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6/29/2015
1
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.
6/29/2015
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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)
Fingolimod 0.5 mg (n = 368)
−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.
Spinal fluid neurofilament levels
“Post‐inflammatory slow‐burn”
Trapp et al. NEJM 1998
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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”
Trapp et al. NEJM 1998
Petzold et al. J Neurol Neurosurg Psychiatry. 2005 Feb;76(2):206‐11.
Spinal fluid neurofilament levels
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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
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)
Fingolimod 0.5 mg (n = 368)
−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
Gunnarsson et al. Ann Neurol 2010; Epub.
Gunnarsson et al. Ann Neurol 2010; Epub.
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
Trapp et al. NEJM 1998
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
Therapeutic window 2
Therapeutic window 4
Upper limb sensory
Upper limb motor
Cognition
Vision
Etc.
Therapeutic window 6
Therapeutic window 7
Therapeutic window 8
Therapeutic window 9
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