Treatment Highlights ECTRIMS 2012

Treatment Highlights

Gavin Giovannoni

Barts and The London School of Medicine and Dentistry

TOWER

The efficacy and safety of teriflunomide in patients with relapsing MS: results from TOWER, a Phase III placebo-controlled study

Ludwig Kappos,1 Giancarlo Comi,2 Christian Confavreux,3 Mark S. Freedman,4 Aaron E. Miller,5 Tomas P. Olsson,6

Jerry S. Wolinsky,7 Teresa Bagulho,8 Jean-Luc Delhay,9 Yan Zheng,8 Philippe Truffinet9 and Paul O’ Connor10

NCT00751881

1University Hospital Basel, Basel, Switzerland; 2University Vita-Salute San Raffaele, Milan, Italy; 3Université Claude Bernard Lyon 1, Lyon, France; 4University of Ottawa, Ottawa, ON, Canada; 5Mount Sinai School of Medicine, New York, NY, USA; 6Karolinska Institute, Stockholm, Sweden; 7University of Texas Health Science Center, Houston, TX, USA; 8Genzyme, a Sanofi company, Bridgewater, NJ, USA; 9Genzyme, a Sanofi company, Chilly Mazarin, France; 10University of Toronto, Toronto, ON, Canada

#1

TOWER TOWER

3

0.501

0.389

0.319

0

0.1

0.2

0.3

0.4

0.5

0.6

Placebo(n=388)

Teriflunomide 7 mg(n=407)

Teriflunomide 14 mg(n=370)

RRR: 22.3% p=0.0183

RRR: 36.3% p=0.0001

An

nu

alis

ed

re

lap

se r

ate

*

Annualised relapse rate

*Adjusted annualised 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) RRR, relative risk reduction

Primary endpoint

Epstein Bar Virus

Genetics

Vitamin D

Smoking

Risks

Adverse events

Differential Diagnosis

MRI

Evoked Potentials

Lumbar puncture

Blood Tests

Diagnostic Criteria

Cognition

Depression

Fatigue

Bladder

Bowel

Sexual dysfunction Tremor

Pain Swallowing

Spasticity Falls

Balance problems Insomnia

Restless legs Fertility

Clinical trials

Gait

Pressure sores

Oscillopsia

Emotional lability

Seizures

Gastrostomy

Rehab

Suprapubic catheter

Intrathecal baclofern

Physio- therapy

Speech therapy

Occupational Therapy

Functional neurosurgery

Colostomy

Tendonotomy

Studying

Employment Relationships

Travel

Vaccination

Anxiety

Driving

Nurse specialists

Counselling

Family counselling

Relapses

1st line

2nd line

Maintenance Escalation Induction

Monitoring

Disease-free

Disease progression

DMTs

Side Effects

Advanced Directive

Exercise

Diet

Alternative Medicine

Pregnancy Breast Feeding

Research

Insurance

Vision

Palliative Care

Assisted suicide

Social services

Legal aid Family counselling

Prevention

Diagnosis

DMT Symptomatic

Therapist

Terminal

Counselling

Epstein Bar Virus

Genetics

Vitamin D

Smoking

Risks

Adverse events


MRI

Evoked Potentials

Lumbar puncture

Blood Tests

Diagnostic Criteria

Cognition

Depression

Fatigue

Bladder

Bowel


Pain Swallowing

Spasticity Falls



Clinical trials

Gait

Pressure sores

Oscillopsia

Emotional lability

Seizures

Gastrostomy

Rehab

Suprapubic catheter


Physio- therapy

Speech therapy



Colostomy

Tendonotomy

Studying


Travel

Vaccination

Anxiety

Driving

Nurse specialists

Counselling

Family counselling

Relapses

1st line

2nd line


Monitoring

Disease-free

Disease progression

DMTs

Side Effects

Advanced Directive

Exercise

Diet



Research

Insurance

Vision

Palliative Care

Assisted suicide

Social services


Prevention

Diagnosis

DMT Symptomatic

Therapist

Terminal

Counselling

www.ms-res.org

MS-STAT trial

High dose oral Simvastatin

in Secondary Progressive Multiple Sclerosis

Jeremy Chataway

for the MS-STAT Collaborators

CTN:NCT00647348

EUDRACT NUMBER 2006-006347-31

#2

Slides deleted

Where to next?

