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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

Biomarkers and clinical outcome measures ms frontiers 2013

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Page 1: Biomarkers and clinical outcome measures   ms frontiers 2013

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

Page 2: Biomarkers and clinical outcome measures   ms frontiers 2013

“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

Page 3: Biomarkers and clinical outcome measures   ms frontiers 2013

“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

Page 4: Biomarkers and clinical outcome measures   ms frontiers 2013

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”

Page 5: Biomarkers and clinical outcome measures   ms frontiers 2013

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

Page 6: Biomarkers and clinical outcome measures   ms frontiers 2013

Immunological Time-Course of Gd-Enhancing MRI Lesions

Page 7: Biomarkers and clinical outcome measures   ms frontiers 2013

Immunological Time-Course of Gd-Enhancing MRI Lesions

Page 8: Biomarkers and clinical outcome measures   ms frontiers 2013

Immunological Time-Course of Gd-Enhancing MRI Lesions

Giovannoni et al. Eur Neurol 2000;44:222–228.

Page 9: Biomarkers and clinical outcome measures   ms frontiers 2013

Immunological Time-Course of Gd-Enhancing MRI Lesions

Giovannoni et al. Eur Neurol 2000;44:222–228.

Page 10: Biomarkers and clinical outcome measures   ms frontiers 2013

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

Page 11: Biomarkers and clinical outcome measures   ms frontiers 2013
Page 12: Biomarkers and clinical outcome measures   ms frontiers 2013

Clinical - relapses

MRI – Gd-enhancing lesions

“The Iceberg Phenomenon”

Page 13: Biomarkers and clinical outcome measures   ms frontiers 2013

Clinical - relapses

MRI – Gd-enhancing lesions

MRI – Gd-enhancing lesions

Pathology – gray matter & microscopic activity

“The Iceberg Phenomenon”

Page 14: Biomarkers and clinical outcome measures   ms frontiers 2013

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”

Page 15: Biomarkers and clinical outcome measures   ms frontiers 2013

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

Page 16: Biomarkers and clinical outcome measures   ms frontiers 2013

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.

Page 17: Biomarkers and clinical outcome measures   ms frontiers 2013
Page 18: Biomarkers and clinical outcome measures   ms frontiers 2013

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”

Page 19: Biomarkers and clinical outcome measures   ms frontiers 2013
Page 20: Biomarkers and clinical outcome measures   ms frontiers 2013
Page 21: Biomarkers and clinical outcome measures   ms frontiers 2013
Page 22: Biomarkers and clinical outcome measures   ms frontiers 2013

CSF

CSF

Blood

Urine

CSF vs. Blood vs. Urine

Page 23: Biomarkers and clinical outcome measures   ms frontiers 2013

CSF

CSF

Blood

Urine

CSF vs. Blood vs. Urine

Page 24: Biomarkers and clinical outcome measures   ms frontiers 2013

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

Page 25: Biomarkers and clinical outcome measures   ms frontiers 2013
Page 26: Biomarkers and clinical outcome measures   ms frontiers 2013

Neurofilament protein in cerebrospinal fluid: a potential marker of activity in multiple sclerosis

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

Page 27: Biomarkers and clinical outcome measures   ms frontiers 2013

Focal model

Page 28: Biomarkers and clinical outcome measures   ms frontiers 2013
Page 29: Biomarkers and clinical outcome measures   ms frontiers 2013

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

Page 30: Biomarkers and clinical outcome measures   ms frontiers 2013

Acute neuroprotection

Page 31: Biomarkers and clinical outcome measures   ms frontiers 2013
Page 32: Biomarkers and clinical outcome measures   ms frontiers 2013

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

Page 33: Biomarkers and clinical outcome measures   ms frontiers 2013

Acute neuroprotection

Page 34: Biomarkers and clinical outcome measures   ms frontiers 2013

Acute neuroprotection

14 days

Page 35: Biomarkers and clinical outcome measures   ms frontiers 2013

Delayed or post-inflammatory neurodegeneration

Page 36: Biomarkers and clinical outcome measures   ms frontiers 2013

Coles et al. J Neurol. 2006 Jan;253(1):98-108..

