mser version pml update may 2013
TRANSCRIPT
Natalizumab PML Update
May 2013, MSer Version
Gavin Giovannoni
Blizard Institute
Barts and The London, United Kingdom
1
Natalizumab PML Incidence Estimates by Treatment Epoch
Natalizumab PML Incidence Estimates by Treatment Epoch
PML Risk only increases after 12 infusions
As the PML risk only increases after 12 infusions of Natalizumab I will limit further data analysis
to this subgroup of treated Msers.
Use of Natalizumab in the Post-Marketing Setting*
~83,000 MSers have been exposed to >= 12 months of
Natalizumab treatment
Visualisation of Natalizumab exposure
Each dot represents an MSer on
Natalizumab.
There are 10,000 MSers in this plot
Visualisation of Natalizumab Exposure of 12 or more infusions
Each dot represents an MSer on
Natalizumab.
There are 83,000 MSers in this plot, representing those
who have been exposed to
Natalizumab for 12 or more infusions.
~83,000 MSers exposed to 12 or more Natalizumab infusions
Visualisation of the number of MSers with PML
Each dot represents an MSer who has developed PML after
Natalizumab exposure.
There are 359 MSers, or dots, on either of these two plots.
359 MSers with PML
High-density plot
Low-density plot
Data is as of the 6th May 2013
Visualisation of PML Risk
Each dot in these plots
represents an MSer on
Natalizumab.
359 MSers with PML ~83,000 MSers exposed to 12 or more Natalizumab infusions
High-density plot
Low-density plot
PML Risk for MSers treated with Natalizumab for more than 12 months = 359 / ~83,000 = 0.00418
4.18 PML cases per 1000, or 1 in 239, MSers treated with 12 or more infusions
PML Risk Treatment duration 12 or more Natalizumab infusions
Each dot represents a MSer who has been
exposed to Natalizumab for 12 or more infusions.
Your chances of getting
PML are 1 in 239.
Black dot = Mser with PML Purple dots = unaffected MSers
The overall risk of 1 in 239 is not very helpful for individual MSers as we now know of three risk factors that modify the risk of developing PML:
1. Whether or not you have been infected with the JC virus in the past; JCV +ve vs. JCV –ve.
2. How long you have been on Natalizumab; i.e. less than 2 years compared to 2 or more years.
3. Whether or not you have been treated with immunosuppressive therapies in the past.
PML Risk – JC virus negative Treatment duration N/A & previous immunosuppression N/A
Each green dot represents a a JCV negative MSer on
Natalizumab.
Your chances of getting PML are 1 in
14,286
PML Risk – JC virus positive Treatment duration less than 2 years and no previous immunosuppression
Each yellow dot represents a a JCV positive MSer on
Natalizumab for less than 2 years, who has not received previous immunosuppression.
Your chances of getting PML are
1 in 1,667.
PML Risk – JC virus positive Treatment duration less than 2 years and previous immunosuppression
Each orange dot represents a a JCV positive MSer on
Natalizumab for less than 2 years, who has
received previous immunosuppression.
Your chances of getting PML are
1 in 556.
PML Risk – JC virus positive Treatment duration more than 2 years and no previous immunosuppression
Each red dot represents a a JCV positive MSer on Natalizumab for
more than 2 years, who has not received
previous immunosuppression.
Your chances of getting PML are
1 in 192.
PML Risk – JC virus positive Treatment duration more than 2 years and previous immunosuppression
Each dark red dot represents a a JCV positive MSer on Natalizumab for
more than 2 years, who has received
previous immunosuppression.
Your chances of getting PML are
1 in 94.
What has happened to the MSers who have developed PML?
Status of PML Cases
Risk of dying if you develop PML is ~ 1 in 5
Black dots = MSers with PML who survive. Gray dot = MSer with PML who will die from the condition.
What has happens to the MSers who survive PML?
PML outcome: one method is to use the Karnofsky Performance Scale to assess outcome in PML survivors
The following is the Karnofsky Performance Scale:
100% – normal, no complaints, no signs of disease
90% – capable of normal activity, few symptoms or signs of disease
80% – normal activity with some difficulty, some symptoms or signs
70% – caring for self, not capable of normal activity or work
60% – requiring some help, can take care of most personal requirements
50% – requires help often, requires frequent medical care
40% – disabled, requires special care and help
30% – severely disabled, hospital admission indicated but no risk of death
20% – very ill, urgently requiring admission, requires supportive measures or treatment
10% – moribund, rapidly progressive fatal disease processes
0% – death.
