Goals and individuals, MS summit Barcelona June 2013

Goals and Individuals, Evolving Perspectives on Managing MS Gavin Giovannoni

Barts and The London

2

How serious a disease

is multiple sclerosis?

3

Lifespan in MS Patients Is Shortened by 8 to 12 Years

Survival Probability of Norwegian Patients with Relapsing-Remitting MS (RRMS)

(Hordaland County, Western Norway, 1953–2003)

Su

rviv

al

(%)

MS=multiple sclerosis; CI=confidence interval.

Adapted from Torkildsen NG et al. Mult Scler. 2008;14:1191-1198.

4

100

80

60

40

20

0 0 5 10 15 20 25 30 35 40 45 50

30 35 40 45 50 55 60 65 70 75 80

Years After Onset

Approximate Patient Age

General Population

RRMS

95% CI

21-Year Long-term Follow-up of IFNβ-1b Study — Time

from Study Randomization to Death • Early treatment (3 years) with IFNβ-1b was associated with a 47% reduction in the

risk of dying over 21 years compared with initial placebo treatment

IFNβ=interferon beta; HR=hazard ratio.

Goodin DS et al. Neurology. 2012;78:1315-1322.

5

HR=0.532 (95% CI: 0.314–0.902)

46.8% reduction in hazard ratio

Log rank, P=0.0173

0 5 10 15 20

Time (years)

IFNB-1b 250 µg

Placebo

Pro

po

rtio

n o

f P

ati

en

ts W

ho

Are

Sti

ll A

live

100

95

90

85

80

75

70

65

Patients at risk:

IFNβ-1b 250 µg

Placebo

124

123

124

120

121

117

118

109

104

88

Uti

lity

EDSS Score

• EDSS and utility* show a significant

inverse relationship1,†

*Utility measures are derived from EQ-5D using the EuroQoL instrument; †error bars depict 95% CI. Half-points on EDSS are not shown on graph axis,

except at EDSS 6.5.

EDSS=Expanded Disability Status Scale; WHO=World Health Organization; MSIF=Multiple Sclerosis International Federation.

1. Adapted from Orme M et al. Value In Health. 2007;10:54-60; 2. WHO and MSIF. http://apps.who.int/bookorders/anglais/detart1.jsp?sesslan=1&codlan=1

&codcol=15&codcch=747. Accessed October 6, 2010; 3. Compston A et al. McAlpine’s Multiple Sclerosis. 4th ed. London: Churchill Livingstone; 2006.

p. 183-272; 4. Compston A, Coles A. Lancet. 2008; 372:1502-1517.

• MS is one of the most

common causes of

neurological disability in

young adults2

• Natural history studies

indicate that it takes a

median time of 8, 20, and

30 years to reach the

irreversible disability levels

of EDSS 4, 6, and 7,

respectively3

The Effect of MS on Quality of Life

6

0.8

1.0

0.4

0.6

0

0.2

-0.4

-0.2

0 1 2 3 4 5 6 6.5 7 8 9

The Effects of MS on Unemployment

Pfleger CC et al. Mult Scler. 2010;16:121-126.

7

1.0

0.8

0.6

0.4

0.2

0

Pro

bab

ilit

y

Time (Years)

0 5 10 15 20 25

Control Persons

MS Patients

Probability of Remaining in Active Employment After

Onset of Multiple Sclerosis

The Effects of MS on Divorce and Separation

Pfleger CC et al. Mult Scler. 2010;16:878-882.

8

1.0

0.8

0.6

0.4

0.2

0

Pro

bab

ilit

y

Time to Event or End of Observation (years)

0 5 10 15 20 25

Control Persons

MS Patients

Crude Probability of Remaining in a Relationship After

Onset of MS (Life Table Method)

Impact of MS: Cognitive Functioning in the CIS Stage

Cognitive Test Performance in an Exploratory Study*

57

7

0

20

40

60

*40 untreated CIS patients who fulfilled the McDonald dissemination in space criterion compared to a cohort of 30 matched healthy

controls. An extensive battery of neuropsychological tests was used to explore verbal and nonverbal memory, attention, concentration,

speed of information processing, language, and abstract reasoning. Cognitive impairment was present when at least 2 different

neuropsychological tests were failed.

CIS=clinically isolated syndrome.

Feuillet l et al. Mult Scler. 2007;13:3124-3127.

Deficits were found mainly in

memory, speed of information

processing, attention, and

executive functioning

Pa

tien

ts F

ailin

g ≥

2

Co

gn

itiv

e T

ests

(%

)

9

CIS Patients

n=40

Healthy Controls

n=30

P<0.0001

What Is Benign MS?

