Top seminars biomarkers in MS

Biomarkers in MS (preventing end-organ damage)

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.

http://www.ms-res.org/







Why MS 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

MS is an iceberg?

Clinical

MRI

Pathology

Unreported relapses

Documented relapses

Subclinical relapses

focal MRI activity – new T2 and Gd-enhancing T1 lesions

Focal gray and white matter lesions not detected by MRI

Brain atrophy and spinal fluid neurofilament levels

“The MS Iceberg”

“Above the surface”

“Below the surface”

End-organ damage

ESRF end-stage renal failure

Control Multiple sclerosis

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

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

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.

Emerging concepts in MS

Hagan M, et al. Int J Radiat Oncol Biol Phys 2004; 59:329−340.

NEDD – no evidence of detectable disease (oncology)

NEDA - no evident disease activity (msologoy)

DAF – disease activity free

T2T; treat-2-target (rheumatology)

10 9 7 6 5 4 3 2 1 0 8

0.8

0.6

0.4

0.2

0.0

1.0

Adjuvant (n = 50)

Salvage (n = 118)

p = 0.002

Su

rviv

al

Time since radiotherapy (years)

Biochemical relapse-free survival

ZeTo; zero tolerance

No evident disease activity: 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

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

-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

Mean

(S

E)

perc

en

tag

e c

han

ge 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)


−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)

Me

dia

n C

ha

ng

e F

rom

Ba

se

lin

e, %

(9

5%

CI)

Year No. of Patients 371 367 351 323

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

Me

dia

n C

ha

ng

e F

rom

Ba

se

lin

e, %

(9

5%

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

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?

20

Mo

nito

rin

g

Tre

atm

ent

Clin

ica

l O

ccu

p &

so

cia

l

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?

21

Mo

nito

rin

g

Tre

atm

ent

Clin

ica

l O

ccu

p &

so

cia

l

Dec 2007 Jul 2010 Jul 2013

MS is an iceberg?

Clinical

MRI

Pathology

Pathogenic markers

“Inflammation”

“Oligodendrocyte Toxicity & Demyelination”

Axonal Toxicity (conduction block)

Axonal & Neuronal Loss

Gliosis

Remyelination & Axonal Recovery

“Inflammation”

Central Adaptation & Plasticity

Key pathological processes in MS

The Shredder - 11,000 to 1

Trapp, et al. NEJM 1998;338:278-85

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

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

Spinal fluid neurofilament levels

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.

-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

Mean

(S

E)

perc

en

tag

e c

han

ge i

n B

PF

Natalizumab treatment of progressive multiple sclerosis reduces

inflammation and tissue damage

- results of a phase 2A proof-of-concept study

ClinicalTrials.gov Identifier: NCT01077466

J. Romme Christensen1, R. Ratzer1, L. Börnsen1, E. Garde2, M. Lyksborg2, H.R. Siebner2, T.B. Dyrby2, P. Soelberg Sørensen1 and F. Sellebjerg1

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)

Fingolimod has an early and sustained effect on the rate of brain atrophy compared with placebo and IFNb-1a IM

FREEDOMS, 2 years


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)


−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

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

Post-inflammatory neurodegeneration

Axonal damage in R-MS is markedly reduced by Natalizumab



CSF NFL

Active tablet

Placebo tablet

Year 1 Year 2 Year 3

600 MSers

300 MSers

300 MSers

Recruitment Trial Data analysis

6 months

6 months 60 MSers

6 months

LP1 LP2 LP3

30 MSers active tablet

30 MSers placebo tablet

2 years

6 months

600 MSers for 7 years 60 MSers for 2 years

3 LPs = 10x as many trials in a ⅓ of the time

13%

66%

21%

n = 127

MRI Events

1st clinical attack

Time (Years)

