Upload
gavin-giovannoni
View
2.736
Download
1
Embed Size (px)
DESCRIPTION
Citation preview
Natalizumab: Early and Effective Use for the Right Patient Gavin Giovannoni
Natalizumab should be used according to the SmPC
Disclosures
I have received personal compensation for participating on Advisory
Boards in relation to clinical trial design, trial steering committees and
data and safety monitoring committees from: Abbvie, Bayer-Schering
Healthcare, Biogen-Idec, Canbex, Eisai, Elan, Fiveprime, Genzyme,
Genentech, GSK, GW Pharma, Ironwood, Merck-Serono, Novartis,
Pfizer, Roche, Sanofi-Aventis, Synthon BV, Teva, UCB Pharma and
Vertex Pharmaceuticals.
Please note that the contents of Professor Giovannoni’s slides have been
checked by Biogen-Idec to make sure they are compliant with legal
requirements of the Danish authorities and that Professor Giovannoni
has agreed to the necessary changes being made. Professor Giovannoni
would like to acknowledge and thank Mark Hughes and Simon Whiteley,
Infusion Communications, for editorial assistance with preparing these
slides. Please note that the natalizumab data slides have been prepared
by Biogen-Idec.
Why Would You Want to Silence the Disease from the Start?
Clinical
MRI
Pathology
3
MRI=magnetic resonance imaging.
17 yr female,
diagnosed
with CIS
after
presenting
with myelitis
Abnormal MRI; >9
T2 lesions on brain
MRI and spinal cord
lesion at C5
2000 2001
IFN-beta
2002 2003 2004 Oct 2013
Final
year of
school
University
4
Mo
nit
ori
ng
Tre
atm
en
t C
lin
ica
l O
cc
up
& S
oc
ial
CIS=clinically isolated syndrome; MS=multiple sclerosis; IFN=interferon.
18 yr, 1st year
university
diagnosed
with MS after
having L optic
neuritis
Dec 2007 Jan 2008
clumsy
left
hand
pins &
needles
in legs
R optic
neuritis
Bladder dysfunction
Graduate
trainee
marketing
Full
time
employment
Off work
~3 months
of the year
Brainstem
syndrome;
diplopia
and ataxia
High lesion
load with
brain
atrophy
Splits from
her partner
depression,
anxiety, and fatigue Reduced mobility
5
Mo
nit
ori
ng
Tre
atm
en
t C
lin
ica
l O
cc
up
& S
oc
ial
Abnormal MRI; >9
T2 lesions on brain
MRI and spinal cord
lesion at C5
IFN-beta
2000 2001 2002 2003 2004 Dec 2007 Oct 2013
Final
year of
school
17 yr female,
diagnosed
with CIS
after
presenting
with myelitis
18 yr, 1st year
university
diagnosed
with MS after
having L optic
neuritis
University
Jan 2008
MS Is a Devastating Disease
Cognitive Dysfunction
• Prevalence: 43% to 65%1,2
• Affects employment,
activities of daily living,
and social functioning2
Life Shortening
• 5- to 11-year decrease in
life expectancy3-7
• 2- to 7-fold increase in
suicide risk5,8
• 50% MS patients die of
disease-related causes5,6,8
1. Rao SM et al. Neurology. 1991;41:685-691; 2. Rao SM et al. Neurology. 1991;41:692-696; 3. Sadovnick AD et al. Neurology. 1992;42:991-994;
4. Ebers GC. J Neurol Neurosurg Psychiatry. 2001;71:16-19; 5. Torkildsen G et al. Mult Scler. 2008;14:1191-1198; 6. Smestad C et al. Mult Scler.
2009;15:1263-1270; 7. Kingwell E et al. J Neurol Neurosurg Psychiatry. 2012;83:61-66; 8. Sadovnick AD et al. Neurology. 1991;41:1193-1196;
9. Orme M et al. Value Heath. 2007;10:54-60; 10. De Marco R et al. Diabetes Care. 1999;22:756-761; 11. Petty DW et al. Mayo Clin Proc.
2005;80:1001-1008; 12. Hooning MJ et al. Int J Radiat Oncol Biol Phys. 2006;64:1081-1091; 13. Pfleger CC et al. Mult Scler. 2010;16:121-126;
14. Beg J et al. Eur J Health Econ. 2006;7(suppl 2):S75-S85.
*In this study, utility measures were derived from EQ-5D using the EuroQoL instrument; †in patients with type 2 diabetes; ‡in patients with valvular heart disease in Olmsted County,
Minnesota; §MS patients with EDSS ≥6.
EDSS=Expanded Disability Status Scale; QOL=quality of life; CV=cardiovascular;
EQ-5D=European Quality of Life-5 Dimensions.
QOL EDSS and utility* have shown a
significant inverse relationship9
Mortality Mortality ratio of patients with MS
exceeds CV disease,†,10 stroke,‡,11 and
early breast cancer12
Employment 50% of patients with MS are
unemployed as of EDSS 3.0 and/or
after 10 years from diagnosis13
Healthcare costs Bulk of cost attributed to services
(28.5%) and long-term sick leave and
early retirement (30%)§,14
Relationships Compared with general population, patients
with MS have a higher probability of
separating/divorcing and doing so sooner13
MS has a negative
impact on…
6
Consequences of Increasing EDSS Scores:
Loss of Employment1
7
0
10
20
30
40
50
60
70
80
90
Work Capacity by Disability Level
0.0/1.0 2.0 3.0 4.0 5.0 6.0 6.5 7.0 8.0/9.0
EDSS Score
Pro
po
rtio
n o
f P
ati
en
ts ≤
65
Ye
ars
Old
Wo
rkin
g (
%)
The proportion of patients employed or on long-term sick leave is calculated as a percentage of patients aged 65 or younger.
