Progressive MS Trials

Gavin Giovannoni

Barts and The London

Disclosures

Professor Giovannoni has received personal compensation for participating on Advisory Boards in relation to clinical trial design, trial steering committees and data and safety monitoring committees from: Abbvie, Bayer-Schering Healthcare, Biogen-Idec, Canbex, Eisai, Elan, Fiveprime, Genzyme, Genentech, GSK, GW Pharma, Ironwood, Merck-Serono, Novartis, Pfizer, Roche, Sanofi-Aventis, Synthon BV, Teva, UCB Pharma and Vertex Pharmaceuticals.

Regarding www.ms-res.org survey results in this presentation: please note that no personal identifiers were collected as part of these surveys and that by completing the surveys participants consented for their anonymous data to be analysed and presented by Professor Giovannoni.

Professor Giovannoni would like to acknowledge and thank the pharmaceutical companies and collaborators for making available their data and slides for this presentation.

The current dogma wrong

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.

Post-inflammatory neurodegeneration

The current dogma wrong

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

?

? ?

?

Brain atrophy

Control Multiple sclerosis

Brain atrophy: the pathological integrator

Brain atrophy occurs across all stages of the disease

De Stefano, et al. Neurology 2010

n= 963 MSers

Sormani et al. Ann Neurol 2013, In Press.

Treatment effect on brain atrophy correlates

with treatment effect on disability in MS

Treatment effect on brain atrophy correlates

with treatment effect on disability in MS

Sormani et al. Ann Neurol 2013, In Press.

Rationale for sodium channel blockade

Waxman SG. Nat Rev Neurosci. 2006 Dec;7(12):932-41. Videos courtesy Hugh Bostock, Inst. Neurol., UCL

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

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

Gnanapavan et al. PLoS One. 2013 Aug 1;8(8):e70019.

MS-STAT trial: high dose oral simvastatin in secondary progressive MS

change whole brain volume (%/yr)

CTN:NCT00647348

EUDRACT NUMBER 2006-006347-31 Chataway et al. in press 2013.

BSI

Boundary Shift Integral

1. Whole brain atrophy (mean Δ) = -0.254%/year [95% CI -0.423 to -0.085], p=0.003 2. EDSS = -0.254 [-0.464 to -0.069], p<0.01 3. MSIS-29 = -4.78 [-9.39 to -0.02], p<0.05

EDSS

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

Cannabinoid use in progressive inflammatory brain disease: CUPID study

Slides courtesy of Prof. John Zajicek

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

Cannabinoid use in progressive inflammatory brain disease: CUPID study

Slides courtesy of Prof. John Zajicek

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

Cannabinoid use in progressive inflammatory brain disease: CUPID study

Slides courtesy of Prof. John Zajicek

Active tablet

Placebo tablet

Year 1 Year 2 Year 3

600 MS’ers

300 MS’ers

300 MS’ers

Year +1 Year +2 Year +3 Year +4 Year +5

IFNbeta-1b

Placebo No treatment

Interferon beta-1b for the treatment of primary progressive MS 5-year clinical trial follow-up

Tur et al. Arch Neurol. 2011;68(11):1421-1427.

Progression

from

inflammation

in years +3.

Note the

slopes are

parallel

because

IFNbeta was

stopped after

year +2

Progression from

inflammation in

years +1 and +2.

Note PPMSers treated with

IFNbeta in years +1 and +2 do

better in years +3 and + 4 due

to the delayed effect of

suppressing inflammation.

Progression from

inflammation in

years -2 and -1

Year -2 Year -1 Year +1 Year +2 Year +3 Year +4 Year +5

IFNbeta-1b

Placebo

Delayed effect on disability

progression from IFNbeta

treatment in years 1 & 2

ED

SS

/ M

SF

C / c

og

nit

ion

/ b

rain

atr

op

hy

No treatment No treatment

Neurofilaments

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

Spinal fluid neurofilament levels

Gunnarsson et al. Ann Neurol 2010; Epub.

CSF NFL

600 MS’ers for 7 years 60 MS’ers for 2 years

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

OCT

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

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

Al-Izki et al. 2013 In Press

Trapp et al. NEJM 1998

Adaptive design

UK Clinical Trial Network (CTN): phase 3 adaptive design

primary outcome EDSS progression

SMART STUDY

Ibudilast Riluzole

Amiloride

vs.

Placebo

Targeting pathology

B cell follicle-like structures and disease progression

Schmierer-Lab, Blizard Institute

Magliozzi et al. Brain (2007), 130, 1089^1104

Rituximab in PPMS results of a randomized double-blind placebo-controlled trial. The OLYMPUS STUDY

Hawker et al. Ann Neurol 2009;66:460–471.

Ocrelizumab phase 2 extension study: reduction in Gd-enhancing T1 lesions by OCR is maintained through 144 Weeks

1. Kappos L, et al. Lancet. 2011;378(9805):1779–87; 2. Kappos L, et al. Abstract presented (P362) ECTRIMS 2012 , October 12

*p<0.0001 for both OCR doses vs placebo, N (for primary analysis): Placebo=54, OCR 600 mg=51, OCR 1000 mg=52, IFN-β1a=522

aPatients who withdrew during earlier treatment cycles were also included in the follow-up periods

REMYELINATION

ANTI-INFLAMMATORY

NEURO RESTORATION

NEUROPROTECTION

The therapeutic pyramid: combination therapies

Existing strategies or drugs in progressive MS

Fingolimod has an early and sustained effect on the rate of brain atrophy compared with placebo and IFNb-1a IM

FREEDOMS, 2 years

Fingolimod 0.5 mg (n = 356)

