Multiple sclerosis: an unmet need

Biomarkers in MS

Gavin Giovannoni

Barts and The London

Disclosures

Professor Giovannoni has received personal compensation for participating on Advisory Boards in relation to clinical trial design, trial steering committees and data and safety monitoring committees from: Abbvie, Bayer-Schering Healthcare, Biogen-Idec, Canbex, Eisai, Elan, Fiveprime, Genzyme, Genentech, GSK, GW Pharma, Ironwood, Merck-Serono, Novartis, Pfizer, Roche, Sanofi-Aventis, Synthon BV, Teva, UCB Pharma and Vertex Pharmaceuticals.

Regarding www.ms-res.org survey results in this presentation: please note that no personal identifiers were collected as part of these surveys and that by completing the surveys participants consented for their anonymous data to be analysed and presented by Professor Giovannoni.

Professor Giovannoni would like to acknowledge and thank Biogen-Idec, Genzyme, Merck-Serono and Novartis for making available data slides on natalizumab, alemtuzumab, oral cladribine and fingolimod for this presentation.

Why biomarkers?

• Diagnostic testing

• Positive & negative predictive testing

• Pathogenesis

• Immunology

• Aetiology

• Disease progression & recovery

• Disease heterogeneity

• Pharmacovigilance

• Monitor disease processes

• Prognosis (high vs. low risk patients)

• Monitoring effect of therapeutic interventions

Diagnostic markers

The evolving clinical definition of MS

1. Schumacher, et al. Problems of Experimental Trials of Therapy in Multiple Sclerosis: Report by

the Panel on the Evaluation of Experimental Trials of Therapy in Multiple Sclerosis. Ann N Y

Acad Sci 1965;122:552-68.

2. Poser, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols.

Ann Neurol 1983;13:227-31.

3. McDonald, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the

International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001;50:121-7.

4. Polman, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the "McDonald

Criteria". Ann Neurol 2005;58:840-6.

5. Polman, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald

criteria. Ann Neurol. 2011;69:292-302.

Will Rogers Phenomenon in Multiple Sclerosis

1879 - 1935

“When the Okies left Oklahoma and moved to California, they raised the average intelligence level in both states.”

Will Rogers Phenomenon in Multiple Sclerosis

Sormani et al. Ann Neurol 2008;64:428–433.

Poser

McDonald

Inactive CIS Active CIS RRMS

MS diagnosed according the old Poser Criteria

Inactive CIS

Less active RRMS

More Active RRMS

MS diagnosed according the New McDonald Criteria

Intrathecal synthesis of IgG

Images courtesy of Prof. Ed Thompson.

Isoelectric focusing with immunfixation

Diagnostic criteria for Primary Progressive MS

Polman et al. Ann Neurol 2005;58:840-6.

Accumulation of disability in PPMS: stratified by intrathecal IgG abnormalities

Proportion Progressing as Percent

Epoch CSF- CSF+

6 mo 7.3 9.8

12 mo 15.0 20.4

18 mo 22.8 28.1

24 mo 25.4 34.3

Years to Progression

2.43 2.26

Based on data from a second meeting of the DSMB and assume no therapeutic effect

Slide courtesy of Jerry Wolinsky

0 1 2 3 Years

0.0

0.2

0.4

0.6

0.8

1.0

Pro

po

rtio

n P

rogr

essi

ng

Positive Negative

CSF

P =0.03

Not PPMS Not PPMS PPMS OCB+ve

PPMS MS diagnosed according the initial McDonald Criteria

Not PPMS

PPMS OCB-ve

PPMS OCB+ve

PPMS diagnosed according the New McDonald Criteria

Dobson R, et al. J Neurol Neurosurg Psychiatry 2013;0:1–6.

Unmet need:

Evidence-based diagnostic criteria

What constitutes a useful diagnostic test or set of criteria?

TARGET DISORDER

PRESENT ABSENT

DIAGNOSTIC TEST RESULT

+ a b a + b

- c d c + d

a + c b + d a + b + c + d

From these we determine the sensitivity and specificity as follows: SENSITIVITY = a/(a+c) > 80% SPECIFICITY = d/(b+d) > 80%

Neurobiol Aging 1998; 19:109-116.

