Profesional natalizumab benefit risk update may 2013

TY-PAN-0597 Date of preparation: May 2013 FOR HEALTHCARE PROFESSIONALS ONLY

TYSABRI (natalizumab)

Benefit/Risk Update &

PML Risk Stratification


This information has been provided

by Biogen Idec Medical Affairs

for healthcare professional use only,

in response to your request.


Benefit / Risk

Benefit

Risk

TYSABRI

81% reduction in

relapse rate1

64% reduction in

disability

progression1

>1 in 3 patients free

of disease activity2

PML risk ≈

3.04 in 1,000 3

Other Adverse

Events Per

Labelling

1. Hutchinson M, et al. J Neurol. 2009;256:405-415.

2. Havrdova E, et al. Lancet Neurol. 2009;8(3):254-60.

3. Biogen Idec, data on file.


PML Risk Update


VP1=viviparous 1; RR=regulatory region;

CNS=central nervous system.

1. Presence of

asymptomatic JCV

2. Viral factors:

VP1 mutations,

RR permutations

3. Host factors:

peripheral immune function,

genetics

4. Drug effects that reduce

CNS immune surveillance

45 nm

JC virion

What causes PML?

• PML is uncommon and likely caused by interplay between multiple factors


PML Risk

• Duration of natalizumab dosing prior to PML diagnosis ranged from 8 to 77

doses1

– Mean duration of natalizumab dosing at time of PML diagnosis was approximately

39.0 months1

• Overall incidence: 3.04 per 1000 patients (95% CI: 2.74 to 3.38 per 1000

patients)1

– Currently the average post-marketing natalizumab exposure worldwide is

approximately 2 or more years of natalizumab exposure

• Factors that increase the risk of PML have been identified2 – JCV exposure indicated by anti-JCV antibody positive status

– Receiving an immunosuppressant prior to receiving natalizumab

– Natalizumab treatment duration, especially >2 years


2. TYSABRI Summary of Product Characteristics


Natalizumab PML Incidence Estimates by

Treatment Duration

Biogen Idec, data on file.

Calculations based on exposure through 30 April 2013 and 359 confirmed cases as of 6 May 2013

Inc

ide

nc

e p

er

10

00

pa

tie

nts

3.38

4.64

5.28

5.83 5.64

5.52

5.18

4.35

3.97

3.42

2.74

3.76

4.26

4.67

4.40 4.18

3.76

2.92

2.43

1.78

3.04

4.18

4.75

5.23 4.99

4.81

4.43

3.58

3.13

2.50

0.0

1.0

2.0

3.0

4.0

5.0

6.0


Natalizumab PML Incidence Estimates by

Treatment Epoch In

cid

en

ce p

er

10

00

pa

tie

nts

Calculations based on exposure through 30 April 2013 and 359 confirmed cases as of 6 May 2013


3.38

0.11

0.83

2.22

2.87 3.00

2.81

2.74

0.02

0.47

1.51

1.91 1.81

1.29

3.04

0.05

0.63

1.84

2.36 2.35

1.95

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0


Use of Natalizumab in the Post-Marketing Setting*

Patients


Worldwide post-marketing data from 23 Nov 2004 to 31 March 2013

279,196 Patient-Years

of natalizumab exposure

*Post-marketing data includes patients exposed since 23 November 2004. This excludes approximately 5,100 patients exposed

in clinical trials; 2,200 exposed for ≥12 months; 1,900 exposed for ≥18 months; 1,700 exposed for ≥24 months; 1,300 were

exposed ≥30 months; 1,000 were exposed ≥36 months; 700 were exposed ≥42 months; and 700 were exposed for ≥48

months. Exposures are estimates and may not fully reflect treatment interruptions that are used in certain patients.

115,400

83,000

70,100

59,100

49,200

41,100

33,600

26,600

OverallExposure

≥12 Months

≥18 Months

≥24 Months

≥30 Months

≥36 Months

≥42 Months

≥48 Months Patients


Geographic Distribution of PML Cases

• Of the 359 cases reported through 6th May 2013:

– 123 are from the United States

– 212 are from the European Economic Area

– 24 are from the rest of the world



Status of PML Cases

• As of 6th May 2013:

– 83 patients have died (23%)

– 276 patients are alive (77%)

• It is too early to draw conclusions about the outcomes of patients who develop PML while on natalizumab treatment

• PML may be fatal or result in severe disability1

The median time to death was 2.2 months (range, 0.1 to 15.2 months) for 44 deaths as of 29th February 2012.




