Biogen idec satellite symposium ectrims giovannoni gg7

Natalizumab: Early and Effective Use for the Right Patient Gavin Giovannoni

Natalizumab should be used according to the SmPC

Disclosures

I have 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.

Please note that the contents of Professor Giovannoni’s slides have been

checked by Biogen-Idec 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 Mark Hughes and Simon Whiteley,

Infusion Communications, for editorial assistance with preparing these

slides. Please note that the natalizumab data slides have been prepared

by Biogen-Idec.

Why Would You Want to Silence the Disease from the Start?

Clinical

MRI

Pathology

3

MRI=magnetic resonance imaging.

17 yr female,

diagnosed

with CIS

after

presenting

with myelitis

Abnormal MRI; >9

T2 lesions on brain

MRI and spinal cord

lesion at C5

2000 2001

IFN-beta

2002 2003 2004 Oct 2013

Final

year of

school

University

4

Mo

nit

ori

ng

Tre

atm

en

t C

lin

ica

l O

cc

up

& S

oc

ial

CIS=clinically isolated syndrome; MS=multiple sclerosis; IFN=interferon.

18 yr, 1st year

university

diagnosed

with MS after

having L optic

neuritis

Dec 2007 Jan 2008

clumsy

left

hand

pins &

needles

in legs

R optic

neuritis

Bladder dysfunction

Graduate

trainee

marketing

Full

time

employment

Off work

~3 months

of the year

Brainstem

syndrome;

diplopia

and ataxia

High lesion

load with

brain

atrophy

Splits from

her partner

depression,

anxiety, and fatigue Reduced mobility

5

Mo

nit

ori

ng

Tre

atm

en

t C

lin

ica

l O

cc

up

& S

oc

ial

Abnormal MRI; >9

T2 lesions on brain

MRI and spinal cord

lesion at C5

IFN-beta

2000 2001 2002 2003 2004 Dec 2007 Oct 2013

Final

year of

school

17 yr female,

diagnosed

with CIS

after

presenting

with myelitis

18 yr, 1st year

university

diagnosed

with MS after

having L optic

neuritis

University

Jan 2008

MS Is a Devastating Disease

Cognitive Dysfunction

• Prevalence: 43% to 65%1,2

• Affects employment,

activities of daily living,

and social functioning2

Life Shortening

• 5- to 11-year decrease in

life expectancy3-7

• 2- to 7-fold increase in

suicide risk5,8

• 50% MS patients die of

disease-related causes5,6,8

1. Rao SM et al. Neurology. 1991;41:685-691; 2. Rao SM et al. Neurology. 1991;41:692-696; 3. Sadovnick AD et al. Neurology. 1992;42:991-994;

4. Ebers GC. J Neurol Neurosurg Psychiatry. 2001;71:16-19; 5. Torkildsen G et al. Mult Scler. 2008;14:1191-1198; 6. Smestad C et al. Mult Scler.

2009;15:1263-1270; 7. Kingwell E et al. J Neurol Neurosurg Psychiatry. 2012;83:61-66; 8. Sadovnick AD et al. Neurology. 1991;41:1193-1196;

9. Orme M et al. Value Heath. 2007;10:54-60; 10. De Marco R et al. Diabetes Care. 1999;22:756-761; 11. Petty DW et al. Mayo Clin Proc.

2005;80:1001-1008; 12. Hooning MJ et al. Int J Radiat Oncol Biol Phys. 2006;64:1081-1091; 13. Pfleger CC et al. Mult Scler. 2010;16:121-126;

14. Beg J et al. Eur J Health Econ. 2006;7(suppl 2):S75-S85.

*In this study, utility measures were derived from EQ-5D using the EuroQoL instrument; †in patients with type 2 diabetes; ‡in patients with valvular heart disease in Olmsted County,

Minnesota; §MS patients with EDSS ≥6.

EDSS=Expanded Disability Status Scale; QOL=quality of life; CV=cardiovascular;

EQ-5D=European Quality of Life-5 Dimensions.

QOL EDSS and utility* have shown a

significant inverse relationship9

Mortality Mortality ratio of patients with MS

exceeds CV disease,†,10 stroke,‡,11 and

early breast cancer12

Employment 50% of patients with MS are

unemployed as of EDSS 3.0 and/or

after 10 years from diagnosis13

Healthcare costs Bulk of cost attributed to services

(28.5%) and long-term sick leave and

early retirement (30%)§,14

Relationships Compared with general population, patients

with MS have a higher probability of

separating/divorcing and doing so sooner13

MS has a negative

impact on…

6

Consequences of Increasing EDSS Scores:

Loss of Employment1

7

0

10

20

30

40

50

60

70

80

90

Work Capacity by Disability Level

0.0/1.0 2.0 3.0 4.0 5.0 6.0 6.5 7.0 8.0/9.0

EDSS Score

Pro

po

rtio

n o

f P

ati

en

ts ≤

65

Ye

ars

Old

Wo

rkin

g (

%)

The proportion of patients employed or on long-term sick leave is calculated as a percentage of patients aged 65 or younger.

