IPMSC Meeting Milan - Giovannoni Phase 2 Biomarker Studies
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Transcript of IPMSC Meeting Milan - Giovannoni Phase 2 Biomarker Studies
Study design and biomarkers for disease modifying treatment phase II clinical trials
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
Coles et al. J Neurol. 2006 Jan;253(1):98-108..
The window of therapeutic opportunity in multiple sclerosis
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
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
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
Frequency of sampling
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Daily Weekly
Biweekly Monthly
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
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
Gunnarsson et al. Ann Neurol 2010; Epub.
CSF NFL
38 year old woman with left optic neuritis
sTE fFLAIR images
Baseline 52 weeks
Hickman et al. Neuroradiology 2001;43:123-8.
Trapp et al. N Engl J Med 1998.
Acute mono-focal lesion
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
Acute neuroprotection
Me
an
Ro
taR
od
pe
rfo
rma
nc
e ±
SE
M (
s)
0
50
100
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250Vehicle
Oxcarbazepine from onset + 4 days
Pre treatment (RM1) Post treatment (RM2)Days Post EAE induction
33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48
Me
an
clin
ica
l s
co
re ±
SE
M
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
Vehicle
Oxcarbamazepine from onset + 4 days
Mean
Ro
taR
od
perf
orm
an
ce± S
EM
(s)
0
50
100
150
200
250vehicle
Oxcarbazepine from onset, 10mg/kg
Oxcarbazepine from onset + 2 days, 10mg/kg
Pre treatment (RM1) Post treatment (RM2)
Days post EAE induction
26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48
Me
an
clin
ica
l s
co
re ±
SE
M
0.0
0.5
1.0
1.5
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2.5
3.0
3.5
4.0 Oxcarbazepine from onset, 10mg/kg
Oxcarbazepine from onset + 2 days,10mg/kg
Vehicle
Dru
g-i
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uc
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ne
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tec
tio
n
THERAPEUTIC WINDOW OF
SODIUM CHANNEL BLOCKERS
Sodium Channel Blockers Induce Neuroprotection During Blood Brain Barrier Dysfunction
Period of Treatment
Period of Treatment
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
Slide courtesy of Klaus Schmierer, Neurology 2009.
Demyelination
Remyelination
Nogo, MAG, OMgP
Lingo-1-NgR-p75NTR
GAP-43
NCAM
Neuregulin
Nerve growth promoters and myelin inhibitors
NCAM in MS
Massaro Mult Scler 1998, 4:228-231.
CSF NCAM levels in neurological disorders
Gnanapavan et al. J Neuroimmunology, 2010, 225(1-2): 118-122
CSF NCAM levels in neurological disorders
Gnanapavan et al. J Neuroimmunology, 2010, 225(1-2): 118-122
Kapoor et al. Lancet Neurol 2010; 9: 681–88.
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
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1.0
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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
MS-STAT (Simvastatin): change in whole brain volume
Chataway J, et al. ECTRIMS 2012. Oral presentation 38a.
Ch
an
ge W
BV
%/y
ear
Mean Individual values
3
2
1
0
–2
–1
0 to 12 months 12 to 25 months 0 to 25 months
MS-STAT (simvastatin) secondary outcomes: disability
Model adjusting for minimisation variables and baseline Chataway J, et al. ECTRIMS 2012. Oral presentation 38a.
Outcome Mean (SD) placebo
Mean (SD) simvastatin
Difference in means (95% CI)
EDSS (score 0 to 10)
6.35 (0.83) 5.93 (1.11) –0.254 (–0.464 to –0.069)
MSIS total (score 29 to 116)
76.1 (16.3) 70.1 (15.6) –4.78 (–9.39 to –0.02)
MSIS physical (score 20 to 80)
56.3 (11.8) 51.7 (11.4) –3.73 (–7.18 to –0.28)
MSIS psychological (score 9 to 36)
19.8 (6.0) 18.3 (5.8) –1.09 (–2.83 to 0.84)
MSFC Z score -1.21 (2.59) -0.78 (2.06) 0.289 (–0.333 to 0.961)
MSFC walk (speed ft/s)
1.55 (1.19) 1.83 (1.61) 0.085 (–0.249 to 0.533)
MSFC peg test (1/s)
0.030 (0.014) 0.033 (0.010) 0.002 (–0.001 to 0.004)
MSFC PASAT (score 0 to 60)
35.2 (18.0) 38.3 (15.4) 4.45 (–0.11 to 8.84)
REMYELINATION
ANTI-INFLAMMATORY
NEURO RESTORATION
NEUROPROTECTION
1) OCT
2) CSF NF
3) Adaptive Design
PROMISE 2010 follow-on clinical trials
Phenytoin
Oxcarbazepine
Riluzole / Ibudilast / Amiloride
What are your expectations of a therapy for
progressive MS?
www.ms-res.org
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
• Dan Altman
• John Zajicek
• UK MS Clinical Trial Network
• BioMS