Risk Stratification Tool: The Presence of Anti-JCV Antibodies,

Prior Immunosuppressant Use, Treatment Duration*

0.07/1000 95% CI 0-0.38

No Yes

Anti-JCV

Antibody Status

Negative Positive

Prior IS Use


Natalizumab

Exposure No Prior IS Use Prior IS Use

1–24 months 0.6/1000 95% CI 0.4-0.9

1.8/1000 95% CI 1.1-2.8

25–48 months 5.2/1000 95% CI 4.3-6.2

10.6/1000 95% CI 8.1-13.8

Data beyond 4 years of treatment are limited. *Based on natalizumab exposure and 285 confirmed PML cases as of September 5, 2012. Prior IS data in overall natalizumab-treated patients based

on proportion of patients with IS use prior to natalizumab therapy in TYGRIS as of May 2011; and prior IS data in PML patients as of September 5,

2012. The analysis assumes that 55% of natalizumab-treated MS patients were anti-JCV antibody positive and that all PML patients test positive for

anti-JCV antibodies prior to the onset and diagnosis of PML. The estimate of PML incidence in anti-JCV antibody negative patients is based on the

assumption that all patients received at least 1 dose of natalizumab . Assuming that all patients received at least 18 doses of natalizumab , the

estimate of PML incidence in anti-JCV antibody negative patients was generally consistent (0.1/1000; 95% CI 0.00–0.62).


Risk Stratification Tool: The Presence of Anti-JCV Antibodies,

Prior Immunosuppressant Use, Treatment Duration*

0.07/1000 95% CI 0-0.38

No Yes

Anti-JCV

Antibody Status

Negative Positive

Prior IS Use


Natalizumab

Exposure No Prior IS Use Prior IS Use

1–24 months 0.6/1000 95% CI 0.4-0.9

1.8/1000 95% CI 1.1-2.8

25–48 months 5.2/1000 95% CI 4.3-6.2

10.6/1000 95% CI 8.1-13.8

1 in 14,286

1 in 192

1 in 1,667

1 in 94

1 in 556

Data beyond 4 years of treatment are limited. *Based on natalizumab exposure and 285 confirmed PML cases as of September 5, 2012. Prior IS data in overall natalizumab-treated patients based

on proportion of patients with IS use prior to natalizumab therapy in TYGRIS as of May 2011; and prior IS data in PML patients as of September 5,

2012. The analysis assumes that 55% of natalizumab-treated MS patients were anti-JCV antibody positive and that all PML patients test positive for

anti-JCV antibodies prior to the onset and diagnosis of PML. The estimate of PML incidence in anti-JCV antibody negative patients is based on the

assumption that all patients received at least 1 dose of natalizumab . Assuming that all patients received at least 18 doses of natalizumab , the

estimate of PML incidence in anti-JCV antibody negative patients was generally consistent (0.1/1000; 95% CI 0.00–0.62).


Putting risk into context:

Benefits of natalizumab therapy


• Initiation or continuation of natalizumab therapy

should be based upon an assessment of the

potential for benefit and risk1

• Benefits and risks of natalizumab therapy are

individual, and should be considered by both the

physician and the patient1

Putting risk into context



Putting risk into context: AFFIRM efficacy1,2

In patients with highly active RRMS (≥2 relapses in the prior year and ≥1 Gd+ lesion at baseline)

1. Hutchinson M, et al. J Neurol. 2009; 256:405-15, 1035-7.


0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

An

nu

ali

ze

d R

ela

ps

e R

ate

1.46

0.28

Natalizumab n=148

Placebo n=61

81%

reduction

(p<0.001)

Number of Patients at Risk

Placebo

Natalizumab

Pro

po

rtio

n W

ith

Su

sta

ine

d D

isa

bil

ity P

rog

ress

ion

0.0

0.1

0.2

0.4

0.5

Weeks

24

Placebo 26%

Natalizumab 10%

61 57 54 51

148 144 141 140

0 120

0.3

72 108 96 48

47 46 45 42 39 36

137 131 130 128 123 123

12 36 60 84

64% risk reduction

Hazard ratio=0.36

(p=0.004)

• Annualized relapse rate at 2 years • Sustained disability progression

(confirmed for 24 weeks)

Post hoc analysis of AFFIRM. AFFIRM was a 2 year, phase 3, randomized, double-blind, placebo-controlled, multicentre study of

natalizumab in RRMS (N=942). RRMS=relapsing remitting multiple sclerosis.


