Tysabri benefit risk update april 2014 ty pan 0597

TY-PAN-0597(11) Date of preparation: April 2014FOR HEALTHCARE PROFESSIONALS ONLY

TYSABRI (natalizumab) Benefit/Risk Update & PML Risk Stratification


Benefit / Risk

Benefit

Risk

Natalizumab

81% reduction in relapse rate1

64% reduction in disability progression1

>1 in 3 patients free of disease activity2

PML risk ≈3.563 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

• Factors that increase the risk of PML have been identified1

– The presence of anti-JCV antibodies– Receiving an immunosuppressant prior to receiving natalizumab – Natalizumab treatment duration, especially >2 years

• As of 3rd April 2014, overall incidence: 3.563 per 1000 patients (95% CI: 3.243 to 3.905 per 1000 patients)2

– 76% of patients are alive with varying levels of disability

• As of 3rd April 2014, the duration of natalizumab dosing prior to PML diagnosis ranged from 8 to 92 doses; approximately 16% had between 1-24 doses and 84% had >24 doses at the time of PML diagnosis.2

– Mean duration of natalizumab dosing at time of PML diagnosis was approximately 42 months2

1. Tysabri Summary of Product Characteristics2. Biogen Idec, data on file.


Natalizumab PML Incidence Estimates by Treatment Epoch

Calculations based on exposure through 31st March 2014 and 454 confirmed cases as of 3rd April 2014

Biogen Idec, data on file.

3.91

0.12

0.84

2.09

2.732.93

2.693.24

0.03

0.50

1.45

1.87 1.88

1.46

3.56

0.06

0.66

1.75

2.27 2.36

2.01

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

Inci

denc

e pe

r 100

0 pa

tient

s


Natalizumab PML Incidence Estimates by Treatment Epoch (Apr 2010 – Apr 2014)


0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

Apr

. 201

0

Jul.

2010

Oct

. 201

0

Jan.

201

1

Apr

. 201

1

Jul.

2011

Oct

. 201

1

Jan.

201

2

Apr

. 201

2

Jul.

2012

Oct

. 201

2

Jan.

201

3

Apr

. 201

3

Jul.

2013

Oct

. 201

3

Jan.

201

4

Apr

. 201

4

Inci

denc

e pe

r 100

0 pa

tient

s

1-12 infusions

13-24 infusions

25-36 infusions

37-48 infusions

49-60 infusions

61-72 infusions


Use of Natalizumab in the Post-Marketing Setting*

Patients


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

*Post-marketing data includes patients exposed since 23 November 2004. This excludes approximately 5,100 patients exposedin clinical trials; 2,200 exposed for ≥12 months; 1,900 exposed for ≥18 months; 1,700 exposed for ≥24 months; 1,300 wereexposed ≥30 months; 1,000 were exposed ≥36 months; 700 were exposed ≥42 months; and 700 were exposed for ≥48months. Exposures are estimates and may not fully reflect treatment interruptions that are used in certain patients.

329,554 Patient-Years of natalizumab exposure

123,000

93,400

79,800

67,600

57,400

48,100

40,300

33,400

OverallExposure

≥12 Months

≥18 Months

≥24 Months

≥30 Months

≥36 Months

≥42 Months

≥48 Months

Patients


0.1/100095% CI 0.01-0.35

No Yes

Anti-JCVAntibody Status

Negative Positive

Prior IS Use

NatalizumabExposure No Prior IS Use Prior IS Use

1–24 months 0.7/100095% CI 0.5-1.0

1.8/100095% CI 1.1-2.7

25–48 months 5.3/100095% CI 4.4-6.2

11.2/100095% CI 8.6-14.3

49–72 months 6.1/100095% CI 4.8-7.8

Insufficient data

Data beyond 4 years of treatment are limited. There are insufficient data to adequately determine PML risk in anti-JCV antibody positive patients with prior IS use and >48 months of natalizumab exposure.

*Based on natalizumab exposure and 343 confirmed PML cases as of 5th March 2013. 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 5th March 2013. 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 (0.16/1000; 95% CI 0.02–0.56).

