Tysabri safety and pml risk stratification ty pan-0463s october giovannoni gg1

TY-PAN-0463s Date of preparation: October 2012

TYSABRI Safety Update & PML

Risk Stratification

Barts and The London

October 2012

Professor Gavin Giovannoni


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 ≈

2.71 in 1,000 3

Other Adverse

Events Per

Labelling

How can the risk of PML be minimised?

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 Hypothesis PML is rare and likely caused by interplay between multiple factors

Patients at higher risk of developing PML are

likely those:

• Who have JC virus and have the

pathogenic form of the virus (i.e. has an

altered NCCR and has a pathogenic

mutation in VP1).

• Who have a compromised immune system

that permits viral replication in the brain

• Who may have other risk factors such as

host genetic factors that make them

susceptible to JC virus infection and/or

PML development VP1 mutations

NCCR rearrangements

Immune function

Host genetic factors

Immunomodulating therapy


A Hypothetical Risk Stratification Tool

Anti-JCV Antibody Status

Negative Positive

Prior Immunosuppressant

Use

Natalizumab Treatment

>2 Years


>2 Years

No Yes

No Yes No Yes

Lowest Highest

Relative PML Risk


A Hypothetical Risk Stratification Tool

Anti-JCV Antibody Status

Negative Positive

Prior Immunosuppressant

Use


>2 Years


>2 Years

No Yes

No Yes No Yes

Lowest Highest

Relative PML Risk

1 in 1,786 1 in 217 1 in 625 1 in 90 < 1 in 11,000


Key Learnings: PML Risk

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

76 doses.1

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

approximately 38.1 months1

• Overall incidence: 2.71 per 1000 patients (95% CI; range: 2.41 to 3.04

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 identified 2 – JCV exposure indicated by anti-JCV antibody positive status

– Receiving an immunosuppressant prior to receiving TYSABRI

– TYSABRI treatment duration, especially >2 years.


2. TYSABRI SPC


Natalizumab PML Incidence Estimates by

Treatment Duration

Biogen Idec, data on file.

Calculations based on exposure through September 30, 2012 and 298 confirmed cases as of October 3, 2012

Inc

ide

nc

e p

er

10

00

pa

tie

nts

3.04

4.31

4.92

5.49 5.24 5.06

4.78

3.98

2.41

3.42 3.89

4.29 3.96

3.69 3.29

2.47

2.71

3.85

4.38

4.86 4.57

4.33 3.98

3.16

0.0

1.0

2.0

3.0

4.0

5.0

6.0


Natalizumab PML Incidence Estimates by

Treatment Epoch

Inc

ide

nc

e p

er

10

00

pa

tie

nts

3.04

0.11

0.82

2.27

2.84 2.76

2.41

0.02

0.45

1.51

1.82

1.49

2.71

0.05

0.62

1.86

2.29 2.05

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

Calculations based on exposure through September 30, 2012 and 298 confirmed cases as of October 3, 2012



Use of Natalizumab in the Post-Marketing Setting*

Patients

Patients

Worldwide post-marketing data from 23 Nov 2004 to 30 June 2012

224,718 Patient-Years

of Natalizumab exposure

*Post-marketing data includes patients exposed since 23 November 2004. This excludes approximately 5,000 patients exposed

in clinical trials: 2,200 exposed for ≥ 12 months; 1,900 exposed for ≥ 18 months; 1,600 exposed for ≥ 24 months; 1,300

exposed for ≥ 30 months; 1,000 exposed for ≥ 36 months; and 700 exposed for ≥ 42 months. Exposure are estimates and may

not fully reflect treatment interruptions that are used in certain patients.

104,300

72,400

60,300

50,300

41,400

33,500

26,100

19,600

OverallExposure

≥12 Months

≥18 Months

≥24 Months

≥30 Months

≥36 Months

≥42 Months

≥48 Months



Anti-JCV Antibody testing

• Current data on the assay as a risk stratification tool:

- Irrespective of MS treatment, across studies in MS patients, approximately 50-60% of

the population tested anti-JCV antibody positive1

- Preliminary data suggest that ~2-3% of patients seroconvert annually2.

• Seroconversion is defined as a patient who changed from negative to positive and remained

positive

- Low false negative rate

• STRATA: 2.5% (95% CI 0.05-4.9%)2,3

• STRATIFY-1: 2.7% (95% CI 0.9-6.2%)4

- Preliminary data suggest that ~5-10% of patients will change serostatus from anti-JCV

antibody negative to positive on retest. These patients include true seroconverters, and

those with anti-JCV antibody levels that fluctuate around the cut-point of the anti-JCV

assay2.

1. Bozic et al. Presented at AAN: April 21-28, 2012; New Orleans, LA. S41.002


3. Gorelik et al. Ann Neurol 2010. 68: 295-303

4. Bozic et al. Ann Neurol 2011 Nov;70(5):742-50



• As of 3rd October 2012, 98 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 98

patients:

– 96 (98%) patients tested anti-JCV antibody positive at all time points where samples were available.

– 1 recent patient (1%) tested anti-JCV antibody negative 9 months prior to PML diagnosis and anti-

JCV antibody positive 6.5 months prior to PML diagnosis. The patient had > 5 years of natalizumab

therapy + prior IS use.