1. Havrdova E, et al. Lancet Neurol. 2009;8(3):254-60.

Pro

po

rtio

n o

f D

isease

-Fre

e P

ati

en

ts (

%)

n=304 n=600 n=59 n=146

Overall Population

P<0.0001

Highly Active Patients †

P<0.0001

7.2

1.7

36.7

27.4

0

10

20

30

40

50 Placebo Natalizumab

5 vs placebo

16 vs placebo

Putting risk into context: freedom from disease activity*1

Post hoc analysis of AFFIRM. *Freedom from disease activity defined as the composite of freedom from clinical disease activity

(no relapses and no increase in EDSS) and freedom from radiologic disease activity (no new or enlarging T2 lesions and no Gd+

lesions). † Patients with ≥2 relapses in the prior year and ≥1 Gd+ lesion at baseline. EDSS=Expanded Disability Status Scale.


Putting risk into context: real life data from STRATA1

1. Kappos L, et al. ECTRIMS 2012; P520.

Cessation/

Treatment Gap

n=

381

n=

707

n=

381

n=

707

n=

328

n=

641

n=

385

n=

709

n=

282

n=

584

n=

385

n=

709

n=

244

n=

519

n=

203

n=

456

n=

249

n=

528

†

1 Year 2 Years 3 Years 4 Years 5 Years

Original Placebo

Original Natalizumab

Original Placebo – Now on Natalizumab

Un

ad

juste

d A

nn

ualized

Rela

pse R

ate

STRATA is an ongoing, open-label, multinational study to evaluate the long-term safety and efficacy of natalizumab in RRMS patients who completed the feeder studies AFFIRM, SENTINEL and GLANCE. *Includes data on patients dosed with natalizumab; †includes all available on-treatment relapse data.


Putting risk into context: real life data from STRATA1

1. Kappos L, et al. ECTRIMS 2012; P520.

n=

380

n=

707

n=

381

n=

707

n=

280

n=

552

n=

385

n=

709

n=

275

n=

575

n=

71

n=

142

n=

224

n=

490

n=

205

n=

450

n=

236

n=

491

†

1 Year 2 Years 3 Years 4 Years 5 Years

Cessation/

Treatment Gap*

Original Placebo

Original Natalizumab

Original Placebo – Now on Natalizumab

Mea

n E

DS

S S

co

re

STRATA is an ongoing, open-label, multinational study to evaluate the long-term safety and efficacy of natalizumab in RRMS patients who completed the feeder studies AFFIRM, SENTINEL and GLANCE. *P<0.0001; †includes data on patients dosed with natalizumab. EDSS=Expanded Disability Status Scale.


Putting risk into context: real life data from TOP1

N=3976

(P<0.0001)

• Annualized relapse rate remained low

after 4 years on therapy

1. Kappos L, et al. AAN 2012; P04.134.

n=3963 n=3971

• The median EDSS score remained

stable up to 4 years of follow-up

TOP is an ongoing, open-label, prospective, multicentre, observational study generating long-term outcomes data for

natalizumab in RRMS patients in the post-marketing setting. 66% of patients (n=2624) analyzed had been followed for ≥1 year;

32% (n=1259) had been followed for ≥2 years; 12% (n=458) had been followed for ≥3 years.


Supporting information:

PML risk factors & outcomes


• The 2-step anti-JCV antibody assay has been developed to help identify

patients who have been exposed to the JC virus. It is designed to detect the

presence of antibodies to JCV in the serum or plasma.

• Anti-JCV antibody testing may be considered for: – All MS patients with disease activity who are contemplating a start/change in MS

therapy where antibody status could be a factor in assessing therapeutic choice;

– Patients treated with natalizumab who have not had their serostatus assessed.

