Natalizumab PML Update

May 2013, MSer Version

Gavin Giovannoni

Blizard Institute

Barts and The London, United Kingdom

1

Natalizumab PML Incidence Estimates by Treatment Epoch

Natalizumab PML Incidence Estimates by Treatment Epoch

PML Risk only increases after 12 infusions

As the PML risk only increases after 12 infusions of Natalizumab I will limit further data analysis

to this subgroup of treated Msers.

Use of Natalizumab in the Post-Marketing Setting*

~83,000 MSers have been exposed to >= 12 months of

Natalizumab treatment

Visualisation of Natalizumab exposure

Each dot represents an MSer on

Natalizumab.

There are 10,000 MSers in this plot

Visualisation of Natalizumab Exposure of 12 or more infusions

Each dot represents an MSer on

Natalizumab.

There are 83,000 MSers in this plot, representing those

who have been exposed to

Natalizumab for 12 or more infusions.

~83,000 MSers exposed to 12 or more Natalizumab infusions

Visualisation of the number of MSers with PML

Each dot represents an MSer who has developed PML after

Natalizumab exposure.

There are 359 MSers, or dots, on either of these two plots.

359 MSers with PML

High-density plot

Low-density plot

Data is as of the 6th May 2013

Visualisation of PML Risk

Each dot in these plots

represents an MSer on

Natalizumab.

359 MSers with PML ~83,000 MSers exposed to 12 or more Natalizumab infusions

High-density plot

Low-density plot

PML Risk for MSers treated with Natalizumab for more than 12 months = 359 / ~83,000 = 0.00418

4.18 PML cases per 1000, or 1 in 239, MSers treated with 12 or more infusions

PML Risk Treatment duration 12 or more Natalizumab infusions

Each dot represents a MSer who has been

exposed to Natalizumab for 12 or more infusions.

Your chances of getting

PML are 1 in 239.

Black dot = Mser with PML Purple dots = unaffected MSers

The overall risk of 1 in 239 is not very helpful for individual MSers as we now know of three risk factors that modify the risk of developing PML:

1. Whether or not you have been infected with the JC virus in the past; JCV +ve vs. JCV –ve.

2. How long you have been on Natalizumab; i.e. less than 2 years compared to 2 or more years.

3. Whether or not you have been treated with immunosuppressive therapies in the past.

PML Risk – JC virus negative Treatment duration N/A & previous immunosuppression N/A

Each green dot represents a a JCV negative MSer on

Natalizumab.

Your chances of getting PML are 1 in

14,286

PML Risk – JC virus positive Treatment duration less than 2 years and no previous immunosuppression

Each yellow dot represents a a JCV positive MSer on

Natalizumab for less than 2 years, who has not received previous immunosuppression.

Your chances of getting PML are

1 in 1,667.

PML Risk – JC virus positive Treatment duration less than 2 years and previous immunosuppression

Each orange dot represents a a JCV positive MSer on

Natalizumab for less than 2 years, who has

received previous immunosuppression.

Your chances of getting PML are

1 in 556.

PML Risk – JC virus positive Treatment duration more than 2 years and no previous immunosuppression

Each red dot represents a a JCV positive MSer on Natalizumab for

more than 2 years, who has not received

previous immunosuppression.

Your chances of getting PML are

1 in 192.

PML Risk – JC virus positive Treatment duration more than 2 years and previous immunosuppression

Each dark red dot represents a a JCV positive MSer on Natalizumab for

more than 2 years, who has received

previous immunosuppression.

Your chances of getting PML are

1 in 94.

What has happened to the MSers who have developed PML?

Status of PML Cases

Risk of dying if you develop PML is ~ 1 in 5

Black dots = MSers with PML who survive. Gray dot = MSer with PML who will die from the condition.

What has happens to the MSers who survive PML?