– 1 patient (1%) tested anti-JCV antibody negative 9 months prior to PML diagnosis; no additional pre-

PML samples were available. The patient had received ~ 3-4 years of therapy + no prior IS use.

• A sample obtained from one CD clinical trial patient prior to PML diagnosis tested positive.

• In addition, one MS patient tested anti-JCV antibody negative 15 months prior to PML

diagnosis and tested positive two months before PML diagnosis. The patient had received >

3 years of natalizumab + no prior IS use. At the time of testing positive, the patient had

detectable IgM and IgG antibodies. The patient changed antibody status at some point, but

the time of serochange is unknown. The patient’s anti-JCV antibody status 6 months prior to

PML diagnosis is unknown.




1. TYSABRI SPC


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

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


Geographic Distribution

• Of the 298 cases reported through 3rd October 2012:

– 105 are from the United States

– 176 are from the European Economic Area

– 17 are from the rest of the world



Status of PML Cases

* TYSABRI SPC


• As of 3rd October 2012:

– 63 patients have died (21%)

– 235 patients are alive (79%)

• 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 disability*

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


Estimated PML Risk Associated with Prior IS Use

• Prior IS use in the overall natalizumab-treated population was not

known and was therefore estimated from TYGRIS*

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

therapy, patients with prior IS use have ~3-4-fold greater risk of PML

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



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

Immunosuppressant Use, Treatment Duration*

Data beyond 4 years of treatment are limited. *Based on TYSABRI exposure data as of February 29, 2012; PML incidence data based on 212 confirmed PML cases as of February 29, 2012; prior IS

data in overall natalizumab-treated patients based on proportion of patients with IS use prior to TYSABRI therapy in TYGRIS as of May 2011; and prior

IS data in PML patients as of September 1, 2011. 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 TYSABRI and assumes 1 hypothetical PML case that

tested negative for anti-JCV antibodies prior the onset and diagnosis of PML. Assuming that all patients received at least 18 doses of TYSABRI and

that there was 1 hypothetical PML case that tested anti-JCV antibody negative prior to PML diagnosis, the estimate of PML incidence in anti-JCV

antibody negative patients was generally consistent, 0.14 (95% CI: 0.00–0.79).

≤0.09/1000 95% CI 0-0.48

No Yes

Anti-JCV

Antibody Status

Negative Positive

Prior IS Use

Natalizumab

Exposure No Prior IS Use Prior IS Use

1–24 months 0.56/1000 95% CI 0.36-0.83

1.6/1000 95% CI 0.91-2.6

25–48 months 4.6/1000 95% CI 3.7-5.6

11.1/1000 95% CI 8.3-14.5

Bloomgren G, et al. N Engl J Med. 2012;366:1870-80.


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

Immunosuppressant Use, Treatment Duration*

≤0.09/1000 95% CI 0-0.48

No Yes

Anti-JCV

Antibody Status

Negative Positive

Prior IS Use

Natalizumab

Exposure No Prior IS Use* Prior IS Use*

1–24 months 0.56/1000 95% CI 0.36-0.83

1.6/1000 95% CI 0.91-2.6

25–48 months 4.6/1000 95% CI 3.7-5.6

11.1/1000 95% CI 8.3-14.5

Bloomgren et al. N Engl J Med. 2012;366:1870-80

1 in 1,786

1 in 217

1 in 625

1 in 90 < 1 in 11,000

*IS = immunosuppression


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.


• 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 appear to be

associated with decreased

survival 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


Clinical Status of PML Cases

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 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


Clinical Status of PML Cases Based on outcomes from the 140 survivors out of the 175 confirmed PML cases as of 21st

October 2011

Follow-up Time From PML Diagnosis (months)

Survivors at Follow-up Time with Karnofsky** reported, n

Functional Status of Survivors

Mild Disability,

n (%)

Moderate Disability,

n (%)

Severe Disability, n

(%)

≥ 6 58 6 (10%) 29 (50%) 23 (40%)*

≥ 9 28 3 (11%) 16 (57%) 9 (32%)

*Majority of patients with severe disability at ≥ 6 months from diagnosis (21/23, 91%) had Karnofsky scores of 40

which is at the interface between moderate and severe disability

• Of the 58 patients with ≥ 6 months follow-up and Karnofsky scores, 19 patients also had pre-PML Karnofsky scores

reported:

• Mean change in Karnofsky following PML: Decrease by 26

• Median change in Karnofsky following PML: Decrease by 20

Biogen Idec, Data on file.

** Karnofsky DA, Burchenal JH. In: MacLeod CM, ed. Evaluation of Chemotherapeutic Agents.

New York, NY: Columbia University Press; 1948:196.

Pre-PML Functional Status (N=19) Functional Status following PML

Mild disability pre-PML (N=12) Mild Disability 2 (16%)

Moderate Disability 5 (42%)

Severe Disability 5 (42%)

Moderate disability pre-PML (N=7) Moderate Disability 6 (86%)

Severe Disability 1 (14%)

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Tysabri safety and pml risk stratification ty pan-0463s october giovannoni gg1