Anti-JCV Antibody Testing


• Current data on the assay as a risk stratification tool from STRATIFY-1 (n=1096) – 46% anti-JCV antibody negative and 54% anti-JCV antibody positive at baseline1

– False negative rate: 2.2% at baseline2 and 2.4% over 18 months3

– Over 18 months, with testing every 6 months:1

• 38% of subjects remained consistently anti-JCV antibody negative

• 52% remained consistently anti-JCV antibody positive

• 10% changed serostatus

– In patients who tested anti-JCV antibody negative at baseline:1

• 84% (274/328) remained negative at 18 months

• 16% (54/328) changed serostatus

– In the subjects who changed serostatus:1

• 31% (17/54) had intermittent positive results

• 69% (37/54) changed to anti-JCV antibody positive and remained positive for the duration of the study

• The probability of consistently testing anti-JCV antibody negative over time

increases with the number of sequential anti-JCV antibody negative test results. – In subjects who tested anti-JCV antibody negative at baseline (n=328), the probability of remaining

anti-JCV antibody negative after 3 tests performed at 6-monthly intervals was 93.5% over 18 months1

– In subjects who tested anti-JCV antibody negative at baseline in AFFIRM (n=241), the probability of

remaining anti-JCV antibody negative after 3 tests performed at 6-monthly intervals was 95%3

1. Plavina T, et al. Presented at AAN: March 18-23, 2013, San Diego, CA. S30.001.

2. Lee P, et al. J Clin Virol. 2013;57(2):141-6.





• As of 6th May 2013,147 natalizumab-treated MS PML patients with known pre-

PML anti-JCV antibody status who had samples tested for anti-JCV antibodies, all

of which were collected at least 6 months prior to PML diagnosis (range 6-187

months). Of these 147 patients, 145 (98.6%) tested anti-JCV antibody positive

prior to diagnosis and 2 (1.4%) tested anti-JCV antibody negative.

• Serum samples obtained prior to PML in two natalizumab-treated CD patients

(one from clinical trials and one post-marketing) both tested anti-JCV antibody

positive.






• Re-testing of anti-JCV antibody negative patients every 6 months is

recommended.1

• The anti-JCV antibody assay should not be used to diagnose PML.1

• Data from a Biogen Idec study of plasma exchange (PLEX) in natalizumab-

treated MS patients demonstrated that anti-JCV antibody levels are

decreased by 2-5 fold after PLEX and thus may lead to an anti-JCV antibody

negative result in some patients with a relatively low titer before PLEX. Anti-

JCV antibody testing should not be performed during or for at least two weeks

following plasma exchange due to the removal of antibodies from the serum.1

• One sample, collected from a patient at the time of PML diagnosis following a

cycle of PLEX tested negative for anti-JCV antibodies. Because this sample

was collected immediately following PLEX, and PLEX removes antibodies

from the circulation, the information obtained from this sample is unreliable.2


• As of 4th March 2011, 39 of 93 patients (42%) with PML and known prior IS

status had been treated with IS therapy before initiating natalizumab. Of the

total 102 confirmed PML patients as of 4th March 2011, prior IS status was

unknown for 9 patients and they were excluded from the analysis.

• As of 23rd November 2010, the proportion of all patients treated with

natalizumab in the TYGRIS Observational Study* who had been treated with

an IS prior to receiving natalizumab was 20.3% (13.9% in US and 23.6% in

EU/ROW).

• Compared to patients who have never been treated with a prior IS therapy,

patients with prior IS use had a ~3-4-fold greater risk of PML.

• In patients with PML, there was no specific pattern in: – type of prior IS therapy

– duration of prior IS therapy

– time from last dose of IS to initiation of natalizumab therapy

Estimated PML Risk Associated with Prior IS Use

*http://clinicaltrials.gov/ct2/show/NCT00477113

http://clinicaltrials.gov/ct2/show/NCT00483847



No Specific Pattern in Type of Prior IS Use

Identified in Patients with PML

• Type of prior IS use varied

• Some patients had received more than one type of IS therapy

• Types of prior IS use included:

– Mitoxantrone (n=38)

– Azathioprine (n=11)

– Methotrexate (n=9)

– Cyclophosphamide (n=14)

– Mycophenolate (n=6)

– Other (n=8)


Data based on prior IS agents reported in 68 out of 197 patients with PML as of 29th February 2012

(Prior IS status was unknown for 15 patients and they were excluded from the analysis).


