Neuroprotective strategies in MS: addressing an unmet need

PROMISE 2010 UPDATE

Gavin Giovannoni

Barts and The London School of Medicine and Dentistry

WWW.MS-RES.ORG

Broken promises?

Our “Promise 2010” goals

1. “We will develop and validate effective experimental models for studying the

intricate relationship between inflammation, neuroprotection and

neurorestoration.”

2. “These experimental models will then be used to study specific

neuroprotective and neurorestorative therapeutic strategies.“

3. “In parallel we will develop novel clinical trial designs aimed at studying focal

nervous system repair and more global neuroprotection strategies in people

with MS.”

4. “Using both the experimental models and clinical studies in subjects with MS

we will identify biomarkers to non-invasively monitor nervous system repair and

protection.”

Goal 4

1. “We will develop and validate effective experimental models for studying the

intricate relationship between inflammation, neuroprotection and

neurorestoration.”

2. “These experimental models will then be used to study specific

neuroprotective and neurorestorative therapeutic strategies.“

3. “In parallel we will develop novel clinical trial designs aimed at studying focal

nervous system repair and more global neuroprotection strategies in people

with MS.”

4. “Using both the experimental models and clinical studies in subjects with MS

we will identify biomarkers to non-invasively monitor nervous system repair and

protection.”

Waxman SG. Nat Rev Neurosci. 2006 Dec;7(12):932-41.

Rationale for sodium channel blockade

Bechtold et al. Ann Neurol 2004;55:607–616

Kapoor et al. Lancet Neurol 2010; 9: 681–88.

Kapoor et al. Lancet Neurol 2010; 9: 681–88.

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

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

Spinal fluid neurofilament levels

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

Spinal fluid neurofilament levels

NfH Absent

Below median

Above median

% complting test

0

10

20

30

40

50

60

70

80

90

100

Seconds

0 30 60 90 120 150 180 210 240

Blood neurofilament levels & 25-foot walk (secs)

Gnanapavan et al. Submitted 2012.

New trial design

Are you prepared to have 3 LPs?

Active tablet

Placebo tablet

Year 1 Year 2 Year 3

600 MSers

300 MSers

300 MSers

Year 3 Year 4 Year 5

600 MSers

300 MSers

300 MSers

Year 1 Year 2 Year 6 Year 7

Recruitment Trial Data analysis Registration

7 years

Axonal damage in relapsing MS is markedly reduced by natalizumab

Gunnarsson et al. Ann Neurol 2010; Epub.

=

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

Results: Secondary endpoints

CSF markers of axonal damage and demyelination:

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

600 MSers for 7 years 60 MSers for 2 years

3 LPs = 10x as many trials in a ⅓ of the time

13%

66%

21%

n = 127

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

The window of therapeutic opportunity in multiple sclerosis

Goal 1

1. “We will develop and validate effective experimental models for studying the

intricate relationship between inflammation, neuroprotection and

neurorestoration.”

2. “These experimental models will then be used to study specific

neuroprotective and neurorestorative therapeutic strategies.“

3. “In parallel we will develop novel clinical trial designs aimed at studying focal

nervous system repair and more global neuroprotection strategies in people

with MS.”

4. “Using both the experimental models and clinical studies in subjects with MS

we will identify biomarkers to non-invasively monitor nervous system repair and

protection.”

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

T cell deletion prior to intravenous antigen induces tolerance that inhibits EAE

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

Pryce et al. J Neuroimmunol 2005.

Kappos et al. N Engl J Med. 2010 Feb 4;362(5):387-401.

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

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

Goal 3

1. “We will develop and validate effective experimental models for studying the

intricate relationship between inflammation, neuroprotection and

neurorestoration.”

2. “These experimental models will then be used to study specific

neuroprotective and neurorestorative therapeutic strategies.“

3. “In parallel we will develop novel clinical trial designs aimed at studying focal

nervous system repair and more global neuroprotection strategies in people

with MS.”