Pathological diagnosis

Dia

gno

stic

Cri

teri

a

A clinico-pathoanatomical study of multiple sclerosis diagnosis

SENSITIVITY = True+ve /(True+ve + False-ve)

Eye Department, Hvidovre Hospital, Denmark.

• Neuropathological examination of 518 consecutive patients with clinically definite MS revealed a correct diagnosis in 485 cases (94%).

• Clinical diagnosis had been established by a neurologist in all cases.

• Erroneous diagnosis included a variety of other neurological disorders.

• Also investigated was a randomly selected series of 33 patients with a clinical diagnosis of probable MS:

• post mortem confirmation of MS was obtained in circa 66%.

• The remainder the error pattern was similar to the above.

Engell T. Acta Neurol Scand. 1988 Jul;78(1):39-44.

A clinico-pathoanatomical study of multiple sclerosis diagnosis.

SPECIFICITY = True-ve /(True-ve + False+ve)

~25% of cases of MS are undiagnosed in life (asymptomatic or benign cases)

Engell T. Acta Neurol Scand. 1989 May;79(5):428-30..

Potential consequences of a misdiagnosis

Potential consequences of a misdiagnosis

Kleinschmidt-DeMasters,et al. N Engl J Med. 2005 Jul 28;353(4):369-74.

PML complicating treatment with natalizumab and IFNb-1a for MS

Potential fatal consequences of a misdiagnosis

TARGET DISORDER

PRESENT ABSENT

DIAGNOSTIC TEST RESULT

+ a b a + b

- c d c + d

a + c b + d a + b + c + d

What constitutes a useful diagnostic test or set of criteria?

From these we determine the sensitivity and specificity as follows: SENSITIVITY = a/(a+c) > 80% SPECIFICITY = d/(b+d) > 80% Neurobiol Aging 1998; 19:109-116.

Poser Criteria

McD

on

ald

Cri

teri

a

X Diagnostic tautology

McDonald MS

Poser MS

Response or non-response markers

17yr female,

diagnosed

with CIS

after

presenting

with myelitis

18yr, 1st year

university

diagnosed

with MS after

having L optic

neuritis

Abnormal MRI; >9

T2 lesions on brain

MRI and spinal cord

lesion at C5

2000 2001

clumsy

left

hand

pins &

needles

in legs

IFN-beta

2002 2003

R optic

neuritis

2004

Bladder dysfunction

Graduate

trainee

marketing

Full

time

employment

Off work

~3 months

of the year

Dec 2007

Brainstem

syndrome;

diplopia

and ataxia

? glatiramer

acetate

Cervical cord

relapse

weak L arm

with pain

High lesion

load with

brain

atrophy

Gd-enhancing

lesion of upper

cervical cord

Splits from

her partner

depression ,

anxiety and fatigue

Reduced mobility

Occupational

health

assessment

natalizumab

New

partner

New job

junior management

position

Residual deficits:

Normal walking 300m, unable to run &

exercise. Intermittent sensory symptoms

in L arm. Mild urinary frequency

Jan 2008

JCV

positive

3-monthly MRI

monitoring

? fingolimod

Oct 2013

Annual MRI

monitoring

JCV

high positive

Final

year of

school

University

24

Monitorin

g

Tre

atm

ent

Clin

ical

Occup &

socia

l

NAB

-ve

17yr female,

diagnosed

with CIS

after

presenting

with myelitis

18yr, 1st year

university

diagnosed

with MS after

having L optic

neuritis

Abnormal MRI; >9

T2 lesions on brain

MRI and spinal cord

lesion at C5

2000 2001

clumsy

left

hand

pins &

needles

in legs

IFN-beta

2002 2003

R optic

neuritis

2004

Bladder dysfunction

Graduate

trainee

marketing

Full

time

employment

Off work

~3 months

of the year

Dec 2007

Brainstem

syndrome;

diplopia

and ataxia

? glatiramer

acetate

Cervical cord

relapse

weak L arm

with pain

High lesion

load with

brain

atrophy

Gd-enhancing

lesion of upper

cervical cord

Splits from

her partner

depression ,

anxiety and fatigue

Reduced mobility

Occupational

health

assessment

natalizumab

New

partner

New job

junior management

position

Residual deficits:

Normal walking 300m, unable to run &

exercise. Intermittent sensory symptoms

in L arm. Mild urinary frequency

Jan 2008

JCV

positive

3-monthly MRI

monitoring

? fingolimod

Oct 2013

Annual MRI

monitoring

JCV

high positive

Final

year of

school

University

25

Monitorin

g

Tre

atm

ent

Clin

ical

Occup &

socia

l

NAB

-ve

Clinical importance of neutralising antibodies against interferon beta in patients with relapsing-remitting multiple sclerosis

Sorensen et al. Lancet 2003; 362: 1184–91.

Anti-natalizumab Antibodies

Number of Patients at Risk

Placebo

Antibody Negative

Transiently Positive

Persistently Positive

315

568

20

37

296

550

19

32

283

538

18

26

264

526

16

25

248

506

16

24

240

487

16

22

229

480

15

22

216

470

14

19

208

460

14

16

200

449

14

15

Weeks

0.0

0.1

0.2

0.3

0.4

0.5

0 12 24 36 48 60 72 84 96 108 120

29%

Placebo

17%

Antibody Negative

17%

Transiently Antibody Positive

34%Persistently Antibody Positive

Cu

mu

lati

ve

Pro

po

rtio

n o

f P

ati

en

ts

wit

h S

us

tain

ed

Dis

ab

ilit

y

Pro

gre

ss

ion

(E

DS

S) *,†

*p ≤0.05 vs. antibody-negative patients†p=0.66 vs. placebo

Number of Patients at Risk

Placebo

Antibody Negative

Transiently Positive

Persistently Positive

315

568

20

37

296

550

19

32

283

538

18

26

264

526

16

25

248

506

16

24

240

487

16

22

229

480

15

22

216

470

14

19

208

460

14

16

200

449

14

15

Weeks

0.0

0.1

0.2

0.3

0.4

0.5

0 12 24 36 48 60 72 84 96 108 120

29%

Placebo

17%

Antibody Negative

17%

Transiently Antibody Positive

34%Persistently Antibody Positive

Cu

mu

lati

ve

Pro

po

rtio

n o

f P

ati

en

ts

wit

h S

us

tain

ed

Dis

ab

ilit

y

Pro

gre

ss

ion

(E

DS

S) *,†

*p ≤0.05 vs. antibody-negative patients†p=0.66 vs. placebo

0.73

0.220.16

0.48*

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

Ad

jus

ted

An

nu

ali

ze

d R

ela

pse

Ra

te (

95

% C

I)

Placebo

(n=315)

Antibody Negative

(n=568)

Transiently

Antibody Positive

( n=20)

Persistently

Antibody Positive

(n=37)

*p=0.009 vs. antibody-negative patients

0.73

0.220.16

0.48*

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

Ad

jus

ted

An

nu

ali

ze

d R

ela

pse

Ra

te (

95

% C

I)

Placebo

(n=315)

Antibody Negative

(n=568)

Transiently

Antibody Positive

( n=20)

Persistently

Antibody Positive

(n=37)

*p=0.009 vs. antibody-negative patients

Calabresi et al, Neurol 2007

Impact of anti-natalizumab antibodies on . . . . .

Annualized relapse rate Progressive disability

17yr female,

diagnosed

with CIS

after

presenting

with myelitis

18yr, 1st year

university

diagnosed

with MS after

having L optic

neuritis

Abnormal MRI; >9

T2 lesions on brain

MRI and spinal cord

lesion at C5

2000 2001

clumsy

left

hand

pins &

needles

in legs

IFN-beta

2002 2003

R optic

neuritis

2004

Bladder dysfunction

Graduate

trainee

marketing

Full

time

employment

Off work

~3 months

of the year

Dec 2007

Brainstem

syndrome;

diplopia

and ataxia

? glatiramer

acetate

Cervical cord

relapse

weak L arm

with pain

High lesion

load with

brain

atrophy

Gd-enhancing

lesion of upper

cervical cord

Splits from

her partner

depression ,

anxiety and fatigue

Reduced mobility

Occupational

health

assessment

natalizumab

New

partner

New job

junior management

position

Residual deficits:

Normal walking 300m, unable to run &

exercise. Intermittent sensory symptoms

in L arm. Mild urinary frequency

Jan 2008

JCV

positive

3-monthly MRI

monitoring

? fingolimod

Oct 2013

Annual MRI

monitoring

JCV

high positive

Final

year of

school

University

28

Monitorin

g

Tre

atm

ent

Clin

ical

Occup &

socia

l

NAB

-ve

Natalizumab PML risk stratification tool

Anti-JC virus antibody status

Negative Positive

Prior immunosuppressant use

Natalizumab treatment

>2 Years

Natalizumab treatment

>2 Years

No Yes

No Yes No Yes

Lowest Highest Relative PML Risk

< 1 in 10,000 1 in 94 1 in 256 1 in 668 1 in 1887

Mitoxantrone

Azathioprine

Methotrexate

Cyclophosphamide

Mycophenolate

Cladribine

Rituximab

Etc.

17yr female,

diagnosed

with CIS

after

presenting

with myelitis

18yr, 1st year

university

diagnosed

with MS after

having L optic

neuritis

Abnormal MRI; >9

T2 lesions on brain

MRI and spinal cord

lesion at C5

2000 2001

clumsy

left

hand

pins &

needles

in legs

IFN-beta

2002 2003

R optic

neuritis

2004

Bladder dysfunction

Graduate

trainee

marketing

Full

time

employment

Off work

~3 months

of the year

Dec 2007

Brainstem

syndrome;

diplopia

and ataxia

? glatiramer

acetate

Cervical cord

relapse

weak L arm

with pain

High lesion

load with

brain

atrophy

Gd-enhancing

lesion of upper

cervical cord

Splits from

her partner

depression ,

anxiety and fatigue

Reduced mobility

Occupational

health

assessment

natalizumab

New

partner

New job

junior management

position

Residual deficits:

Normal walking 300m, unable to run &

exercise. Intermittent sensory symptoms

in L arm. Mild urinary frequency

Jan 2008

JCV

positive

3-monthly MRI

monitoring

? fingolimod

Oct 2013

Annual MRI

monitoring

JCV

high positive

Final

year of

school

University

30

Monitorin

g

Tre

atm

ent

Clin

ical

Occup &

socia

l

NAB

-ve

Use of JC virus antibody index to stratify risk of progressive multifocal leukoencephalopathy in natalizumab-treated patients with multiple sclerosis

Plavina et al. ENS 2013

www.ms-res.org; >750,000 views

17yr female,

diagnosed

with CIS

after

presenting

with myelitis

18yr, 1st year

university

diagnosed

with MS after

having L optic

neuritis

Abnormal MRI; >9

T2 lesions on brain

MRI and spinal cord

lesion at C5

2000 2001

clumsy

left

hand

pins &

needles

in legs

IFN-beta

2002 2003

R optic

neuritis

2004

Bladder dysfunction

Graduate

trainee

marketing

Full

time

employment

Off work

~3 months

of the year

Dec 2007

Brainstem

syndrome;

diplopia

and ataxia

? glatiramer

acetate

Cervical cord

relapse

weak L arm

with pain

High lesion

load with

brain

atrophy

Gd-enhancing

lesion of upper

cervical cord

Splits from

her partner

depression ,

anxiety and fatigue

Reduced mobility

Occupational

health

assessment

natalizumab

New

partner

New job

junior management

position

Residual deficits:

Normal walking 300m, unable to run &

exercise. Intermittent sensory symptoms

in L arm. Mild urinary frequency

Jan 2008

JCV

positive

3-monthly MRI

monitoring

? fingolimod

Oct 2013

Annual MRI

monitoring

JCV

high positive

Final

year of

school

University

33

Monitorin

g

Tre

atm

ent

Clin

ical

Occup &

socia

l

NAB

-ve

Early Detection of PML improves clinical outcome

Dong-Si et al. Presented at AAN; March 16–23, 2013; San Diego, CA. P04.271.