PML outcome: one method is to use the Karnofsky Performance Scale to assess outcome in PML survivors

The following is the Karnofsky Performance Scale:

100% – normal, no complaints, no signs of disease

90% – capable of normal activity, few symptoms or signs of disease

80% – normal activity with some difficulty, some symptoms or signs

70% – caring for self, not capable of normal activity or work

60% – requiring some help, can take care of most personal requirements

50% – requires help often, requires frequent medical care

40% – disabled, requires special care and help

30% – severely disabled, hospital admission indicated but no risk of death

20% – very ill, urgently requiring admission, requires supportive measures or treatment

10% – moribund, rapidly progressive fatal disease processes

0% – death.

PML outcomes: Karnofsky scores

Dong-Si T, et al. ECTRIMS 2012; P1098. In general MSers who develop PML don’t do very well.

PML outcome: another method is to use the EDSS to assess outcome in PML survivors

PML outcomes: EDSS

Dong-Si T, et al. ECTRIMS 2012; P1098. In general MSers who develop PML don’t do very well.

It is not all bad news.

If the PML is detected early, before it causes symptoms, the outcome

is better?

PML outcomes: asymptomatic vs symptomatic

Dong-Si T, et al. AAN 2013; P04.271.

MSers with PML diagnosed when asymptomatic do better than MSers who are diagnosed when symptomatic.

PML outcomes: asymptomatic vs symptomatic

Dong-Si T, et al. AAN 2013; P04.271.

MSers with PML diagnosed when asymptomatic do better than MSers who are diagnosed when symptomatic.

You will notice in the previous slides that asymptomatic PML is detected with MRI monitoring.

At the moment the recommendation, by PML experts, is that if

you are at high risk of developing PML you need to have an MRI every 3 months.

You may need to discuss this issue with your neurologist.

How do you know if you have, or are developing, PML?

The simple answer is vigilance, you

need to watch out for new symptoms suggestive of PML.

PML Presenting Symptoms

How do you treat PML?

There is no anti-viral treatments for PML. At the moment we simply wash out the natalizumab with a technique called plasma exchange. Plasma exchange removes the natalizumab and allows your immune

cells to re-enter the brain to fight the infection.

Plasma Exchange

What happens to PML once natalizumab is out of your body?

Your immune cells are capable or re-entering the brain to fight the PML. This causes an encephalitis that we call IRIS (immune reconstitution inflammatory syndrome). The IRIS in itself can

cause a neurological deterioration and may need to be treated with steroids.

IRIS Presents as Clinical Decline

Are there any predictors of a poor outcome from PML?

Factors that may affect survival in Msers with PML

What are the risks of MS?

Apologies, I am not trying to be patronising, but you may not need to be reminded of some

facts to help you weigh-up the risks and benefits of natalizumab therapy.

Lifespan in MSers Is Shortened by 8 to 12 Years

• Survival probability of Norwegian MSers with relapsing-remitting MS (RRMS) (Hordaland County, Western Norway, 1953–2003)

38

RRMS % s

urv

ival

MS=multiple sclerosis; CI=confidence interval.

Population-Based MS Mortality Studies

First Author

Population

and Time Period

Size

of Cohort

Standardized

Mortality Ratio Additional Survival Measures

GryttenTorkildsen

Mult Scler 2008

Western Norway

1953–2003 878

2.66

(95% CI: 2.31–3.06)

• Median survival time from onset: 41 years MS vs 49 years general population

− 8 years life lost in MS

Smestad

Mult Scler 2009

Oslo

1940–1980 368

2.47

(95% CI: 2.09–2.90)

• Reduction of median life expectancy vs general population

− Female: 11.2 years

− Male: 7.4 years

Bronnum-Hansen

Brain 2004

Danish MS Registry

1949–1996 9881

2.89

(95% CI: 2.81±2.98)

• Median survival time (from disease onset) vs general population:

− ≈10 years life lost in MS

Hirst

JNNP 2008

South Wales

1985–2006 373

2.79

(95% CI: 2.44 to 3.18)

• Median age of death: 63.1 years MS vs 70.6 years general population

− 7.5 years life lost in MS

Sumelahti

Mult Scler 2010

Finland

1964–1993 1595

2.8

(95% CI: 2.6–3.1)

