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Biomarkers and clinical outcome measures: challenges for progressive MS trials
Soluble body fluid biomarkers
Gavin Giovannoni
Barts and The London School of Medicine and Dentistry
“the current dogma” or “working hypothesis”
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
“the current dogma” or “working hypothesis”
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
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
“the current dogma” or “working hypothesis”
Selective trafficking of activated memory T-
cells
Antigen- presenting cell
apoptosis
T-cell elimination
B-cells
IL-4/5
CD4+-Th
Th2
Th1
Anti-myelin IgM/G
Astrocyte
Macrophage microglia
IFN-g / TNF-a/b
Th-r / Th-s
Astrocytosis / gliosis
Progenitor cells
Oligodendrocyte precursors
Acute axonal damage and transection
Oligoclonal CD8+ T-cells
g/dT-cells
NK-cells
Neomyelin-antigen presentation
CD8+, g/d T-cells and NK-cells
Focal lesion pathology: MS or EAE Pathogenesis
Immunological Time-Course of Gd-Enhancing MRI Lesions
Immunological Time-Course of Gd-Enhancing MRI Lesions
Immunological Time-Course of Gd-Enhancing MRI Lesions
Giovannoni et al. Eur Neurol 2000;44:222–228.
Immunological Time-Course of Gd-Enhancing MRI Lesions
Giovannoni et al. Eur Neurol 2000;44:222–228.
Frequency of sampling
100
1000
1000
0
1000
00
0 7 14 21 28 35 42 49 56 63 70 77 84
Days
Urin
ary N
eo
pte
rin
:Cre
ati
nin
e R
ati
o
mm
ol/
mo
l
100
1000
1000
0
1000
00
0 7 14 21 28 35 42 49 56 63 70 77 84
Days
Urin
ary N
eo
pte
rin
:Cre
ati
nin
e R
ati
o
mm
ol/
mo
l
100
1000
1000
0
1000
00
0 7 14 21 28 35 42 49 56 63 70 77 84
Days
Urin
ary N
eo
pte
rin
:Cre
ati
nin
e R
ati
o
mm
ol/
mo
l
100
1000
1000
0
1000
00
0 7 14 21 28 35 42 49 56 63 70 77 84
Days
Urin
ary N
eo
pte
rin
:Cre
ati
nin
e R
ati
o
mm
ol/
mo
l
Daily Weekly
Biweekly Monthly
Clinical - relapses
MRI – Gd-enhancing lesions
“The Iceberg Phenomenon”
Clinical - relapses
MRI – Gd-enhancing lesions
MRI – Gd-enhancing lesions
Pathology – gray matter & microscopic activity
“The Iceberg Phenomenon”
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
“the current dogma” or “working hypothesis”
Inflammatory markers • CSF vs. blood (serum or plasma) vs. urine
• Cells vs. mRNA vs. proteins
• Cells: static vs. functional assays
• Qualitative vs. quantitative analyses
• Target different components of the immune system
• Blood-brain-barrier: MMP-9/TIMP1
• Trafficking signals: sVCAM-1, CXCL13
• Microglia/Macrophage activation: sCD14, neopterin, ferritin
• B-cell markers: FLCs
• T-cells: phenotypic cytokine profiles
• In general inflammatory markers are poorly validated and not suitable as primary outcome measures
• Pre-analytical
• Analytical
• Validation
1. J Clin Oncol. 2005 Sep 19; Epub.
2. Nat Clin Pract Oncol. 2005 Aug;2(8):416-22.
3. Br J Cancer. 2005 Aug 22;93(4):387-91.
4. J Natl Cancer Inst. 2005 Aug 17;97(16):1180-4.
5. Eur J Cancer. 2005 Aug;41(12):1690-6.
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
“the current dogma” or “working hypothesis”
CSF
CSF
Blood
Urine
CSF vs. Blood vs. Urine
CSF
CSF
Blood
Urine
CSF vs. Blood vs. Urine
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
Lycke et al. J Neurol Neurosurg Psychiatry 1998;64:402–404.
