyelination
Acute axonal transection and loss
“autoimmune endophenotype”
axonal plasticity &
remyelination
delayed neuroaxonal loss
and gliosis
Gd-enhancement
T2 & T1 lesions
brain & spinal cord atrophy
release of soluble markers
Clinical Attack
Disease Progression
Clinical Recovery
– biology
– clinical outcomes
– biomarkers
focal inflammation
Is the current dogma wrong?
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Post-inflammatory neurodegeneration
Coles A, et al. J Neurol 2006; 253:98–108.
Change in EDSS from baseline Change in EDSS from baseline
Years after Campath-1H Months after Campath-1H
5.0
3.0
1.0
–1.0
–3.0
–5.0
–7.0
0 6 12 18
24 30 36
0 2 4 6 8 16
5.0
3.0
1.0
–1.0
–3.0
–5.0
–7.0
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• In CARE-MS I, there was no significant difference between treatments on
EDSS-based endpoints2
a Defined as a decrease of at least 1 EDSS point lasting at least 6 months, assessed in patients with a baseline EDSS ≥ 2.0. 1. Coles A, et al. Lancet 2012; 31 Oct [Epub ahead of print]. 2. Cohen J, et al. Lancet 2012; 31 Oct [Epub ahead of print].
CARE-MS II: alemtuzumab disability
improvement
Sustained reduction in
disability (SRD)a1
Mean EDSS change from
baseline1
Pa
tien
ts w
ith
SR
D (
%)
Follow-up Month
Hazard ratio: 2.57
p = 0.0002
29%
13% ‒0.17
p = 0.0044
p < 0.0001
0.24
p = 0.0064
Me
an
ED
SS
Sc
ore
Follow-up Month
Alemtuzumab 12 mg
IFN β-1a SC
IFN β-1a SC
Alemtuzumab 12 mg
40
30
20
10
0
0 3 6 9 12 15 18 21 24
3.25
3.00
2.75
2.50
2.25
0 3 6 9 12 15 18 21 24
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immune activation innate and
adaptive responses BBB breakdown
oligodendrocyte toxicity & demyelination
Acute axonal transection and loss
“autoimmune endophenotype”
axonal plasticity &
remyelination
delayed neuroaxonal loss
and gliosis
Gd-enhancement
T2 & T1 lesions
brain & spinal cord atrophy
release of soluble markers
Clinical Attack
Disease Progression
Clinical Recovery
– biology
– clinical outcomes
– biomarkers
focal inflammation
Is the current dogma wrong?
![Page 50: ECTRIM Highlights 17 November 2012](https://reader033.vdocument.in/reader033/viewer/2022042613/54920d02ac795916288b46b2/html5/thumbnails/50.jpg)
immune activation innate and
adaptive responses BBB breakdown
oligodendrocyte toxicity & demyelination
Acute axonal transection and loss
“autoimmune endophenotype”
axonal plasticity &
remyelination
delayed neuroaxonal loss
and gliosis
Gd-enhancement
T2 & T1 lesions
brain & spinal cord atrophy
release of soluble markers
Clinical Attack
Disease Progression
Clinical Recovery
– biology
– clinical outcomes
– biomarkers
focal inflammation
Virus?
Is the current dogma wrong?
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immune activation innate and
adaptive responses BBB breakdown
oligodendrocyte toxicity & demyelination
Acute axonal transection and loss
“autoimmune endophenotype”
axonal plasticity &
remyelination
delayed neuroaxonal loss
and gliosis
Gd-enhancement
T2 & T1 lesions
brain & spinal cord atrophy
release of soluble markers
Clinical Attack
Disease Progression
Clinical Recovery
– biology
– clinical outcomes
– biomarkers
focal inflammation
Virus?
Is the current dogma wrong?
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From environment to MS
TOWER
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Perron H, et al. ECTRIMS 2012. P470; Curtin F, et al. ECTRIMS 2012. P558.
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Perron H, et al. ECTRIMS 2012. P470; Curtin F, et al. ECTRIMS 2012. P558.
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• Has the emergence of monoclonal therapies cracked relapsing disease?
– How do we define a cure?
– Is DAF status the new treatment aim?
• Progressive MS remains a problem
– The challenge is doing affordable Phase II and III trials
– Do we need new outcome measures (including CSF)?
• How do relapses and progression relate to each other?
– Are the laquinimod and daclizumab results trying to tell us something?
• Is the dogma wrong?
– Does MS need a paradigm shift?
• We need a holistic approach to MS
– MS is a life-long disease with many problems that need to be solved
Conclusions