1

27 November 2015, Milan, Italy

23rd Annual Meeting of the

European Charcot Foundation

Brain health:

why time matters

in multiple sclerosis

This event is hosted by the Oxford Health Policy Forum and is funded by grants from AbbVie and Genzyme and by

educational grants from Biogen, F. Hoffmann-La Roche and Novartis, all of whom had no influence on the content

#MSTimeMatters

2

Queen Mary University London, Blizard Institute,

Barts and The London School of Medicine and Dentistry,

London, UK

Gavin Giovannoni

Brain health:

why time matters

in multiple sclerosis

This event is hosted by the Oxford Health Policy Forum and is funded by grants

from AbbVie and Genzyme and by educational grants from Biogen, F. Hoffmann-

La Roche and Novartis, all of whom had no influence on the content

3

Disclosures

■ G Giovannoni has received consultancy fees for advisory board meetings from Biogen

Idec, Genzyme Sanofi, Merck Serono and Novartis, relating to a phase 3 trial

programme in MS from GSK, relating to data safety monitoring board activities from

Synthon BV, and for his role as an author of the report, Brain health: time matters in

multiple sclerosis, from Oxford PharmaGenesis, UK, funded by F. Hoffmann-La Roche;

has served on steering committees for AbbVie, Biogen Idec, Novartis, Roche and Teva;

and has received honoraria for speaking at medical education meetings from Genzyme

Sanofi and at a physicians’ summit from Biogen Idec

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The MS journey

Epstein Bar Virus

Genetics

Vitamin D

Smoking

Risks

Adverse events

DifferentialDiagnosis

MRI

EvokedPotentials

Lumbar puncture

BloodTests

DiagnosticCriteria

Cognition

Depression

Fatigue

Bladder

Bowel

Sexual dysfunction Tremor

PainSwallowing

SpasticityFalls

Balance problems Insomnia

Restless legsFertility

Clinical trials

Gait

Pressuresores

Oscillopsia

Emotionallability

Seizures

Gastrostomy

Rehab

Suprapubiccatheter Intrathecal

baclofen

Physio-therapy

Speech therapy

OccupationalTherapy

Functional neurosurgery

Colostomy

Tendonotomy

Studying

EmploymentRelationships

Travel

Vaccination

Anxiety

Driving

Nurse specialists

Family counselling

Relapses

1st line

2nd line

Maintenance Escalation Induction

Monitoring

Disease-free

Disease progression

DMTs

Side Effects

Advanced Directive

Exercise

Diet

AlternativeMedicine

PregnancyBreastFeeding

Research

Insurance

Visual loss

PalliativeCare

Assistedsuicide

Socialservices

Legalaid

Genetic counselling

Prevention

Diagnosis

DMT

Symptomatic

Therapist

Terminal

Counselling

Intrathecalphenol

Fractures

Movement disorders

Osteopaenia

Brain atrophy

Hearing loss

Tinnitus

Photophobia

Hiccoughs

DVLA

Neuroprotection

Psychosis

Depersonaliation

BrainHealth

CognitiveReserve

Sudden death

Suicide

OCD

Narcolepsy

Apnoea

Carers

Respite

Hospice

Respite

Dignitas

Advanced Directive

Rhiztomy

Wheelchair

Walking aids

Blood/Organdonation

Brain donation

Exercise therapy

NABs

Autoimmunity

Infections

Outcome measures

WebResources

Pathogenesis

Doublevision

What isMS?

NEDA

T2TOCT

Neurofilaments

JCV statusPharma

Anaesthesia

www.ms-res.org

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Rapid adoption of innovations has

the potential to improve MS care

Reproduced and adapted from Rogers EM. Diffusion of innovation. New York: Simon and Schuster, 2003

100

80

60

40

20

0

Pro

po

rtio

n o

f ad

op

ters

(%

)

Innovators

Early adopters

Majority adopters

Late adopters

Laggards

30% tipping point

Time

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Slow adoption of innovations results

in healthcare inequity

Perf

orm

ance

Time1 2

1st line

2nd and 3rd line

Old

New

Newer

3rd line

2nd line

1st line

7

Australia

Norway

Denmark

Sweden

Belgium

Austria

Germany

France

Finland

Spain

Italy

Slovenia

United Kingdom

Poland

0 20 40 60 80 100

Large disparities exist in access to

disease-modifying therapies

DMT, disease-modifying therapy

1. Hollingworth S et al. J Clin Neurosci 2014;21:2083–7; 2. World Bank, 2015. http://data.worldbank.org/indicator/SP.POP.TOTL; 3. MSIF, 2013. http://www.atlasofms.org; 4.

