tysabri safety and pml risk stratification ty pan-0463q august

TY-PAN-0463q Date of preparation: July 2012

TYSABRI Safety Update & PML Risk Stratification

Barts Health NHS Trust

25th AugustProfessor 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 ≈2.50 in 1,000

Other Adverse Events Per Labelling

How can the risk of PML be minimised?

1. Hutchinson et al. J Neurol 2009;256:405-415.2. Havrdova E et al. Lancet Neurol 2009;8(3):254-603. 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 developmentVP1 mutations

NCCR rearrangements

Immune functionHost genetic factors

Immunomodulating therapy


A Hypothetical Risk Stratification Tool

Anti-JCV Antibody Status

Negative Positive

Prior Immunosuppressant Use

Natalizumab Treatment>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



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 71 doses.1

– Mean duration of natalizumab dosing at time of PML diagnosis was approximately 36.8 months1

• Overall incidence: 2.50 per 1000 patients (95% CI; range: 2.20 to 2.82 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.

1. Biogen Idec Data on file.

2. TYSABRI SPC


Natalizumab PML Incidence Estimates by Treatment Duration

Biogen Idec Data on File

Calculations based on exposure through 30th June 2012 and 264 confirmed cases as of 3rd July 2012

Inci

den

ce

per

100

0 p

atie

nts


Natalizumab PML Incidence Estimates by Treatment Epoch

Biogen Idec Data on File

Calculations based on exposure through 30th June 2012 and 264 confirmed cases as of 3rd July 2012

Inci

den

ce

per

100

0 p

atie

nts


Use of Natalizumab in the Post-Marketing Setting*

PatientsPatients

≥36 Months

≥30 Months

≥24 Months

≥18 Months

≥12 Months

Overall Exposure

≥42 Months

Worldwide post-marketing data from 23 Nov 2004 to 31 March 2012

211,243 Patient-Years of Natalizumab exposure

*Post-marketing data includes patients exposed since 23 November 2004. This excludes approximately 4,900 patients exposed in clinical trials: 2,100 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.Biogen Idec, Data on file.

23,600

30,600

38,700

47,600

57,100

68,700

99,600


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. S41.0022. Biogen Idec, data on file.3. Gorelik et al. Ann Neurol 2010. 68: 295-3034. Bozic et al. Ann Neurol 2011 Nov;70(5):742-50



• As of 3rd July 2012, 81 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 81 patients:

– 79 (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 ~ 2 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.

Biogen Idec, data on file.



• As of 3rd July, 2012, there are 108 natalizumab-treated MS PML patients who had at least one sample collected at or around the time of PML diagnosis. All tested anti-JCV antibody positive1.

– In addition, a sample collected at the time of PML diagnosis after plasma exchange (PLEX) tested negative1.

– Data from a Biogen Idec study of PLEX in natalizumab-treated MS patients demonstrated that anti-JCV antibody levels are decreased 2-5 fold after PLEX and may lead to a negative result in some patients. Anti-JCV antibody testing should not be performed during or for at least two weeks following PLEX2.

1. Biogen Idec, data on file.

2. TYSABRI SPC


Geographic Distribution

• Of the 264 cases reported through 3rd July 2012:– 95 are from the United States – 157 are from the European Economic Area– 12 are from the rest of the world

Biogen Idec Data on file.


Status of PML Cases

*TYSABRI SPCBiogen Idec Data on file.

• As of 3rd July 2012:– 58 patients have died (22%)

• Most of the deaths have occurred within approximately 2-3 months after PML diagnosis

– 206 patients are alive (78%)• 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.The median duration of follow-up in survivors was 13.7 months (0.5 – 44.3 months) for 166 survivors 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/NCT00483847Biogen Idec Data on file.


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)

*Based on 68 out of 197 patients with PML as of February 29 th 2012 (Prior IS status was unknown for 15 patients and they were excluded from the analysis).Biogen Idec Data on file.


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 29 th February 2012 (prior IS status was unknown for 15 patients and they were excluded from the analysis)Biogen Idec Data on file.


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).

≤0.09/100095% CI 0-0.48

No Yes

Anti-JCVAntibody Status

Negative Positive

Prior IS Use

NatalizumabExposure

No Prior IS Use Prior IS Use

1–24 months 0.56/100095% CI 0.36-0.83

1.6/100095% CI 0.91-2.6

25–48 months 4.6/100095% CI 3.7-5.6

11.1/100095% CI 8.3-14.5

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


Risk Stratification Tool: The Presence of Anti-JCV Antibodies, Prior Immunosuppressant Use, Treatment Duration*

≤0.09/100095% CI 0-0.48

No Yes

Anti-JCVAntibody Status

Negative Positive

Prior IS Use

NatalizumabExposure

No Prior IS Use* Prior IS Use*

1–24 months 0.56/100095% CI 0.36-0.83

1.6/100095% CI 0.91-2.6

25–48 months 4.6/100095% CI 3.7-5.6

11.1/100095% 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;9:438–4462. Biogen Idec Data on file.

• 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 – 1704Biogen Idec Data on file.

• 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

survivalFactors 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 CasesBased 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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