Months From PML Diagnosis

60,000

70,000

80,000

90,000

100,000

110,000

120,000

130,000

0

5

10

15

20

25A

pr-

10

Jun

-10

Au

g-10

Oct

-10

Dec

-10

Feb-

11

Ap

r-11

Jun

-11

Au

g-11

Oct

-11

Dec

-11

Feb

-12

Ap

r-12

Jun

-12

Au

g-12

Oct

-12

Dec

-12

Feb

-13

Ap

r-13

Jun

-13

Au

g-13

Oct

-13

Dec

-13

Feb

-14

Ap

r-14

Total n

um

be

r on

natalizu

mab

treatmen

t N

um

ber

of

PM

L ca

ses

pe

r m

on

th

Month

As of the 3rd April 2014 there are 454 confirmed

cases of PML

De-risking natalizumab treatment

Source: Data has been taken from Biogen-Idec’s monthly natalizumab risk/benefit and PML stratification update.

Biomarkers in the near future

Is NEDA good enough?

NEDA = no evident disease activity

17yr female,

diagnosed

with CIS

after

presenting

with myelitis

18yr, 1st year

university

diagnosed

with MS after

having L optic

neuritis

Abnormal MRI; >9

T2 lesions on brain

MRI and spinal cord

lesion at C5

2000 2001

clumsy

left

hand

pins &

needles

in legs

IFN-beta

2002 2003

R optic

neuritis

2004

Bladder dysfunction

Graduate

trainee

marketing

Full

time

employment

Off work

~3 months

of the year

Dec 2007

Brainstem

syndrome;

diplopia

and ataxia

? glatiramer

acetate

Cervical cord

relapse

weak L arm

with pain

High lesion

load with

brain

atrophy

Gd-enhancing

lesion of upper

cervical cord

Splits from

her partner

depression ,

anxiety and fatigue

Reduced mobility

Occupational

health

assessment

natalizumab

New

partner

New job

junior management

position

Residual deficits:

Normal walking 300m, unable to run &

exercise. Intermittent sensory symptoms

in L arm. Mild urinary frequency

Jan 2008

JCV

positive

3-monthly MRI

monitoring

? fingolimod

Oct 2013

Annual MRI

monitoring

JCV

high positive

Final

year of

school

University

Early or late?

37

Monitorin

g

Tre

atm

ent

Clin

ical

Occup &

socia

l

Dec 2007 Jul 2010 Jul 2013

Relapses

Unreported relapses

Clinical disease progression

Subclinical relapses: focal MRI activity

Focal gray and white matter lesions not detected by MRI

Brain atrophy

Spinal fluid neurofilament levels

The unmet need: treating-2-target

Clinical activity

Focal MRI activity

Hidden focal and diffuse MRI activity

Microscopic or biochemical pathology

Biomarkers

Rheumatoid arthritis End-stage joint disease

Control Multiple sclerosis

Brain atrophy occurs across all stages of the disease

De Stefano, et al. Neurology 2010

n= 963 MSers

Treatment effect on disability predicted by effect on T2-lesion load and brain atrophy

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.

-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

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

Reduction in brain atrophy on alemtuzumab

Alemtuzumab Improves Brain MRI Outcomes

in Patients With Active Relapsing-Remitting

Multiple Sclerosis: Three-Year Follow-up of the

CARE-MS Studies

Douglas L Arnold,1,2 Elizabeth Fisher,3 Jeffrey A Cohen,4 Frederik Barkhof,5

Krzysztof W Selmaj,6 David H Margolin,7 Jeffrey Palmer,7 Edward J Fox8

AAN 2014

Blitz S65-008

1NeuroRx Research, Montréal, Québec, Canada, and 2Department of Neurology and Neurosurgery, Montreal

Neurological Institute, McGill University, Montreal, Québec, Canada; 3Department of Biomedical Engineering,

Cleveland Clinic, Cleveland, OH, USA; 4Cleveland Clinic, Cleveland, OH, USA; 5VU University Medical Centre,

Amsterdam, Netherlands; 6Department of Neurology, Medical University of Łódź, Łódź, Poland; 7Genzyme, a

Sanofi company, Cambridge, MA, USA; 8University of Texas Medical Branch, Round Rock, TX, USA

CARE-MS I & II Three-Year MRI Outcomes Change in Brain Parenchymal Fraction (BPF)