1. Kobelt G et al. J Neurol Neurosurg Psychiatry. 2006;77:918-926;

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

Spain

Sweden

Switzerland

United Kingdom

Netherlands

Italy

Germany

Belgium

Austria

~10 yrs2

7

? glatiramer

acetate

8

Mo

nit

ori

ng

Tre

atm

en

t C

lin

ica

l O

cc

up

& S

oc

ial

Graduate

trainee

marketing

Full

time

employment

Off work

~3 months

of the year

Splits from

her partner

Final

year of

school

University

High lesion

load with

brain

atrophy

Abnormal MRI; >9

T2 lesions on brain

MRI and spinal cord

lesion at C5

IFN-beta

2000 2001 2002 2003 2004 Dec 2007 Oct 2013

clumsy

left

hand

pins &

needles

in legs

R optic

neuritis

Bladder dysfunction

Brainstem

syndrome;

diplopia

and ataxia

depression,

anxiety, and fatigue Reduced mobility 17 yr female,

diagnosed

with CIS

after

presenting

with myelitis

18 yr, 1st year

university

diagnosed

with MS after

having L optic

neuritis

Jan 2008

MRI – High Lesion Load

9

? glatiramer

acetate

10

Mo

nit

ori

ng

Tre

atm

en

t C

lin

ica

l O

cc

up

& S

oc

ial

Graduate

trainee

marketing

Full

time

employment

Off work

~3 months

of the year

Splits from

her partner

Final

year of

school

University

High lesion

load with

brain

atrophy

Abnormal MRI; >9

T2 lesions on brain

MRI and spinal cord

lesion at C5

IFN-beta

2000 2001 2002 2003 2004 Dec 2007 Jan 2008 Oct 2013

clumsy

left

hand

pins &

needles

in legs

R optic

neuritis

Bladder dysfunction

Brainstem

syndrome;

diplopia

and ataxia

depression,


diagnosed

with CIS

after

presenting

with myelitis

18 yr, 1st year

university

diagnosed

with MS after

having L optic

neuritis

Gd-enhancing

lesion of upper

cervical cord

Occupational

health

assessment

Cervical cord

relapse

weak L arm

with pain

MRI – Acute Cervical Cord Lesion

11

Jan 2008

How Can We Optimise Natalizumab Patient Management?

In EU, natalizumab is indicated for use as a single disease-modifying

therapy in highly active RRMS for the following adult patient groups:

EU=European Union; RRMS=relapsing-remitting MS; IFNβ=interferon beta; GA=glatiramer acetate; Gd+=gadolinium-enhancing.

http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000603/WC500044686.pdf.

Accessed September 7, 2013.

High disease activity despite a full and adequate course with IFNβ or GA (normally ≥1 year of treatment)

≥1 relapse in the last year while on therapy, ≥9 T2-hyperintense lesions,

or ≥1 Gd+ lesion or a “nonresponder”, defined as patient with unchanged or increased relapse

rate or ongoing severe relapses, compared with the previous year

Rapidly evolving severe RRMS

≥2 disabling relapses in 1 year, ≥1 Gd+ lesion or significant increase in T2 lesion load

12

? glatiramer

acetate

13

Mo

nit

ori

ng

Tre

atm

en

t C

lin

ica

l O

cc

up

& S

oc

ial

Graduate

trainee

marketing

Full

time

employment

Off work

~3 months

of the year

Splits from

her partner

Final

year of

school

University

High lesion

load with

brain

atrophy

Abnormal MRI; >9

T2 lesions on brain

MRI and spinal cord

lesion at C5

IFN-beta

2000 2001 2002 2003 2004 Dec 2007 Oct 2013

clumsy

left

hand

pins &

needles

in legs

R optic

neuritis

Bladder dysfunction

Brainstem

syndrome;

diplopia

and ataxia

depression,


diagnosed

with CIS

after

presenting

with myelitis

18 yr, 1st year

university

diagnosed

with MS after

having L optic

neuritis

Jan 2008

Occupational

health

assessment

Gd-enhancing

lesion of upper

cervical cord

Cervical cord

relapse

weak L arm

with pain

natalizumab

Treat-2-Target Proposed NEDA Treatment Algorithm for

Relapsing MS

NEDA=no evidence of disease activity.

A

B

C

D

E N M

Y X Moderate

Efficacy

Intermediate

Efficacy

High

Efficacy

14

Early Treatment Choice and Management Has the Potential

to Delay MS Disease Progression

15

Adapted from Miller JR. J Manag Care Pharm. 2004;10(suppl S-b):S4-S11.