Slides deleted

It is time to change the way we measure change:

demonstration, explanation, recommendation

Jeremy Hobart, Stefan Cano, Alan Thompson, David Andrich

Plymouth, London, Perth AU

ECTRIMS Lyon 12 October 2012

#4

1. Delayed Progression 2. Stabilised Progression

3. Improved Function 4. Recovered Function

WHAT ARE YOUR EXPECTATIONS OF A THERAPY FOR PROGRESSIVE MS?

16

1

2

3

www.ms-res.org

Current Dogma

immune activation innate and adaptive responses

focal inflammation

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

Current Dogma


focal inflammation

BBB breakdown






Gd-enhancement

T2 & T1 lesions



Clinical Attack

Disease Progression

Clinical Recovery

- biology

- clinical outcomes

- biomarkers

56.0

42.0

27.0

74.0

51.0

39.0

0

10

20

30

40

50

60

70

80

Clinical disease

activity-free

MRI

activity-free

MS disease

activity-free

CARE-MS I: Alemtuzumab Disease Activity Status – Proportion of Patients Free of MS Disease Activity

A significantly greater proportion of patients were disease-free with alemtuzumab vs. SC IFNB-1a in CARE-MS I

41.1

Pa

tie

nts

(%

)

Note: Clinical disease activity-free defined as absence of relapse or SAD; MRI activity-free defined as absence of new Gd-enhancing

lesion or new or enlarging T2 hyperintense lesion; MS disease activity-free defined as absence of clinical disease activity or MRI activity.

Giovannoni et al. ENS 2012.

p<0.0001

p=0.0388

p=0.0064

SC IFNB-1a

Alem 12 mg #6

#7

Epstein Bar Virus

Genetics

Vitamin D

Smoking

Risks

Adverse events


MRI

Evoked Potentials

Lumbar puncture

Blood Tests

Diagnostic Criteria

Cognition

Depression

Fatigue

Bladder

Bowel


Pain Swallowing

Spasticity Falls



Clinical trials

Gait

Pressure sores

Oscillopsia

Emotional lability

Seizures

Gastrostomy

Rehab

Suprapubic catheter


Physio- therapy

Speech therapy



Colostomy

Tendonotomy

Studying


Travel

Vaccination

Anxiety

Driving

Nurse specialists

Counselling

Family counselling

Relapses

1st line

2nd line


Monitoring

Disease-free

Disease progression

DMTs

Side Effects

Advanced Directive

Exercise

Diet



Research

Insurance

Vision

Palliative Care

Assisted suicide

Social services


Prevention

Diagnosis

DMT Symptomatic

Therapist

Terminal

Counselling

**

Placebo Laquinimod

21% reduction

in annualized

relapse rates

(P=0.0005)

ANNUALIZED RELAPSE RATE

23

* 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. Presented at 64th American Academy of Neurology Annual meeting, New Orleans 2012 Session S01.007

#8

LAQUINIMOD REDUCED THE RISK FOR 3-MONTH

CONFIRMED DISABILITY PROGRESSION

Placebo (n=1006)

Laquinimod 0.6 mg (n=984)

Hazard ratio, 0.658

P=0.0017

34.2%

24 Vollmer T et al. Presented at 64th American Academy of Neurology Annual meeting, New Orleans 2012 Session S01.007

LAQUINIMOD REDUCED THE RISK FOR 6-MONTH

CONFIRMED DISABILITY PROGRESSION

Placebo (n=1006)

Laquinimod 0.6 mg (n=984)

Hazard ratio, 0.54

P=0.0001

46%

25 Vollmer T et al. Presented at 64th American Academy of Neurology Annual meeting, New Orleans 2012 Session S01.007

36 month extension: confirmed disability progression for patients completing 1 year in the extension

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

Time to Progression-Days

% o

f Su

bje

cts

wit

h C

on

firm

ed

Pro

gre

ssio

n

Delayed Start n=363 346 337 321 316 308 298 293 Early Start n=372 365 362 358 347 337 337 330

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

27

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.

28

27.5% Reduction P<0.0001

28

*Adjusted for baseline characteristics.