Alemtuzumab slowed brain volume loss over 3 years, as assessed by change in BPF

For both patient populations, the median percentage reduction in BPF observed in in Year 3 (0.19% and 0.10%, respectively) was smaller than that observed in Year 1 (0.59% and 0.48%) and Year 2 (0.25% and 0.22%)

Percentage Change in BPF in Formerly Treatment-Naive Patients (CARE-MS I)

Percentage Change in BPF in Patients Who Relapsed on Prior Therapy (CARE-MS II)

Med

ian

Ch

an

ge F

rom

Baselin

e,

% (

95%

CI)

Year No. of Patients 371 367 351 323

% Change from Previous Year – –0.59% –0.25% –0.19%

Med

ian

Ch

an

ge F

rom

Baselin

e,

% (

95%

CI)

Year 428 414 405 359

– –0.48% –0.22% –0.10%

No. of Patients

% Change from Previous Year

0 1 2 3

-1 .5 0

-1 .2 5

-1 .0 0

-0 .7 5

-0 .5 0

-0 .2 5

0 .0 0

0 1 2 3

-1 .5 0

-1 .2 5

-1 .0 0

-0 .7 5

-0 .5 0

-0 .2 5

0 .0 0

AAN 2014

Blitz S65-008

CARE-MS I & II Three-Year MRI Outcomes Proportion of Patients Free of Gd Lesions, T2 Lesions, and MRI Activity

The majority of alemtuzumab-treated patients were free of MRI activity (absence of Gd-enhancing lesions and new/enlarging T2 hyperintense lesions) at Year 2 and Year 3

MRI activity-free: absence of both Gd-enhancing and new or enlarging T2 hyperintense lesions; CARE-MS=Comparison of

Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis; CI=confidence interval; DMT=disease-modifying therapy; Gd=gadolinium;

MRI=magnetic resonance imaging; Y=year

No. of Patients 359 370 336 356 370 325 354 369 326

Y1 Y2 Y3 Y1 Y2 Y3 Y1 Y2 Y3

Pro

po

rtio

n o

f P

ati

en

ts,

% (

95

% C

I)

0

20

40

60

80

100

Gd-enhancing

lesion-free

New/enlarging

T2 lesion-free

MRI

activity-free

% MRI Activity Free in Treatment-Naive

Patients (CARE-MS I)

% MRI Activity Free in Patients Who

Relapsed on Prior Therapy (CARE-MS II)

No. of Patients 412 421 364 405 423 361

Gd-enhancing

lesion-free

New/enlarging MRI

activity-free

402 414 361

Pro

po

rtio

n o

f P

ati

en

ts,

% (

95

% C

I)

0

20

40

60

80

100

Y1 Y2 Y3 Y1 Y2 Y3 Y1 Y2 Y3

T2 lesion-free

Patients were treated with alemtuzumab 12 mg at baseline and 12 months later

Re-treatment in Year 3 was administered upon recurrence of disease activity

18% of CARE-MS I patients and 20% of CARE-MS II patients were re-treated

with alemtuzumab in Year 3; <3% were treated with another DMT in Year 3

AAN 2014

Blitz S65-008

CARE-MS I & II Three-Year MRI Outcomes Change in Brain Parenchymal Fraction (BPF)

Alemtuzumab slowed brain volume loss over 3 years, as assessed by change in BPF

For both patient populations, the median percentage reduction in BPF observed in in Year 3 (0.19% and 0.10%, respectively) was smaller than that observed in Year 1 (0.59% and 0.48%) and Year 2 (0.25% and 0.22%)

Percentage Change in BPF in Formerly Treatment-Naive Patients (CARE-MS I)

Percentage Change in BPF in Patients Who Relapsed on Prior Therapy (CARE-MS II)

Med

ian

Ch

an

ge F

rom

Baselin

e,

% (

95%

CI)

Year No. of Patients 371 367 351 323

% Change from Previous Year – –0.59% –0.25% –0.19%

Med

ian

Ch

an

ge F

rom

Baselin

e,

% (

95%

CI)