Time Symptom

Onset

Dis

ab

ilit

y

Later

treatment

Earlier

treatment

Optimal

window of

opportunity

Early treatment AND earlier management

Later treatment

Natural course of MS

15

83% reduction in

T2-hyperintense lesions*

37% vs 7% Freedom from disease

activity/disease activity

free‡

92% reduction in Gd+ lesions

30% vs 19% with sustained

improvement in function†

68% reduction in

relapse rate

42% to 54% reduction of

disability progression

Natalizumab Reduces Both Clinical and

MRI Measures of Disease

*Decrease in new or newly enlarging hyperintense lesions; †baseline EDSS >2.0, with 1.0-point decrease in EDSS sustained for >12 weeks; ‡Post hoc analysis of patients with no relapse, no 12-week sustained EDSS progression, no new or enlarging T2-hyperintense lesions, and no Gd+ lesions. AFFIRM: a 2-year, randomised, multicenter, double-blind, placebo-controlled study of 942 patients that evaluated the effect of natalizumab on annualised relapse rate and disability progression; all differences were statistically significant (P<0.05). Polman C et al. N Engl J Med. 2006;354:899-910; Havrdová E et al. Lancet Neurol. 2009;8:254-260; Phillips JT et al. Mult Scler. 2011;17:970-979.

Primary

Outcomes

Secondary

Outcomes

Exploratory

Outcomes

AFFIRM Overall Patients: Natalizumab vs Placebo

16

18 15

51

70

0

20

40

60

80

100

Year 0–1 Year 1–2

Pe

rce

nta

ge

of

Pa

tie

nts

(%

)

Placebo Natalizumab

Havrdová E. et al. Lancet Neurol. 2009;8:254-226.

Natalizumab and Freedom from Disease

Activity/Disease Activity Free (AFFIRM)

Freedom from Disease Activity/Disease Activity Free:

Post hoc analysis of patients with no relapses, no sustained (12-week) disability

progression, no Gd+ lesions, no new or enlarging T2-hyperintense lesions

Non-Highly Active Disease <2 relapses in past 12 months or

no Gd+ lesions at study entry

3 4

34

65

0

20

40

60

80

100

Year 0–1 Year 1–2

Pe

rce

nta

ge

of

Pa

tie

nts

(%

)

n=248 n=458 n=228 n=407 n=59 n=146 n=56 n=137

P<0.0001 P<0.0001 P<0.0001 P<0.0001

Highly Active Disease ≥2 relapses in past 12 months and

≥1 Gd+ lesion at study entry

17

-2.5

-1.5

-0.5

0.5

1.5

2.5

Me

an

Pe

rce

nt

Ch

an

ge

Fro

m

Bas

eli

ne

in

SF

-36

Sc

ore

Week 104

Placebo Natalizumab

MCS PCS

P<0.05 P<0.01

IMSE Swedish registry2

Multiple Sclerosis Impact Scale (MSIS-29)

Natalizumab and Quality of Life

MCS=mental component summary.

1. Rudick RA et al. Ann Neurol. 2007;62:335-346; 2. Holmén C et al. Mult Scler. 2011;17:708-719.

AFFIRM1

Short Form-36 (SF-36)

-15

-13

-11

-9

-7

-5

-3

-1

Month 24

Me

an

Pe

rce

nt

Ch

an

ge

F

rom

Bas

eli

ne

in

MS

IS-2

9

Sc

ore

P<0.05

P<0.05

Physical

Psychological WORSENING

IMPROVEMENT

IMPROVEMENT

18

Escalation to Natalizumab Is More Effective Than Switching

Between IFN/GA

0

25

50

75

100

% P

ati

en

ts

Escalate to Natalizumab, n=106

Switch Between IFN/GA, n=161

Data from a postmarketing, prospective, observational study in 285 RRMS patients for whom treatment with IFNβ or GA therapy failed.

After failure of IFNβ or GA therapy, patients were switched to either natalizumab (n=106) or IFNβ/GA (n=161).

*There were no differences at 12 month between the two groups in proportions of patients free from relapse, disability progression, MRI

activity, and combined activity.

Prosperini L et al. Mult Scler. 2012;18:64-71.

No EDSS

Progression

No MRI

Activity

Disease

Activity Free

P<0.0001 P=0.0003 P<0.0001

51

36

51

21

83

67 77

59

No

Relapses

P<0.0045

Over 24 months*

19

Escalation to Natalizumab Is More Effective Than Switching

Between IFN/GA

0

25

50

75

100

% P

ati

en

ts

Escalate to Natalizumab, n=106

Switch Between IFN/GA, n=161

Data from a postmarketing, prospective, observational study in 285 RRMS patients for whom treatment with IFNβ or GA therapy failed.

After failure of IFNβ or GA therapy, patients were switched to either natalizumab (n=106) or IFNβ/GA (n=161).

*There were no differences at 12 month between the two groups in proportions of patients free from relapse, disability progression, MRI

activity, and combined activity.

Prosperini L et al. Mult Scler. 2012;18:64-71.