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



0.1/100095% CI 0.01-0.35

No Yes

Anti-JCVAntibody Status

Negative Positive

Prior IS Use

NatalizumabExposure No Prior IS Use Prior IS Use

1–24 months 0.7/100095% CI 0.5-1.0

1.8/100095% CI 1.1-2.7

25–48 months 5.3/100095% CI 4.4-6.2

11.2/100095% CI 8.6-14.3

49–72 months 6.1/100095% CI 4.8-7.8

Insufficient data

Data beyond 4 years of treatment are limited. There are insufficient data to adequately determine PML risk in anti-JCV antibody positive patients with prior IS use and >48 months of natalizumab exposure.

*Based on natalizumab exposure and 343 confirmed PML cases as of 5th March 2013. 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 5th March 2013. 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 (0.16/1000; 95% CI 0.02–0.56).

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

1 in 10,000

1 in 1,4291 in 556

1 in 89

1 in 164

1 in 189



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

1. Tysabri Summary of Product Characteristics


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. 2. Tysabri Summary of Product Characteristics

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

Ann

ualiz

ed R

elap

se R

ate

1.46

0.28

Natalizumabn=148

Placebon=61

81%reduction(p<0.001)

Number of Patients at RiskPlaceboNatalizumab

Prop

ortio

n W

ithSu

stai

ned

Dis

abili

ty P

rogr

essi

on

0.0

0.1

0.2

0.4

0.5

Weeks24

Placebo 26%

Natalizumab 10%

61 57 54 51148 144 141 140

0 120

0.3

72 1089648

47 46 45 42 39 36137 131 130 128 123 123

12 36 60 84

64% risk reductionHazard 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.

TY-PAN-0597(11) Date of preparation: April 2014FOR HEALTHCARE PROFESSIONALS ONLY1. Havrdova E, et al. Lancet Neurol. 2009;8(3):254-60.

Prop

ortio

n of

Dis

ease

-Fre

e Pa

tient

s (%

)

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

Overall PopulationP<0.0001

Highly Active Patients †

P<0.0001

7.2

1.7

36.7

27.4

0

10

20

30

40

50 PlaceboNatalizumab

5vs placebo

16vs 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: long-term efficacy data from STRATA1

1. Rudick, et al. ECTRIMS 2013; P593.

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.


Putting risk into context: long-term efficacy data from STRATA1

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.EDSS=Expanded Disability Status Scale.

1. Rudick, et al. ECTRIMS 2013; P593.


Putting risk into context: real life data from TOP1

• Overall, after a median treatment duration of 22 months (range: 1–74 months), mean ARR decreased from 1.99 at baseline to 0.31 on natalizumab therapy (P<0.0001)

1. Butzkueven et al. J Neurol Neurosurg Psychiatry 2014. Published online

• Mean EDSS remained stable over 4 years

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. As of 1st December 2012, 4821 patients were enrolled.

§P value is from the negative binomial model for the comparison of ARRs before and after natalizumab treatment

ARR per 12-month interval over time Overall mean EDSS scores over time

3.53.3 3.3 3.3 3.3

1

1.5

2

2.5

3

3.5

4

Baseline Year 1 Year 2 Year 3 Year 4

n=4797 n=2064 n=1304 n=744 n=325


Putting risk into context: real life data from TOP in the UK1

• Annualised relapse rate significantly decreased on natalizumab regardless of baseline relapse history

1. Hanna J, et al. ABN 2013; P140.

• Annualised relapse rate significantly decreased on natalizumab regardless of baseline disability status (EDSS)

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. As of 1st December 2012, 119 patients were enrolled in the UK; 80.7% of patients (n=96) had been followed for ≥ 12 months; 60.5% (n=72) had been followed for ≥ 18 months.

N=3976(P<0.0001)

P<0.0001 for all baseline versus postbaseline comparisons shown.CI=confidence interval.

P<0.0001 for both baseline versus postbaseline comparisons shown.

Baseline and on-treatment ARR, overall and by relapse history Baseline and on-treatment ARR by baseline EDSS score

TY-PAN-0597(11) Date of preparation: April 2014FOR HEALTHCARE PROFESSIONALS ONLY1. Tysabri Summary of Product Characteristics

Summary

• As of 31st December 2013, approximately 123,000 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


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):141-6.3. Biogen Idec, data on file.




