Natalizumab benefit risk update November 2013

TY-PAN-0597(6) Date of preparation: November 2013 FOR HEALTHCARE PROFESSIONALS ONLY

TYSABRI (natalizumab)

Benefit/Risk Update &

PML Risk Stratification


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 ≈

3.40 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 5th November 2013, overall incidence: 3.40 per 1000 patients

(95% CI: 3.08 to 3.74 per 1000 patients)2

– 77% of patients are alive with varying levels of disability

• As of 5th November 2013, the duration of natalizumab dosing prior to

PML diagnosis ranged from 8 to 91 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

41 months2

1. TYSABRI Summary of Product Characteristics



Natalizumab PML Incidence Estimates by

Treatment Epoch In

cid

en

ce p

er

10

00

pa

tie

nts

Calculations based on exposure through 31st October 2013 and 418 confirmed cases as of 5th November 2013

Biogen Idec, data on file.

3.74

0.12

0.86

2.21

2.85 2.92 2.83

3.08

0.02

0.51

1.53

1.94 1.82

1.48

3.40

0.06

0.67

1.84

2.36 2.33

2.08

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0


Natalizumab PML Incidence Estimates by

Treatment Epoch (Apr 2010 – Nov 2013)


0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

Apr.

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

No

v. 2

013

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


Use of Natalizumab in the Post-Marketing Setting*

Patients


Worldwide post-marketing data from 23 Nov 2004 to 30 Sep 2013

*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.

313,560 Patient-Years

of natalizumab exposure

120,500

90,400

76,600

64,900

54,600

45,700

38,100

31,200

OverallExposure

≥12 Months

≥18 Months

≥24 Months

≥30 Months

≥36 Months

≥42 Months

≥48 Months

Patients


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 0.7/1000 95% CI 0.5-1.0

1.8/1000 95% CI 1.1-2.7

25–48 months 5.3/1000 95% CI 4.4-6.2

11.2/1000 95% CI 8.6-14.3

49–72 months 6.1/1000 95% 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 5 th 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*


0.1/1000 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 0.7/1000 95% CI 0.5-1.0

1.8/1000 95% CI 1.1-2.7

25–48 months 5.3/1000 95% CI 4.4-6.2

11.2/1000 95% CI 8.6-14.3

49–72 months 6.1/1000 95% 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 5 th 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 1,429 1 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




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


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.



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.



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.



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. Wiendl H, et al. ENS 2013; P372.

• Median 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 median EDSS scores over time



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



Summary

• As of 30th September 2013, approximately 120,500 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.





• As of 5th November 2013, there are 191 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 191

patients, 189 (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 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.


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 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

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


PML Research at Biogen Idec

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

Health & Medicine

Natalizumab benefit risk update November 2013