Tysabri benefit risk update Q3 2015

FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0683(2) Date of preparation: September 2015 FOR HEALTHCARE PROFESSIONALS ONLY

TYSABRI (natalizumab)

Benefit/Risk Update &

PML Risk Stratification

FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0683(2) Date of preparation: September 2015

This information has been provided

by Biogen Medical Affairs

for healthcare professional use only,

in response to your request.


Benefit / Risk

Benefit

Risk

Natalizumab

In highly active patients

at 2 years:

• 81% reduction in

relapse rate vs.

placebo1

(ARR 0.28 natalizumab vs.

1.46 placebo)

• 64% reduction in

disability progression

vs. placebo1

(10% natalizumab vs. 26%

placebo)

• 27% of patients free of

disease activity vs. 2%

of placebo patients 2

PML risk ≈

4.03 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, 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


• 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 4th September 2015, overall incidence: 4.03 per 1000 patients

(95% CI: 3.71 to 4.36 per 1000 patients)2

• 77% of patients are alive with varying levels of disability*2

• As of 4th September 2015, the duration of natalizumab dosing prior to PML

diagnosis ranged from 8 to 110 doses; approximately 14% had between

1-24 doses and 86% had >24 doses at the time of PML diagnosis.2

• Mean duration of natalizumab dosing at time of PML diagnosis was approximately 45

months2

* Based on follow-up data for at least 6 months after PML diagnosis

1. Tysabri Summary of Product Characteristics


PML Risk in Natalizumab-Treated Patients


Natalizumab PML Incidence Estimates by

Treatment Epoch

Calculations based on exposure through 31st August 2015 and 588 confirmed cases as of 4th September 2015

Biogen, data on file.

4.36

0.12

0.83

1.90

2.63

2.93

2.44

3.71

0.03

0.51

1.34

1.88 2.01

1.47

4.03

0.06

0.65

1.60

2.23 2.44

1.91

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

Inc

ide

nc

e p

er

10

00

pa

tie

nts



Natalizumab PML Incidence Estimates by

Treatment Epoch (Apr 2010 – Sep 2015)

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5A

pr.

201

0

Ju

l. 2

010

Oct. 2

01

0

Ja

n.

20

11

Apr.

201

1

Ju

l. 2

011

Oct. 2

01

1

Ja

n.

20

12

Apr.

201

2

Ju

l. 2

012

Oct. 2

01

2

Ja

n.

20

13

Apr.

201

3

Ju

l. 2

013

Oct. 2

01

3

Ja

n.

20

14

Apr.

201

4

Ju

l. 2

014

Oct. 2

01

4

De

c. 2

014

Ma

r. 2

01

5

Ju

n.

20

15

Sep

. 20

15

Inc

ide

nc

e p

er

10

00

pa

tie

nts

1-12 infusions

13-24 infusions

25-36 infusions

37-48 infusions

49-60 infusions

61-72 infusions


142,000

108,400

94,400

83,100

72,600

63,000

53,800

46,000

OverallExposure

≥12 Months

≥18 Months

≥24 Months

≥30 Months

≥36 Months

≥42 Months

≥48 Months Patients

Use of Natalizumab in the

Post-Marketing Setting*

Patients


*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 exposed for ≥30 months; 1,000

exposed for ≥36 months; 700 exposed for ≥42 months; and 700 exposed for ≥48 months. Exposures are estimates and may not fully

reflect treatment interruptions that are used in certain patients.

Worldwide post-marketing data from 23 Nov 2004 to 30 Jun 2015

433,208 Patient-Years

of natalizumab exposure


The PML risk estimates are based on post-marketing data from approximately 125,000 natalizumab exposed patients.

Data beyond 6 years of treatment are limited.


Risk Stratification Tool

0.1/1000 95% CI 0.01-0.35

No Yes

Anti-JCV

Antibody Status

Negative Positive

Prior IS Use

Natalizumab

Exposure No Prior IS Use Prior IS Use

1–24 months 1/1000 2/1000

25–48 months 5/1000 11/1000

49-72 months 6/1000 9/1000


The PML risk estimates are based on post-marketing data from approximately 125,000 natalizumab exposed patients.