PML outcomes: Karnofsky scores
Dong-Si T, et al. ECTRIMS 2012; P1098. In general MSers who develop PML don’t do very well.
PML outcome: another method is to use the EDSS to assess outcome in PML survivors
PML outcomes: EDSS
Dong-Si T, et al. ECTRIMS 2012; P1098. In general MSers who develop PML don’t do very well.
It is not all bad news.
If the PML is detected early, before it causes symptoms, the outcome
is better?
PML outcomes: asymptomatic vs symptomatic
Dong-Si T, et al. AAN 2013; P04.271.
MSers with PML diagnosed when asymptomatic do better than MSers who are diagnosed when symptomatic.
PML outcomes: asymptomatic vs symptomatic
Dong-Si T, et al. AAN 2013; P04.271.
MSers with PML diagnosed when asymptomatic do better than MSers who are diagnosed when symptomatic.
You will notice in the previous slides that asymptomatic PML is detected with MRI monitoring.
At the moment the recommendation, by PML experts, is that if
you are at high risk of developing PML you need to have an MRI every 3 months.
You may need to discuss this issue with your neurologist.
How do you know if you have, or are developing, PML?
The simple answer is vigilance, you
need to watch out for new symptoms suggestive of PML.
PML Presenting Symptoms
How do you treat PML?
There is no anti-viral treatments for PML. At the moment we simply wash out the natalizumab with a technique called plasma exchange. Plasma exchange removes the natalizumab and allows your immune
cells to re-enter the brain to fight the infection.
Plasma Exchange
What happens to PML once natalizumab is out of your body?
Your immune cells are capable or re-entering the brain to fight the PML. This causes an encephalitis that we call IRIS (immune reconstitution inflammatory syndrome). The IRIS in itself can
cause a neurological deterioration and may need to be treated with steroids.
IRIS Presents as Clinical Decline
Are there any predictors of a poor outcome from PML?
Factors that may affect survival in Msers with PML
What are the risks of MS?
Apologies, I am not trying to be patronising, but you may not need to be reminded of some
facts to help you weigh-up the risks and benefits of natalizumab therapy.
Lifespan in MSers Is Shortened by 8 to 12 Years
• Survival probability of Norwegian MSers with relapsing-remitting MS (RRMS) (Hordaland County, Western Norway, 1953–2003)
38
RRMS % s
urv
ival
MS=multiple sclerosis; CI=confidence interval.
Population-Based MS Mortality Studies
First Author
Population
and Time Period
Size
of Cohort
Standardized
Mortality Ratio Additional Survival Measures
GryttenTorkildsen
Mult Scler 2008
Western Norway
1953–2003 878
2.66
(95% CI: 2.31–3.06)
• Median survival time from onset: 41 years MS vs 49 years general population
− 8 years life lost in MS
Smestad
Mult Scler 2009
Oslo
1940–1980 368
2.47
(95% CI: 2.09–2.90)
• Reduction of median life expectancy vs general population
− Female: 11.2 years
− Male: 7.4 years
Bronnum-Hansen
Brain 2004
Danish MS Registry
1949–1996 9881
2.89
(95% CI: 2.81±2.98)
• Median survival time (from disease onset) vs general population:
− ≈10 years life lost in MS
Hirst
JNNP 2008
South Wales
1985–2006 373
2.79
(95% CI: 2.44 to 3.18)
• Median age of death: 63.1 years MS vs 70.6 years general population
− 7.5 years life lost in MS
Sumelahti
Mult Scler 2010
Finland
1964–1993 1595
2.8
(95% CI: 2.6–3.1)
• Survival decreases with disease progression
− SMR, 2–9.9 years after diagnosis: 2.4
− SMR, ≥10 years after diagnosis: 3.1
Wallin
Brain 2000
USA
1956–1996 2489
2.18
(Not specified)
• Healthy soldier effect speculated to have a
favorable effect on survival
Leray
Mult Scler 2007
West France
1976–2004 1879
1.3
(95% CI: 1.01–1.7)
• Mean follow-up duration=12.7 years from
clinical onset; may be basing estimate on
relatively immature dataset
SMR=standardized mortality ratio.