1. Kobelt G et al. J Neurol Neurosurg Psychiatry. 2006;77:918-926;
2. Pfleger CC et al. Mult Scler. 2010;16:121-126.
Spain
Sweden
Switzerland
United Kingdom
Netherlands
Italy
Germany
Belgium
Austria
~10 yrs2
7
? glatiramer
acetate
8
Mo
nit
ori
ng
Tre
atm
en
t C
lin
ica
l O
cc
up
& S
oc
ial
Graduate
trainee
marketing
Full
time
employment
Off work
~3 months
of the year
Splits from
her partner
Final
year of
school
University
High lesion
load with
brain
atrophy
Abnormal MRI; >9
T2 lesions on brain
MRI and spinal cord
lesion at C5
IFN-beta
2000 2001 2002 2003 2004 Dec 2007 Oct 2013
clumsy
left
hand
pins &
needles
in legs
R optic
neuritis
Bladder dysfunction
Brainstem
syndrome;
diplopia
and ataxia
depression,
anxiety, and fatigue Reduced mobility 17 yr female,
diagnosed
with CIS
after
presenting
with myelitis
18 yr, 1st year
university
diagnosed
with MS after
having L optic
neuritis
Jan 2008
MRI – High Lesion Load
9
? glatiramer
acetate
10
Mo
nit
ori
ng
Tre
atm
en
t C
lin
ica
l O
cc
up
& S
oc
ial
Graduate
trainee
marketing
Full
time
employment
Off work
~3 months
of the year
Splits from
her partner
Final
year of
school
University
High lesion
load with
brain
atrophy
Abnormal MRI; >9
T2 lesions on brain
MRI and spinal cord
lesion at C5
IFN-beta
2000 2001 2002 2003 2004 Dec 2007 Jan 2008 Oct 2013
clumsy
left
hand
pins &
needles
in legs
R optic
neuritis
Bladder dysfunction
Brainstem
syndrome;
diplopia
and ataxia
depression,
anxiety, and fatigue Reduced mobility 17 yr female,
diagnosed
with CIS
after
presenting
with myelitis
18 yr, 1st year
university
diagnosed
with MS after
having L optic
neuritis
Gd-enhancing
lesion of upper
cervical cord
Occupational
health
assessment
Cervical cord
relapse
weak L arm
with pain
MRI – Acute Cervical Cord Lesion
11
Jan 2008
How Can We Optimise Natalizumab Patient Management?
In EU, natalizumab is indicated for use as a single disease-modifying
therapy in highly active RRMS for the following adult patient groups:
EU=European Union; RRMS=relapsing-remitting MS; IFNβ=interferon beta; GA=glatiramer acetate; Gd+=gadolinium-enhancing.
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000603/WC500044686.pdf.
Accessed September 7, 2013.
High disease activity despite a full and adequate course with IFNβ or GA (normally ≥1 year of treatment)
≥1 relapse in the last year while on therapy, ≥9 T2-hyperintense lesions,
or ≥1 Gd+ lesion or a “nonresponder”, defined as patient with unchanged or increased relapse
rate or ongoing severe relapses, compared with the previous year
Rapidly evolving severe RRMS
≥2 disabling relapses in 1 year, ≥1 Gd+ lesion or significant increase in T2 lesion load
12
? glatiramer
acetate
13
Mo
nit
ori
ng
Tre
atm
en
t C
lin
ica
l O
cc
up
& S
oc
ial
Graduate
trainee
marketing
Full
time
employment
Off work
~3 months
of the year
Splits from
her partner
Final
year of
school
University
High lesion
load with
brain
atrophy
Abnormal MRI; >9
T2 lesions on brain
MRI and spinal cord
lesion at C5
IFN-beta
2000 2001 2002 2003 2004 Dec 2007 Oct 2013
clumsy
left
hand
pins &
needles
in legs
R optic
neuritis
Bladder dysfunction
Brainstem
syndrome;
diplopia
and ataxia
depression,
anxiety, and fatigue Reduced mobility 17 yr female,
diagnosed
with CIS
after
presenting
with myelitis
18 yr, 1st year
university
diagnosed
with MS after
having L optic
neuritis
Jan 2008
Occupational
health
assessment
Gd-enhancing
lesion of upper
cervical cord
Cervical cord
relapse
weak L arm
with pain
natalizumab
Treat-2-Target Proposed NEDA Treatment Algorithm for
Relapsing MS
NEDA=no evidence of disease activity.
A
B
C
D
E N M
Y X Moderate
Efficacy
Intermediate
Efficacy
High
Efficacy
14
Early Treatment Choice and Management Has the Potential
to Delay MS Disease Progression
15
Adapted from Miller JR. J Manag Care Pharm. 2004;10(suppl S-b):S4-S11.