No EDSS

Progression

No MRI

Activity

Disease

Activity Free

P<0.0001 P=0.0003 P<0.0001

51

36

51

21

83

67 77

59

No

Relapses

P<0.0045

Over 24 months*

20

×

? glatiramer

acetate

21

Mo

nit

ori

ng

Tre

atm

en

t C

lin

ica

l O

cc

up

& S

oc

ial

Graduate

trainee

marketing

Full

time

employment

Off work

~3 months

of the year

Splits from

her partner

Final

year of

school

University

High lesion

load with

brain

atrophy

Abnormal MRI; >9

T2 lesions on brain

MRI and spinal cord

lesion at C5

IFN-beta

2000 2001 2002 2003 2004 Dec 2007 Oct 2013

clumsy

left

hand

pins &

needles

in legs

R optic

neuritis

Bladder dysfunction

Brainstem

syndrome;

diplopia

and ataxia

depression,


diagnosed

with CIS

after

presenting

with myelitis

18 yr, 1st year

university

diagnosed

with MS after

having L optic

neuritis

Jan 2008

Occupational

health

assessment

Gd-enhancing

lesion of upper

cervical cord

Cervical cord

relapse

weak L arm

with pain

natalizumab

New

partner

New job

junior management

position

Residual deficits:

Normal walking 300 m, unable to run &

exercise. Intermittent sensory symptoms

in L arm. Mild urinary frequency

Annual MRI

monitoring


Natalizumab and Functional Benefit – Double-blind, Placebo-

controlled Study (AFFIRM)

1. Phillips JT et al., Mult Scler 2011;17:970-979; 2. Munschauer F et al., ECTRIMS Meeting September 9–12, 2009, Dusseldorf, Germany,

P434; 3. Balcer LJ et al., J Neurol Sci 2012;318:119-24; 4. Weinstock-Guttmanen B et al., J Neurol 2012;259:898–905.

Compared with placebo, Natalizumab showed sustained improvement in

• EDSS1

• Upper limb2

• Walking2

• Vision3

and reduced the risk of progression of cognitive deficit4

-0.30.20.71.21.72.22.73.23.74.2

0.5 5

Hazard Ratio (95% Confidence Interval)

0.5 1.0 1.5 2.0 3.0 4.0 5.0

Favours placebo Favours natalizumab

Cognitive deficit – PASAT-3 (P=0.013)

Vision – 1.25% low contrast acuity (P=0.014)

Vision - 2.5% low contrast acuity (P=0.012)

Timed 25-foot walk (P=0.028)

9-hole peg test (P=0.044)

EDSS (P=0.006)

Favours natalizumab Favours placebo

22


Treatment with natalizumab has also been shown to improve

Bladder function (TRUST)1 and Fatigue (TYNERGY)2

Confirmation of improvements in:

Walking 6-minute (TYNERGY2) and 100 meter (TIMER3) tests

Cognition Improvement in single digit modalities test (IMSE Swedish registry4)

Natalizumab and Functional Improvement –

Post-approval Studies

-8

-7

-6

-5

-4

-3

-2

-1

0

0 4 8 12 16 20 24

Me

an

ch

an

ge

fro

m b

as

eli

ne

Time (Weeks)

Urogenital Distress Impact Questionnaire

Incontinence Impact Questionnaire

1. Khatri B et al. ECTRIMS Meeting October 19–22, 2011; Amsterdam, The Netherlands, P1040; 2. Svenningsson A et al. PLoS One

2013;8:e58643; 3. Nehrych T et al. ENS Meeting June 8-11, 2013, Barcelona, Spain, P369; 4. Holmén C et al. Mult Scler 2011;17:708-719.

25

30

35

40

45

50

55

60

65

70

75

Baseline Month 3 Month 6 Month 9 Month 12

Me

an

FM

SC

sc

ore

Total Score Motor Score Cognitive Score

P<0.0001 for time effect

P<0.0001 for time effect

P<0.0001

P<0.0001

P<0.0001

Change from

baseline at

Month 12

23


17yr female,

diagnosed

with CIS

after

presenting

with myelitis

18yr, 1st year

university

diagnosed

with MS after

having L optic

neuritis

Abnormal MRI; >9

T2 lesions on brain

MRI and spinal cord

lesion at C5

2000 2001

clumsy

left

hand

pins &

needles

in legs

IFN-beta

2002 2003

R optic

neuritis

2004

Bladder dysfunction

Graduate

trainee

marketing

Full

time

employment

Off work

~3 months

of the year

Dec 2007

Brainstem

syndrome;

diplopia

and ataxia

? glatiramer

acetate

Cervical cord

relapse

weak L arm

with pain

High lesion

load with

brain

atrophy

Gd-enhancing

lesion of upper

cervical cord

Splits from

her partner

depression ,

anxiety and fatigue

Reduced mobility

Occupational

health

assessment

natalizumab

New

partner

New job

junior management

position

Residual deficits:

Normal walking 300m, unable to run &



Jan 2008 Oct 2013

Annual MRI

monitoring

Final

year of

school

University

24

Mo

nito

rin

g

Tre

atm

en

t C

linic

al

Occu

p &

so

cia

l


First

Relapse

3 6 9 12 15 18 21 24 27 30

Months Since Relapse

0

10

20

30

40

50

60

70

80

90

100

Pati

en

ts w

ith

co

mp

lete

reco

very

(%

)

Placebo Natalizumab

Natalizumab and Clinical Recovery from Relapses

Lublin F. et al. ECTRIMS 2013, Copenhagen October 3rd , Poster P524.