Wilsdon T et al. 2013. http://crai.com/sites/default/files/publications/CRA-Biogen-Access-to-MS-Treatment-Final-Report.pdf

Newer DMT

Established DMT

No DMT

All people with MS (%)

All data are from 2013

4

4

4

4

4

4

4

4

4

4

4

4

4

1–3

Established DMTs

DMTs approved for

relapsing forms of MS

during the 1990s and

reformulations or generic

versions of these

substances.

Newer DMTs

DMTs approved for

relapsing forms of MS

that have a different

mechanism of action

from established DMTs.

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Conventional

step care

TNF

antagonist

± IMS

Corticosteroids

+ IMS

Corticosteroids

Corticosteroids

+ IMS

Corticosteroids

TNF

antagonist

± IMS

TNF

antagonist

± IMS

Conventional

step care

TNF

antagonist

± IMS

Corticosteroids

+ IMS

Corticosteroids

Conventional

step care

Accelerated

step care

Corticosteroids

+ IMS

Treating to target in inflammatory

bowel diseases

IMS, immunosuppressant; TNF, tumour necrosis factor

Reproduced from Gut, Ordás I, Feagan BG and Sandborn WJ, 1754–63, 2011 with permission

from BMJ Publishing Group Ltd.

Moderate

Severe

IMS + TNF

antagonist

Early top-down

Level

of

dis

ease

Flipping the

pyramid

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Brain health: time matters

in multiple sclerosis

■ Brain health perspective

■ Multidisciplinary international

author group

■ Structured discussions during

2015

■ Evidence-based consensus

recommendations on:

□ diagnosis

□ therapeutic strategies

□ access to treatment

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Intervene early to

maximize lifelong

brain health

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Untreated MS progresses to

increased disability

■ RRMS

□ 85% of people with MS

at onset1

■ SPMS

□ 70–90% of people with MS over

lifetime if untreated

■ PPMS

□ 15% of people with MS, with 1

in 3 ultimately relapsing2

1. McAlpine D. Multiple sclerosis: a reappraisal. In: McAlpine D et al. (eds), Diagnosis and classification of multiple sclerosis, 2nd ed. 1972. Churchill

Livingstone, Edinburgh, UK; 2. Antel J et al. Acta Neuropathol 2012;123:627–38

Figure Reproduced with permission from Oxford PharmaGenesis from Giovannoni G et al. Brain health: time matters in multiple sclerosis, © 2015 Oxford

PharmaGenesis Ltd. Available at: www.msbrainhealth.org

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Cognitive impairment and brain

atrophy predict disability progression

■ Cognitive impairment at diagnosis predicted 10-year disability progression

and conversion to SPMS (155 patients)1

□ People with cognitive impairment at diagnosis were three times more likely to reach

EDSS 4.0 and twice as likely to develop SPMS

■ Cognitive impairment at entry predicted disability progression in placebo-

treated clinical trial participants (meta-analysis of 1562 patients)2

■ Preserving brain volume protected against disability progression (meta-

analysis of >13 500 patients)3

■ Cognitive reserve and brain volume protected against disease-related

cognitive decline (62 patients)4

1. Moccia M et al. Mult Scler J 2015. doi:10.1177/1352458515599075; 2. Raghupathi K et al. Poster presented at the 31st ECTRIMS congress, 7 –

10 October 2015, Barcelona, Spain 3. Sormani MP et al. Ann Neurol 2014;75:43–9;

4. Sumowski JF et al. Neurology 2013;80:2186–93;

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aLesion score was determined on unenhanced images by T2-weighting and a semiquantitative scoring system; the score represents the number of lesions

on the initial scan

Numbers in parentheses indicate the total number of new, persistently enhancing and re-enhancing lesions in cases where not all enhancing lesions were

new lesions. Table adapted with permission from Barkhof F et al. Am J Roentgenol 1992;159:1041–7

Case number

1 2 3 4 5 6 7

Lesion scorea 79 11 97 129 27 50 50

Number of new contrast-enhancing lesions

Month 1 0 0 5 0 2 0 1

Month 2 0 1 10 (13) 3 1 0 0

Month 3 1 0 2 (6) 2 1 0 0

Month 4 0 0 2 (3) 2 0 0 1

Month 5 – 0 1 (2) 1 3 0 0

Month 6 – 0 2 1 1 0 0

Month 7 – 0 2 1 0 0 –

Month 8 – 0 0 0 (1) 0 – –

Month 9 – 1 0 0 2 – –

Month 10 – 0 1 – 0 – –

Month 11 – 0 – – – – –

Month 12 – 0 – – – – –

MRI lesion associated

with a clinical relapse

No examination–

■ Monthly MRI in

seven patients over

1 year

□ 50 new contrast-

enhancing lesions

□ Only 5 relapses

Most brain lesions are

clinically silent

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Subclinical brain lesions drive brain