• Survival decreases with disease progression

− SMR, 2–9.9 years after diagnosis: 2.4

− SMR, ≥10 years after diagnosis: 3.1

Wallin

Brain 2000

USA

1956–1996 2489

2.18

(Not specified)

• Healthy soldier effect speculated to have a

favorable effect on survival

Leray

Mult Scler 2007

West France

1976–2004 1879

1.3

(95% CI: 1.01–1.7)

• Mean follow-up duration=12.7 years from

clinical onset; may be basing estimate on

relatively immature dataset

SMR=standardized mortality ratio.

The survival disadvantage in MS is greater than in some other chronic diseases

Standardized Mortality Ratios in Chronic Diseases

Disease SMR (RANGE)

Cardiovascular disease1* 1.34 (1.23–1.44)

Ischemic stroke2† 1.75(1.38–2.19)

Early breast cancer3 2.0 (1.6–2.7)

Crohn’s disease4 2.8

MS5 2.8 (2.6–3.1)

MS (2–9.9 years after diagnosis)5 2.4 (1.9–2.9)

MS (≥10 years after diagnosis)5 3.1 (2.8–3.4)

Parkinson’s disease6 3.66 (3.37–3.95)

Type 2 diabetes1 4.47 (3.91–5.10)

*In patients with type 2 diabetes; †in patients with valvular heart disease in Olmsted County, Minnesota.

1. De Marco R et al Diabetes Care. 1999;22:756-761; 2. Petty GW et al. Mayo Clin Proc. 2005;80:1001-1008; 3. Hooning MJ et al. Int J Radiat Oncol Biol Phys.

2006;64:1081-1091; 4. South East England Public Health Observatory, Mortality trends. 2006; 5. Sumelahti ML et al. Mult Scler. 2010;16:1437-1442;

6. Hristova DR. Folia Medica. 2009;51:40-45.

Uti

lity

EDSS Status

EDSS and utility* show a significant

inverse relationship1,†

*Utility measures are derived from EQ-5D using the EuroQoL instrument; †error bars depict 95% confidence intervals. 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. Confavreaux, Compston. McAlpine’s multiple Sclerosis. 4th edn. Churchill Livingstone Elsevier; 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

The Effects of MS on Unemployment

42

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

The Effects of MS on Divorce and Separation

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

CIS Patients

n = 40

Impact of MS: Cognitive Functioning in the CIS Stage

Cognitive Test Performance in an Exploratory Study*

44

57%

7%

-20%

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 non-verbal 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;13:3124-127.

Healthy Controls

n = 30

p < 0.0001

Deficits were found mainly in

memory, speed of information

processing, attention, and

executive functioning

Pati

en

ts f

ailin

g

≥2 c

og

nit

ive t

ests

Consequences of increasing EDSS scores: loss of employment

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

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

Austria

Belgium

Germany

Italy

Netherlands

Spain

Sweden

Switzerland

United Kingdom

Work Capacity by Disability Level P

rop

ort

ion

of

Pa

tie

nts

≤6

5 Y

ea

rs O

ld

Wo

rkin

g (

%)

0

10

20

30

40

50

60

70

80

90

0.0/1.0 2.0 3.0

EDSS Score

Msers’ QoL decreases tremendously dependent on the EDSS score

Mean utility

Utilities at early

disease

Utility at severe disease

Austria 0.55 0.90 0.05

Belgium 0.51 0.85 0.06

Germany 0.62 0.86 0.10

Italy 0.53 0.80 0.06

Netherlands 0.61 0.85 0.05

Spain 0.55 0.87 0.08

Sweden 0.546 0.825 0.047

Switzerland 0.59 0.89 0.1

UK 0.51 0.92 0.18

EQ-5D was used to calculate utilities: Utility is a measure of people's well-being or preferences for outcomes.