Time Symptom
Onset
Dis
ab
ilit
y
Later
treatment
Earlier
treatment
Optimal
window of
opportunity
Early treatment AND earlier management
Later treatment
Natural course of MS
15
83% reduction in
T2-hyperintense lesions*
37% vs 7% Freedom from disease
activity/disease activity
free‡
92% reduction in Gd+ lesions
30% vs 19% with sustained
improvement in function†
68% reduction in
relapse rate
42% to 54% reduction of
disability progression
Natalizumab Reduces Both Clinical and
MRI Measures of Disease
*Decrease in new or newly enlarging hyperintense lesions; †baseline EDSS >2.0, with 1.0-point decrease in EDSS sustained for >12 weeks; ‡Post hoc analysis of patients with no relapse, no 12-week sustained EDSS progression, no new or enlarging T2-hyperintense lesions, and no Gd+ lesions. AFFIRM: a 2-year, randomised, multicenter, double-blind, placebo-controlled study of 942 patients that evaluated the effect of natalizumab on annualised relapse rate and disability progression; all differences were statistically significant (P<0.05). Polman C et al. N Engl J Med. 2006;354:899-910; Havrdová E et al. Lancet Neurol. 2009;8:254-260; Phillips JT et al. Mult Scler. 2011;17:970-979.
Primary
Outcomes
Secondary
Outcomes
Exploratory
Outcomes
AFFIRM Overall Patients: Natalizumab vs Placebo
16
18 15
51
70
0
20
40
60
80
100
Year 0–1 Year 1–2
Pe
rce
nta
ge
of
Pa
tie
nts
(%
)
Placebo Natalizumab
Havrdová E. et al. Lancet Neurol. 2009;8:254-226.
Natalizumab and Freedom from Disease
Activity/Disease Activity Free (AFFIRM)
Freedom from Disease Activity/Disease Activity Free:
Post hoc analysis of patients with no relapses, no sustained (12-week) disability
progression, no Gd+ lesions, no new or enlarging T2-hyperintense lesions
Non-Highly Active Disease <2 relapses in past 12 months or
no Gd+ lesions at study entry
3 4
34
65
0
20
40
60
80
100
Year 0–1 Year 1–2
Pe
rce
nta
ge
of
Pa
tie
nts
(%
)
n=248 n=458 n=228 n=407 n=59 n=146 n=56 n=137
P<0.0001 P<0.0001 P<0.0001 P<0.0001
Highly Active Disease ≥2 relapses in past 12 months and
≥1 Gd+ lesion at study entry
17
-2.5
-1.5
-0.5
0.5
1.5
2.5
Me
an
Pe
rce
nt
Ch
an
ge
Fro
m
Bas
eli
ne
in
SF
-36
Sc
ore
Week 104
Placebo Natalizumab
MCS PCS
P<0.05 P<0.01
IMSE Swedish registry2
Multiple Sclerosis Impact Scale (MSIS-29)
Natalizumab and Quality of Life
MCS=mental component summary.
1. Rudick RA et al. Ann Neurol. 2007;62:335-346; 2. Holmén C et al. Mult Scler. 2011;17:708-719.
AFFIRM1
Short Form-36 (SF-36)
-15
-13
-11
-9
-7
-5
-3
-1
Month 24
Me
an
Pe
rce
nt
Ch
an
ge
F
rom
Bas
eli
ne
in
MS
IS-2
9
Sc
ore
P<0.05
P<0.05
Physical
Psychological WORSENING
IMPROVEMENT
IMPROVEMENT
18
Escalation to Natalizumab Is More Effective Than Switching
Between IFN/GA
0
25
50
75
100
% P
ati
en
ts
Escalate to Natalizumab, n=106
Switch Between IFN/GA, n=161
Data from a postmarketing, prospective, observational study in 285 RRMS patients for whom treatment with IFNβ or GA therapy failed.
After failure of IFNβ or GA therapy, patients were switched to either natalizumab (n=106) or IFNβ/GA (n=161).
*There were no differences at 12 month between the two groups in proportions of patients free from relapse, disability progression, MRI
activity, and combined activity.
Prosperini L et al. Mult Scler. 2012;18:64-71.
No EDSS
Progression
No MRI
Activity
Disease
Activity Free
P<0.0001 P=0.0003 P<0.0001
51
36
51
21
83
67 77
59
No
Relapses
P<0.0045
Over 24 months*
19
Escalation to Natalizumab Is More Effective Than Switching
Between IFN/GA
0
25
50
75
100
% P
ati
en
ts
Escalate to Natalizumab, n=106
Switch Between IFN/GA, n=161
Data from a postmarketing, prospective, observational study in 285 RRMS patients for whom treatment with IFNβ or GA therapy failed.
After failure of IFNβ or GA therapy, patients were switched to either natalizumab (n=106) or IFNβ/GA (n=161).
*There were no differences at 12 month between the two groups in proportions of patients free from relapse, disability progression, MRI
activity, and combined activity.
Prosperini L et al. Mult Scler. 2012;18:64-71.