10

163 patients with “benign” MS

(disease duration >15 years and

EDSS <3.5):

1. 45% cognitive impairment

2. 49% fatigue

3. 54% depression

Benign multiple sclerosis

Cognitive, psychological, and social

aspects in a clinical cohort

Maria Pia Amato

Valentina Zipoli

Benedetta Goretti

Emilio Portaccio

Maria Fara De Caro

Laura Ricchiuti

Gianfranco Siracusa

Medena Masini

Sandro Sorbi

Maria Trojano

J Neurol. 2006;253:1054-1059.

Clinical Prognostic Factors

Good Prognosis

• Optic neuritis

• Isolated sensory symptoms

• Long interval to

second relapse

• No disability after

5 years

• Normal MRI or low

lesion load

Poor Prognosis

• Multifocal CIS

• Efferent systems affected

• High relapse rate in first

2–5 years

• Substantial disability after

5 years

• Abnormal MRI with large

lesion load

MRI=magnetic resonance imaging.

Miller D et al. Lancet Neurol. 2005;4:281-288.

11

Relapses Can Result in Residual Deficits

• MS exacerbations can produce a measurable and sustained effect

on accrued impairment and disability1

• Therefore, treatments that reduce the frequency of relapses should

be beneficial

1. Lublin FD et al. Neurology. 2003;61:1528-1532.

27 29 30

42 44 41

0

10

20

30

40

50

30–59 60–89 ≥90

Pa

tie

nts

(%

)

Days After Exacerbation

Patients (%) with a ≥1.0 or ≥0.5 Change in EDSS Score After Relapse

≥1.0 EDSS Point

≥0.5 EDSS Point

Adapted from Lublin et al 2003.

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Theoretical Model: Treat Early and Aggressively

Time

Disease Onset

Treatment

at diagnosis

Natural course

of disease

Later intervention

Intervention

at diagnosis

Dis

ab

ilit

y

Later

treatment

13

Survival

analysis

What Is Your Treatment Philosophy?

Maintenance-Escalation vs Induction

14

Survival

analysis

“hit hard and early ”

What Is Your Treatment Philosophy?

Maintenance-Escalation vs Induction

15

survival

analysis

“hit hard and early ”

MS is an autoimmune

disease hypothesis

15-20 year

experiment

What Is Your Treatment Philosophy?

Maintenance-Escalation vs Induction

16

17

Many Factors Beyond Benefit and Risk Need to be

Considered to Achieve Best Patient Outcomes

Adapted from Giovannoni G et al. Curr Opin Neurol. 2012;25(suppl1):S20-S27.

• Evolution away from

physician-decided therapy

towards a patient and

prescriber concordance

• General agreement on goals

of therapy

• Helps MS patients make

informed treatment decisions

• Leads to an individualized

treatment plan based on the

patient’s needs

Treatment

Choice

?

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MS Treatment Decisions Are Complex:

Some Factors to Consider…….

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Patient Preferences

Therapy Attributes

Efficacy

Safety

Tolerability

Administration (route/frequency)

Monitoring requirements

Biomarkers (eg, NAb)

Ease of use/convenience

Socio-demographic profile

(lifestyle, work, family)

Risk tolerance

Likelihood of adherence

Geographic/Economic Factors

Patient and Disease Profile

Age, gender

Disease activity (MRI/clinical)

Impairment/disability

Treatment history

Comorbidities

Biomarkers (eg, Anti-JCV Ab)

Label

Reimbursement/access to drug

Shared Treatment

Decision

Shared treatment decision

that optimally weighs these

considerations to arrive at

the therapy that best meets

the patient’s needs

JCV=JC virus; Ab=antibody; NAb=neutralizing antibody.

X Y Z

Right Therapy, Right Patient, Right Time

Key Treatment Decision Steps

Monitoring:

Choosing therapy

Define the individual’s

multiple sclerosis

no

Treatment failure? yes

• Patient’s preferences?

• Your choice?

Individual measures:

• Evidence of disease activity?

• Tolerability/safety?

• Adherence?

• Drug or inhibitory markers?

Monitoring

20

• Patient

• MS prognosis

• Life style and goals

• Your goals for therapy

Right Therapy, Right Patient, Right Time

Key Treatment Decision Steps

Monitoring:

Choosing therapy

X Y Z

Define the individual’s

multiple sclerosis

no

Treatment failure? yes

• Patient

• MS prognosis

• Life style and goals

• Your goals for therapy

• Patient’s preferences?