Mean utilities and EDSS in Germany 1= perfect health; 0 = worst health/dead

Source: based on G. Kobelt et al.: The European Journal of Health Economics, Volume 7; suppl. 2006

0,45

0,55

0,60

0,75

0,80

0,65

0,70

0,50

0,72 - mean utility of patients with rheumatoid arthritis

at stage 1 (Kobelt G. et al. 1999)

0,00 - Worst possible status

1,00 - Best possible health status

0,55 - mean utility of MSers (Kobelt G. et al. 2001)

0,48 - mean utility of severe haemophilia patients with inhibitors (Ekert H. et al. 2001)

0,82 - mean utility of aging patients with osteoporosis,

no fracture (Oleksik A et al. 2000)

0,58 - mean utility of patients with Parkinson’s Disease (Siderowf A. et al. 2002)

Utilities make diseases comparable

What are the benefits of natalizumab treatment?

Apologies, you may not need to be

reminded of natalizumab’s effectiveness.

AFFIRM: Reduction in ARR and Risk of

Disability Progression with Natalizumab

Week

Polman CH et al. N Engl J Med. 2006;354:899-910; Polman CH et al. Presented at AAN; April 9–16, 2005; Miami, FL.

Placebo (n=315)

Natalizumab (n=627)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

AR

R (

95%

CI)

P<0.001

0.73

0.23

Years 0–2

68% reduction in

ARR vs placebo

Number of Msers at Risk

Placebo

Natalizumab

315 296 283 264 248 240 229 216 208 200

627 601 582 567 546 525 517 503 490 478

199

473

3-Month Sustained Disability Progression

29%

17%

0

0.1

0.2

0.3

0.4

0 12 24 36 48 60 72 84 96 108 120

Pro

po

rtio

n w

ith

Su

sta

ined

Pro

gre

ssio

n

HR=0.58

P<0.001

42%

Placebo

Natalizumab

AFFIRM: MSers with Highly Active MS (>2 Relapses and Gd+ Lesions at Baseline)

ARR Reduction*

Reduction in Risk of 12-Week

(3-Month) Sustained EDSS Progression†

Red

ucti

on

(%

)

53

(P=0.029)

81

(P<0.001)

*Natalizumab ARR reduction vs placebo: 0.28 vs 1.46; †EDSS progression calculated from 1–HR, 1–0.47 for natalizumab.

Tysabri [summary of product characteristics]; Hutchinson M et al. J Neurol. 2009;254:405-415 & 1035-1037.

Red

ucti

on

(%

)

AFFIRM: Natalizumab Increases the Proportion of MSers Free of Clinical and MRI Disease Activity

MSers with No

Disease Activity over 2 Years

Placebo (n=304) 7% P<0.0001

Natalizumab (n=600) 37%

P<0.0001, natalizumab vs placebo, for all individual and combined disease measures.

MRI=magnetic resonance imaging; Gd+=gadolinium-enhancing.

Havrdová E et al. Lancet Neurol. 2009;8:254-260.

64%

Free of Clinical

Disease Activity

58%

Free of MRI

Disease Activity

58%

Free of

T2 Lesions

95%

Free of

Gd+ Lesions

84%

Free of

Progression

37%

Free of

Disease

Activity

71%

Free of

Relapses

7.2

15.4 13.0

36.7

46.7

68.4

0

10

20

30

40

50

60

70

80

Year 0-2 Year 0-1 Year 1-2

Patients

without

com

bin

ed

dis

ease a

ctivity (

%)

Placebo Natalizumab

AFFIRM: Proportion of MSers Without Disease

Activity* Increases from Year 1 to Year 2

*Absence of disease activity on the composite of clinical and radiological measures was defined as no relapse, no progression

of disability (sustained for 12 weeks), no gadolinium-enhancing lesions, and no new or enlarging T2-hyperintense lesions.