-27.4% Improvement P<0.0001 -1.4

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

LAQUINIMOD 0.6mg

PLACEBO

-1.14% -0.83% Percent Brain Volume

Change* (Months 0-24)

-1.25%

AVONEX® 30mcg

+9% Deterioration P=0.14

Primary Results of the SELECTION Trial of

Daclizumab HYP in Relapsing Multiple

Sclerosis

Gavin Giovannoni1, Ralf Gold2, Krzysztof Selmaj3,

Eva Havrdova4, Xavier Montalban5, Ernst-Wilhelm

Radue6, Dusan Stefoski7, Manjit McNeill8, Jitesh

Rana8, Jacob Elkins8, and Gilmore O’Neill8

1Queen Mary University of London, Barts and The London School of Medicine and Dentistry, London,

UK; 2St. Josef-Hospital/Ruhr-University Bochum, Bochum, Germany; 3Medical University of Lodz, Lodz,

Poland; 4Charles University in Prague, Prague, Czech Republic; 5Hospital Vall d'Hebron University,

Barcelona, Spain; 6University Hospital Basel, Basel, Switzerland. 7Rush University Medical Center,

Chicago, IL. USA; 8Biogen Idec, Cambridge, MA, USA

Reduction in ARR was sustained during

year 2 of DAC HYP treatment

30

0.434 (0.347, 0.544)

Year 2 of DAC HYP

62% reduction vs.

SELECT pbo

Year 1 of DAC HYP

66% reduction vs.

SELECT pbo

0.148 (0.096, 0.229)

Placebo

n=163

Year 1 Year 1 Year 2 DAC HYP

n=129

DAC HYP

n=129

An

nu

ali

ze

d R

ela

pse

Rate

#9

Low rate (12%) of confirmed disability

progression over 2 years of DAC HYP treatment

0.0

0.1

0.2

0.3

DAC HYP continuous

0 12 2463 9 15 18 21

DAC HYP Placebo

Placebo

6%

13%

50% risk reduction(95% CI, 12-71%; P=0.015)

Time on study (months)

Pro

po

rtio

n o

f p

ati

en

ts w

ith

co

nfi

rmed

dis

ab

ilit

y p

rog

ressio

n

0.0

0.1

0.2

0.3

DAC HYP continuous

0 12 2463 9 15 18 21

DAC HYP

Placebo

Placebo

6%

13%12%


Pro

po

rtio

n o

f p

ati

en

ts w

ith

co

nfi

rmed

dis

ab

ilit

y p

rog

ressio

n

0.0

0.1

0.2

0.3

DAC HYP continuous

0 12 2463 9 15 18 21

DAC HYP

Placebo

Placebo

16%

12%

DAC HYP

DAC HYP after placebo

6%

13%

Placebo patients startDAC HYP


Pro

po

rtio

n o

f p

ati

en

ts w

ith

co

nfi

rmed

dis

ab

ilit

y p

rog

ressio

nLow rate (12%) of confirmed disability

progression over 2 years of DAC HYP treatment

Reduced confirmed 3-month disability progression

after initiation of DAC HYP

10%

5%

0%

2%

4%

6%

8%

10%

12%

Reduction = 50% P = 0.033

17 subjects

with progression

Year 1 Year 2

7 subjects

with progression

Placebo

n=163

DAC HYP

n=163

Pe

rce

nt

of

pati

en

ts w

ith

co

nfi

rme

d

dis

ab

ilit

y p

rog

res

sio

n

#10

Do these two examples suggest that relapses are not related to disease progression?

Is the current dogma wrong?


focal inflammation

BBB breakdown






Gd-enhancement

T2 & T1 lesions



Clinical Attack

Disease Progression

Clinical Recovery

- biology

- clinical outcomes

- biomarkers



focal inflammation

BBB breakdown






Gd-enhancement

T2 & T1 lesions



Clinical Attack

Disease Progression

Clinical Recovery

- biology

- clinical outcomes

- biomarkers

Coles et al. J Neurol. 2006 Jan;253(1):98-108..

Post-inflammatory neurodegeneration

CARE-MS II: Alemtuzumab Disability Improvement

*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. Cohen J et al. AAN 2012; 2. Coles A et al. ECTRIMS 2011.

Sustained Reduction in

Disability (SRD)*: CARE-MS II1

Mean EDSS Change from

Baseline: CARE-MS II1

Pa

tien

ts w

ith

SR

D (

%)

40

30

20

10

0 0 3 6 9 12 15 18 21 24

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

3.25

3.00

2.75

2.50

2.25

Follow-up Month

Alemtuzumab 12 mg

SC IFNB-1a

0 3 6 9 12 15 18 21 24

SC IFNB-1a

Alemtuzumab 12 mg

In CARE-MS I, there was no significant difference between treatments

on EDSS-based endpoints2

#11



focal inflammation

BBB breakdown






Gd-enhancement

T2 & T1 lesions



Clinical Attack

Disease Progression

Clinical Recovery

- biology

- clinical outcomes

- biomarkers

Virus?

