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DO NOT COPY OR DISTRIBUTE 1 2011 Genzyme Corporation

The Challenges of Disease Management in MS:

Navigating the Changing Landscape

October 4, 2013

ECTRIMS Annual Meeting A Genzyme-sponsored Symposium

Agenda

Time Title Presenter

6:00 pm Welcome and Introduction Prof. Per Soelberg Sørensen

(Chair) Copenhagen University Hospital,

Copenhagen, Denmark

6:05 pm Evolving Considerations for Patient Management &

Treatment Selection

Prof. Gavin Giovannoni Blizard Institute, Barts and The

London School of Medicine and

Dentistry, Queen Mary University of

London – United Kingdom

6:20 pm Highlights from the Changing Landscape of MS

• Alemtuzumab for Treatment of Relapsing-Remitting

MS

• Teriflunomide for Treatment of Patients with MS

Prof. Tjalf Ziemssen

Center of Clinical Neuroscience

University of Technology,

Dresden, Germany

Patricia K Coyle, MD MS Comprehensive Care Center,

Stony Brook University, New York

6:50 pm Questions and Answers

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Evolving Considerations for Patient Management and Treatment Selection

Professor Gavin Giovannoni Blizard Institute, Barts and The London School of

Medicine and Dentistry, London, UK

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; Almirall; Bayer-Schering Healthcare; Biogen-Idec; Canbex; Eisai; Elan; Fiveprime; Genzyme, a Sanofi Company; Genentech; GSK; GW Pharma; Ironwood; Merck-Serono; Novartis; Pfizer; Roche; Sanofi-Aventis; Synthon BV; Teva; UCB Pharma; and Vertex Pharmaceuticals.

Please note that the contents of Professor Giovannoni’s slides have been checked by Genzyme to make sure they are compliant with legal requirements of the Danish authorities and that Professor Giovannoni has agreed to the necessary changes being made.

Professor Giovannoni would like to acknowledge and thank Yasamin Mir-Shekari, Evidence Scientific, for editorial assistance with preparing these slides.

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Why Treat Early in MS?

Reduce axonal loss

Pathology

Slow brain volume loss

Imaging

Delay or prevent disability

Clinical

5

Trapp et al, 1998

Confavreaux, Compston, 2005

Losseff et al,1996

Axonal and Brain Volume Loss Starts Early in MS

Subclinical inflammation, demyelination, and neurodegeneration may be present for

months, or even years, before a patient experiences clinical symptoms1

MRI=magnetic resonance imaging; RRMS=relapsing-remitting MS; SPMS=secondary progressive MS

1. Stüve O et al. Drugs 2008;68:73-83; Image adapted from Compston A, Coles AJ. Lancet 2008;372:1502-17.

MRI Events

SPMS First

clinical

event

Time (Years)

RRMS Subclinical

disease

Inflammation

Brain volume

Axonal loss

Dis

ea

se

Se

ve

rity

SPMS RRMS

6

The Burden of MS Increases with Disability Progression

7

1.0

0.8

0.6

0.4

0.2

0

–0.2

–0.4

0 1 2 3 4 5 6 6.5 7 8 9

Uti

lity

Sc

ore

Expanded Disability Status Scale

Essentially restricted to bed,

chair, or wheelchair

Austria

Belgium

Germany

Italy

The Netherlands

Spain

Sweden

Switzerland

UK

UKa

UKa

(Perfect health)

(Death)

a Utility score <0 indicates that patients felt their health state was worse than death.

1. Orme M et al. Value Health 2007;10:54-60; 2. Morales-Gonzales. Mult Scler 2004;10:47-54; 3. Zwibel HL, Smrtka J. Am J Managed Care

2011;17:S139-S45; 4. Gilchrist AC, Creed FH. J Psychosomatic Res 1994;38:193-201. Image adapted from Naci et al. J Med Econ 2010;13:78-89.

As disability increases in MS patients, health status deteriorates1

– At least two-thirds of patients with RRMS are unemployed due to the disease2

– Approximately 21% of patients with MS for less than 5 years are unemployed3

– Social relationships are impacted by multiple interrelated factors related to physical disability

and psychological status4

– Reduced ability to work, pursue leisure activities, and carry on usual life roles due to MS results

in diminished quality of life5

Question: What Prognostic Group Does the Patient Fall Into?

Good Prognosis:

Younger age at onset1,2

Female sex1-3

Optic neuritis4

Isolated sensory symptoms4

Complete recovery from first attack5

Long interval to second relapse4

No disability after 5 years4

Normal MRI / low lesion load4

CSF negative for oligoclonal bands2,6

Poor Prognosis:

Older age of onset1,2

Male sex1-3

“Multifocal” onset4

Efferent systems affected (motor, cerebellar, bladder)4

Incomplete recovery from first attack5

High relapse rate in the first 2–5 years4

Substantial disability after 5 years4

Abnormal MRI with large lesion load4

CSF positive for oligoclonal bands2,6

8

CSF=cerebrospinal fluid

1. Scalfari A et al. J Neurol Neurosurg Pschiatry 2013;00:1-9; 2. Fernandez O. J Neurol Sci 2013;331:10-3; 3. Damasceno A et al. J Neurol Sci

2013;324:29-33; 4. Miller D et al. Lancet Neurol 2005:4;281-8; 5. Confavreux C et al. Brain 2003;126:770-82; 6. Villar LM et al. J Clin Invest

2005;115:187-94.

