natalizumab safety and pml risk stratification march 2013
TRANSCRIPT
TY-PAN-0587(2) Date of preparation: March 2013
Natalizumab Safety Update &
PML Risk Stratification
Professor Gavin Giovannoni
Barts and The London
TY-PAN-0587(2) Date of preparation: March 2013
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 ≈
2.96 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-0587(2) Date of preparation: March 2013 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-0587(2) Date of preparation: March 2013
Key Learnings: PML Risk
• Duration of natalizumab dosing prior to PML diagnosis ranged from 8 to 76
doses1
– Mean duration of natalizumab dosing at time of PML diagnosis was approximately
39.0 months1
• Overall incidence: 2.96 per 1000 patients (95% CI: 2.65 to 3.29 per 1000
patients)1
– Currently the average post-marketing natalizumab exposure worldwide is
approximately 2 or more years of natalizumab exposure
• Factors that increase the risk of PML have been identified2 – JCV exposure indicated by anti-JCV antibody positive status
– Receiving an immunosuppressant prior to receiving Natalizumab
– Natalizumab treatment duration, especially >2 years
1. Biogen Idec, data on file.
2. Natalizumab Summary of Product Characteristics
TY-PAN-0587(2) Date of preparation: March 2013
Natalizumab PML Incidence Estimates by
Treatment Duration
Biogen Idec, data on file.
Calculations based on exposure through 28 February 2013 and 343 confirmed cases as of 5 March 2013
Inc
ide
nc
e p
er
10
00
pa
tie
nts
3.29
4.57
5.19
5.75 5.52
5.34
5.05
4.24
3.93
3.59
2.65
3.69
4.17
4.58
4.26
4.00
3.62
2.78
2.35
1.80
2.96
4.11
4.66
5.14
4.86 4.63
4.29
3.46
3.07
2.59
0.0
1.0
2.0
3.0
4.0
5.0
6.0
TY-PAN-0587(2) Date of preparation: March 2013
Natalizumab PML Incidence Estimates by
Treatment Epoch In
cid
en
ce p
er
10
00
pa
tie
nts
Calculations based on exposure through 28 February 2013 and 343 confirmed cases as of 5 March 2013
Biogen Idec, data on file.
3.29
0.11
0.85
2.26
2.85 2.97 3.06
2.65
0.02
0.49
1.53
1.88 1.74
1.36
2.96
0.05
0.65
1.87
2.33 2.30 2.09
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
TY-PAN-0587(2) Date of preparation: March 2013
Use of Natalizumab in the Post-Marketing Setting*
Patients
Biogen Idec, data on file.
112,200
79,100
67,100
56,100
46,700
38,700
31,200
24,300
OverallExposure
≥12 Months
≥18 Months
≥24 Months
≥30 Months
≥36 Months
≥42 Months
≥48 Months
Patients
Worldwide post-marketing data from 23 Nov 2004 to 31 December 2012
261,990 Patient-Years
of natalizumab exposure
*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.
TY-PAN-0587(2) Date of preparation: March 2013
• 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-0587(2) Date of preparation: March 2013
• 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 et al. Presented at AAN: March 18-23, 2013, San Diego, CA. S30.001
2. Lee et al. J Clin Virol. 2013 [Epub ahead of print]
3. Biogen Idec, data on file.
Anti-JCV Antibody Testing
TY-PAN-0587(2) Date of preparation: March 2013
Anti-JCV Antibody Testing
• As of 5th March 2013, 133 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 133
patients:
– 131 (98%) patients tested anti-JCV antibody positive at all time points where samples were available.
– 1 patient (1%) tested anti-JCV antibody negative 9 months prior to PML diagnosis and anti-JCV
antibody positive 6.5 months prior to PML diagnosis. The patient had >5 years of natalizumab
therapy + prior IS use.
– 1 patient (1%) tested anti-JCV antibody negative 9 months prior to PML diagnosis; no additional pre-
PML samples were available. The patient had received ~ 3-4 years of natalizumab therapy + no prior
IS use.
• A sample obtained from one CD clinical trial patient prior to PML diagnosis tested positive.