Harvrdova E at al. Lancet Neurol. 2009;8:254-260.

p<0.0001 for all comparisons

n=304 n=600 n=305 n=604 n=284 n=544

AFFIRM: Natalizumab Provided More MSers with Freedom from Disease Activity

Pati

en

ts F

ree o

f

Dis

ease

Acti

vit

y (

%)

n=59

Overall Population

P<0.0001

Highly Active MSers*

P<0.0001

7.2

1.7

36.7

27.4

0

10

20

30

40

50 Placebo

Natalizumab

n=304 n=600 n=146

Post hoc analysis of AFFIRM; natalizumab vs placebo for both overall population and patients with highly active disease.

*MSers with ≥2 relapses in prior year and ≥1 Gd+ lesion at baseline.

Havrdová E et al. Lancet Neurol. 2009;8:254-260.

Havrdova et al., Lancet Neurol. 2009, 8:254-60.

*Highly active disease was defined as at least two relapses in the year before study entry and at least one gadolinium-enhancing lesion at

study entry; non-highly active disease was defined as fewer than two relapses or no lesions at study entry.

AFFIRM: Freedom from Disease Activity in

Highly Active and Non-highly Active MSers

3% 4%

34%

65%

0%

20%

40%

60%

80%

100%

Year 1 Year 2

n=59 n=56 n=137 n=146

Pa

tie

nts

Dis

ea

se

Ac

tivit

y F

ree

(%

)

18%15%

51%

70%

0%

20%

40%

60%

80%

100%

Year 1 Year 2

P<0.0001

P<0.0001

P<0.0001

Placebo

Natalizumab

Highly active MSers* Non-highly active MSers *

P<0.0001

n=246 n=228 n=407 n=458 P

ati

en

ts D

ise

as

e A

cti

vit

y F

ree

(%

)

AFFIRM: Brain Parenchymal Fraction (BPF)

*Change in BPF of natalizumab group at year 1 probably reflects “pseudoatrophy” from reduced edema/inflammation.

Miller DH. Neurology. 2007;68:1390-1401.

Placebo (n=315)

Natalizumab (n=627)

−1.0

−0.8

−0.6

−0.4

−0.2

0

Mean

Perc

en

tag

e C

han

ge i

n B

PF

−0.82

−0.80

P=0.822

vs placebo

Time (Years) 2 0 1

*

−0.39

−0.56

P=0.002

vs placebo

55

Real Life: Escalation to Natalizumab is More

Effective Than Switching Among GA/IFN

% Patients

2nd year*

Escalate to natalizumab n=106

Switch between GA/IFN n=161

Data from a post-marketing, prospective, observational study in 285 RRMS patients who failed treatment with IFNβ or GA therapy. After failure of IFNβ

or GA therapy patients were switched to either natalizumab (n=106) or IFNβ/GA (n=161); EDSS=Expanded Disability Status Scale; GA=glatiramer

acetate; IFNβ=interferon beta; MRI=magnetic resonance imaging; MS=multiple sclerosis; RRMS=relapsing remitting MS

*At 12 months there were no differences 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(1):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 72

59

No relapses

p<0.0045

Natalizumab (TOP) Reduces Risk of Relapse Compared to IFN and GA ( )

• Natalizumab treatment in TOP was associated with a significant reduction in risk of relapse, compared with a prospective outcome registry of RRMS patients experiencing at least one relapse on treatment IFN-GA (MS-COMET).

• In unmatched, unadjusted sample (left panel), risk of relapse was 1.68-fold (95% CI, 1.10–2.19-fold) greater among MSCOMET compared to TOP MS patients despite a higher disease activity/severity profile in the TOP cohort at baseline.

• In propensity matched sample (right panel), relapse risk in MSCOMET patients was increased 2.73-fold (95% CI, 2.10–3.55-fold).

0.00

0.25

0.50

0.75

1.00

Pro

port

ion n

ot re

lap

sed

0 .5 1

Years since baseline

MSCOMET TOP

Unmatched, unadjusted

0.00

0.25

0.50

0.75

1.00

Pro

port

ion n

ot re

lap

sed

0 .5 1

Years since baseline

MSCOMET TOP

Propensity matched

Spelman T et al. Presented at ECTRIMS; October 10-13, 2012, New Orleans, LA. P303.

IFN=interferon; GA=glatiramer acetate.