No Specific Pattern in Duration of Prior IS Use or

Time from Last Dose of IS in Patients with PML

• Duration of prior IS use varied:

– Mean 19.9 months, median 12.5 months (minimum 0.03 month,

maximum 204 months)

• Time from last dose of IS until start of natalizumab varied:

– Mean 25.8 months, median 17.2 months (minimum 0.5 months and

maximum 95.4 months)


Data based on prior IS agents reported in 68 out of 197 patients with PML as of 29th February 2012

(Prior IS status was unknown for 15 patients and they were excluded from the analysis).


1. Clifford DB, et al. Lancet Neurol. 2010;9:438–446.


• Heightened clinical vigilance led to prompt natalizumab discontinuation

upon first signs or symptoms suggestive of PML – Median duration from symptom onset to PML diagnosis is approximately 1

month 1

• The majority of patients who developed PML in the post-marketing

setting received plasma exchange (PLEX) and/or immunoadsorption

(IA) to accelerate removal of natalizumab

• In the majority of natalizumab-treated patients with PML, Immune

Reconstitution Inflammatory Syndrome (IRIS) has occurred after

discontinuation or removal (by PLEX) of natalizumab

• In patients who have undergone PLEX, IRIS has occurred within days

to several weeks2

Key Learnings: PML Management


At this time, there are insufficient data to predict survival outcomes in patients treated with natalizumab who develop PML.

Longer-term data are required in order to more accurately predict such outcomes.

Factors that may affect survival in patients with PML

Vermersch P, et al. Neurology. 2011;76:1697-1704.


Factors that appear to be

associated with decreased

survival

• Gender

• Prior immunosuppressant

therapy

• MS duration

• Natalizumab exposure at

PML diagnosis

• JCV DNA load in CSF at PML

diagnosis

• Gd enhancement on MRI at

diagnosis

Factors that do not appear to affect

survival

Factors that appear to be

associated with improved

survival

• Younger age at PML

diagnosis

• Lower pre-PML EDSS

• Shorter time from first

symptoms of PML to

diagnosis

• Localized PML extension

on MRI at diagnosis


PML Presenting Symptoms

PML symptom % PML cases with symptom

Cognitive/behavioral 49%

Motor (eg: hemiparesis) 37%

Speech (eg: dysarthria, aphasia) 31%

Visual (eg: hemianopsia) 26%

Cerebellar (eg: ataxia) 17%

Seizure (eg: focal motor, generalized) 17%

Sensory (eg: paresthesia) 3%

Neurologic deficits evolved over several weeks

Individual PML cases frequently presented with symptoms in multiple categories


Based on the first 35 PML cases.


IRIS Presents as Clinical Decline

IRIS symptom % PML cases with symptom

Motor (eg; hemiparesis) 66%

Speech (eg; dysarthria, aphasia) 38%

Cognitive/behavioral 34%

Seizure 19%

Visual (eg; hemianopsia) 13%

Cerebellar (eg; ataxia) 13%

Fever 6%

May be rapid, can lead to serious neurological complications or death

Individual cases frequently presented with IRIS symptoms in multiple categories.

Based on the first 35 PML cases.

At the time of the analysis, 32 of 35 PML cases reported the occurrence of IRIS.