Overall population : Subjects with an increase of EDSS ≥ 1.0 point at relapse *Based on Cox Proportional Hazards model adjusted for baseline EDSS, age, gender, relapses in year prior to enrollment, disease

duration, baseline Gd-enhancing lesions and baseline T2 lesion volume.

AFFIRM: Probability of 12-week confirmed complete

recovery from relapses

76.0%

43.1%

Adjusted HR for natalizumab vs placebo=1.673

(95% CI:1.046–2.678); 67% increase; P=0.0319*

25

Placebo (N=86) Natalizumab (N=70)


Natalizumab and Clinical Recovery from Relapses

84%91%

70%71% 74%68%

0%

20%

40%

60%

80%

100%

Overallpopulation

BaselineEDSS<3.0

Baseline EDSS≥3.0

n=140 n=93 n=80 n=143

Pro

po

rtio

n o

f p

ati

en

ts (

%)

Placebo

Natalizumab

**P=0.0088 **P=0.0019 P=0.8259

At least 0.5 point EDSS increase

n=47 n=63

At least 1.0 point EDSS increase

61%71%

43%49% 50% 48%

0%

20%

40%

60%

80%

100%

Overallpopulation

BaselineEDSS<3.0

Baseline EDSS≥3.0

n=140 n=93 n=80 n=143

Pro

po

rtio

n o

f p

ati

en

ts (

%)

*P=0.0349 **P=0.0048 P=0.5976

n=47 n=63

Lublin F. et al. ECTRIMS 2013, Copenhagen October 3rd , Poster P524.

Disabling Magnitude of Relapses in AFFIRM

EDSS change from pre-relapse to at relapse

26



27

Adapted from Miller JR. J Manag Care Pharm. 2004;10(suppl S-b):S4-S11.

Time Symptom

Onset

Dis

ab

ilit

y

Later

treatment

Earlier

treatment

Optimal

window of

opportunity


Later treatment


27


Patient Management Using the Anti-JCV Antibody Assay

Negative* Positive

Anti-JCV

Antibody Status

Using this assay, anti-JCV antibodies were detected

in 172 of 174 (99%) natalizumab-treated patients

assessed more than 6 months prior to PML diagnosis.

0.1/1000

28

JCV=JC virus; PML=progressive multifocal leukoencephalopathy; IS=immunosuppressant; CI=confidence interval.

*Medical information website. Boston, MA, USA: Biogen Idec Inc. https://medinfo.biogenidec.com/medinfo. Accessed August 5, 2013.


17yr female,

diagnosed

with CIS

after

presenting

with myelitis

18yr, 1st year

university

diagnosed

with MS after

having L optic

neuritis

Abnormal MRI; >9

T2 lesions on brain

MRI and spinal cord

lesion at C5

2000 2001

clumsy

left

hand

pins &

needles

in legs

IFN-beta

2002 2003

R optic

neuritis

2004

Bladder dysfunction

Graduate

trainee

marketing

Full

time

employment

Off work

~3 months

of the year

Dec 2007

Brainstem

syndrome;

diplopia

and ataxia

? glatiramer

acetate

Cervical cord

relapse

weak L arm

with pain

High lesion

load with

brain

atrophy

Gd-enhancing

lesion of upper

cervical cord

Splits from

her partner

depression ,

anxiety and fatigue

Reduced mobility

Occupational

health

assessment

natalizumab

New

partner

New job

junior management

position

Residual deficits:




Jan 2008

JCV

positive

Oct 2013

Annual MRI

monitoring

Final

year of

school

University

29

Mo

nito

rin

g

Tre

atm

en

t C

linic

al

Occu

p &

so

cia

l


Natalizumab

Exposure

1–24

months

25–48

months

49–72

months

PML Risk 0.7/1000 5.3/1000 6.1/1000

No Prior IS Use

*https://medinfo.biogenidec.com/medinfo. Accessed August 5, 2013. Data as of March 2013 indicate estimated risk of PML patients with prior

immunosuppressant use is 1.8/1000 for natalizumab exposure of 1–24 months and 11.2/1000 for exposure of 25–48 months.

Negative Positive*

Anti-JCV

Antibody Status 1 in 189

30


Risk of PML is ≤1/1000 for all patients with no prior IS use in the first 2 years

https://medinfo.biogenidec.com/medinfo


17yr female,

diagnosed

with CIS

after

presenting

with myelitis

18yr, 1st year

university

diagnosed

with MS after

having L optic

neuritis

Abnormal MRI; >9

T2 lesions on brain

MRI and spinal cord

lesion at C5

2000 2001

clumsy

left

hand

pins &

needles

in legs

IFN-beta

2002 2003

R optic

neuritis

2004

Bladder dysfunction

Graduate

trainee

marketing

Full

time

employment

Off work

~3 months

of the year

Dec 2007

Brainstem

syndrome;

diplopia

and ataxia

? glatiramer

acetate

Cervical cord

relapse

weak L arm

with pain

High lesion

load with

brain

atrophy

Gd-enhancing

lesion of upper

cervical cord

Splits from

her partner

depression ,

anxiety and fatigue

Reduced mobility

Occupational

health

assessment

natalizumab

New

partner

New job

junior management

position

Residual deficits:




Jan 2008

JCV

positive

? fingolimod

Oct 2013

Annual MRI

monitoring

Final

year of

school

University

31

Mo

nito

rin

g

Tre

atm

en

t C

linic

al

Occu

p &

so

cia

l


Recent Report of Higher Anti-JCV Antibody Levels in Anti-

JCV Positive Patients Who Developed PML

• Higher normalised optical

densities (Gen1) were

observed in the patients

who developed PML (n=9)

as compared with those

who did not develop PML

(n=2253)

0

0.5

1

1.5

Pre-PML Non-PML(seropositive)

nOD450=normalised optical density.