atrophy in CIS and MS

■ As the number and

volume of newly active

brain lesions increases,

the rate of brain volume

loss increases1

■ Brain atrophy

(neurodegeneration)

occurs early in CIS and

MS and proceeds

throughout the disease

course2

CIS, clinically isolated syndrome

1. Paolillo A et al. J Neurol 2004;251:432–9; 2. De Stefano N et al. Neurology 2010;74:1868–76

Increasing number of newly active lesions

Increasing volume of newly active lesions

De

cre

as

ing

bra

in v

olu

me

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Treatment should begin as early as

possible after diagnosis of MS

Reproduced with permission from Oxford PharmaGenesis from Giovannoni G et al. Brain health: time matters in

multiple sclerosis, © 2015 Oxford PharmaGenesis Ltd. Available at: www.msbrainhealth.org

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Implement a shared

decision-making process

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Engaged patients do better

1. Rieckmann et al. Mult Scler Relat Disord. 2015;4:202–18.

Patient engagement in their own healthcare has been

described as the ‘blockbuster drug of the century’1

■ Take time to engage patients

■ Facilitate two way communication

■ Encourage patients to manage their MS

18

Monitor disease activity

and treat to a target

19

Candidate parameters for treating to

target in multiple sclerosis

Disability

progression

RelapsesUnreported

relapsesPatient-reported outcomes

Brain

atrophy

Neurofilament levels

Lesions detectable using

standard clinical MRI

techniques (white matter)

Lesions currently

undetectable using standard

clinical MRI techniques

(white and grey matter)

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Treat to target as a therapeutic

strategy in MS

MRI,magnetic resonance imaging

The best drug for the patient is

the drug that:

stops relapses

stops disability

progression

stops (or minimizes) new

MRI lesion development

and brain atrophy

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Regular MRI scans have multiple

benefits

■ Measure new lesion development

■ Assess brain volume loss (atrophy)

■ Provide evidence of treatment failure as a prompt

for switching

□ Increase T2 lesion load

□ New Gd-enhancing lesions

□ Possibly a high rate of brain atrophy

22

Generate and consult real

world evidence

23

Registry data can be used to

investigate therapeutic strategies

■ Switch to a higher efficacy DMT vs switch

between established platform DMTs

DMT, disease-modifying therapy

Spelman T et al. Ann Clin Transl Neurol 2015;2:373–87

Injectable DMT

Relapse Change to another

injectable DMT

Change to a higher

efficacy DMT

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0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

Newer DMT EstablishedDMT

Annualized relapse rates were lower

after switching to a higher efficacy DMT

ARR, annualized relapse rate

Spelman T et al. Ann Clin Transl Neurol 2015;2:373–87

66% relative reduction

in ARR, p < 0.0001

AR

R in t

he f

irst year

after

treatm

ent

sw

itchin

g

Injectable

DMT

Higher efficacy

DMT

25

Adopt a comprehensive

economic approach

26

The economic perspective

■ Long-term outcome is what matters in economic assessments of

chronic progressive diseases

■ The value of disease treatment and management is assessed from

the change in the long-term outcome

■ In Brain health: time matters in multiple sclerosis we argue that:

□ the biggest change in long-term outcome will come from targeted early

intervention to maximize lifelong brain health

□ we should generate and use real-world registry data to prove that this is

the case

27

Effects on employment occur early

in the disease course

EDSS, Kurtzke Extended Disability Status Scale

Reproduced and adapted from J Neurol Neurosurg Psychiatry, Kobelt G et al., 77, 918–26, 2006 with permission from BMJ Publishing Group Ltd

28

Disability progression drives

long-term costs

EDSS, Kurtzke Extended Disability Status Scale; PPP, purchasing power parity

Reproduced from J Neurol Neurosurg Psychiatry, Kobelt G et al., 77, 918–26, 2006 with permission from BMJ Publishing Group Ltd

0

10 000

20 000

30 000

40 000

50 000

60 000

70 000

80 000

90 000

AU BE GE IT NL ES SE CH UK AU BE GE IT NL ES SE CH UK AU BE GE IT NL ES SE CH UK

PP

P (

€)

Indirect costs

Direct costs

EDSS 0–3 EDSS 4–6.5 EDSS 7–9

Direct costs

Indirect costs

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Real-world evidence

Early referral

and diagnosis

Comprehensive

economic

approach

Shared

decision-makingAccess to DMTs

Swift action on

evidence of

disease activity

Early treatment

Monitoring

Use

Generate Consult

Goal: maximize lifelong brain health

Leads toTherapeutic strategyRecommendation

The goal of treating MS should be

to maximize lifelong brain health

Lifestyle and

other factors

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Be an early adopter

www.msbrainhealth.org

Pledge your support of the report’s

recommendations at www.msbrainhealth.org

“Our vision is to create a better future

for people with MS and their families”

Your voice will help to effect this change