No EDSS
Progression
No MRI
Activity
Disease
Activity Free
P<0.0001 P=0.0003 P<0.0001
51
36
51
21
83
67 77
59
No
Relapses
P<0.0045
Over 24 months*
20
×
? glatiramer
acetate
21
Mo
nit
ori
ng
Tre
atm
en
t C
lin
ica
l O
cc
up
& S
oc
ial
Graduate
trainee
marketing
Full
time
employment
Off work
~3 months
of the year
Splits from
her partner
Final
year of
school
University
High lesion
load with
brain
atrophy
Abnormal MRI; >9
T2 lesions on brain
MRI and spinal cord
lesion at C5
IFN-beta
2000 2001 2002 2003 2004 Dec 2007 Oct 2013
clumsy
left
hand
pins &
needles
in legs
R optic
neuritis
Bladder dysfunction
Brainstem
syndrome;
diplopia
and ataxia
depression,
anxiety, and fatigue Reduced mobility 17 yr female,
diagnosed
with CIS
after
presenting
with myelitis
18 yr, 1st year
university
diagnosed
with MS after
having L optic
neuritis
Jan 2008
Occupational
health
assessment
Gd-enhancing
lesion of upper
cervical cord
Cervical cord
relapse
weak L arm
with pain
natalizumab
New
partner
New job
junior management
position
Residual deficits:
Normal walking 300 m, unable to run &
exercise. Intermittent sensory symptoms
in L arm. Mild urinary frequency
Annual MRI
monitoring
Natalizumab should be used according to the SmPC
Natalizumab and Functional Benefit – Double-blind, Placebo-
controlled Study (AFFIRM)
1. Phillips JT et al., Mult Scler 2011;17:970-979; 2. Munschauer F et al., ECTRIMS Meeting September 9–12, 2009, Dusseldorf, Germany,
P434; 3. Balcer LJ et al., J Neurol Sci 2012;318:119-24; 4. Weinstock-Guttmanen B et al., J Neurol 2012;259:898–905.
Compared with placebo, Natalizumab showed sustained improvement in
• EDSS1
• Upper limb2
• Walking2
• Vision3
and reduced the risk of progression of cognitive deficit4
-0.30.20.71.21.72.22.73.23.74.2
0.5 5
Hazard Ratio (95% Confidence Interval)
0.5 1.0 1.5 2.0 3.0 4.0 5.0
Favours placebo Favours natalizumab
Cognitive deficit – PASAT-3 (P=0.013)
Vision – 1.25% low contrast acuity (P=0.014)
Vision - 2.5% low contrast acuity (P=0.012)
Timed 25-foot walk (P=0.028)
9-hole peg test (P=0.044)
EDSS (P=0.006)
Favours natalizumab Favours placebo
22
Natalizumab should be used according to the SmPC
Treatment with natalizumab has also been shown to improve
Bladder function (TRUST)1 and Fatigue (TYNERGY)2
Confirmation of improvements in:
Walking 6-minute (TYNERGY2) and 100 meter (TIMER3) tests
Cognition Improvement in single digit modalities test (IMSE Swedish registry4)
Natalizumab and Functional Improvement –
Post-approval Studies
-8
-7
-6
-5
-4
-3
-2
-1
0
0 4 8 12 16 20 24
Me
an
ch
an
ge
fro
m b
as
eli
ne
Time (Weeks)
Urogenital Distress Impact Questionnaire
Incontinence Impact Questionnaire
1. Khatri B et al. ECTRIMS Meeting October 19–22, 2011; Amsterdam, The Netherlands, P1040; 2. Svenningsson A et al. PLoS One
2013;8:e58643; 3. Nehrych T et al. ENS Meeting June 8-11, 2013, Barcelona, Spain, P369; 4. Holmén C et al. Mult Scler 2011;17:708-719.
25
30
35
40
45
50
55
60
65
70
75
Baseline Month 3 Month 6 Month 9 Month 12
Me
an
FM
SC
sc
ore
Total Score Motor Score Cognitive Score
P<0.0001 for time effect
P<0.0001 for time effect
P<0.0001
P<0.0001
P<0.0001
Change from
baseline at
Month 12
23
Natalizumab should be used according to the SmPC
17yr female,
diagnosed
with CIS
after
presenting
with myelitis
18yr, 1st year
university
diagnosed
with MS after
having L optic
neuritis
Abnormal MRI; >9
T2 lesions on brain
MRI and spinal cord
lesion at C5
2000 2001
clumsy
left
hand
pins &
needles
in legs
IFN-beta
2002 2003
R optic
neuritis
2004
Bladder dysfunction
Graduate
trainee
marketing
Full
time
employment
Off work
~3 months
of the year
Dec 2007
Brainstem
syndrome;
diplopia
and ataxia
? glatiramer
acetate
Cervical cord
relapse
weak L arm
with pain
High lesion
load with
brain
atrophy
Gd-enhancing
lesion of upper
cervical cord
Splits from
her partner
depression ,
anxiety and fatigue
Reduced mobility
Occupational
health
assessment
natalizumab
New
partner
New job
junior management
position
Residual deficits:
Normal walking 300m, unable to run &
exercise. Intermittent sensory symptoms
in L arm. Mild urinary frequency
Jan 2008 Oct 2013
Annual MRI
monitoring
Final
year of
school
University
24
Mo
nito
rin
g
Tre
atm
en
t C
linic
al
Occu
p &
so
cia
l
Natalizumab should be used according to the SmPC
First
Relapse
3 6 9 12 15 18 21 24 27 30
Months Since Relapse
0
10
20
30
40
50
60
70
80
90
100
Pati
en
ts w
ith
co
mp
lete
reco
very
(%
)
Placebo Natalizumab
Natalizumab and Clinical Recovery from Relapses
Lublin F. et al. ECTRIMS 2013, Copenhagen October 3rd , Poster P524.
Overall population : Subjects with an increase of EDSS ≥ 1.0 point at relapse *Based on Cox Proportional Hazards model adjusted for baseline EDSS, age, gender, relapses in year prior to enrollment, disease
duration, baseline Gd-enhancing lesions and baseline T2 lesion volume.