Trampe AK et al. Neurology 2012;78:1736–174.

nO

D4

50

P=0.0178

32


PML risk estimates for anti-JCV antibody index thresholds were calculated based on the current PML risk stratification algorithm (September 2012)

and predicted probabilities (using data from patients with no prior IS use: 2242 non-PML patients and 51 patients who developed PML using all

available anti-JCV antibody index data at least 6 months prior to PML diagnosis) for the population at or below that particular index (0.9−1.5) and

for the population above an index of 1.5. For index thresholds below 0.9, patient numbers were insufficient to allow for calculation of risk estimates.

Anti-JCV Antibody Index Values May Differentiate PML Risk

For Those With No Prior IS Use

Index 1−24 months

≤0.9 0.1 (0, 0.41)

≤1.1 0.1 (0, 0.34)

≤1.3 0.1 (0.01, 0.39)

≤1.5 0.1 (0.03, 0.42)

>1.5 1.0 (0.64, 1.41)

33

PML risk estimates (95% CI) per 1000 patients with no prior IS use

Plavina T et al. Poster DX51, CMSC May 29–June 1 2013, Orlando, USA; Ticho B. et al, Presented at ENS, June 8–11 2013, Barcelona, Spain O228.

33

Further evaluation of this new hypothesis correlating anti-JCV antibody index and PML risk assessment is

ongoing

25−48 months 49−72 months

0.3 (0.04, 1.13)

0.4 (0.01, 2.15)

0.7 (0.21, 1.53)

0.7 (0.08, 2.34)

1.0 (0.48, 1.98)

1.2 (0.31, 2.94)

1.2 (0.64, 2.15)

1.3 (0.41, 2.96)

8.1 (6.64, 9.80)

8.5 (6.22, 11.38)


17yr female,

diagnosed

with CIS

after

presenting

with myelitis

18yr, 1st year

university

diagnosed

with MS after

having L optic

neuritis

Abnormal MRI; >9

T2 lesions on brain

MRI and spinal cord

lesion at C5

2000 2001

clumsy

left

hand

pins &

needles

in legs

IFN-beta

2002 2003

R optic

neuritis

2004

Bladder dysfunction

Graduate

trainee

marketing

Full

time

employment

Off work

~3 months

of the year

Dec 2007

Brainstem

syndrome;

diplopia

and ataxia

? glatiramer

acetate

Cervical cord

relapse

weak L arm

with pain

High lesion

load with

brain

atrophy

Gd-enhancing

lesion of upper

cervical cord

Splits from

her partner

depression ,

anxiety and fatigue

Reduced mobility

Occupational

health

assessment

natalizumab

New

partner

New job

junior management

position

Residual deficits:




Jan 2008

JCV

positive

Oct 2013

Annual MRI

monitoring

JCV

high positive

Final

year of

school

University

34

Mo

nito

rin

g

Tre

atm

en

t C

linic

al

Occu

p &

so

cia

l


Use of anti-JC virus antibody index may further define risk of PML in anti-

JCV antibody positive natalizumab-treated patients with MS.

Plavina T et al. Presented at CMSC, May 29 – June 1 2013, Orlando, USA DX51.

Ticho B. et al, Presented at ENS, June 8–11 2013, Barcelona, Spain O228.

Natalizumab

Exposure

1–24

months

25–48

months

49–72

months

PML Risk 0.7/1000 5.3/1000 6.1/1000

No Prior IS Use

The earlier, the smaller, the better for natalizumab-associated PML: in MRI

vigilance veritas? Phan-Ba R. et al. Neurology 2012;79:1067-1069.

*https://medinfo.biogenidec.com/medinfo. Accessed August 5, 2013. Data as of March 2013 indicate estimated risk of PML patients with prior

immunosuppressant use is 1.8/1000 for natalizumab exposure of 1–24 months and 11.2/1000 for exposure of 25–48 months.