Data beyond 6 years of treatment are limited.


Risk Stratification Tool

0.1/1000 95% CI 0.01-0.35

No Yes

Anti-JCV

Antibody Status

Negative Positive

Prior IS Use

Natalizumab

Exposure No Prior IS Use Prior IS Use

1–24 months 1/1000 2/1000

25–48 months 5/1000 11/1000

49-72 months 6/1000 9/1000

1 in 10,000 1 in 1,000

1 in 200

1 in 167

1 in 91

1 in 500

1 in 111


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


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

aliz

ed R

ela

pse

Ra

te

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

ined

Dis

abili

ty P

rog

ressio

n

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.


AFFIRM efficacy1,2


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

Pro

po

rtio

n o

f D

ise

ase

-Fre

e P

atie

nts

(%

)

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

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.


freedom from disease activity1


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.


long-term efficacy data from STRATA1

1. O’Connor P, et al. Neurology. 2014; 83(1):78-86.


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; LOCF=last observation carried forward.

1. O’Connor P, et al. Neurology. 2014; 83(1):78-86.


long-term efficacy data from STRATA1


• 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 H, et al. J Neurol Neurosurg Psychiatry. 2014; 85(11):1190-7.

• 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


real life data from TOP1


• Annualised relapse rate significantly

decreased on natalizumab regardless

of treatment history

1. Nicholas R, et al. ABN 2015; P067.

• Annualised relapse rate significantly decreased on natalizumab in patients who did not respond to a course (≥ 1 year) of IFN beta or GA

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 May 2014, 134 patients were enrolled in the UK; 111 had

been followed for ≥ 1 year; 96 had been followed for ≥ 2 years; 42 had been followed for ≥ 3 years.

*P<0.0001, CI=confidence interval.

Baseline and on-treatment ARR by treatment history Baseline and on-treatment ARR in IFN beta/GA non-responders (n=28)


real life data from TOP in the UK1

P<0.0001, CI=confidence interval.


• As of 30th June 2015, approximately 142,000 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: • Younger age at diagnosis2

• Less functional disability prior to diagnosis2

• Lower JC viral load at diagnosis2

• More localised brain involvement by MRI at the time of diagnosis2

• Asymptomatic at diagnosis3


2. Dong-Si T, et al. J Neurovirol. 2015; Mar 14 [Epub ahead of print].

3. Dong-Si T, et al. Ann Clin Transl Neurol. 2014; 1(10):755-64.

Summary


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 4th September 2015, there are 312 natalizumab-treated MS PML

patients with pre-PML samples collected at least 6 months prior to PML

diagnosis. Of these 312 patients, 308 (~99%) tested anti-JCV antibody

positive prior to diagnosis and 4 (~1%) tested anti-JCV antibody negative.

• Serum samples obtained prior to PML in three natalizumab-treated Crohn’s

Disease patients (one from clinical trials and two post-marketing) all 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 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

*http://clinicaltrials.gov/ct2/show/NCT00477113; http://clinicaltrials.gov/ct2/show/NCT00483847


Estimated PML Risk Associated with

Prior IS Use


• 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 Type of Prior IS

Use Identified 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).

No Specific Pattern in Duration of Prior

IS Use or Time from Last Dose of IS in

Patients with PML


• Clinical vigilance remains the most important factor in monitoring PML and

natalizumab should be discontinued in suspected cases until the presence of PML can

be ruled out.

• Further investigations include an MRI evaluation and lumbar puncture with CSF

evaluation.

• If there are clinical and/or radiological features consistent with the diagnosis of PML,

detection of JCV DNA in the CSF strongly supports a diagnosis of PML.

• A negative CSF JCV DNA test does not necessarily rule out PML, e.g. if the level is

too low to detect. If suspicion of PML remains then additional testing may be

warranted.