Epstein Bar Virus

Genetics

Vitamin D

Smoking

Risks

Adverse events


MRI

Evoked Potentials

Lumbar puncture

Blood Tests

Diagnostic Criteria

Cognition

Depression

Fatigue

Bladder

Bowel


Pain Swallowing

Spasticity Falls



Clinical trials

Gait

Pressure sores

Oscillopsia

Emotional lability

Seizures

Gastrostomy

Rehab

Suprapubic catheter


Physio- therapy

Speech therapy



Colostomy

Tendonotomy

Studying


Travel

Vaccination

Anxiety

Driving

Nurse specialists

Counselling

Family counselling

Relapses

1st line

2nd line


Monitoring

Disease-free

Disease progression

DMTs

Side Effects

Advanced Directive

Exercise

Diet



Research

Insurance

Vision

Palliative Care

Assisted suicide

Social services


Prevention

Diagnosis

DMT Symptomatic

Therapist

Terminal

Counselling

Epstein Bar Virus

Genetics

Vitamin D

Smoking

Risks

Adverse events


MRI

Evoked Potentials

Lumbar puncture

Blood Tests

Diagnostic Criteria

Cognition

Depression

Fatigue

Bladder

Bowel


Pain Swallowing

Spasticity Falls



Clinical trials

Gait

Pressure sores

Oscillopsia

Emotional lability

Seizures

Gastrostomy

Rehab

Suprapubic catheter


Physio- therapy

Speech therapy



Colostomy

Tendonotomy

Studying


Travel

Vaccination

Anxiety

Driving

Nurse specialists

Counselling

Family counselling

Relapses

1st line

2nd line


Monitoring

Disease-free

Disease progression

DMTs

Side Effects

Advanced Directive

Exercise

Diet



Research

Insurance

Vision

Palliative Care

Assisted suicide

Social services


Prevention

Diagnosis

DMT Symptomatic

Therapist

Terminal

Counselling

#12

#13

Epstein Bar Virus

Genetics

Vitamin D

Smoking

Risks

Adverse events


MRI

Evoked Potentials

Lumbar puncture

Blood Tests

Diagnostic Criteria

Cognition

Depression

Fatigue

Bladder

Bowel


Pain Swallowing

Spasticity Falls



Clinical trials

Gait

Pressure sores

Oscillopsia

Emotional lability

Seizures

Gastrostomy

Rehab

Suprapubic catheter


Physio- therapy

Speech therapy



Colostomy

Tendonotomy

Studying


Travel

Vaccination

Anxiety

Driving

Nurse specialists

Counselling

Family counselling

Relapses

1st line

2nd line


Monitoring

Disease-free

Disease progression

DMTs

Side Effects

Advanced Directive

Exercise

Diet



Research

Insurance

Vision

Palliative Care

Assisted suicide

Social services


Prevention

Diagnosis

DMT Symptomatic

Therapist

Terminal

Counselling

Epstein Bar Virus

Genetics

Vitamin D

Smoking

Risks

Adverse events


MRI

Evoked Potentials

Lumbar puncture

Blood Tests

Diagnostic Criteria

Cognition

Depression

Fatigue

Bladder

Bowel


Pain Swallowing

Spasticity Falls



Clinical trials

Gait

Pressure sores

Oscillopsia

Emotional lability

Seizures

Gastrostomy

Rehab

Suprapubic catheter


Physio- therapy

Speech therapy



Colostomy

Tendonotomy

Studying


Travel

Vaccination

Anxiety

Driving

Nurse specialists

Counselling

Family counselling

Relapses

1st line

2nd line


Monitoring

Disease-free

Disease progression

DMTs

Side Effects

Advanced Directive

Exercise

Diet



Research

Insurance

Vision

Palliative Care

Assisted suicide

Social services


Prevention

Diagnosis

DMT Symptomatic

Therapist

Terminal

Counselling

Conclusions

• 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 2 & 3 trials

– Do we need new outcome measures (including CSF)?

• How does 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 an holistic approach to MS

– MS is a life-long disease with many problems that need to be solved

One-stop shopping for researchers in the field of MS

www.msdiscovery.org

• Reported news about research articles and conference presentations • A database of drugs in the pipeline • Discussion forums • Listings of tissue repositories, scientific meetings, and more • Classic paper summaries

MassGeneral Institute for Neurodegenerative Disease

Health & Medicine

Treatment Highlights ECTRIMS 2012