Negative Positive*

Anti-JCV

Antibody Status > 1 in 189

35


Risk of PML is ≤1/1000 for all patients with no prior IS use in the first 2 years

https://medinfo.biogenidec.com/medinfo


17yr female,

diagnosed

with CIS

after

presenting

with myelitis

18yr, 1st year

university

diagnosed

with MS after

having L optic

neuritis

Abnormal MRI; >9

T2 lesions on brain

MRI and spinal cord

lesion at C5

2000 2001

clumsy

left

hand

pins &

needles

in legs

IFN-beta

2002 2003

R optic

neuritis

2004

Bladder dysfunction

Graduate

trainee

marketing

Full

time

employment

Off work

~3 months

of the year

Dec 2007

Brainstem

syndrome;

diplopia

and ataxia

? glatiramer

acetate

Cervical cord

relapse

weak L arm

with pain

High lesion

load with

brain

atrophy

Gd-enhancing

lesion of upper

cervical cord

Splits from

her partner

depression ,

anxiety and fatigue

Reduced mobility

Occupational

health

assessment

natalizumab

New

partner

New job

junior management

position

Residual deficits:




Jan 2008

JCV

positive

3-monthly MRI

monitoring

? fingolimod

Oct 2013

Annual MRI

monitoring

JCV

high positive

Final

year of

school

University

36

Mo

nito

rin

g

Tre

atm

en

t C

linic

al

Occu

p &

so

cia

l


Early Detection of PML and Clinical

Outcome

37

Detection of PML on routine MRI (confirmed by CSF analysis) has been

demonstrated in asymptomatic patients1–5

– Asymptomatic PML patients have improved survival and less functional disability compared

with symptomatic patients6

MRI=magnetic resonance imaging; CSF=cerebrospinal fluid; FLAIR=fluid-attenuated inversion recovery. 1. Vermersch P et al. Neurology. 2011;76:1697-1704.

2. Phan-Ba R et al. Neurology. 2012;79:1067-1069; 3. Blair NF et al. Neurology. 2012;78:507-508; 4. Ayzenberg I et al. J Neurol. 2012;259:1732-1733;

5. Yousry TA et al. Ann Neurol. 2012;72:779-787; 6. Dong-Si et al. Presented at AAN; March 16–23, 2013; San Diego, CA. P04.271.

Months From PML Diagnosis


When is the Right Time to Start Natalizumab ?

38


17yr female,

diagnosed

with CIS

after

presenting

with myelitis

18yr, 1st year

university

diagnosed

with MS after

having L optic

neuritis

Abnormal MRI; >9

T2 lesions on brain

MRI and spinal cord

lesion at C5

2000 2001

clumsy

left

hand

pins &

needles

in legs

IFN-beta

2002 2003

R optic

neuritis

2004

Bladder dysfunction

Graduate

trainee

marketing

Full

time

employment

Off work

~3 months

of the year

Dec 2007

Brainstem

syndrome;

diplopia

and ataxia

? glatiramer

acetate

Cervical cord

relapse

weak L arm

with pain

High lesion

load with

brain

atrophy

Gd-enhancing

lesion of upper

cervical cord

Splits from

her partner

depression ,

anxiety and fatigue

Reduced mobility

Occupational

health

assessment

natalizumab

New

partner

New job

junior management

position

Residual deficits:




Jan 2008

JCV

positive

3-monthly MRI

monitoring

? fingolimod

Oct 2013

Annual MRI

monitoring

JCV

high positive

Final

year of

school

University

39

Mo

nito

rin

g

Tre

atm

en

t C

linic

al

Occu

p &

so

cia

l

Early or late?


STRATA: Patients Had Stable EDSS Scores for

Up to 5 Years

*P<0.0001

Kappos L et al. Presented at ECTRIMS; October 10–13, 2012; Lyon, France P520.

2.36

2.69 2.54

3.13 3.07 3.22 3.24 3.21 3.15

2.38 2.36 2.39

2.90

2.69 2.72 2.84 2.85 2.79

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

FeederStudy

Baseline

FeederStudyEnd

SafetyStudyEnd

STRATABaseline

STRATA48 Weeks

STRATA96 Weeks

STRATA144 Weeks

STRATA192 Weeks

STRATA240 Weeks

1 Year 2 Years 3 Years 4 Years 5 Years

Cessation/

Treatment Gap* Original Placebo

Original Natalizumab

Original Placebo – Now on Natalizumab

Mean

ED

SS

Sco

re

n = 380 707 381 707 280 552 385 709 274 569 230 479 205 462 194 427 174 393

40


TOP: Earlier Natalizumab Treatment Favours Annualised

Relapse Rate Outcomes

P values from a negative binomial regression model adjusted for gender, baseline EDSS score (<3.0 vs ≥3.0l), relapse status in the prior

year (≤1 vs >1), prior DMT use (<3 vs ≥3), disease duration (<8 vs ≥8 years), and treatment duration (≥3 vs <3 years), except for the factor

of interest. Error bars represent 95% CIs.

DMT=disease-modifying therapy; CI=confidence interval.

Wiendl et al. Presented at ENS; June 8–11, 2013; Barcelona, Spain,. P372.

41


TOP: Natalizumab Stabilises EDSS Scores in Patients with

Either a High or Low Starting EDSS Score at Baseline

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

0 6 12 18 24 30 36 42 48

Med

ian

ED

SS

Sco

re

Time (months)

Kappos L et al. Presented at ENS; June 9–12, 2012; Prague, Czech Republic. O261.