• Physician’s preferences?

Individual measures:

• Evidence of disease activity?

• Tolerability/safety?

• Adherence?

• Drug or inhibitory markers?

Monitoring

21

vs

1

2

3

Clinical

MRI

NAbs

22

100 MS patients

Who are the

responders?

23

~20%

responders

~40% suboptimal

responders

~40% nonresponders

24

Emerging Concepts in MS

NEDA (no evidence of disease activity)

TTT (treat-to-target)

25

1 2 3 4 5 6 7 8 9 10

0

0.2

0.4

0.6

0.8

1.0

Su

rviv

al

P=0.002 Salvage

Adjuvant

Current Treatment Goal: Treat-to-Target

No evidence of disease activity*

*Defined as no relapse, no 12-week sustained EDSS progression, no new or enlarging T2 lesions, and no Gd+ lesions.

Gd+=gadolinium-enhancing.

26

Treat-to-Target Proposed NEDA Treatment

Algorithm for Relapsing MS

27

SPMS=secondary progressive MS.

No Yes

No Yes

No Yes

No Yes

1

Yes

Yes No

No

Yes

Yes

No

?

Yes

No

Yes

No

Radiologically isolated

syndrome

Clinically isolated

syndrome

Relapsing-remitting MS

(RRMS)

High risk of

conversion?

High risk of

conversion?

Active

disease?

Highly active RRMS

Highly active

disease?

Current 1st-line treatments Interferon-beta,

glatiramer acetate

6-12 monthly assessments

NAb+?

Switch?

1

Responder?

Active

disease?

Highly active

disease? Escalation therapies

natalizumab, fingolimod, mitoxantrone

6–12 monthly assessments

Too risky?

SPMS?

SPMS

Switch?

Responder?

De-escalation?

Active RRMS

Yes

Factors Predicting the Ultimate Goal of Disease

Activity Silencing

Havrdova E et al. Presented at ECTRIMS; October 13–16, 2010; Gothenburg, Sweden. Poster 905.

Havrdova E et al. Neurology 2010;74:S3-7.

Variables Associated with Overall Freedom from Disease Activity (No Clinical or MRI Activity)

over 2 Years in a Multivariate Logistic Regression Analysis

AFFIRM

Patients treated with natalizumab with fewer relapses, fewer MRI lesions, and lower EDSS scores at

therapy initiation and who did not develop persistent anti-natalizumab antibodies were more likely to

achieve freedom from disease activity over the course of the 2-year AFFIRM study.

28

Variable Odds Ratio 95% CI P Value

Natalizumab-treated patients

≤3 relapses in past 3 years 1.58 1.03–2.42 0.035

Baseline EDSS score ≤2.0 1.55 1.10–2.20 0.013

No baseline Gd+ lesions 1.74 1.24–2.44 0.002

Persistently anti-natalizumab

antibody positive 0.31 0.11–0.82 <0.019

Placebo-treated patients

No baseline Gd+ lesions 5.86 1.70–20.24 0.005

0

500

1000

1500

2000

2500

3000

3500

SPRMSPretreatment

SPRMSAfter

(6)-12 Mo

RRMSPretreatment

RRMSAfter

(6)-12 Mo

HealthyControls

Potential Markers to Decrease the Future Threshold

of Tolerance for Ongoing Disease

Error bars: +/- 2 standard error.

NFL=neurofilament light; SPRMS=secondary progressive-relapsing MS; DMT=disease-modifying therapy;

IFNβ=interferon beta; GA=glatiramer acetate; RIS=radiologically isolated syndrome.

Gunnarsson M et al. Ann Neurol. 2011;69:83-89.

NFL Levels in Patients and Healthy Controls

NF

L (

ng

/L)

n=9 n=9 n=83 n=83 n=28

29

The Relapsing MS DMT Doughnut

Natalizumab

RIS or Asymptomatic MS

Fingolimod

IFNβ

or GA IFNβ

Highly Active RRMS

Inactive RRMS

CIS

Active RRMS

Suboptimal responders?

Conclusions

• We have entered a new era of personalised medicine

• Is it time for another paradigm shift?

• Should we adopt treat-to-target from our rheumatology colleagues?

• NEDA, TTT, and DAF have entered the neurology lexicon

• Who should make the decision regarding early aggressive treatment?

• Regulators

• Payers

• Neurologists

• MS patients

• What is your treatment philosophy?

• Maintenance-escalation vs induction

• Is it fair to make MS patients wait 20 years for the outcome of an

experiment before adopting the treatment paradigm of “hard

and early”?

30

DAF=disease activity free..