• As of 3rd April 2014, there are 217 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 217 patients, 215 (99%) tested anti-JCV antibody positive prior to diagnosis and 2 (1%) tested anti-JCV antibody negative.

• Serum samples obtained prior to PML in two natalizumab-treated Crohn’sDisease patients (one from clinical trials and one post-marketing) both tested anti-JCV antibody positive.




1. Tysabri Summary of Product Characteristics2. Biogen Idec, data on file.

• 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/NCT00477113http://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;9:438–446.2. 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;76:1697-1704.Biogen Idec, data on file.

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 affectsurvival

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 monthsMean 81.1 49.4 53.1 49.6 52.6

Median 80 50 50 50 50n 33 32 45 27 25

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

0

10

20

30

40

50

60

70

80

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100

Kar

nofs

ky S

core

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

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.


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

EDSS

Sco

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 monthsMean 3.7 5.2 6.3 6.4 6.6

Median 3.5 5.5 6.4 6.8 7n 90 75 28 16 21

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


PML outcomes: asymptomatic vs symptomatic

• As of 5th June 2013, 372 PML cases had been confirmed in the post-marketing setting; of these 372 patients 30 (8.1%) were identified as asymptomatic and 342 (91.9%) 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


Mean EDSS and KPS scores over time in asymptomatic and symptomatic PML patients

P value from Mann-Whitney-Wilcoxon test.EDSS=Expanded Disability Status Scale; KPS=Karnofsky Performance Scale


• Over time, EDSS scores scores were consistently better in asymptomatic PML patients than in symptomatic PML patients. − Similar results were seen with KPS scores (EDSS-KPS correlation coefficient, 0.712).


PML outcomes: asymptomatic vs symptomatic

Outcome Asymptomatic PML patients (n=30)

Symptomatic PML patients (n=342)

All PML patients(n=372)

Survival, n (%) 29 (96.7) 258 (75.4) 287 (77.2)

Death, n (%) 1 (3.3)a 84 (24.6) 85 (22.8)aDeath was reported as suicide caused by depression that was secondary to increasing disability and PML sequelae.

02

46

810

ED

SS

Sco

re

−30 −24 −18 −12 −6 diagnosis 6 12 18 24 30

SymptomaticAsymptomatic

Months From PML Diagnosis

• Natalizumab-associated PML may be associated with better survival in asymptomatic patients than in patients who were symptomatic at diagnosis


PML Research at Biogen IdecOur Mission: Via innovative clinical and laboratory research, gain deeper insights into PML

pathogenesis, and develop PML risk stratification, diagnosis and management tools

Clear and effective risk stratification

algorithm

New tools for PML risk

stratification Tools for early PML diagnosis

Therapeutic approaches and management of

PML

ObjectivesObjectives

Sample Collection

• JCV assay performance

• JCV antibody serostability

• JCV antibody levels

• Defining host factors

• Improving and developing new systems and animal models

• Infection dynamics in tissues (JCV and other pathogens)

• Clinical trials• Biobanking initiatives• Outreach to physicians

• Pre-PML and at-PML diagnosis longitudinal samples are essential for discovery and validation of new biomarkers. ‐ Serum/plasma‐ PBMC‐ CSF‐ DNA‐ RNA‐ Biopsies (brain, skin)

• Pharmacovigilance and clinical data collection

• Treatment duration/interruption

• MRI use for early PML detection

• Immune reconstitution• Prevention and treatment of

IRIS• Research on PML outcome

and management• Anti-JCV drug screening

• BIIB internal research• BIIB - supported SRAs and IITs• Innovative technology partnerships• PML Consortia-sponsored research

JCV Biology ResearchJCV SerologyClinical

Research

JCV antibody assay JCV antibody assay and further

understanding JCV serology

Better understanding of PML outcomes

• Integrated clinical and analytical data analysis

• Genomics (host, viral)

• Blood-based biomarkers (host and JCV mutations)‐ Hypothesis-driven

(targeted)‐ Discovery

(“omics”)• CSF biomarkers• Cell-based/immune

system biomarkers

Biomarker Discovery

Tysabri benefit risk update april 2014 ty pan 0597

Health & Medicine