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.
FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0683(2) Date of preparation: September 2015
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.
FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0683(2) Date of preparation: September 2015 FOR HEALTHCARE PROFESSIONALS ONLY
PML Risk Update
FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0683(2) Date of preparation: September 2015
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
FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0683(2) Date of preparation: September 2015
• 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
2. Biogen, data on file.
PML Risk in Natalizumab-Treated Patients
FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0683(2) Date of preparation: September 2015
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
FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0683(2) Date of preparation: September 2015
Biogen, data on file.
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
FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0683(2) Date of preparation: September 2015
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
Biogen, data on file.
*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
FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0683(2) Date of preparation: September 2015
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.
Biogen, data on file.
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
FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0683(2) Date of preparation: September 2015
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.
Biogen, data on file.
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
FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0683(2) Date of preparation: September 2015 FOR HEALTHCARE PROFESSIONALS ONLY
Putting risk into context:
Benefits of natalizumab therapy
FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0683(2) Date of preparation: September 2015
• 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
1. Tysabri Summary of Product Characteristics
Putting risk into context
FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0683(2) Date of preparation: September 2015
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
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.
Putting risk into context:
AFFIRM efficacy1,2
FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0683(2) Date of preparation: September 2015
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.
Putting risk into context:
freedom from disease activity1
FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0683(2) Date of preparation: September 2015
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
1. O’Connor P, et al. Neurology. 2014; 83(1):78-86.
FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0683(2) Date of preparation: September 2015
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.
Putting risk into context:
long-term efficacy data from STRATA1
FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0683(2) Date of preparation: September 2015
• 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
Putting risk into context:
real life data from TOP1
FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0683(2) Date of preparation: September 2015
• 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)
Putting risk into context:
real life data from TOP in the UK1
P<0.0001, CI=confidence interval.
FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0683(2) Date of preparation: September 2015
• 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
1. Tysabri Summary of Product Characteristics
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
FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0683(2) Date of preparation: September 2015 FOR HEALTHCARE PROFESSIONALS ONLY
Supporting information:
PML risk factors & outcomes
FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0683(2) Date of preparation: September 2015
• 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
FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0683(2) Date of preparation: September 2015
• 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, data on file.
Anti-JCV Antibody Testing
FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0683(2) Date of preparation: September 2015
• 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.
Biogen, data on file.
Anti-JCV Antibody Testing
FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0683(2) Date of preparation: September 2015
1. Tysabri Summary of Product Characteristics
2. Biogen, 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 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
Anti-JCV Antibody Testing
FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0683(2) Date of preparation: September 2015
• 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
Biogen, data on file.
Estimated PML Risk Associated with
Prior IS Use
FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0683(2) Date of preparation: September 2015
• 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, 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).
No Specific Pattern in Type of Prior IS
Use Identified in Patients with PML
FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0683(2) Date of preparation: September 2015
• 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, 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).
No Specific Pattern in Duration of Prior
IS Use or Time from Last Dose of IS in
Patients with PML
FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0683(2) Date of preparation: September 2015
• 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
1. Tysabri Summary of Product Characteristics
FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0683(2) Date of preparation: September 2015
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
FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0683(2) Date of preparation: September 2015
• 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
FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0683(2) Date of preparation: September 2015
1. Clifford DB, et al. Lancet Neurol. 2010;9:438–446.
2. Biogen, 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
FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0683(2) Date of preparation: September 2015
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
FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0683(2) Date of preparation: September 2015
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, data on file.
Based on the first 35 PML cases.
PML Presenting Symptoms
FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0683(2) Date of preparation: September 2015
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, data on file.
IRIS Presents as Clinical Decline
FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0683(2) Date of preparation: September 2015
• 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
FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0683(2) Date of preparation: September 2015
• 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
FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0683(2) Date of preparation: September 2015
• 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
FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0683(2) Date of preparation: September 2015
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
FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0683(2) Date of preparation: September 2015
• 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
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
Dong-Si T, et al. Ann Clin Transl Neurol. 2014; 1(10):755-64.
PML outcomes:
asymptomatic vs symptomatic
FOR HEALTHCARE PROFESSIONALS ONLY TY-PAN-0683(2) Date of preparation: September 2015
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
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