TY-PAN-0597(14) Date of preparation: July 2014 FOR HEALTHCARE PROFESSIONALS ONLY
TYSABRI (natalizumab)
Benefit/Risk Update &
PML Risk Stratification
TY-PAN-0597(14) Date of preparation: July 2014 FOR HEALTHCARE PROFESSIONALS ONLY
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 ≈
3.63 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.
TY-PAN-0597(14) Date of preparation: July 2014 FOR HEALTHCARE PROFESSIONALS ONLY
PML Risk Update
TY-PAN-0597(14) Date of preparation: July 2014 FOR HEALTHCARE PROFESSIONALS ONLY
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
TY-PAN-0597(14) Date of preparation: July 2014 FOR HEALTHCARE PROFESSIONALS ONLY
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 8th July 2014, overall incidence: 3.63 per 1000 patients
(95% CI: 3.32 to 3.98 per 1000 patients)2
– 77% of patients are alive with varying levels of disability
• As of 8th July 2014, the duration of natalizumab dosing prior to PML
diagnosis ranged from 8 to 92 doses; approximately 15% had between
1-24 doses and 85% had >24 doses at the time of PML diagnosis.2
– Mean duration of natalizumab dosing at time of PML diagnosis was approximately
43 months2
1. Tysabri Summary of Product Characteristics
2. Biogen Idec, data on file.
TY-PAN-0597(14) Date of preparation: July 2014 FOR HEALTHCARE PROFESSIONALS ONLY
Natalizumab PML Incidence Estimates by
Treatment Epoch
Calculations based on exposure through 30th June 2014 and 475 confirmed cases as of 8th July 2014
Biogen Idec, data on file.
3.98
0.13
0.86
2.03
2.61
2.92 2.69
3.32
0.03
0.52
1.41
1.80 1.89
1.52
3.63
0.07
0.67
1.70
2.18 2.36
2.04
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
Incid
en
ce p
er
100
0 p
ati
en
ts
TY-PAN-0597(14) Date of preparation: July 2014 FOR HEALTHCARE PROFESSIONALS ONLY
Natalizumab PML Incidence Estimates by
Treatment Epoch (Apr 2010 – July 2014)
Biogen Idec, data on file.
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
Jul. 2
01
0
Oct. 2
01
0
Jan. 2011
Apr.
201
1
Jul. 2
01
1
Oct. 2
01
1
Jan. 2012
Apr.
201
2
Jul. 2
01
2
Oct. 2
01
2
Jan. 2013
Apr.
201
3
Jul. 2
01
3
Oct. 2
01
3
Jan. 2014
Apr.
201
4
Jul. 2
01
4
Incid
en
ce p
er
100
0 p
ati
en
ts
1-12 infusions
13-24 infusions
25-36 infusions
37-48 infusions
49-60 infusions
61-72 infusions
TY-PAN-0597(14) Date of preparation: July 2014 FOR HEALTHCARE PROFESSIONALS ONLY
Use of Natalizumab in the Post-Marketing Setting*
Patients
Biogen Idec, data on file.
Worldwide post-marketing data from 23 Nov 2004 to 31 Mar 2014
*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.
347,082 Patient-Years
of natalizumab exposure
125,800
95,900
83,000
70,600
59,800
50,700
42,400
35,300
OverallExposure
≥12 Months
≥18 Months
≥24 Months
≥30 Months
≥36 Months
≥42 Months
≥48 Months
Patients
TY-PAN-0597(14) Date of preparation: July 2014 FOR HEALTHCARE PROFESSIONALS ONLY
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 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*
Biogen Idec, data on file.
TY-PAN-0597(14) Date of preparation: July 2014 FOR HEALTHCARE PROFESSIONALS ONLY
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 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 1,429 1 in 556
1 in 89
1 in 164
1 in 189
Biogen Idec, data on file.
TY-PAN-0597(14) Date of preparation: July 2014 FOR HEALTHCARE PROFESSIONALS ONLY
Putting risk into context:
Benefits of natalizumab therapy
TY-PAN-0597(14) Date of preparation: July 2014 FOR HEALTHCARE PROFESSIONALS ONLY
• 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
TY-PAN-0597(14) Date of preparation: July 2014 FOR HEALTHCARE PROFESSIONALS ONLY
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
An
nu
alized
Rela
pse 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
isab
ilit
y 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.