AFFIRM: Probability of 12-week confirmed complete
recovery from relapses
76.0%
43.1%
Adjusted HR for natalizumab vs placebo=1.673
(95% CI:1.046–2.678); 67% increase; P=0.0319*
25
Placebo (N=86) Natalizumab (N=70)
Natalizumab should be used according to the SmPC
Natalizumab and Clinical Recovery from Relapses
84%91%
70%71% 74%68%
0%
20%
40%
60%
80%
100%
Overallpopulation
BaselineEDSS<3.0
Baseline EDSS≥3.0
n=140 n=93 n=80 n=143
Pro
po
rtio
n o
f p
ati
en
ts (
%)
Placebo
Natalizumab
**P=0.0088 **P=0.0019 P=0.8259
At least 0.5 point EDSS increase
n=47 n=63
At least 1.0 point EDSS increase
61%71%
43%49% 50% 48%
0%
20%
40%
60%
80%
100%
Overallpopulation
BaselineEDSS<3.0
Baseline EDSS≥3.0
n=140 n=93 n=80 n=143
Pro
po
rtio
n o
f p
ati
en
ts (
%)
*P=0.0349 **P=0.0048 P=0.5976
n=47 n=63
Lublin F. et al. ECTRIMS 2013, Copenhagen October 3rd , Poster P524.
Disabling Magnitude of Relapses in AFFIRM
EDSS change from pre-relapse to at relapse
26
Early Treatment Choice and Management Has the Potential
to Delay MS Disease Progression
27
Adapted from Miller JR. J Manag Care Pharm. 2004;10(suppl S-b):S4-S11.
Time Symptom
Onset
Dis
ab
ilit
y
Later
treatment
Earlier
treatment
Optimal
window of
opportunity
Early treatment AND earlier management
Later treatment
Natural course of MS
27
Natalizumab should be used according to the SmPC
Patient Management Using the Anti-JCV Antibody Assay
Negative* Positive
Anti-JCV
Antibody Status
Using this assay, anti-JCV antibodies were detected
in 172 of 174 (99%) natalizumab-treated patients
assessed more than 6 months prior to PML diagnosis.
0.1/1000
28
JCV=JC virus; PML=progressive multifocal leukoencephalopathy; IS=immunosuppressant; CI=confidence interval.
*Medical information website. Boston, MA, USA: Biogen Idec Inc. https://medinfo.biogenidec.com/medinfo. Accessed August 5, 2013.
Natalizumab should be used according to the SmPC
17yr female,
diagnosed
with CIS
after
presenting
with myelitis
18yr, 1st year
university
diagnosed
with MS after
having L optic
neuritis
Abnormal MRI; >9
T2 lesions on brain
MRI and spinal cord
lesion at C5
2000 2001
clumsy
left
hand
pins &
needles
in legs
IFN-beta
2002 2003
R optic
neuritis
2004
Bladder dysfunction
Graduate
trainee
marketing
Full
time
employment
Off work
~3 months
of the year
Dec 2007
Brainstem
syndrome;
diplopia
and ataxia
? glatiramer
acetate
Cervical cord
relapse
weak L arm
with pain
High lesion
load with
brain
atrophy
Gd-enhancing
lesion of upper
cervical cord
Splits from
her partner
depression ,
anxiety and fatigue
Reduced mobility
Occupational
health
assessment
natalizumab
New
partner
New job
junior management
position
Residual deficits:
Normal walking 300m, unable to run &
exercise. Intermittent sensory symptoms
in L arm. Mild urinary frequency
Jan 2008
JCV
positive
Oct 2013
Annual MRI
monitoring
Final
year of
school
University
29
Mo
nito
rin
g
Tre
atm
en
t C
linic
al
Occu
p &
so
cia
l
Natalizumab should be used according to the SmPC
Natalizumab
Exposure
1–24
months
25–48
months
49–72
months
PML Risk 0.7/1000 5.3/1000 6.1/1000
No Prior IS Use
*https://medinfo.biogenidec.com/medinfo. Accessed August 5, 2013. Data as of March 2013 indicate estimated risk of PML patients with prior
immunosuppressant use is 1.8/1000 for natalizumab exposure of 1–24 months and 11.2/1000 for exposure of 25–48 months.
Negative Positive*
Anti-JCV
Antibody Status 1 in 189
30
Patient Management Using the Anti-JCV Antibody Assay
Risk of PML is ≤1/1000 for all patients with no prior IS use in the first 2 years
Natalizumab should be used according to the SmPC
17yr female,
diagnosed
with CIS
after
presenting
with myelitis
18yr, 1st year
university
diagnosed
with MS after
having L optic
neuritis
Abnormal MRI; >9
T2 lesions on brain
MRI and spinal cord
lesion at C5
2000 2001
clumsy
left
hand
pins &
needles
in legs
IFN-beta
2002 2003
R optic
neuritis
2004
Bladder dysfunction
Graduate
trainee
marketing
Full
time
employment
Off work
~3 months
of the year
Dec 2007
Brainstem
syndrome;
diplopia
and ataxia
? glatiramer
acetate
Cervical cord
relapse
weak L arm
with pain
High lesion
load with
brain
atrophy
Gd-enhancing
lesion of upper
cervical cord
Splits from
her partner
depression ,
anxiety and fatigue
Reduced mobility
Occupational
health
assessment
natalizumab
New
partner
New job
junior management
position
Residual deficits:
Normal walking 300m, unable to run &
exercise. Intermittent sensory symptoms
in L arm. Mild urinary frequency
Jan 2008
JCV
positive
? fingolimod
Oct 2013
Annual MRI
monitoring
Final
year of
school
University
31
Mo
nito
rin
g
Tre
atm
en
t C
linic
al
Occu
p &
so
cia
l
Natalizumab should be used according to the SmPC
Recent Report of Higher Anti-JCV Antibody Levels in Anti-
JCV Positive Patients Who Developed PML
• Higher normalised optical
densities (Gen1) were
observed in the patients
who developed PML (n=9)
as compared with those
who did not develop PML
(n=2253)
0
0.5
1
1.5
Pre-PML Non-PML(seropositive)
nOD450=normalised optical density.