• In addition, one MS patient tested anti-JCV antibody negative 15 months prior to PML
diagnosis and tested positive two months before PML diagnosis. The patient had received
>3 years of natalizumab + no prior IS use. At the time of testing positive, the patient had
detectable IgM and IgG antibodies. The patient changed antibody status at some point, but
the time of serochange is unknown. The patient’s anti-JCV antibody status 6 months prior to
PML diagnosis is unknown.
Biogen Idec, data on file.
TY-PAN-0587(2) Date of preparation: March 2013
Anti-JCV Antibody Testing
1. Natalizumab 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-0587(2) Date of preparation: March 2013
Geographic Distribution of PML Cases
• Of the 343 cases reported through 5th March 2013:
– 121 are from the United States
– 201 are from the European Economic Area
– 21 are from the rest of the world
Biogen Idec, data on file.
TY-PAN-0587(2) Date of preparation: March 2013
Status of PML Cases
• As of 5th March 2013:
– 79 patients have died (23%)
– 264 patients are alive (77%)
• It is too early to draw conclusions about the outcomes of patients who develop PML while on natalizumab treatment
• PML may be fatal or result in severe disability1
The median time to death was 2.2 months (range, 0.1 to 15.2 months) for 44 deaths as of 29th February, 2012.
1. Natalizumab Summary of Product Characteristics
2. Biogen Idec, data on file.
TY-PAN-0587(2) Date of preparation: March 2013
• As of 4 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 4 March 2011, prior IS status was
unknown for 9 patients and they were excluded from the analysis.
• As of 23 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 and http://clinicaltrials.gov/ct2/show/NCT00483847
Biogen Idec, data on file.
TY-PAN-0587(2) Date of preparation: March 2013
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).
Biogen Idec, data on file.
TY-PAN-0587(2) Date of preparation: March 2013
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).
Biogen Idec, data on file.
TY-PAN-0587(2) Date of preparation: March 2013
Risk Stratification Tool: The Presence of Anti-JCV Antibodies,
Prior Immunosuppressant Use, Treatment Duration*
0.07/1000 95% CI 0-0.38
No Yes
Anti-JCV
Antibody Status
Negative Positive
Prior IS Use
Biogen Idec, data on file.
Natalizumab
Exposure No Prior IS Use Prior IS Use
1–24 months 0.6/1000 95% CI 0.4-0.9
1.8/1000 95% CI 1.1-2.8
25–48 months 5.2/1000 95% CI 4.3-6.2
10.6/1000 95% CI 8.1-13.8
Data beyond 4 years of treatment are limited. *Based on natalizumab exposure and 285 confirmed PML cases as of September 5, 2012. 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 September 5, 2012. 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 (0.1/1000; 95% CI 0.00–0.62).
TY-PAN-0587(2) Date of preparation: March 2013
Risk Stratification Tool: The Presence of Anti-JCV Antibodies,
Prior Immunosuppressant Use, Treatment Duration*
Data beyond 4 years of treatment are limited. *Based on natalizumab exposure and 285 confirmed PML cases as of September 5, 2012. 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 September 5, 2012. 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 (0.1/1000; 95% CI 0.00–0.62).
0.07/1000 95% CI 0-0.38
No Yes
Anti-JCV
Antibody Status
Negative Positive
Prior IS Use
Biogen Idec, data on file.
Natalizumab
Exposure No Prior IS Use Prior IS Use
1–24 months 0.6/1000 95% CI 0.4-0.9
1.8/1000 95% CI 1.1-2.8
25–48 months 5.2/1000 95% CI 4.3-6.2
10.6/1000 95% CI 8.1-13.8
1 in 14,286
1 in 192
1 in 1,667
1 in 94
1 in 556
TY-PAN-0587(2) Date of preparation: March 2013
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-0587(2) Date of preparation: March 2013
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.
• 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 appear to be
associated with decreased
survival 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-0587(2) Date of preparation: March 2013
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.
Biogen Idec, data on file.
TY-PAN-0587(2) Date of preparation: March 2013
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-0587(2) Date of preparation: March 2013
Clinical Status of PML Cases: 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 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-0587(2) Date of preparation: March 2013
Clinical Status of PML Cases: 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 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-0587(2) Date of preparation: March 2013 1. Natalizumab Summary of Product Characteristics
Summary
• As of 31st December 2012, approximately 112,200 patients received
natalizumab in 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