Year 428 414 405 359

– –0.48% –0.22% –0.10%

No. of Patients

% Change from Previous Year

0 1 2 3

-1 .5 0

-1 .2 5

-1 .0 0

-0 .7 5

-0 .5 0

-0 .2 5

0 .0 0

0 1 2 3

-1 .5 0

-1 .2 5

-1 .0 0

-0 .7 5

-0 .5 0

-0 .2 5

0 .0 0

AAN 2014

Blitz S65-008

Relapses

Unreported relapses

Clinical disease progression

Subclinical relapses: focal MRI activity

Focal gray and white matter lesions not detected by MRI

Brain atrophy

Spinal fluid neurofilament levels

The unmet need: treating-2-target

Clinical activity

Focal MRI activity

Hidden focal and diffuse MRI activity

Microscopic or biochemical pathology

Biomarkers

Petzold, J Neurol Sci. 2005 Jun 15;233(1-2):183-98.

Neurofilament protein in cerebrospinal fluid: a potential marker of activity in multiple sclerosis

Lyke et al. J Neurol Neurosurg Psychiatry 1998;64:402–404.

Petzold et al. J Neurol Neurosurg Psychiatry. 2005 Feb;76(2):206-11.

Spinal fluid neurofilament levels

Axonal damage in R-MS is markedly reduced by Natalizumab

Gunnarsson et al. Ann Neurol 2010; Epub.

Natalizumab treatment of progressive MS reduces inflammation and tissue damage: CSF markers of axonal damage

Romme Christensen et al. ECTRIMS 2012.

Bas

elin

e

Follow-u

p

0

500

1000

1500

2000

2500

NfL

(p

g/m

l)

Cerebrospinal fluid NfL Fingolimod 0.5mg/1.25 mg versus placebo treated patients

p<0.001

Fingolimod, n=23 Placebo, n=12

p=0.470

Fingolimod 0.5 mg Fingolimod 1.25 mg

Baseline Follow-up Baseline Follow-up

Median (pg/ml)

644 321 (-50%) 886 738 (-17%)

*Non-parametric Wilcoxon matched pairs test; p value is calculated with inclusion of outliers Dr Jens Khule, ECTRIMS 2013

0

1000

2000

10000

NfL

(p

g/m

l)

Axonal damage in R-MS is markedly reduced by Natalizumab

Gunnarsson et al. Ann Neurol 2010; Epub.

Gunnarsson et al. Ann Neurol 2010; Epub.

CSF NFL

Relapses

Unreported relapses

Clinical disease progression

Subclinical relapses: focal MRI activity

Focal gray and white matter lesions not detected by MRI

Brain atrophy

Spinal fluid neurofilament levels

The unmet need: treating-2-target

Clinical activity

Focal MRI activity

Hidden focal and diffuse MRI activity

Microscopic or biochemical pathology

Biomarkers

NEDA

Gd, gadolinium. 1. Havrdova E, et al. Lancet Neurol 2009; 8:254–260; 2. Giovannoni G, et al. Lancet Neurol 2011; 10:329–337.

Treat-2-target

Should brain volume loss and CSF neurofilament levels be included in future definitions of NEDA?

No evidence of disease activity defined as:1,2

× No relapses

× No sustained disability progression

× No MRI activity

× No new or enlarging T2 lesions

× No Gd-enhancing lesions

Biomarkers are also needed to optimise the risks associated with the emerging therapies

Conclusions

• MS is a bad disease • Mortality, disability, unemployment, divorce, cognitive impairment, etc.

• Early highly-effective therapy is the only realistic option of preventing end-organ damage • Now an established treatment option in the EU

• NEDA (DAF) and T2T are entering the neurology lexicon

• Zero tolerance or ZeTo

• We need an acceptable working definition of an MS cure • NEDA x 15 years?

• We will need to include other biomarkers in the definition

If you want a copy of these slides you can download from www.ms-res.org

Back-up slides

Control Multiple sclerosis

Another infographic: end-organ damage

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Average

Upper limit of normal

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MS Upper limit

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-30%

Hypothetical treatment effects

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-30%

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highly-effective

treatment

late very

highly-effective

treatment

-15%

Hypothetical treatment effects

Treatment-effect on atrophy correlates with treatment-effect on disability

Sormani et al. Ann Neurol 2014;75:43–49.

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

Post-inflammatory neurodegeneration