Trampe AK et al. Neurology 2012;78:1736–174.
nO
D4
50
P=0.0178
32
Natalizumab should be used according to the SmPC
PML risk estimates for anti-JCV antibody index thresholds were calculated based on the current PML risk stratification algorithm (September 2012)
and predicted probabilities (using data from patients with no prior IS use: 2242 non-PML patients and 51 patients who developed PML using all
available anti-JCV antibody index data at least 6 months prior to PML diagnosis) for the population at or below that particular index (0.9−1.5) and
for the population above an index of 1.5. For index thresholds below 0.9, patient numbers were insufficient to allow for calculation of risk estimates.
Anti-JCV Antibody Index Values May Differentiate PML Risk
For Those With No Prior IS Use
Index 1−24 months
≤0.9 0.1 (0, 0.41)
≤1.1 0.1 (0, 0.34)
≤1.3 0.1 (0.01, 0.39)
≤1.5 0.1 (0.03, 0.42)
>1.5 1.0 (0.64, 1.41)
33
PML risk estimates (95% CI) per 1000 patients with no prior IS use
Plavina T et al. Poster DX51, CMSC May 29–June 1 2013, Orlando, USA; Ticho B. et al, Presented at ENS, June 8–11 2013, Barcelona, Spain O228.
33
Further evaluation of this new hypothesis correlating anti-JCV antibody index and PML risk assessment is
ongoing
25−48 months 49−72 months
0.3 (0.04, 1.13)
0.4 (0.01, 2.15)
0.7 (0.21, 1.53)
0.7 (0.08, 2.34)
1.0 (0.48, 1.98)
1.2 (0.31, 2.94)
1.2 (0.64, 2.15)
1.3 (0.41, 2.96)
8.1 (6.64, 9.80)
8.5 (6.22, 11.38)
Natalizumab should be used according to the SmPC
17yr female,
diagnosed
with CIS
after
presenting
with myelitis
18yr, 1st year
university
diagnosed
with MS after
having L optic
neuritis
Abnormal MRI; >9
T2 lesions on brain
MRI and spinal cord
lesion at C5
2000 2001
clumsy
left
hand
pins &
needles
in legs
IFN-beta
2002 2003
R optic
neuritis
2004
Bladder dysfunction
Graduate
trainee
marketing
Full
time
employment
Off work
~3 months
of the year
Dec 2007
Brainstem
syndrome;
diplopia
and ataxia
? glatiramer
acetate
Cervical cord
relapse
weak L arm
with pain
High lesion
load with
brain
atrophy
Gd-enhancing
lesion of upper
cervical cord
Splits from
her partner
depression ,
anxiety and fatigue
Reduced mobility
Occupational
health
assessment
natalizumab
New
partner
New job
junior management
position
Residual deficits:
Normal walking 300m, unable to run &
exercise. Intermittent sensory symptoms
in L arm. Mild urinary frequency
Jan 2008
JCV
positive
Oct 2013
Annual MRI
monitoring
JCV
high positive
Final
year of
school
University
34
Mo
nito
rin
g
Tre
atm
en
t C
linic
al
Occu
p &
so
cia
l
Natalizumab should be used according to the SmPC
Use of anti-JC virus antibody index may further define risk of PML in anti-
JCV antibody positive natalizumab-treated patients with MS.
Plavina T et al. Presented at CMSC, May 29 – June 1 2013, Orlando, USA DX51.
Ticho B. et al, Presented at ENS, June 8–11 2013, Barcelona, Spain O228.
Natalizumab
Exposure
1–24
months
25–48
months
49–72
months
PML Risk 0.7/1000 5.3/1000 6.1/1000
No Prior IS Use
The earlier, the smaller, the better for natalizumab-associated PML: in MRI
vigilance veritas? Phan-Ba R. et al. Neurology 2012;79:1067-1069.
*https://medinfo.biogenidec.com/medinfo. Accessed August 5, 2013. Data as of March 2013 indicate estimated risk of PML patients with prior
immunosuppressant use is 1.8/1000 for natalizumab exposure of 1–24 months and 11.2/1000 for exposure of 25–48 months.