Baseline EDSS Score ≤3.0 (n=1591)

Baseline EDSS Score >3.0 (n=1840)

42


17yr female,

diagnosed

with CIS

after

presenting

with myelitis

18yr, 1st year

university

diagnosed

with MS after

having L optic

neuritis

Abnormal MRI; >9

T2 lesions on brain

MRI and spinal cord

lesion at C5

2000 2001

clumsy

left

hand

pins &

needles

in legs

IFN-beta

2002 2003

R optic

neuritis

2004

Bladder dysfunction

Graduate

trainee

marketing

Full

time

employment

Off work

~3 months

of the year

Dec 2007

Brainstem

syndrome;

diplopia

and ataxia

? glatiramer

acetate

Cervical cord

relapse

weak L arm

with pain

High lesion

load with

brain

atrophy

Gd-enhancing

lesion of upper

cervical cord

Splits from

her partner

depression ,

anxiety and fatigue

Reduced mobility

Occupational

health

assessment

natalizumab

New

partner

New job

junior management

position

Residual deficits:




Jan 2008

JCV

positive

3-monthly MRI

monitoring

? fingolimod

Oct 2013

Annual MRI

monitoring

JCV

high positive

Final

year of

school

University

Early or late?

43

Mo

nito

rin

g

Tre

atm

en

t C

linic

al

Occu

p &

so

cia

l




44 Adapted from Miller JR. J Manag Care Pharm. 2004;10(suppl S-b):S4-S11.

Time Symptom

Onset

Dis

ab

ilit

y

Later

treatment

Earlier

treatment

Optimal

window of

opportunity


Later treatment


44


T2T - NEDA

Zero

Tolerance

Treatment Objectives in Relapsing MS

Freedom from

disease

activity/disease

activity free

Reduced ongoing

damage

Treat Early

45


T2T - NEDA

Zero

Tolerance

Treatment Objectives in Relapsing MS

Freedom from

disease

activity/disease

activity free

Reduced ongoing

damage

Functional

Improvement

Maintain reserve

capacity

CNS Repair

Healthy

ageing

Improved Quality of Life

Treat Early

46


What does the future hold?

47

17yr female,

diagnosed with CIS

after presenting

with myelitis

18yr, 1st year

university diagnosed

with MS after having

L optic neuritis

Abnormal MRI; >9 T2 lesions

on brain MRI and spinal cord

lesion at C5

2000 2001

clumsy

left hand

pins &

needles in

legs

IFN-beta

2001 2003

R optic

neuritis

2004

Bladder dysfunction

Graduate

trainee

marketing

Full

time employment

Off work

~3 months of the

year

Dec 2007

Brainstem

syndrome;

diplopia and

ataxia

? glatiramer acetate

Cervical cord relapse

weak L arm with pain

High lesion load

with brain

atrophy Gd-enhancing lesion

of upper cervical

cord

Splits from her

partner

depression , anxiety and

fatigue

Reduced mobility

Occupational health

assessment

natalizumab

New

partner

New job

junior management

position

Residual deficits:

Normal walking 300m, unable to run & exercise. Intermittent

sensory symptoms in L arm. Mild urinary frequency

Jan 2008

JCV

positive

3-monthly MRI

monitoring

? fingolimod

Oct 2013

Annual MRI

monitoring

mo

nit

ori

ng

trea

tmen

t cl

inic

al

Occ

up

. & s

oci

al

JCV

high positive

Final

year of

school

University

Pregnancy Old

Age


Optimizing Use of Natalizumab

• Freedom from disease activity* was achieved in 65% to 70% patients during the

second year of treatment in AFFIRM1

• Natalizumab in AFFIRM reduced the rate of brain atrophy in the second year2

and also significantly reduced the rate of conversion of new Gd+ lesions to T1

hypointense lesions over 12 months3

• Risk of PML is very low (1 in 10,000) in in anti-JCV antibody–negative patients4

• In anti-JCV antibody-positive patients without prior IS use, risk of PML in first 2

years is low (≤1 in 1000)3; use of natalizumab for > 2 years is based on a case-

by-case decision

• In clinical practice, when used mostly in patients on an injectable DMT with

uncontrolled disease:

• A stable EDSS score is observed in most patients especially when used earlier in the

disease course5,6

• Improvements in fatigue, cognition, bladder function, and QoL are seen following

switch to natalizumab7-9

48

*Post hoc analysis of patients with no relapses, no sustained (12-week) disability progression, no Gd+ lesions, no new or enlarging T2-hyperintense

lesions. 1. Havrdová E. et al. Lancet Neurol. 2009;8:254-226; 2. Miller DH et al. Neurology. 2007;68:1390-1401; 3. Dalton CM et al. J Neurol.

2004;251:407-413; 4. Bloomgren G et al. N Engl J Med. 2012;366:1870-1880; 5. Kappos L et al. Presented at ENS; June 9–12, 2012; Prague, Czech

Republic. O261; 6. Kallweit U et al. Clin Neuropharmacol. 2012;35:77-80; 7. Svenningsson A et al. PLoS One. 2013;8:e58643; 8. Khatri B et al.

Presented at ECTRIMS; October 19–22, 2011; Amsterdam, The Netherlands. P1040; 9. Holmen C et al. Mult Scler. 2011;17:708-719.

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