The survival disadvantage in MS is greater than in some other chronic diseases
Standardized Mortality Ratios in Chronic Diseases
Disease SMR (RANGE)
Cardiovascular disease1* 1.34 (1.23–1.44)
Ischemic stroke2† 1.75(1.38–2.19)
Early breast cancer3 2.0 (1.6–2.7)
Crohn’s disease4 2.8
MS5 2.8 (2.6–3.1)
MS (2–9.9 years after diagnosis)5 2.4 (1.9–2.9)
MS (≥10 years after diagnosis)5 3.1 (2.8–3.4)
Parkinson’s disease6 3.66 (3.37–3.95)
Type 2 diabetes1 4.47 (3.91–5.10)
*In patients with type 2 diabetes; †in patients with valvular heart disease in Olmsted County, Minnesota.
1. De Marco R et al Diabetes Care. 1999;22:756-761; 2. Petty GW et al. Mayo Clin Proc. 2005;80:1001-1008; 3. Hooning MJ et al. Int J Radiat Oncol Biol Phys.
2006;64:1081-1091; 4. South East England Public Health Observatory, Mortality trends. 2006; 5. Sumelahti ML et al. Mult Scler. 2010;16:1437-1442;
6. Hristova DR. Folia Medica. 2009;51:40-45.
Uti
lity
EDSS Status
EDSS and utility* show a significant
inverse relationship1,†
*Utility measures are derived from EQ-5D using the EuroQoL instrument; †error bars depict 95% confidence intervals. Half points on
EDSS are not shown on graph axis, except at EDSS 6.5.
EDSS=Expanded Disability Status Scale; WHO=World Health Organization; MSIF=Multiple Sclerosis International Federation.
1. Adapted from Orme M et al. Value In Health. 2007;10:54-60. 2. WHO and MSIF.
http://apps.who.int/bookorders/anglais/detart1.jsp?sesslan=1&codlan=1 &codcol=15&codcch=747. Accessed October 6, 2010.
3. Confavreaux, Compston. McAlpine’s multiple Sclerosis. 4th edn. Churchill Livingstone Elsevier; 2006. p. 183–272. 4. Compston A,
Coles A. Lancet 2008; 372:1502-1517.
• MS is one of the most common
causes of neurological disability
in young adults2
• Natural history studies indicate
that it takes a median time of 8,
20, and 30 years to reach the
irreversible disability levels of
EDSS 4, 6, and 7, respectively3
The effect of MS on Quality of Life
The Effects of MS on Unemployment
42
Pfleger CC et al. Mult Scler. 2010;16:121-126.
The Effects of MS on Divorce and Separation
Pfleger CC et al. Mult Scler. 2010;16:878-882
CIS Patients
n = 40
Impact of MS: Cognitive Functioning in the CIS Stage
Cognitive Test Performance in an Exploratory Study*
44
57%
7%
-20%
0%
20%
40%
60%
*40 untreated CIS patients who fulfilled the McDonald dissemination in space criterion compared to a cohort of 30 matched healthy
controls. An extensive battery of neuropsychological tests was used to explore verbal and non-verbal memory, attention, concentration,
speed of information processing, language and abstract reasoning. Cognitive impairment was present when at least 2 different
neuropsychological tests were failed.
CIS=clinically isolated syndrome.
Feuillet l et al. Mult Scler. 2007;13:3124-127.
Healthy Controls
n = 30
p < 0.0001
Deficits were found mainly in
memory, speed of information
processing, attention, and
executive functioning
Pati
en
ts f
ailin
g
≥2 c
og
nit
ive t
ests
Consequences of increasing EDSS scores: loss of employment
The proportion of patients employed or on long-term sick leave is calculated as a percentage of patients aged 65 or younger.
Kobelt G et al. J Neurol Neurosurg Psychiatry. 2006;77:918-926.