TY-PAN-0597(14) Date of preparation: July 2014 FOR HEALTHCARE PROFESSIONALS ONLY
1. Havrdova E, et al. Lancet Neurol. 2009;8(3):254-60.
Pro
po
rtio
n o
f D
ise
as
e-F
ree 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
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.
TY-PAN-0597(14) Date of preparation: July 2014 FOR HEALTHCARE PROFESSIONALS ONLY
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.
TY-PAN-0597(14) Date of preparation: July 2014 FOR HEALTHCARE PROFESSIONALS ONLY
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.
TY-PAN-0597(14) Date of preparation: July 2014 FOR HEALTHCARE PROFESSIONALS ONLY
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
TY-PAN-0597(14) Date of preparation: July 2014 FOR HEALTHCARE PROFESSIONALS ONLY
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(14) Date of preparation: July 2014 FOR HEALTHCARE PROFESSIONALS ONLY
1. Tysabri Summary of Product Characteristics
Summary
• As of 31st March 2014, approximately 125,800 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
TY-PAN-0597(14) Date of preparation: July 2014 FOR HEALTHCARE PROFESSIONALS ONLY
Supporting information:
PML risk factors & outcomes
TY-PAN-0597(14) Date of preparation: July 2014 FOR HEALTHCARE PROFESSIONALS ONLY
• 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
TY-PAN-0597(14) Date of preparation: July 2014 FOR HEALTHCARE PROFESSIONALS ONLY
• 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.
Anti-JCV Antibody Testing
TY-PAN-0597(14) Date of preparation: July 2014 FOR HEALTHCARE PROFESSIONALS ONLY
Anti-JCV Antibody Testing
• As of 8th July 2014, there are 229 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 229 patients, 227 (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’s
Disease patients (one from clinical trials and one post-marketing) both
tested anti-JCV antibody positive.
Biogen Idec, data on file.
TY-PAN-0597(14) Date of preparation: July 2014 FOR HEALTHCARE PROFESSIONALS ONLY
Anti-JCV Antibody Testing
1. Tysabri Summary of Product Characteristics
2. 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
TY-PAN-0597(14) Date of preparation: July 2014 FOR HEALTHCARE PROFESSIONALS ONLY
• 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
Biogen Idec, data on file.
TY-PAN-0597(14) Date of preparation: July 2014 FOR HEALTHCARE PROFESSIONALS ONLY
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)
Biogen Idec, data on file.
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).
TY-PAN-0597(14) Date of preparation: July 2014 FOR HEALTHCARE PROFESSIONALS ONLY
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)
Biogen Idec, data on file.
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).
TY-PAN-0597(14) Date of preparation: July 2014 FOR HEALTHCARE PROFESSIONALS ONLY
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
TY-PAN-0597(14) Date of preparation: July 2014 FOR HEALTHCARE PROFESSIONALS ONLY
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 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
TY-PAN-0597(14) Date of preparation: July 2014 FOR HEALTHCARE PROFESSIONALS ONLY
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
Biogen Idec, data on file.
Based on the first 35 PML cases.
TY-PAN-0597(14) Date of preparation: July 2014 FOR HEALTHCARE PROFESSIONALS ONLY
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.
Biogen Idec, data on file.
TY-PAN-0597(14) Date of preparation: July 2014 FOR HEALTHCARE PROFESSIONALS ONLY
• 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
TY-PAN-0597(14) Date of preparation: July 2014 FOR HEALTHCARE PROFESSIONALS ONLY
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
TY-PAN-0597(14) Date of preparation: July 2014 FOR HEALTHCARE PROFESSIONALS ONLY
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.
Dong-Si T, et al. ECTRIMS 2012; P1098.
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
TY-PAN-0597(14) Date of preparation: July 2014 FOR HEALTHCARE PROFESSIONALS ONLY
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. ECTRIMS 2013; P879.
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
TY-PAN-0597(14) Date of preparation: July 2014 FOR HEALTHCARE PROFESSIONALS ONLY
• 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).
Dong-Si T, et al. ECTRIMS 2013; P879.
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
Months From PML Diagnosis
Ka
rno
fsky S
core
−30 −24 −18 −12 −6 diagnosis 6 12 18 24 30
Symptomatic
Asymptomatic
Months From PML Diagnosis
• Natalizumab-associated PML may be associated with better survival in
asymptomatic patients than in patients who were symptomatic at diagnosis
TY-PAN-0597(14) Date of preparation: July 2014 FOR HEALTHCARE PROFESSIONALS ONLY
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