Focal model
29
Reduced Nerve Damage
Normal mouse
Mea
n r
etin
a ce
ll d
ensi
ty (
cells
/mm
2)
1000
1100
1200
1300
1400
1500
1600
1700
1800
1900
OPTIC NEURITIS
+ Vehicle OPTIC NEURITIS +
CFM6104
CFM6104 Induces Neuroprotection in Optic Neuritis (Nerve Content)
P<0.01
NEUROPROTECTIVE STRATEGIES
IMMUNE-DEPENDENT NEURODEGENERATION
Acute neuroprotection
Ischemic penumbra
Neu
rop
rote
ctio
n
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-D48 Hindlimb
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)
***
Neu
ropr
otec
tion
Mea
n N
euro
logi
cal
Sco
re ±
SEM
Tim
e of
on
Acc
eler
atin
g R
otaR
od (
s)
CFMA Induces Neuroprotection in EAE
Immunologic penumbra
Acute neuroprotection
Acute neuroprotection
14 days
Delayed or post-inflammatory neurodegeneration
Coles et al. J Neurol. 2006 Jan;253(1):98-108..
The window of therapeutic opportunity in multiple sclerosis
Limp tail
Impaired righting reflex
hindlimb paralysis
Moribund
partial paralysis
Normal
Remission
Day 7 0
1
2
3
4
5
(1)
Clinical Score
Induction and assessment of chronic relapsing experimental allergic
encephalomyelitis
Day 0
Spinal cord homogenate in Freund’s complete adjuvant in ABH
Slide courtesy David Baker
Average disease course
ACUTE RELAPSE 1 RELAPSE 2
RELAPSE 3 CHRONIC
Slide courtesy Sam Jackson & Ian Duncan.
ctrl Day 29 Day 58
Day 105 Early-tolerisation Late-tolerisation
Slide courtesy David Hampton
Post-inflammatory SPMS
Prevention of relapsing CREAE after three paralytic episodes does not inhibit secondary progression and deterioration of mobility
Pryce et al. J Neuroimmunol 2005.
Secondary progressive EAE
Pryce et al. Brain 2003;126:2191-202.
Time (Days)
10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85
Mea
n C
linic
al S
core
± S
EM
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
Vehicle Cannabinoids
TREATMENT
Neuroprotection
CUPID (THC): EDSS progression over 3 years
Zajicek J, et al. ECTRIMS 2012. Oral presentation 161X.
Treatment group
Placebo
Active
0.0
0.2
0.4
0.6
0.8
1.0
0 200 400 600 800 1000 1200
P (
ED
SS
pro
gre
ss
ion
)
Time to EDSS progression (days)
CUPID (THC): EDSS progression according to
baseline EDSS score
Zajicek J, et al. ECTRIMS 2012. Oral presentation 161X.
Baseline EDSS score
6.5
5 5.5
4.5 4
6
0.0
0.2
0.4
0.6
0.8
1.0
0 200 400 600 800 1000 1200
P (
ED
SS
pro
gre
ss
ion
)
Time to EDSS progression (days)
Log rank test P = 0.01
CUPID (THC): EDSS progression in patients
with baseline EDSS <6 (post-hoc analysis)
Zajicek J, et al. ECTRIMS 2012. Oral presentation 161X.
n = 110
0.0
0.2
0.4
0.6
0.8
1.0
0 200 400 600 800 1000 1200
P (
ED
SS
pro
gre
ss
ion
)
Time to EDSS progression (days)
Treatment group
Placebo
Active
Petzold et al. J Neurol Neurosurg Psychiatry. 2005 Feb;76(2):206-11.
Spinal fluid neurofilament levels
Serum NfL in spinal cord injury
Bas
elin
e
Day
1
Day
2
Day
3
Day
4
Day
5
Day
6
Day
7
0
500
1000 Complete SCI
Incomplete SCI
Central cord
syndrome
* * ** ** ** ** ** ** * * * * * * *
Se
rum
NfL
(p
g/m
l)
(Mean and SEM*: p<0.05; **: p<0.01 for the comparison of complete SCI versus central cord syndrome)
Jens Kuhle, unpublished data
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
Phase 2A study: CSF markers of axonal damage and demyelination (secondary endpoints)
Romme Christensen J, et al. ECTRIMS 2012. Oral presentation 170.