Placebo (n = 329)

***

* **

6 0 12 24

Time (months)

0

-0.4

-0.8

-1.2

-1.6

-2.0

−38%

vs placebo p<0.001

Ch

ange

in m

ean

BV

fro

m

bas

elin

e (%

)

TRANSFORMS, 1 year

0 12

Time (months)

0.0

-0.4

-0.6

-1.0

IFNb-1a IM (n = 359)

Fingolimod 0.5 mg (n = 368)

−40%

vs IFNb-1a IM p<0.001

*** -0.2

-0.8

Ch

ange

in m

ean

BV

fro

m

bas

elin

e (%

)

ITT population with evaluable MRI images. Note: n numbers for FREEDOMS data reflect the number of patients with available data at 24 months. *p<0.05; **p<0.01; ***p<0.001 vs comparator; p-values are for comparisons over Months 0-6, Months 0-12, Months 0-24 BV, brain volume; ITT, intent-to-treat. Gilenya™ Prescribing Information 19 April 2012. Reproduced with permission. Kappos L et al. N Engl J Med 2010; 362: 387-401, and Cohen JA et al. N Engl J Med 2010; 362: 402-415. Copyright © 2011 Massachusetts Medical Society. All rights reserved

-1.0%

-0.8%

-0.6%

-0.4%

-0.2%

0.0% Years 0-2

-0.82%

-0.80%

P=0.822†

Placebo (N=315) Natalizumab (N=627)

Year 0-1* Year 1-2

-0.40%

-0.56%

-0.43%

-0.24%

P=0.004†

P=0.002†

†Difference between treatments; ‡Change from baseline; Miller DH et al. Neurology 2007;68:1390-1401.

AFFIRM: natalizumab and brain atrophy

Mean

(S

E)

perc

en

tag

e c

han

ge i

n B

PF

Other potential drugs for progressive MS

BRAVO: reduced rate of brain volume loss

*Adjusted for baseline characteristics.

Reference: 1. Vollmer T et al. Presented at: 5th Joint Triennial Congress of the European and Americas Committee for Treatment and Research in Multiple Sclerosis; October 19-22, 2011; Amsterdam, Netherlands. Abstract 148. Mult Scler. 2011;17:S507.

44

27.5% Reduction P<0.0001

-1.4

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

-27.4% Improvement P<0.0001

LAQUINIMOD 0.6mg

PLACEBO

-1.14% -0.83% Percent Brain Volume

Change* (Months 0-24)

-1.25%

AVONEX® 30mcg

+9% Deterioration P=0.14

Laquinimod: Percent of brain volume

change from baseline to month 24

% C

ha

ng

e F

rom

Ba

se

line

-1.2

-0.4

-1.6

-0.8

Placebo (n = 1006)

Laquinimod 0.6 mg (n = 984)

0

-1.188

-0.834

POOLED

30% P<0.0001

Vollmer T et al. Presented at 64th American Academy of Neurology Annual meeting, New Orleans 2012 Session S01.007

Keap1 Nrf2

ARE

Nrf

2

Maf Jun

ATF4

Nucleus

Keap1

• Detoxification enzymes • Antioxidant enzymes • NADPH-generating enzymes

(NQ01) • GSH biosynthesis enzymes • Chaperones • Ubiquitination / proteasome

• Detoxification • Normalization of energy metabolism • Repair / degradation of damaged proteins

O

O

O

O DMF (BG00012)

BG12 or DMF Nrf2 signaling pathway regulates cellular response to oxidative stress

Cell Body

Kappos L et al. Lancet 2008; 372:1463–72

Arnold et al. ECTRIMS 2012, Lyon.

BG12: brain atrophy in the DEFINE study

Alemtuzumab: brain atrophy in the CARE-MS I & II studies

Daclizumab HYP in RRMS: SELECTION extension study

Giovannoni et al. AAN 2013, San Diego.

Brain atrophy: daclizumab SELECTION study

Radue et al. ECTRIMS 2013, Copenhagen.

1) OCT

2) CSF NF

3) Adaptive Design

Conclusions

• Shift in paradigm to prevention of progressive MS

• Could early highly effective treatments, particularly induction therapies, prevent SPMS?

• Treatment pyramid

• anti-inflammatory – neuroprotection – remyelination - neurorestoration

• Neurodegeneration

• Present from the outset; CIS and the pre-symptomatic stage

• Brain atrophy and other biomarkers, in particular CSF neurofilament levels, are very promising

• Time course of neurodegeneration needs to be better defined; may need 4-5 year studies

• Combination therapy trials needed; for example alemtuzumab and laquinimod

• Large number of targets

• Several phase 3 studies underway

• PPMS – fingolimod, ocrelizumab

• SPMS – natalizumab, siponimod

• More in the pipeline

• Several phase 2 trials in progress

• What to do about the repurposing of existing drugs?

• Big Pharma Alternative

• Manage expectations of people with MS

WHAT ARE YOUR EXPECTATIONS OF A THERAPY FOR PROGRESSIVE MS?

53

1

2

3

www.ms-res.org

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

• John Zajicek

• Doug Brown

• UK MS Clinical Trial Network

• BioMS

Theoretical model: treat early and effectively

Natural course of disease

Later intervention

Later treatment

Treatment at diagnosis Intervention

at diagnosis

Time Disease Onset

Dis

abili

ty

Time is brain

The current dogma

Image adapted from Compston A, Coles AJ. Lancet 2008;372:1502-17.

MRI Events

Time (Years)

Inflammation

Brain volume

Axonal loss

Dis

eas

e S

eve

rity

SPMS RRMS CIS RIS