Question: What Prognostic Group Does the Patient Fall Into?

9

Favorable

(inactive)

Indeterminate

(active)

Poor

(active) Time

Aim of

treatment

Question: Does the Patient Have Active MS?

10

vs.

1

2

3

Clinical

MRI

Biomarkers

The Traditional Treatment Paradigm in MS: The Treatment Ladder

Heterogeneity of disease course across different patients and over time can affect treatment response1-3

– While some patients will benefit from modest efficacy therapies, others will not1

Given that early inflammatory events predict long-term disability,4

early, appropriate intervention is critical

11 1. Rio J et al. Ann Neurol 2006;59:344-52; 2. Miller A et al. J Neurol Sci 2008;274:68-75; 3. Rudick RA et al. Lancet Neurol 2009;545-59. 4. Coyle PK,

Hartung H-P. Mult Scler 2002;8:2-9; Figure adapted from Rio J et al. Curr Opin Neurol 2011, 24:230-7.

A

B

C

D

E

K J Y X

Moderate

efficacy

High

efficacy

Very high

efficacy

Evolving Paradigm: Individualized Treatment Based on Projected Disease Course

12 Gd=gadolinium; NAbs=neutralizing antibodies

Ongoing Assessment: • Clinical

– Relapse

– Disability progression

• MRI

– T2 lesions

– T1 Gd-enhancing lesions

• Biomarkers of reduced drug activity

and/or safety

– NAbs

• Tolerability

• Safety event

• Adherence

The Individual MS Patient: • MS prognosis

• Patient preferences

• Treatment history

• Potential to remain adherent

Discuss therapy options

with patient/

Choose therapy

Define the individual MS

patient profile

Stable on treatment?

yes

Therapy Choice: • Therapy choice tailored to individual

patient profile, including MS prognosis

and consideration of the context of MS

disease progression when evaluating

risk of treatment no

Ongoing assessment

Case Study

Case: Woman with RRMS

14

38 years old

Optic neuritis at age 33 – full recovery; turned down the option of an MRI

Sensory spinal cord syndrome at age 35 – MRI compatible with MS (>9 T2 lesions) – No lumbar puncture – Full recovery; except for mild intermittent symptoms when she exercises

First-line injectable for 3 years (good adherence)

Relapse with a mild left sensory loss

Referred for a second opinion

Switched to alternative injectable with mild persistent side-effects

What Prognostic Group Does the Patient Fall Into?

15

Indeterminate

Good Prognosis:

Young

Female sex

Optic neuritis

Isolated sensory symptoms

Complete recovery from attack

Long interval to second relapse

No disability after 5 years

Normal MRI / low lesion load

CSF negative for oligoclonal bands

Case: Woman with RRMS

16

2 years later (40 years old)

Forced to retire due to cognitive impairment and severe fatigue

Developed depression and anxiety

Neutralizing antibodies negative

In her spare time, she becomes an expert patient

– Widely read and became internet-savvy

– Requests an MRI

17

Does the Patient Have Active MS?

18

vs.

1

2

3

Clinical

MRI

Biomarkers

NO

NO

YES

Case: Woman with RRMS

19

40 years old

Hidden symptoms (cognitive impairment, fatigue, depression and anxiety)

Subclinical activity (new T2 and Gd-enhancing lesions)

Q1: Should she be offered escalation therapy?

Q2: What would be the outcome had she been offered a highly effective therapy from the outset?

The Traditional Treatment Paradigm in MS: The Treatment Ladder

20

A

B

C

D

E

K J Y X

5 years

Moderate

efficacy

High

efficacy

Very high

efficacy

Conclusions

MS is a serious neurological disease – Disability, unemployment, negative impact on social relationships, diminished

QoL, etc.

Traditional treatment approaches based on trial and error may lead to suboptimal treatment outcomes and continued disease progression in MS

Era of individualized profiling – Prognosis, risk, treatment and monitoring

Evolving treatment paradigm – Individualizing treatment to intervene early and appropriately, to impact long-term

disability

– Individualized treatment should include treatment adherence considerations; oral therapies may be of benefit in this regard

– Early treatment with high/very high efficacy therapy should be considered in appropriate patients who are aware of and willing to accept the associated risks

– Monitoring treatment for early signs of suboptimal response before overt clinical decline

– New treatment paradigm of treat-to-target of no evidence of disease activity (NEDA)

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