• PML has been reported following discontinuation of natalizumab in patients who did

not have findings suggestive of PML at the time of discontinuation. Patients and

Physicians should continue to be alert for any new signs or symptoms that may be

suggestive of PML for approximately six months following discontinuation of

natalizumab.1

PML Diagnosis



Reference CSF JCV DNA testing is available from Unilabs (Denmark) and

Focus Diagnostics (US). Both laboratories offer a real time PCR assay with

a Limit of Detection (LoD) of ~10 copies/ml. Biogen are not in a position to

certify any laboratory, however benefits of the Unilabs option include:

• No customs invoices required for samples sent to Unilabs (within EU)

• Test results can be emailed or faxed (Focus Diagnostics fax results only)

• Turnaround time for receipt of Unilabs test results is up to 5 working days

CSF JCV DNA Testing Facilities


• The test is available for patients previously or currently treated with

natalizumab to facilitate the diagnosis of a suspected case of PML in

clinical practice

• A suspected case in this context is one where the patient either has

symptoms and/or an MRI scan potentially suggestive of PML

• In the absence of clinical suspicion, if positive, this test does not make

the diagnosis of PML. The diagnosis of PML is based on either detection

of JCV infection on brain tissue, or detection of JCV DNA in the CSF of

patients with radiological findings and/or a clinical presentation consistent

with PML.

CSF JCV DNA Testing


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.

Vermersch P, et al. Neurology. 2011;76:1697-1704; Dong-Si T, et al. J Neurovirol. 2015; Mar 14 [Epub ahead of print];

Dong-Si T, et al. Ann Clin Transl Neurol. 2014; 1(10):755-64; Biogen, data on file.

Factors that appear to be

associated with decreased

survival

• Gender

• Prior immunosuppressant therapy

• MS duration

• Natalizumab exposure 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

• Lower JC viral load at

diagnosis

• More localised brain

involvement by MRI at the time

of diagnosis

• Asymptomatic at diagnosis

Factors that may affect survival in

patients with PML


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.

PML Presenting Symptoms


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.


IRIS Presents as Clinical Decline


• 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


• Each point represents the Karnofsky Performance Scale (KPS) score of an individual patient at the indicated interval

relative to PML diagnosis.

• Analysis: weighted polynomial regression using the LOWESS algorithm.

• In this analysis, 254 of 336 patients (76%) were survivors and 82 of 336 patients (24%) were nonsurvivors.

• The mean follow-up time from PML diagnosis was 16.1 months for survivors.

Dong-Si T, et al. J Neurovirol. 2015; Mar 14 [Epub ahead of print].

Surviving PML patients demonstrated stabilised functional disability at 6 months post-PML diagnosis

and remained relatively stable even beyond 18 months post PML diagnosis

PML outcomes: Karnofsky scores


• Each point represents the EDSS score of an individual patient at the indicated interval relative to PML diagnosis.

• Analysis: weighted polynomial regression using the LOWESS algorithm.

• In this analysis, 254 of 336 patients (76%) were survivors and 82 of 336 patients (24%) were nonsurvivors.

• The mean follow-up time from PML diagnosis was 16.1 months for survivors.

EDSS scores increased at PML diagnosis but remained relatively stable during the follow up period.

Increases at diagnosis were more marked in non-survivors.

Dong-Si T, et al. J Neurovirol. 2015; Mar 14 [Epub ahead of print].

PML outcomes: EDSS scores


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

Dong-Si T, et al. Ann Clin Transl Neurol. 2014; 1(10):755-64.

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).

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

Functional Assessments Relative to Diagnosis0

20

40

60

80

100

Months From PML Diagnosis

Ka

rno

fsky S

core

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

Symptomatic

Asymptomatic

02

46

810

ED

SS

Sco

re

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

Functional Assessments Relative to Diagnosis

020

40

60

80

100


Ka

rno

fsky S

core

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

Symptomatic

Asymptomatic


• Natalizumab-associated PML may be associated with better survival in

asymptomatic patients than in patients who were symptomatic at diagnosis

Dong-Si T, et al. Ann Clin Transl Neurol. 2014; 1(10):755-64.

PML outcomes:

asymptomatic vs symptomatic


Our 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

Objectives

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 Research

JCV Serology Clinical

Research

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

PML Research at Biogen

Tysabri benefit risk update Q3 2015

Health & Medicine

Transcript of Tysabri benefit risk update Q3 2015