4. “Using both the experimental models and clinical studies in subjects with MS

we will identify biomarkers to non-invasively monitor nervous system repair and

protection.”

Acute neuroprotection

Year 3 Year 4 Year 5

600 MSers

300 MSers

300 MSers

Year 1 Year 2 Year 6 Year 7

Recruitment Trial Data analysis Registration

7 years

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

?

Gunnarsson et al. Ann Neurol 2010; Epub.

CSF NFL

Goal 2

1. “We will develop and validate effective experimental models for studying the

intricate relationship between inflammation, neuroprotection and

neurorestoration.”

2. “These experimental models will then be used to study specific

neuroprotective and neurorestorative therapeutic strategies.“

3. “In parallel we will develop novel clinical trial designs aimed at studying focal

nervous system repair and more global neuroprotection strategies in people

with MS.”

4. “Using both the experimental models and clinical studies in subjects with MS

we will identify biomarkers to non-invasively monitor nervous system repair and

protection.”

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

0 200 400 600 800 1000 1200

0.0

0.2

0.4

0.6

0.8

1.0

Time to EDSS progression (days)

P(E

DS

S p

rog

ressio

n)

Treatment group

Active

Placebo

0 200 400 600 800 1000 1200

0.0

0.2

0.4

0.6

0.8

1.0

Time to EDSS progression (days)

P(E

DS

S p

rog

ressio

n)

Baseline EDSS score

4

4.5

5

5.5

6

6.5

0 200 400 600 800 1000 1200

0.0

0.2

0.4

0.6

0.8

1.0

Time to EDSS progression (days)

P(E

DS

S p

rog

ressio

n)

Treatment group

Active

Placebo

Log rank test P = 0.01

X X

Not 7 years, but 10 years

Cannabinoid Use in Progressive Inflammatory brain Disease (CUPID)

Year 3 Year 4 Year 5

600 MSers

300 MSers

300 MSers

Year 1 Year 2 Year 6 Year 7

Recruitment Trial Data analysis Registration

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

Broken promises?

Did we achieve our “Promise 2010” goals?

1. “We will develop and validate effective experimental models for studying the

intricate relationship between inflammation, neuroprotection and

neurorestoration.”

2. “These experimental models will then be used to study specific

neuroprotective and neurorestorative therapeutic strategies.“

3. “In parallel we will develop novel clinical trial designs aimed at studying focal

nervous system repair and more global neuroprotection strategies in people

with MS.”

4. “Using both the experimental models and clinical studies in subjects with MS

we will identify biomarkers to non-invasively monitor nervous system repair and

protection.”

1) OCT

2) CSF NF

3) Adaptive Design

Follow-on grants – clinical trials

Follow-on grants – basic science or preclinical

1. David Selwood & David Baker, NMSS FastForward: Development of a

selective cyclophilin D (CyP-D) blocker as a new MS drug.

2. David Baker, Yuti Chernajovsky, Robin Franklin, Charles ffrench-Constant,

Siddharthan Chandran. NMSS. Engineered precursors as a delivery

mechanism for neuroprotective therapies.

3. David Baker, Pete Coffey, Gianvito Martino: UK Stem cell Foundation &

MS Society. Transplanting neural stem cells in optic neuritis.

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

Segmentation

• Then repeat and screening scans are registered using a 12dof affine registration. – Linear transformation (rotation, translation, scaling and shear) to spatially align repeat scan

to the baseline scan.

• This registration step allows for the automatic quantification of longitudinal changes with the BSI (Boundary Shift Integral).

Whole brain segmentation in Native Space

3D rendered image

Whole brain volumes generated

Change whole brain volume (%/yr)

Secondary outcomes: Disability

Model adjusting for minimisation variables and baseline

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)

Where to next?

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

• Jeremy Chataway

• David Miller

• Alan Thompson

• Klaus Schmierer

• Ben Turner

• Dan Altman

• John Zajicek

• Doug Brown

• UK MS Clinical Trial Network

• BioMS

Questions