Subclinical disease

Inflammation

Brain volume loss

Neuroaxonal loss

Dis

eas

e S

eve

rity

SPMS RRMS

1st MRI lesion

Relapses

CIS RIS R-SPMS

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

SPMS: Natalizumab, Siponimod

Late SPMS: SMART STUDY ibudilast, amiloride, riluzole

Early SPMS: PROXIMUS oxcarbazepine

CIS: PHENYTOIN RRMS: ? DE-FLAMES STUDY

PPMS

PPMS: Fingolimod, Ocrelizumab, Laquinimod

Brain atrophy occurs across all stages of the disease

De Stefano, et al. Neurology 2010

n= 963 MSers

MRI Events

1st clinical attack

Time (Years)

Subclinical disease

Inflammation

Brain volume loss

Neuroaxonal loss

Dis

eas

e S

eve

rity

SPMS RRMS

1st MRI lesion

Relapses

CIS RIS R-SPMS

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

SPMS: Natalizumab, Siponimod

Late SPMS: SMART STUDY ibudilast, amiloride, riluzole

Early SPMS: PROXIMUS oxcarbazepine

CIS: PHENYTOIN RRMS: ? DE-FLAMES STUDY

PPMS

PPMS: Fingolimod, Ocrelizumab, Laquinimod

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.

Therapeutic Lag

Motor system to legs

Cerebellar or balance systems

Bladder Therapeutic window 1

Therapeutic window 2


Upper limbs

Sensory

Cognition

Vision

Etc.





Therapeutic window 8, etc….

Diagnosis of Progressive MS

Effective DMTs could still target the remaining windows of therapeutic opportunity for individual neurological

systems

The Asynchronous Progressive MS hypothesis

Control Multiple sclerosis

End-organ damage

750

800

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1050

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1250

1300

1350

1400

1450

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30 35 40 45 50 55 60 65 70 75 80

Bra

in V

olu

me

(m

L)

Age (years)

Brain atrophy curves

Lower limit of normal

Average

Upper limit of normal

Hypothetical treatment effects

750

800

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30 35 40 45 50 55 60 65 70 75 80

Bra

in V

olu

me

(m

L)

Age (years)


MS lower limit

MS Average

MS Upper limit

-5%

-30%


-5%

-30%

750

800

850

900

950

1000

1050

1100

1150

1200

1250

1300

1350

1400

1450

1500

30 35 40 45 50 55 60 65 70 75 80

Bra

in V

olu

me

(m

L)

Age (years)


MS Average


-5%

-20%

750

800

850

900

950

1000

1050

1100

1150

1200

1250

1300

1350

1400

1450

1500

30 35 40 45 50 55 60 65 70 75 80

Bra

in V

olu

me

(m

L)

Age (years)


late treatment


750

800

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950

1000

1050

1100

1150

1200

1250

1300

1350

1400

1450

1500

30 35 40 45 50 55 60 65 70 75 80

Bra

in V

olu

me

(m

L)

Age (years)


-5%

-18%

early treatment

late treatment


750

800

850

900

950

1000

1050

1100

1150

1200

1250

1300

1350

1400

1450

1500

30 35 40 45 50 55 60 65 70 75 80

Bra

in V

olu

me

(m

L)

Age (years)


-5% -11%

early very

highly-effective

treatment

late very

highly-effective

treatment

-15%


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

Brain volume loss and CSF neurofilament levels should be included in our definition for 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

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?

• Only possible with induction therapies (alemtuzumab, cladribine, BMT, ? anti-CD20)

• Is it fair to make people with MS wait 20 years for the outcome of an ongoing experiment?

Acknowledgements

• Giovannoni

• Sharmilee Gnanapavan

• David Baker

• Gareth Pryce

• Sarah Al-Izki

• Sam Jackson

• Katie Lidster

• Yuti Chernajovsky

• Alex Annenkov

• Anne Rigby

• Michelle Sclanders

• Larry Steinman

• Peggy Ho

• Charles ffrench-Constant • Robin Franklin

• Siddharthan Chandran • David Hampton

• Ian Duncan • Sam Jackson

• Peter Calabresi • Avi Nath

• Raj Kapoor • John Zajicek • Doug Brown • UK MS Clinical Trial Network • BioMS

• Co-investigators

• NABINMS • Affirm study • Care MS 1 & 2 studies • Select trial

Health & Medicine

Top seminars biomarkers in MS