Austria
Belgium
Germany
Italy
Netherlands
Spain
Sweden
Switzerland
United Kingdom
Work Capacity by Disability Level P
rop
ort
ion
of
Pa
tie
nts
≤6
5 Y
ea
rs O
ld
Wo
rkin
g (
%)
0
10
20
30
40
50
60
70
80
90
0.0/1.0 2.0 3.0
EDSS Score
Msers’ QoL decreases tremendously dependent on the EDSS score
Mean utility
Utilities at early
disease
Utility at severe disease
Austria 0.55 0.90 0.05
Belgium 0.51 0.85 0.06
Germany 0.62 0.86 0.10
Italy 0.53 0.80 0.06
Netherlands 0.61 0.85 0.05
Spain 0.55 0.87 0.08
Sweden 0.546 0.825 0.047
Switzerland 0.59 0.89 0.1
UK 0.51 0.92 0.18
EQ-5D was used to calculate utilities: Utility is a measure of people's well-being or preferences for outcomes.
Mean utilities and EDSS in Germany 1= perfect health; 0 = worst health/dead
Source: based on G. Kobelt et al.: The European Journal of Health Economics, Volume 7; suppl. 2006
0,45
0,55
0,60
0,75
0,80
0,65
0,70
0,50
0,72 - mean utility of patients with rheumatoid arthritis
at stage 1 (Kobelt G. et al. 1999)
0,00 - Worst possible status
1,00 - Best possible health status
0,55 - mean utility of MSers (Kobelt G. et al. 2001)
0,48 - mean utility of severe haemophilia patients with inhibitors (Ekert H. et al. 2001)
0,82 - mean utility of aging patients with osteoporosis,
no fracture (Oleksik A et al. 2000)
0,58 - mean utility of patients with Parkinson’s Disease (Siderowf A. et al. 2002)
Utilities make diseases comparable
What are the benefits of natalizumab treatment?
Apologies, you may not need to be
reminded of natalizumab’s effectiveness.
AFFIRM: Reduction in ARR and Risk of
Disability Progression with Natalizumab
Week
Polman CH et al. N Engl J Med. 2006;354:899-910; Polman CH et al. Presented at AAN; April 9–16, 2005; Miami, FL.
Placebo (n=315)
Natalizumab (n=627)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
AR
R (
95%
CI)
P<0.001
0.73
0.23
Years 0–2
68% reduction in
ARR vs placebo
Number of Msers at Risk
Placebo
Natalizumab
315 296 283 264 248 240 229 216 208 200
627 601 582 567 546 525 517 503 490 478
199
473
3-Month Sustained Disability Progression
29%
17%
0
0.1
0.2
0.3
0.4
0 12 24 36 48 60 72 84 96 108 120
Pro
po
rtio
n w
ith
Su
sta
ined
Pro
gre
ssio
n
HR=0.58
P<0.001
42%
Placebo
Natalizumab
AFFIRM: MSers with Highly Active MS (>2 Relapses and Gd+ Lesions at Baseline)
ARR Reduction*
Reduction in Risk of 12-Week
(3-Month) Sustained EDSS Progression†
Red
ucti
on
(%
)
53
(P=0.029)
81
(P<0.001)
*Natalizumab ARR reduction vs placebo: 0.28 vs 1.46; †EDSS progression calculated from 1–HR, 1–0.47 for natalizumab.
Tysabri [summary of product characteristics]; Hutchinson M et al. J Neurol. 2009;254:405-415 & 1035-1037.
Red
ucti
on
(%
)
AFFIRM: Natalizumab Increases the Proportion of MSers Free of Clinical and MRI Disease Activity
MSers with No
Disease Activity over 2 Years
Placebo (n=304) 7% P<0.0001
Natalizumab (n=600) 37%
P<0.0001, natalizumab vs placebo, for all individual and combined disease measures.
MRI=magnetic resonance imaging; Gd+=gadolinium-enhancing.
Havrdová E et al. Lancet Neurol. 2009;8:254-260.
64%
Free of Clinical
Disease Activity
58%
Free of MRI
Disease Activity
58%
Free of
T2 Lesions
95%
Free of
Gd+ Lesions
84%
Free of
Progression
37%
Free of
Disease
Activity
71%
Free of
Relapses
7.2
15.4 13.0
36.7
46.7
68.4
0
10
20
30
40
50
60
70
80
Year 0-2 Year 0-1 Year 1-2
Patients
without
com
bin
ed
dis
ease a
ctivity (
%)
Placebo Natalizumab
AFFIRM: Proportion of MSers Without Disease
Activity* Increases from Year 1 to Year 2
*Absence of disease activity on the composite of clinical and radiological measures was defined as no relapse, no progression
of disability (sustained for 12 weeks), no gadolinium-enhancing lesions, and no new or enlarging T2-hyperintense lesions.