NIND Mean +/- 95% CI
p=0.03
CSF
Ne
uro
fila
men
t lli
ght
ng/
L
p=0.048
CSF
MB
P n
g/m
l
NIND Mean +/- 95% CI
Recruitment Trial Data analysis
6 months
6 months 60 MS’ers
6 months
LP1 LP2 LP3
30 MS’ers active tablet
30 MS’ers placebo tablet
2 years
6 months
Gunnarsson et al. Ann Neurol 2010; Epub.
CSF NFL
UK Clinical Trial Network (CTN): phase 3 adaptive design
primary outcome EDSS progression
Placebo
Drug A
Drug B
Drug C
Drug D
futility analysis
2yrs 3yrs
7yrs
EDSS 1° outcome
?
UK Clinical Trial Network (CTN): phase 3 adaptive design
primary outcome EDSS progression
Placebo
Drug A
Drug B
Drug C
Drug D
futility analysis
2yrs 3yrs
7yrs
EDSS 1° outcome
?
Combination therapies
CUPID (THC): EDSS progression over 3 years
Zajicek J, et al. ECTRIMS 2012. Oral presentation 161X.
Treatment group
Placebo
Active
0.0
0.2
0.4
0.6
0.8
1.0
0 200 400 600 800 1000 1200
P (
ED
SS
pro
gre
ss
ion
)
Time to EDSS progression (days)
REMYELINATION
ANTI-INFLAMMATORY
NEURO RESTORATION
NEUROPROTECTION
1) OCT
2) CSF NF – PROXIMUS STUDY
3) Adaptive Design – SMART STUDY
Conclusions: PROMISE 2010 follow-on clinical trials
Phenytoin
Oxcarbazepine
Riluzole / Ibudilast / Amiloride
1) OCT
2) CSF NF – PROXIMUS STUDY
3) Adaptive Design – SMART STUDY
Conclusions: PROMISE 2010 follow-on clinical trials
Phenytoin
Oxcarbazepine
Riluzole / Ibudilast / Amiloride
Managing expectations
Key milestones in the development of Fingolimod
1992: Fingolimod (FTY720) first synthesized by Japanese scientists
1997: Fingolimod in-licensed by Novartis for clinical development
1998: First studies in man (Phase 1 trials) and subsequent start of transplantation trials
2003: Start of MS Phase II trial
June 2005: Presentation of Phase II study results followed by publication in NEJM 2006
Jan 2006: Start of Phase III FREEDOMS study in RRMS
May 2006: Start of Phase III TRANSFORMS study in RRMS
June 2006: Start of Phase III FREEDOMS II study in RRMS
July 2008: Start of Phase III INFORMS trial to assess suitability for treatment of PPMS
Dec 2008: Release of TRANSFORMS study results and presentation at AAN April 2009
Sep 2009: Release of FREEDOMS study results and presentation at AAN April 2010
Dec 2009: Regulatory submission to FDA and EMA (ROW submissions in Q1 2010)
Feb 2010: Results of Phase III TRANSFORMS & FREEDOMS studies published in NEJM
Sep 2010: Approval by Russian Health Authority
Sep 2010: Approval by the US FDA for relapsing MS
? 2015: ? approval by the US FDA for PPMS
What are your expectations of a therapy for
progressive MS?
www.ms-res.org
“the elephant in the room”
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
Change whole brain volume (%/yr)
Where to next?
Conclusions • Hypothesis driven
• Human biology
• Animal models
• When to treat?
• Early vs. late?
• Combination therapies
• In combination with an anti-inflammatory
• Targeting multiple pathways
• Smaller more responsive trials
• Biomarkers
• Adaptive design
• Go-no-go
• Manage expectations of the community
• Big Pharma Alternative (BPA)
• Repurposing of off-patent drugs
Acknowledgements
• Giovannoni
• Sharmilee Gnanapavan
• Axel Petzold
• Andrea Malaspina
• Jens Kuhle
• Jo Gaiottino
• Ahuva Nissm
• Amsterdam Group
• David Baker
• Gareth Pryce
• Sarah Al-Izki
• Katie Lidster
• Sam Jackson
• 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
• Jeremy Chataway
• David Miller
• Alan Thompson
• Klaus Schmierer
• Ben Turner
• Monica Marta
• Dan Altman
• John Zajicek
• UK MS Clinical Trial Network
• BioMS