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

150

200

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

2.0

2.5

3.0

3.5

4.0 Oxcarbazepine from onset, 10mg/kg

Oxcarbazepine from onset + 2 days,10mg/kg

Vehicle

Dru

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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

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

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