Harvrdova E at al. Lancet Neurol. 2009;8:254-260.
p<0.0001 for all comparisons
n=304 n=600 n=305 n=604 n=284 n=544
AFFIRM: Natalizumab Provided More MSers with Freedom from Disease Activity
Pati
en
ts F
ree o
f
Dis
ease
Acti
vit
y (
%)
n=59
Overall Population
P<0.0001
Highly Active MSers*
P<0.0001
7.2
1.7
36.7
27.4
0
10
20
30
40
50 Placebo
Natalizumab
n=304 n=600 n=146
Post hoc analysis of AFFIRM; natalizumab vs placebo for both overall population and patients with highly active disease.
*MSers with ≥2 relapses in prior year and ≥1 Gd+ lesion at baseline.
Havrdová E et al. Lancet Neurol. 2009;8:254-260.
Havrdova et al., Lancet Neurol. 2009, 8:254-60.
*Highly active disease was defined as at least two relapses in the year before study entry and at least one gadolinium-enhancing lesion at
study entry; non-highly active disease was defined as fewer than two relapses or no lesions at study entry.
AFFIRM: Freedom from Disease Activity in
Highly Active and Non-highly Active MSers
3% 4%
34%
65%
0%
20%
40%
60%
80%
100%
Year 1 Year 2
n=59 n=56 n=137 n=146
Pa
tie
nts
Dis
ea
se
Ac
tivit
y F
ree
(%
)
18%15%
51%
70%
0%
20%
40%
60%
80%
100%
Year 1 Year 2
P<0.0001
P<0.0001
P<0.0001
Placebo
Natalizumab
Highly active MSers* Non-highly active MSers *
P<0.0001
n=246 n=228 n=407 n=458 P
ati
en
ts D
ise
as
e A
cti
vit
y F
ree
(%
)
AFFIRM: Brain Parenchymal Fraction (BPF)
*Change in BPF of natalizumab group at year 1 probably reflects “pseudoatrophy” from reduced edema/inflammation.
Miller DH. Neurology. 2007;68:1390-1401.
Placebo (n=315)
Natalizumab (n=627)
−1.0
−0.8
−0.6
−0.4
−0.2
0
Mean
Perc
en
tag
e C
han
ge i
n B
PF
−0.82
−0.80
P=0.822
vs placebo
Time (Years) 2 0 1
*
−0.39
−0.56
P=0.002
vs placebo
55
Real Life: Escalation to Natalizumab is More
Effective Than Switching Among GA/IFN
% Patients
2nd year*
Escalate to natalizumab n=106
Switch between GA/IFN n=161
Data from a post-marketing, prospective, observational study in 285 RRMS patients who failed treatment with IFNβ or GA therapy. After failure of IFNβ
or GA therapy patients were switched to either natalizumab (n=106) or IFNβ/GA (n=161); EDSS=Expanded Disability Status Scale; GA=glatiramer
acetate; IFNβ=interferon beta; MRI=magnetic resonance imaging; MS=multiple sclerosis; RRMS=relapsing remitting MS
*At 12 months there were no differences 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(1):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 72
59
No relapses
p<0.0045
Natalizumab (TOP) Reduces Risk of Relapse Compared to IFN and GA ( )
• Natalizumab treatment in TOP was associated with a significant reduction in risk of relapse, compared with a prospective outcome registry of RRMS patients experiencing at least one relapse on treatment IFN-GA (MS-COMET).
• In unmatched, unadjusted sample (left panel), risk of relapse was 1.68-fold (95% CI, 1.10–2.19-fold) greater among MSCOMET compared to TOP MS patients despite a higher disease activity/severity profile in the TOP cohort at baseline.
• In propensity matched sample (right panel), relapse risk in MSCOMET patients was increased 2.73-fold (95% CI, 2.10–3.55-fold).
0.00
0.25
0.50
0.75
1.00
Pro
port
ion n
ot re
lap
sed
0 .5 1
Years since baseline
MSCOMET TOP
Unmatched, unadjusted
0.00
0.25
0.50
0.75
1.00
Pro
port
ion n
ot re
lap
sed
0 .5 1
Years since baseline
MSCOMET TOP
Propensity matched
Spelman T et al. Presented at ECTRIMS; October 10-13, 2012, New Orleans, LA. P303.
