ECTRIM Highlights 17 November 2012

Treatment highlights from ECTRIMS 2012

Gavin Giovannoni

Phase III TOWER study (teriflunomide) Kappos L, et al.

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

Phase II MS-STAT trial (high-dose simvastatin) Chataway J, et al.

• 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

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

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

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)

Variable Placebo (n = 70) Simvastatin (n = 70)

Total cholesterol (mmol/l) 5.64 (0.88) 5.51 (1.07)


– 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.

Variable Placebo (n = 70) Simvastatin (n = 70)

Total cholesterol (mmol/l) 5.64 (0.88) 5.51 (1.07)


– 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)

CUPID study (cannabis) Zajicek J, et al.

• 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

CUPID: EDSS progression over 3 years


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)

CUPID: EDSS progression according to

baseline EDSS score


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

)


Log rank test P = 0.01

CUPID: EDSS progression in patients with

baseline EDSS <6 (post-hoc analysis)


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

)


Treatment group

Placebo

Active

It is time to change the way we measure change:

demonstration, explanation, recommendation Hobart J, et al.

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

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

Phase IIa study (natalizumab) Romme Christensen J, et al.

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


SPMS

PPMSp=0.06

CS

F M

MP

9 n

g/m

l

NIND Mean

(limit of detection)

Phase2A study: change in CSF osteopontin

concentration (primary endpoint)


0

100

200

300

400

500

600

700

800


SPMS

PPMS

NIND Mean

+/- 95% CI

p=0.0004

CS

F O

ste

op

on

tin

ng

/ml

Phase 2A study: CSF markers of axonal damage

and demyelination (secondary endpoints)


0

500

1000

1500

2000

2500


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


SPMS

PPMSp=0.048

CS

F M

BP

ng

/ml

NIND Mean

+/- 95% CI

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

CARE-MS I trial (alemtuzumab) Cohen J, et al.

• 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

SELECT study (daclizumab) Giovannoni G, et al.

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)

ALLEGRO and BRAVO studies (laquinimod) Comi G, et al.

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

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%

Pooled analysis of ALLEGRO and BRAVO: risk

for 6-month confirmed disability progression


Hazard ratio = 0.54

P = 0 .0001


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%

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

Pooled analysis of ALLEGRO and BRAVO: brain

volume change from baseline to 24 months


Ch

an

ge f

rom

baselin

e (

%)


Placebo (n = 1006)

–1.188

–0.834

–1.6

–1.2

–0.8

–0.4

0.0

30% P < 0.0001

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

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

SELECTION trial (daclizumab HYP) Giovannoni G, et al.

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

SELECTION: confirmed disability progression

over 2 years


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%

SELECTION: confirmed disability progression

over 2 years


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)

Confirmed 3-month disability progression after

initiation of DAC HYP


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

SELECT trial (daclizumab HYP) Havrdova E, et al.

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

Do these two examples suggest that relapses

are not related to disease progression?






axonal plasticity &

remyelination


and gliosis

Gd-enhancement

T2 & T1 lesions



Clinical Attack

Disease Progression

Clinical Recovery

– biology


– biomarkers

focal inflammation

Is the current dogma wrong?

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

• 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






axonal plasticity &

remyelination


and gliosis

Gd-enhancement

T2 & T1 lesions



Clinical Attack

Disease Progression

Clinical Recovery

– biology


– biomarkers

focal inflammation







axonal plasticity &

remyelination


and gliosis

Gd-enhancement

T2 & T1 lesions



Clinical Attack

Disease Progression

Clinical Recovery

– biology


– biomarkers

focal inflammation

Virus?


From environment to MS

TOWER

Perron H, et al. ECTRIMS 2012. P470; Curtin F, et al. ECTRIMS 2012. P558.

• 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

ECTRIM Highlights 17 November 2012

Health & Medicine

Transcript of ECTRIM Highlights 17 November 2012