Negative Positive*
Anti-JCV
Antibody Status > 1 in 189
35
Patient Management Using the Anti-JCV Antibody Assay
Risk of PML is ≤1/1000 for all patients with no prior IS use in the first 2 years
Natalizumab should be used according to the SmPC
17yr female,
diagnosed
with CIS
after
presenting
with myelitis
18yr, 1st year
university
diagnosed
with MS after
having L optic
neuritis
Abnormal MRI; >9
T2 lesions on brain
MRI and spinal cord
lesion at C5
2000 2001
clumsy
left
hand
pins &
needles
in legs
IFN-beta
2002 2003
R optic
neuritis
2004
Bladder dysfunction
Graduate
trainee
marketing
Full
time
employment
Off work
~3 months
of the year
Dec 2007
Brainstem
syndrome;
diplopia
and ataxia
? glatiramer
acetate
Cervical cord
relapse
weak L arm
with pain
High lesion
load with
brain
atrophy
Gd-enhancing
lesion of upper
cervical cord
Splits from
her partner
depression ,
anxiety and fatigue
Reduced mobility
Occupational
health
assessment
natalizumab
New
partner
New job
junior management
position
Residual deficits:
Normal walking 300m, unable to run &
exercise. Intermittent sensory symptoms
in L arm. Mild urinary frequency
Jan 2008
JCV
positive
3-monthly MRI
monitoring
? fingolimod
Oct 2013
Annual MRI
monitoring
JCV
high positive
Final
year of
school
University
36
Mo
nito
rin
g
Tre
atm
en
t C
linic
al
Occu
p &
so
cia
l
Natalizumab should be used according to the SmPC
Early Detection of PML and Clinical
Outcome
37
Detection of PML on routine MRI (confirmed by CSF analysis) has been
demonstrated in asymptomatic patients1–5
– Asymptomatic PML patients have improved survival and less functional disability compared
with symptomatic patients6
MRI=magnetic resonance imaging; CSF=cerebrospinal fluid; FLAIR=fluid-attenuated inversion recovery. 1. Vermersch P et al. Neurology. 2011;76:1697-1704.
2. Phan-Ba R et al. Neurology. 2012;79:1067-1069; 3. Blair NF et al. Neurology. 2012;78:507-508; 4. Ayzenberg I et al. J Neurol. 2012;259:1732-1733;
5. Yousry TA et al. Ann Neurol. 2012;72:779-787; 6. Dong-Si et al. Presented at AAN; March 16–23, 2013; San Diego, CA. P04.271.
Months From PML Diagnosis
Natalizumab should be used according to the SmPC
When is the Right Time to Start Natalizumab ?
38
Natalizumab should be used according to the SmPC
17yr female,
diagnosed
with CIS
after
presenting
with myelitis
18yr, 1st year
university
diagnosed
with MS after
having L optic
neuritis
Abnormal MRI; >9
T2 lesions on brain
MRI and spinal cord
lesion at C5
2000 2001
clumsy
left
hand
pins &
needles
in legs
IFN-beta
2002 2003
R optic
neuritis
2004
Bladder dysfunction
Graduate
trainee
marketing
Full
time
employment
Off work
~3 months
of the year
Dec 2007
Brainstem
syndrome;
diplopia
and ataxia
? glatiramer
acetate
Cervical cord
relapse
weak L arm
with pain
High lesion
load with
brain
atrophy
Gd-enhancing
lesion of upper
cervical cord
Splits from
her partner
depression ,
anxiety and fatigue
Reduced mobility
Occupational
health
assessment
natalizumab
New
partner
New job
junior management
position
Residual deficits:
Normal walking 300m, unable to run &
exercise. Intermittent sensory symptoms
in L arm. Mild urinary frequency
Jan 2008
JCV
positive
3-monthly MRI
monitoring
? fingolimod
Oct 2013
Annual MRI
monitoring
JCV
high positive
Final
year of
school
University
39
Mo
nito
rin
g
Tre
atm
en
t C
linic
al
Occu
p &
so
cia
l
Early or late?
Natalizumab should be used according to the SmPC
STRATA: Patients Had Stable EDSS Scores for
Up to 5 Years
*P<0.0001
Kappos L et al. Presented at ECTRIMS; October 10–13, 2012; Lyon, France P520.
2.36
2.69 2.54
3.13 3.07 3.22 3.24 3.21 3.15
2.38 2.36 2.39
2.90
2.69 2.72 2.84 2.85 2.79
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
FeederStudy
Baseline
FeederStudyEnd
SafetyStudyEnd
STRATABaseline
STRATA48 Weeks
STRATA96 Weeks
STRATA144 Weeks
STRATA192 Weeks
STRATA240 Weeks
1 Year 2 Years 3 Years 4 Years 5 Years
Cessation/
Treatment Gap* Original Placebo
Original Natalizumab
Original Placebo – Now on Natalizumab
Mean
ED
SS
Sco
re
n = 380 707 381 707 280 552 385 709 274 569 230 479 205 462 194 427 174 393
40
Natalizumab should be used according to the SmPC
TOP: Earlier Natalizumab Treatment Favours Annualised
Relapse Rate Outcomes
P values from a negative binomial regression model adjusted for gender, baseline EDSS score (<3.0 vs ≥3.0l), relapse status in the prior
year (≤1 vs >1), prior DMT use (<3 vs ≥3), disease duration (<8 vs ≥8 years), and treatment duration (≥3 vs <3 years), except for the factor
of interest. Error bars represent 95% CIs.
DMT=disease-modifying therapy; CI=confidence interval.
Wiendl et al. Presented at ENS; June 8–11, 2013; Barcelona, Spain,. P372.
41
Natalizumab should be used according to the SmPC
TOP: Natalizumab Stabilises EDSS Scores in Patients with
Either a High or Low Starting EDSS Score at Baseline
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
5.0
0 6 12 18 24 30 36 42 48
Med
ian
ED
SS
Sco
re
Time (months)
Kappos L et al. Presented at ENS; June 9–12, 2012; Prague, Czech Republic. O261.