IFN=interferon; GA=glatiramer acetate.
0.0
0.5
1.0
1.5
2.0
2.5
3.0
AFFIRM TOP Danish Switzerland/Germany
Switzerland France Belgium Italy TYSEDMUS
AR
R
Pre-Natalizumab
Natalizumab
Natalizumab: Low ARR Across Registries and Independent Studies
*As of June 1, 2011, 3484 patients were enrolled. Overall in TOP, patients received a mean of 14.6 (±11.21) natalizumab infusions; 57% (n=1981)
of patients analyzed were followed for 1 year; 22% (n=761) were followed for 2 years; 7% (n=230) were followed for 3 years; †median. y=years;
mo=months; wk=weeks. 1. Polman C et al. N Engl J Med. 2006;354:899-910; 2. Hotermans C et al. Presented at WCN; November 12–17, 2011;
Marrakesh, Morocco; 3. Oturai A et al. Eur J Neurol. 2009;16:420-423; 4. Putzki N et al. Eur J Neurol. 2010;17:31-37; 5. Putzki N et al. Eur Neurol.
2010;63:101-106; 6. Outteryck O et al. J Neurol. 2010;257:207-211; 7. Belachew S et al. Eur J Neurol. 2011;18:240-245; 8. Sangalli F et al. Neurol Sci.
2010;31(suppl 3):299-302; 9. Vukusic S et al. Presented at ECTRIMS; October 19–22, 2011; Amsterdam, The Netherlands; P970.
n= 627 3484 234 97 85 384 45 285 456
Mean follow-up 2 y 14.6 mo* 11.3 mo† 1 y 1 y 1 y 44 wk 2 y 3 y
1 2 3
4
5 6 7 8 9
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
Switzerland/Germany
Switzerland France Belgium Sweden TYSEDMUS
EDSS
Sco
re (
me
an)
Pre-NatalizumabNatalizumab
Registries and Independent Studies: Stable EDSS Scores
N 97 85 384 45 901† 2855 Mean follow-up 1 y 1 y 1 y 44 wk 2 y 3 y
EDSS=Expanded Disability Status Scale; RRMS=relapsing-remitting multiple sclerosis.
1. Putzki N et al. Eur J Neurol. 2010;17:31-37; 2rol. 2010;63:101-106; 3. Outteryck O et al. J Neurol. 2010;257:207-211;
4. Belachew S et al. Eur J Neurol. 2011;18:240-245; 5. Holmen C et al. Mult Scler. 2011;17:708-719; 6. Confavreux C et al. Presented at
EMA; May 3–6, 2011; London, England.
1
2 3 4 5 6
3.5 3.3 3.3 3.3
3.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
Baseline Year 1 Year 2 Year 3 Year 4
Me
an
ED
SS
Sc
ore
TOP: Mean EDSS Scores by Natalizumab Treatment Duration
*Sustained (6-month) improvement was defined as a ≥1.0-point decrease in EDSS score from baseline; †sustained (6-month) progression was defined as a ≥1.0-point increase in EDSS score from baseline. EDSS=Expanded Disability Status Scale.
Pellegrini F et al. Presented at the 28th Congress of ECTRIMS, Lyon, France, Oct 10–13, 2012. P519.
n=4402 n=1839 n=1043 n=218 n=461
TOP: Clinically Disease Activity Free
89
65 59
0
20
40
60
80
100
Sustained progressionfree
Relapse free Clinical disease activity-free
Pro
po
rtio
n o
f p
atie
nts
(%
)
Sustained progression was defined as an increase of ≥1.0 point in the EDSS score sustained for 6 months; clinical disease
activity-free was defined as no relapses and no 24-week confirmed EDSS progression.
Pellegrini F et al. Presented at the 28th Congress of ECTRIMS, Lyon, France, Oct 10–13, 2012. P519.
61
Registries and Independent Studies and AFFIRM: % Disease Activity Free on Natalizumab
Over 90% of AFFIRM patients were treatment naïve, and the remainder had been on a previous therapy for no more than 6
months, but not treated in the 6 months prior to enrolment. In contrast, approx 90% of patients in registries and independent
studies were switched to natalizumab after experiencing disease activity on a prior therapy.
*Relapse-free (freedom from progression not reported); EDSS worsening not determined in this analysis.