0.0

0.5

1.0

1.5

2.0

2.5

3.0

AFFIRM TOP Danish Switzerland/Germany

Switzerland France Belgium Italy TYSEDMUS

AR

R

Pre-Natalizumab

Natalizumab

Natalizumab: Low ARR Across Registries and Independent Studies

*As of June 1, 2011, 3484 patients were enrolled. Overall in TOP, patients received a mean of 14.6 (±11.21) natalizumab infusions; 57% (n=1981)

of patients analyzed were followed for 1 year; 22% (n=761) were followed for 2 years; 7% (n=230) were followed for 3 years; †median. y=years;

mo=months; wk=weeks. 1. Polman C et al. N Engl J Med. 2006;354:899-910; 2. Hotermans C et al. Presented at WCN; November 12–17, 2011;

Marrakesh, Morocco; 3. Oturai A et al. Eur J Neurol. 2009;16:420-423; 4. Putzki N et al. Eur J Neurol. 2010;17:31-37; 5. Putzki N et al. Eur Neurol.

2010;63:101-106; 6. Outteryck O et al. J Neurol. 2010;257:207-211; 7. Belachew S et al. Eur J Neurol. 2011;18:240-245; 8. Sangalli F et al. Neurol Sci.

2010;31(suppl 3):299-302; 9. Vukusic S et al. Presented at ECTRIMS; October 19–22, 2011; Amsterdam, The Netherlands; P970.

n= 627 3484 234 97 85 384 45 285 456

Mean follow-up 2 y 14.6 mo* 11.3 mo† 1 y 1 y 1 y 44 wk 2 y 3 y

1 2 3

4

5 6 7 8 9

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

Switzerland/Germany

Switzerland France Belgium Sweden TYSEDMUS

EDSS

Sco

re (

me

an)

Pre-NatalizumabNatalizumab

Registries and Independent Studies: Stable EDSS Scores

N 97 85 384 45 901† 2855 Mean follow-up 1 y 1 y 1 y 44 wk 2 y 3 y

EDSS=Expanded Disability Status Scale; RRMS=relapsing-remitting multiple sclerosis.

1. Putzki N et al. Eur J Neurol. 2010;17:31-37; 2rol. 2010;63:101-106; 3. Outteryck O et al. J Neurol. 2010;257:207-211;

4. Belachew S et al. Eur J Neurol. 2011;18:240-245; 5. Holmen C et al. Mult Scler. 2011;17:708-719; 6. Confavreux C et al. Presented at

EMA; May 3–6, 2011; London, England.

1

2 3 4 5 6

3.5 3.3 3.3 3.3

3.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

Baseline Year 1 Year 2 Year 3 Year 4

Me

an

ED

SS

Sc

ore

TOP: Mean EDSS Scores by Natalizumab Treatment Duration

*Sustained (6-month) improvement was defined as a ≥1.0-point decrease in EDSS score from baseline; †sustained (6-month) progression was defined as a ≥1.0-point increase in EDSS score from baseline. EDSS=Expanded Disability Status Scale.

Pellegrini F et al. Presented at the 28th Congress of ECTRIMS, Lyon, France, Oct 10–13, 2012. P519.

n=4402 n=1839 n=1043 n=218 n=461

TOP: Clinically Disease Activity Free

89

65 59

0

20

40

60

80

100

Sustained progressionfree

Relapse free Clinical disease activity-free

Pro

po

rtio

n o

f p

atie

nts

(%

)

Sustained progression was defined as an increase of ≥1.0 point in the EDSS score sustained for 6 months; clinical disease

activity-free was defined as no relapses and no 24-week confirmed EDSS progression.

Pellegrini F et al. Presented at the 28th Congress of ECTRIMS, Lyon, France, Oct 10–13, 2012. P519.

61

Registries and Independent Studies and AFFIRM: % Disease Activity Free on Natalizumab

Over 90% of AFFIRM patients were treatment naïve, and the remainder had been on a previous therapy for no more than 6

months, but not treated in the 6 months prior to enrolment. In contrast, approx 90% of patients in registries and independent

studies were switched to natalizumab after experiencing disease activity on a prior therapy.

