csf axonal injury...brain atrophy spinal fluid neurofilament levels ms iceberg clinical activity...

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CSF Axonal Injury Markers

Gavin Giovannoni

Barts and The London

Disclosures

Professor Giovannoni has received personal compensation for participating on AdvisoryBoards in relation to clinical trial design, trial steering committees and data and safetymonitoring 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 VertexPharmaceuticals.

Regarding www.ms‐res.org survey results in this presentation: please note that nopersonal identifiers were collected as part of these surveys and that by completing thesurveys participants consented for their anonymous data to be analysed and presented byProfessor Giovannoni.

Professor Giovannoni would like to acknowledge and thank many colleagues, Biogen‐Idec,Genzyme and Novartis for making available slides and data for this presentation.

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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

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

MS Iceberg

Clinical activity

Focal MRI activity

Hidden focal and diffuse MRI activity

Microscopic or biochemical pathology

Biomarkers

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End‐organ damage

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ESRFend‐stage renal failure

Control Multiple sclerosis

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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)

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.

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-targetNo 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

Normalisation of the rate of brain atrophy (NEDA-4)

NEDA-3

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-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

erce

nta

ge

chan

ge

in 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)

***

*

**

60 12 24

Time (months)

0

‐0.4

‐0.8

‐1.2

‐1.6

‐2.0

−38%vs placebop<0.001

Change in

mean BV from

baseline (%

)

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

Change in

mean BV from

baseline (%

)

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

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Reduction in brain atrophy on alemtuzumab

Coles et al. AAN 2015L (7.263)

Residual deficits:• Walking distance >500m• Unable to run • Exercise induces intermittent

sensory symptoms in L arm• Mild urinary frequency

17-yr girl, myelitis

Jun-2000

1st-yr University L-optic neuritis

Feb-2001

clumsy left hand

Jan -2002

pins & needles in legs

Oct-2003

R optic neuritis

Mar-2004

Brainstem syndrome;

diplopia and ataxia

Dec 2007

Cervical cord relapse

weak L arm with pain

Jan 2008

Bladder dysfunction

depression, anxiety and

fatigue

Reduced mobility

Mild urinary frequency

No depression ,anxiety or fatigue

Fully mobile

NEDA (no evident disease activity)

Feb-2008 to May-2014

IFN-beta

Feb-2001

Natalizumab

Jan-2008

ED

SS

IFN-beta NatalizumabJun-2000 May-2014

6.0

3.5 3.5

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MRI – progressive brain atrophy

Dec 2007 Jul 2010 Jul 2013

MS is an iceberg?

Clinical

MRI

Pathology

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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

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Acute axonal transection “Acute inflammatory scissors or shredder”

Delayed secondary neurodegeneration

“Post‐inflammatory slow‐burn”

Acute Neuroprotection

Chronic Neuroprotection

vs.

Trapp et al. NEJM 1998

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

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


“Post‐inflammatory slow‐burn”


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Neurofilament protein in cerebrospinal fluid: apotential marker of activity in multiple sclerosis

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

“Acute inflammatory scissors

orshredder”


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


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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

Mea

n (

SE

) p

erce

nta

ge

chan

ge

in B

PF

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

Romme Christensen et al. Neurology. 2014 Apr 29;82(17):1499‐507.

Natalizumab → SPMS (ASCEND STUDY)ClinicalTrials.gov ID: NCT01416181

Gunnarsson et al. Ann Neurol 2010.

R‐MS

Fingolimod and CSF neurofilament light chain levels in relapsing‐remitting multiple sclerosis

Fingolimod → PPMS (INFORMS STUDY)ClinicalTrials.gov ID:NCT00731692

Siponimod → SPMS (EXPAND STUDY)ClinicalTrials.gov ID: NCT01665144Khule et al. Neurology. 2015 Apr 21;84(16):1639‐43.

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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)

***

*

**

60 12 24

Time (months)

0

‐0.4

‐0.8

‐1.2

‐1.6

‐2.0

−38%vs placebop<0.001

Change in

mean BV from

baseline (%

)

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

Change in

mean BV from

baseline (%

)

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

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Axonal damage in R‐MS is markedly reduced by Natalizumab



CSF NFL

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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

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600MSers for 7 years 60MSers for 2 years

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

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13%

66%

21%

n = 127

MRI Events

1st clinicalattack

Time (Years)

Subclinical disease

Inflammation

Brain volume loss

Neuroaxonal loss

Disease Severity

SPMSRRMS

1st MRI lesion

Relapses

CISRIS 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 STUDYibudilast, amiloride, riluzole

Early SPMS: PROXIMUSoxcarbazepine

CIS: PHENYTOIN RRMS: ? DE‐FLAMES STUDY

PPMS

PPMS: Fingolimod, Ocrelizumab, Laquinimod

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Brain atrophy occurs across all stages of the disease

De Stefano, et al. Neurology 2010

n= 963 MSers

Acute neuroprotection

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Primary outcome: RNFL

• Active‐placebo adjusteddifference 7.15 m(95% CI 1.08, 13.22p=0.02)

• 30% reduction of atrophyin active group

• PP comparison:Active‐placebo adjusteddifference 7.40 m(95% CI 0.76, 14.04p=0.03)

50

10

01

50

RN

FL

ave

rag

e

m

Placebo Phenytoin

baseline UNaffected eye

Placebo Phenytoin

6m affected eye

Bars are standard errors around the unadjusted group means

Kapoor et al. AAN 2015

Ischaemic penumbra

Neuroprotection

Time Post‐Disease Induction (days).