1. Belachew S et al. Eur J Neurol. 2011;18:240-245; 2. Putzki N et al. Eur J Neurol. 2010;17:31-37; 3. Fernandez O et al. J Neurol.
2012 Jan 31 [Epub ahead of print]; 4. Sangalli F et al. Neurol Sci. 2010;31(suppl 3):299-302; 5. Outteryck O et al. Presented at
ECTRIMS; October, 2011; Amsterdam, Netherlands; 6. Havrdová E et al. Lancet Neurol. 2009;8:254-260.
Cohort
Belgium1
(N=45)
Germany/
Switzerland2
(N=97)
Spain3
(N=825)
Italian4
(N=285)
French5
(N=603)
AFFIRM6
(N=942)
Follow-up 44 weeks 1 year 1 years 2 years 2 year 2 years
Freedom from
clinical disease
activity, %
82 63.9 -- 78* 45 64
Freedom from
radiologic disease
activity, %
71 64.9 94.6 69 68 58
Composite clinical
and radiological
freedom from
disease activity, %
62 48.5 63 63 49 37
62
Factors Predicting the Ultimate Goal of Disease Activity Silencing
Havrdova E. et al. ECTRIMS Meeting poster 905, Gothenburg, Sweden 2010.
Havrdova E. et al. Neurology 2010 ;74:S3-7.
Variables Associated with Overall Freedom from Disease Activity (No Clinical or MRI Activity) over 2 Years in a Multivariate Logistic Regression Analysis
AFFIRM
Natalizumab-treated patients with fewer relapses, fewer MRI lesions, and lower EDSS scores at therapy initiation and who did not develop persistent anti-natalizumab antibodies were more likely to achieve freedom from disease activity over the course of the 2-year AFFIRM study.
Factors Predicting the Ultimate Goal of Disease Activity Silencing
Prosperini L et al. J Neurol Sci. 2012;323:104-112.
Real-life
Stepwise logistic regression analysis showing the predictive variables for having a “full” response to natalizumab (i.e. no clinical and MRI activity) during a 24-month follow-up period.
Natalizumab appears to be more prone to induce a clinical and MRI remission of MS if started in patients with less aggressive disease (i.e. few relapses and mild disability)
TOP: Earlier Natalizumab Treatment Favors ARR Outcomes
P value was from the negative binomial model adjusted for gender, baseline relapse status (0 or 1 vs >1 relapse), EDSS score
(0.0–2.0, 2.5–4.0, and 4.5–9.5), disease duration (<8 vs ≥8 years), prior DMT use (0, 1, or >1), and treatment duration (<3 vs ≥3 years).
n=1836 n=2107
Baseline EDSS Score
Po
stb
aselin
e
Mean
An
nu
ali
zed
Rela
pse R
ate
P=0.0003
Number of Prior DMTs
n=366 n=1744 n=1866
P<0.0001
Kappos L et al. Presented at ENS; June 9–12, 2012; Prague, Czech Republic. O261.
TOP: Subgroup Analyses
TOP: Overall Stabilization of EDSS Scores in Patients with Either a High or Low Starting EDSS
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)
Natalizumab should be used according to the SmPC
Natalizumab Effect on Neurofilament Light Levels in Cerebrospinal Fluid of MSers
NFL = Neurofilament light.
Gunnarsson M et al. Ann Neurol. 2011;69:83–89.
Balancing Benefits and Risks of Treatment
vs. Risk of Poorly Controlled MS
Tysabri® (natalizumab) [summary of product characteristics]. Dublin, Ireland: Biogen Idec; 2011.
http://www.medicines.org.uk/EMC/medicine/18447/SPC/TYSABRI+300+mg+concentrate+for+solution+for+infusion/. Accessed April 24, 2012.
Natalizumab Risks
• PML
• Other CNS opportunistic infections
• Treatment during pregnancy if clinically required
• Hypersensitivity
• Other AEs per labelling
• Unknown long-term safety profile
Benefits
• Relapse rate
• Disability progression
• Freedom from disease activity
• Quality of life
• Brain atrophy (neuroprotective)
• Functional improvements
• Consistent effects in long-term real-life clinical use
• Well-defined safety profile and ability to stratify risk
I hope you have found this slide deck informative. It is a work in progress and I will simplify the slides for next month. If
you have any queries please do not hesitate to ask them via the comments
section on the blog.
www.ms-res.org