Baseline EDSS Score ≤3.0 (n=1591)
Baseline EDSS Score >3.0 (n=1840)
42
Natalizumab should be used according to the SmPC
17yr female,
diagnosed
with CIS
after
presenting
with myelitis
18yr, 1st year
university
diagnosed
with MS after
having L optic
neuritis
Abnormal MRI; >9
T2 lesions on brain
MRI and spinal cord
lesion at C5
2000 2001
clumsy
left
hand
pins &
needles
in legs
IFN-beta
2002 2003
R optic
neuritis
2004
Bladder dysfunction
Graduate
trainee
marketing
Full
time
employment
Off work
~3 months
of the year
Dec 2007
Brainstem
syndrome;
diplopia
and ataxia
? glatiramer
acetate
Cervical cord
relapse
weak L arm
with pain
High lesion
load with
brain
atrophy
Gd-enhancing
lesion of upper
cervical cord
Splits from
her partner
depression ,
anxiety and fatigue
Reduced mobility
Occupational
health
assessment
natalizumab
New
partner
New job
junior management
position
Residual deficits:
Normal walking 300m, unable to run &
exercise. Intermittent sensory symptoms
in L arm. Mild urinary frequency
Jan 2008
JCV
positive
3-monthly MRI
monitoring
? fingolimod
Oct 2013
Annual MRI
monitoring
JCV
high positive
Final
year of
school
University
Early or late?
43
Mo
nito
rin
g
Tre
atm
en
t C
linic
al
Occu
p &
so
cia
l
Natalizumab should be used according to the SmPC
Early Treatment Choice and Management Has the Potential
to Delay MS Disease Progression
44 Adapted from Miller JR. J Manag Care Pharm. 2004;10(suppl S-b):S4-S11.
Time Symptom
Onset
Dis
ab
ilit
y
Later
treatment
Earlier
treatment
Optimal
window of
opportunity
Early treatment AND earlier management
Later treatment
Natural course of MS
44
Natalizumab should be used according to the SmPC
T2T - NEDA
Zero
Tolerance
Treatment Objectives in Relapsing MS
Freedom from
disease
activity/disease
activity free
Reduced ongoing
damage
Treat Early
45
Natalizumab should be used according to the SmPC
T2T - NEDA
Zero
Tolerance
Treatment Objectives in Relapsing MS
Freedom from
disease
activity/disease
activity free
Reduced ongoing
damage
Functional
Improvement
Maintain reserve
capacity
CNS Repair
Healthy
ageing
Improved Quality of Life
Treat Early
46
Natalizumab should be used according to the SmPC
What does the future hold?
47
17yr female,
diagnosed with CIS
after presenting
with myelitis
18yr, 1st year
university diagnosed
with MS after having
L optic neuritis
Abnormal MRI; >9 T2 lesions
on brain MRI and spinal cord
lesion at C5
2000 2001
clumsy
left hand
pins &
needles in
legs
IFN-beta
2001 2003
R optic
neuritis
2004
Bladder dysfunction
Graduate
trainee
marketing
Full
time employment
Off work
~3 months of the
year
Dec 2007
Brainstem
syndrome;
diplopia and
ataxia
? glatiramer acetate
Cervical cord relapse
weak L arm with pain
High lesion load
with brain
atrophy Gd-enhancing lesion
of upper cervical
cord
Splits from her
partner
depression , anxiety and
fatigue
Reduced mobility
Occupational health
assessment
natalizumab
New
partner
New job
junior management
position
Residual deficits:
Normal walking 300m, unable to run & exercise. Intermittent
sensory symptoms in L arm. Mild urinary frequency
Jan 2008
JCV
positive
3-monthly MRI
monitoring
? fingolimod
Oct 2013
Annual MRI
monitoring
mo
nit
ori
ng
trea
tmen
t cl
inic
al
Occ
up
. & s
oci
al
JCV
high positive
Final
year of
school
University
Pregnancy Old
Age
Natalizumab should be used according to the SmPC
Optimizing Use of Natalizumab
• Freedom from disease activity* was achieved in 65% to 70% patients during the
second year of treatment in AFFIRM1
• Natalizumab in AFFIRM reduced the rate of brain atrophy in the second year2
and also significantly reduced the rate of conversion of new Gd+ lesions to T1
hypointense lesions over 12 months3
• Risk of PML is very low (1 in 10,000) in in anti-JCV antibody–negative patients4
• In anti-JCV antibody-positive patients without prior IS use, risk of PML in first 2
years is low (≤1 in 1000)3; use of natalizumab for > 2 years is based on a case-
by-case decision
• In clinical practice, when used mostly in patients on an injectable DMT with
uncontrolled disease:
• A stable EDSS score is observed in most patients especially when used earlier in the
disease course5,6
• Improvements in fatigue, cognition, bladder function, and QoL are seen following
switch to natalizumab7-9
48
*Post hoc analysis of patients with no relapses, no sustained (12-week) disability progression, no Gd+ lesions, no new or enlarging T2-hyperintense
lesions. 1. Havrdová E. et al. Lancet Neurol. 2009;8:254-226; 2. Miller DH et al. Neurology. 2007;68:1390-1401; 3. Dalton CM et al. J Neurol.
2004;251:407-413; 4. Bloomgren G et al. N Engl J Med. 2012;366:1870-1880; 5. Kappos L et al. Presented at ENS; June 9–12, 2012; Prague, Czech
Republic. O261; 6. Kallweit U et al. Clin Neuropharmacol. 2012;35:77-80; 7. Svenningsson A et al. PLoS One. 2013;8:e58643; 8. Khatri B et al.
Presented at ECTRIMS; October 19–22, 2011; Amsterdam, The Netherlands. P1040; 9. Holmen C et al. Mult Scler. 2011;17:708-719.