32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

Vehicle

CFMA D33‐D48Hindlimb

Paralysis

Hindlimb

Paresis

Impaired

Right

Reflex

Tail Paresis

Tail

Paralysis

Period of Daily Treatment

No Immunosuppression Evident

ROTAROD ACTIVITY

Measure of Motor Co‐ordination

Pre‐Treatment (Day 27)

0

50

100

150

200

250

300

Post‐ Relapse (Day 48)

***

Neuroprotection

Mean

Neurological Score ±SEM

Time of on

Accelerating

RotaRod (s)

CFMA Induces Neuroprotection in EAE

Immunologic penumbra


Al‐Izki et al. Brain. 2014 Jan;137(Pt 1):92‐108.

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MRI Events

1st clinicalattack

Time (Years)

Subclinical disease

Inflammation

Brain volume loss

Neuroaxonal loss

Disease Severity

SPMSRRMS

1st MRI lesion

Relapses

CISRIS 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 STUDYibudilast, amiloride, riluzole

Early SPMS: PROXIMUSoxcarbazepine

CIS: PHENYTOIN RRMS: ? DE‐FLAMES STUDY

PPMS

PPMS: Fingolimod, Ocrelizumab, Laquinimod

Therapeutic lag

Yr ‐1 Yr ‐2 Yr +1 Yr +2 Yr +3 Yr +4 Yr +5 Yr +6 Yr +7

IFN‐beta‐1b

Placebo

Notreatment

No treatment

9HPT, cognition, brain atrophy

Progression from inflammation in years ‐2 and ‐1

Progression from inflammation in years +1 and +2

Progression from inflammation in years +3 to +5

Note the slopes are now parallel

because IFN‐beta was stopped after

year +2

Delayed effect on disability progression from IFN‐beta treatment in years 1 & 2

TimeTur et al. Arch Neurol. 2011 Nov;68(11):1421‐7.

Therapeutic Lag

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Therapeutic window 5

Asynchronous progressive MS hypothesis

Motor system to legs

Lower limb sensory

BladderTherapeutic window 1



Upper limb sensory

Upper limb motor

Cognition

Vision

Etc.





Therapeutic window 10, etc….

Diagnosis of clinically‐apparent progressive MS

Effective DMTs could still target the remaining windows of therapeutic opportunity for individual neurological systems despite some systems have entered the clinically‐apparent progressive phase of the disease

Cerebellar or balance systems

Control Multiple sclerosis

End‐organ damage

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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-targetNo 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

Normalisation of the rate of brain atrophy (NEDA-4)

Normalisation of CSF neurofilament levels (NEDA-5)

NEDA-3

Fingolimod and CSF neurofilament light chain levels in relapsing‐remitting multiple sclerosis

Fingolimod → PPMS (INFORMS STUDY)ClinicalTrials.gov ID:NCT00731692

Siponimod → SPMS (EXPAND STUDY)ClinicalTrials.gov ID: NCT01665144Khule et al. Neurology. 2015 Apr 21;84(16):1639‐43.

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Remyelination

Nogo, MAG, OMgP

Lingo-1-NgR-p75NTR

GAP-43

NCAM

Neuregulin

Slide courtesy of Klaus Schmierer.

Agents in trial

1. GSK239512: histamine H(3) receptor antagonist

2. BIIB033: anti-LINGO-13. Clemastine: anti-histamine4. IRX4204 & Bexarotene: RXR-

agonists5. Etc.

Conclusions

• MS is an “iceberg” – we need to measure markers of subclinical damage

• Early highly‐effective therapy is a realistic option of preventing end‐organ damage

• Treat‐2‐target of NEDA (DAF) is gradually being adopted

• Zero tolerance or ZeTo

• Markers of end‐organ damage

• Brain atrophy

• OCT

• CSF neurofilament levels

• Neuroprotection

• Acute neuroprotection, e.g. phenytoin in acute optic neuritis

• Delayed neuroprotection, ?

• Remyelination

• Several trials underway

Neuro‐restoration

Remyelination

Neuroprotection

Anti‐inflammatory

Therapeutic pyramid

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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

csf axonal injury...brain atrophy spinal fluid neurofilament levels ms iceberg clinical activity...

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