• Monitoring for development of IRIS and appropriate treatment should be undertaken

• Treatment of IRIS with IV corticosteroids:

– Experts uniformly recommend corticosteroids at onset after PLEX1

– Majority of patients have been treated with IV corticosteroids for IRIS, typically 1 gram IV methylprednisolone daily for 5 days, followed by tapered dose of oral steroids1

– Duration and timing of corticosteroid use remains to be refined. In many cases, repeated courses of IV corticosteroids were given1

– Does not appear to be associated with increased mortality

• Prophylaxis of IRIS with corticosteroids has not been systematically evaluated

– Given the severe nature of IRIS and its consistent presentation in most patients, pre-emptive treatment starting immediately after PLEX might be justified. A randomized comparison of these alternatives would be helpful to refine IRIS management1

1. Clifford DB, et al. Lancet Neurol. 2010;9:438–446.

Key Learnings: Treatment of IRIS


PML outcomes: Karnofsky scores

Karnofsky Performance Scale (KPS) scores for 80 PML survivors for whom data were available. Each point represents

the score of an individual patient at the indicated interval relative to PML diagnosis; only those patients for whom KPS

scores were available for a given interval are shown.

pre-PML PML diagnosis 6-9 months 10-13 months ≥14 months

Mean 81.1 49.4 53.1 49.6 52.6

Median 80 50 50 50 50

n 33 32 45 27 25

Dong-Si T, et al. ECTRIMS 2012; P1098.

0

10

20

30

40

50

60

70

80

90

100

Ka

rno

fsk

y S

co

res pre-PML

PML diagnosis

6-9 Months

10-13 Months

14+ Months

Mean

Median

Pre PML PML diagnosis 6-9 months 10-13 months ≥14 months

On average, Karnofsky scores decrease at PML diagnosis but remain stable through ≥14

months of follow-up


PML outcomes: EDSS scores

EDSS scores for 118 PML survivors for whom data were available. Each point represents the score of an individual patient

at the indicated interval relative to PML diagnosis; only those patients for whom EDSS scores were available for a given

interval are shown.

Dong-Si T, et al. ECTRIMS 2012; P1098.

On average, EDSS scores increase at PML diagnosis but stabilize at 6-9 months and

remain stable through ≥14 months of follow-up

0

1

2

3

4

5

6

7

8

9

10

ED

SS

Sc

ore

s

pre-PML

PML diagnosis

6-9 Months

10-13 Months

14+ Months

Mean

Median

pre-PML PML diagnosis 6-9 months 10-13 months ≥14 months

Mean 3.7 5.2 6.3 6.4 6.6

Median 3.5 5.5 6.4 6.8 7

n 90 75 28 16 21

Pre PML PML diagnosis 6-9 months 10-13 months ≥14 months


PML outcomes: asymptomatic vs symptomatic

• As of 1st January 2013, 319 PML cases had been confirmed in the post-

marketing setting; of these 319 patients 21 (6.6%) were identified as

asymptomatic and 298 were identified as symptomatic at the time of PML

diagnosis − Asymptomatic was defined as patients who had no clinical symptoms of PML, but

had MRI findings consistent with PML at the time of diagnosis

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

EDSSa and KPSb scores over time in asymptomatic and symptomatic PML patients

P value from Mann-Whitney-Wilcoxon test. aThe mean duration of EDSS follow-up was 13.3 months in asymptomatic patients and 9.7 in symptomatic patients. bThe mean duration of KPS follow-up was 12.8 months in asymptomatic patients and 10.0 in symptomatic patients.


• On average, EDSS scores increase at PML diagnosis, but stabilize at 6-9

months and remain stable through up to 24 months of follow-up

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

EDSS scores for asymptomatic and symptomatic PML patients measured over time

Outcome of patients with asymptomatic and symptomatic PML

Polynomial regression using the LOWESS algorithm.

PML outcomes: asymptomatic vs symptomatic



Summary

• As of 31st March 2013, approximately 115,400 patients have received

natalizumab in the post-marketing setting worldwide

• Factors that increase the risk of PML have been identified1 – JCV exposure indicated by anti-JCV antibody positive status

– Receiving an immunosuppressant prior to receiving natalizumab

– Natalizumab treatment duration, especially >2 years

• Clinical vigilance remains key in the early diagnosis of PML – Early diagnosis and aggressive clinical management appears to be associated with

improved survival rates observed in post-marketing cases

– PML may be fatal or result in severe disability1

• The following factors appear to be associated with improved survival after PML: – Shorter duration between symptom onset and PML diagnosis

– Localized PML on MRI at diagnosis

– Younger age

– Lower pre-PML EDSS

• Initiation or continuation of natalizumab therapy should be based upon an

assessment of the potential benefit:risk balance for the patient

Business

Profesional natalizumab benefit risk update may 2013