*Relapse-free (freedom from progression not reported); EDSS worsening not determined in this analysis.

1. Belachew S et al. Eur J Neurol. 2011;18:240-245; 2. Putzki N et al. Eur J Neurol. 2010;17:31-37; 3. Fernandez O et al. J Neurol.

2012 Jan 31 [Epub ahead of print]; 4. Sangalli F et al. Neurol Sci. 2010;31(suppl 3):299-302; 5. Outteryck O et al. Presented at

ECTRIMS; October, 2011; Amsterdam, Netherlands; 6. Havrdová E et al. Lancet Neurol. 2009;8:254-260.

Cohort

Belgium1

(N=45)

Germany/

Switzerland2

(N=97)

Spain3

(N=825)

Italian4

(N=285)

French5

(N=603)

AFFIRM6

(N=942)

Follow-up 44 weeks 1 year 1 years 2 years 2 year 2 years

Freedom from

clinical disease

activity, %

82 63.9 -- 78* 45 64

Freedom from

radiologic disease

activity, %

71 64.9 94.6 69 68 58

Composite clinical

and radiological

freedom from

disease activity, %

62 48.5 63 63 49 37

62

Factors Predicting the Ultimate Goal of Disease Activity Silencing

Havrdova E. et al. ECTRIMS Meeting poster 905, Gothenburg, Sweden 2010.

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

Natalizumab-treated patients 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.

Factors Predicting the Ultimate Goal of Disease Activity Silencing

Prosperini L et al. J Neurol Sci. 2012;323:104-112.

Real-life

Stepwise logistic regression analysis showing the predictive variables for having a “full” response to natalizumab (i.e. no clinical and MRI activity) during a 24-month follow-up period.

Natalizumab appears to be more prone to induce a clinical and MRI remission of MS if started in patients with less aggressive disease (i.e. few relapses and mild disability)

TOP: Earlier Natalizumab Treatment Favors ARR Outcomes

P value was from the negative binomial model adjusted for gender, baseline relapse status (0 or 1 vs >1 relapse), EDSS score

(0.0–2.0, 2.5–4.0, and 4.5–9.5), disease duration (<8 vs ≥8 years), prior DMT use (0, 1, or >1), and treatment duration (<3 vs ≥3 years).

n=1836 n=2107

Baseline EDSS Score

Po

stb

aselin

e

Mean

An

nu

ali

zed

Rela

pse R

ate

P=0.0003

Number of Prior DMTs

n=366 n=1744 n=1866

P<0.0001

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

TOP: Subgroup Analyses

TOP: Overall Stabilization of EDSS Scores in Patients with Either a High or Low Starting EDSS

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)

Natalizumab should be used according to the SmPC

Natalizumab Effect on Neurofilament Light Levels in Cerebrospinal Fluid of MSers

NFL = Neurofilament light.

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

Balancing Benefits and Risks of Treatment

vs. Risk of Poorly Controlled MS

Tysabri® (natalizumab) [summary of product characteristics]. Dublin, Ireland: Biogen Idec; 2011.

http://www.medicines.org.uk/EMC/medicine/18447/SPC/TYSABRI+300+mg+concentrate+for+solution+for+infusion/. Accessed April 24, 2012.

Natalizumab Risks

• PML

• Other CNS opportunistic infections

• Treatment during pregnancy if clinically required

• Hypersensitivity

• Other AEs per labelling

• Unknown long-term safety profile

Benefits

• Relapse rate

• Disability progression

• Freedom from disease activity

• Quality of life

• Brain atrophy (neuroprotective)

• Functional improvements

• Consistent effects in long-term real-life clinical use

• Well-defined safety profile and ability to stratify risk

I hope you have found this slide deck informative. It is a work in progress and I will simplify the slides for next month. If

you have any queries please do not hesitate to ask them via the comments

section on the blog.

www.ms-res.org