The window of therapeutic opportunity in multiple sclerosis

Page 37: Biomarkers and clinical outcome measures   ms frontiers 2013

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

Page 38: Biomarkers and clinical outcome measures   ms frontiers 2013

Average disease course

ACUTE RELAPSE 1 RELAPSE 2

RELAPSE 3 CHRONIC

Slide courtesy Sam Jackson & Ian Duncan.

Page 39: Biomarkers and clinical outcome measures   ms frontiers 2013

ctrl Day 29 Day 58

Day 105 Early-tolerisation Late-tolerisation

Slide courtesy David Hampton

Post-inflammatory SPMS

Page 40: Biomarkers and clinical outcome measures   ms frontiers 2013

Prevention of relapsing CREAE after three paralytic episodes does not inhibit secondary progression and deterioration of mobility

Pryce et al. J Neuroimmunol 2005.

Page 41: Biomarkers and clinical outcome measures   ms frontiers 2013

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

Page 42: Biomarkers and clinical outcome measures   ms frontiers 2013

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)

Page 43: Biomarkers and clinical outcome measures   ms frontiers 2013

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)

Page 44: Biomarkers and clinical outcome measures   ms frontiers 2013

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

Page 45: Biomarkers and clinical outcome measures   ms frontiers 2013
Page 46: Biomarkers and clinical outcome measures   ms frontiers 2013

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

Spinal fluid neurofilament levels

Page 47: Biomarkers and clinical outcome measures   ms frontiers 2013

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

Page 48: Biomarkers and clinical outcome measures   ms frontiers 2013
Page 49: Biomarkers and clinical outcome measures   ms frontiers 2013
Page 50: Biomarkers and clinical outcome measures   ms frontiers 2013

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

Page 51: Biomarkers and clinical outcome measures   ms frontiers 2013

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

Page 52: Biomarkers and clinical outcome measures   ms frontiers 2013
Page 53: Biomarkers and clinical outcome measures   ms frontiers 2013

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

Page 54: Biomarkers and clinical outcome measures   ms frontiers 2013

Gunnarsson et al. Ann Neurol 2010; Epub.

CSF NFL

Page 55: Biomarkers and clinical outcome measures   ms frontiers 2013

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

?

Page 56: Biomarkers and clinical outcome measures   ms frontiers 2013

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

?

Page 57: Biomarkers and clinical outcome measures   ms frontiers 2013

Combination therapies

Page 58: Biomarkers and clinical outcome measures   ms frontiers 2013

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)

Page 59: Biomarkers and clinical outcome measures   ms frontiers 2013
Page 60: Biomarkers and clinical outcome measures   ms frontiers 2013

REMYELINATION

ANTI-INFLAMMATORY

NEURO RESTORATION

NEUROPROTECTION

Page 61: Biomarkers and clinical outcome measures   ms frontiers 2013

1) OCT

2) CSF NF – PROXIMUS STUDY

3) Adaptive Design – SMART STUDY

Conclusions: PROMISE 2010 follow-on clinical trials

Phenytoin

Oxcarbazepine

Riluzole / Ibudilast / Amiloride

Page 62: Biomarkers and clinical outcome measures   ms frontiers 2013

1) OCT

2) CSF NF – PROXIMUS STUDY

3) Adaptive Design – SMART STUDY

Conclusions: PROMISE 2010 follow-on clinical trials

Phenytoin

Oxcarbazepine

Riluzole / Ibudilast / Amiloride

Page 63: Biomarkers and clinical outcome measures   ms frontiers 2013

Managing expectations

Page 64: Biomarkers and clinical outcome measures   ms frontiers 2013

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

Page 65: Biomarkers and clinical outcome measures   ms frontiers 2013

What are your expectations of a therapy for

progressive MS?

www.ms-res.org

Page 66: Biomarkers and clinical outcome measures   ms frontiers 2013

“the elephant in the room”

Page 67: Biomarkers and clinical outcome measures   ms frontiers 2013

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

Page 68: Biomarkers and clinical outcome measures   ms frontiers 2013

Change whole brain volume (%/yr)

Page 69: Biomarkers and clinical outcome measures   ms frontiers 2013

Where to next?

Page 70: Biomarkers and clinical outcome measures   ms frontiers 2013
Page 71: Biomarkers and clinical outcome measures   ms frontiers 2013

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

Page 72: Biomarkers and clinical outcome measures   ms frontiers 2013

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