Bates_EU Neurology 10/03/2010 10:07 Page 62
Multiple Sclerosis
Table 2: Real-life Findings from Clinical Use of Natalizumab in Patient Registries and Cohorts Around the World
Patient Registry/Cohort Reference n Baseline ARR, On-study ARR, % Relapse-free % Discontinuation
EDSS EDSS
Danish registry
46
234
a
2.53 (2.33–2.75) 0.68 (0.57–0.81) 63 15
4.0 (0–8) (median) N/A
Essen, Cologne, Erlangen, St Gallen cohort
47
97
b
2.3±0.6 0.17±0.1 80 8.2
3.6±0.8 (mean) 3.2±0.8 (mean)
Nord-Alsace cohort
48
384 2.19±1.23 0.59± 0.84
c
60
c
9.1
3.53±1.68 (mean) 3.02±1.73
c
(mean)
Tysabri
®
Observational Program (TOP) cohort
49
1,011 2.07±1.08
d
0.26 (0.22, 0.32)
d
N/A 10.6
f
3.8±1.7
e
3.6±1.8
e
(reduction: 0.2±0.97)
a. Proportion of patients with an EDSS 1.0-point progression 0.09, median observation period of 11.3 months (range 3–21.5); b. Mean treatment duration 19.3±6.1 months;
c. Based on 127 patients observed for at least 1 year; d. Based on 587 patients observed for at least 6 months; e. Based on 292 patients observed for at least 12 months;
f. Includes therapy discontinuation and study withdrawal. ARR = annualised relapse rate; EDSS = Expanded Disability Status Scale.
Figure 4: Natalizumab Progressive Multifocal were new or worsening neurological symptoms evolving over several
Leukoencephalopathy Incidence Estimates Based on
weeks, focal neurological signs and other symptoms, such as
Patients Exposed and Treatment Duration
hemiparesis, focal myoclonia, aphasia, retrochiasmal visual deficits
and changes in cognition, behaviour and personality.
3.0
2.80
2.5
MRI assessments of PML cases typically revealed non-enhancing
2.28 T
2
-hyperintense lesions in frontal, temporal, parietal or occipital
2.0
1.96 1.99
regions. Many of these lesions were unifocal, and gadolinium-
enhancing lesions were identified. Analyses using polymerase chain
1.5
reaction detected JC virus DNA in the cerebrospinal fluid of patients
1.29 1.28
1.0
1.00
1.09
1.05
with PML. However, in most patients titres were low (<500 copies/ml).
0.86
0.76
0.79 In PML not associated with natalizumab, new or worsening
0.63
Incidence per 1,000 patients 0.5
0.50 0.54
0.63
0.43
0.48
neurological signs or symptoms, changes in mental status, seizure or
0.29
0.20 fever were usually not associated with gadolinium-enhancing lesions.
38
0.0
0.08
Natalizumab was discontinued when the first signs or symptoms
Clinical trials
12 infusions 18 infusions 24 infusions 30 infusions 36 infusions
and/or MRI findings suggestive of PML were identified. The majority of
Post-marketing
≥ ≥ ≥ ≥ ≥
patients who developed PML in the post-marketing setting received
plasma exchange and/or immunoadsorption to accelerate removal of
Diamonds represent estimated incidence, bars represent confidence intervals.
Data updated 30 November 2009 based on 28 cases.
natalizumab from circulation.
38
Source: Hyde et al., 2009.
During recovery from PML, immune reconstitution recovery syndrome
Table 3: The Multiple Long-term Programmes for
(IRIS) is an expected condition. This appears universal in PML
Monitoring the Safety and Efficacy of Natalizumab in
Clinical Use
associated with natalizumab, unlike PML in AIDS, regardless of whether
natalizumab is removed rapidly or simply discontinued.
40
IRIS generally
occurred four weeks after stopping natalizumab treatment, but in some
Programme STRATA TOUCH TYGRIS TOP
Regulatory Yes (EU) Yes Yes Yes (EU)
cases it occurred earlier. Corticosteroids, sometimes multiple courses,
commitment
given early in the course of IRIS appeared to lead to improvement in
Interventional Yes No No No most patients. To date, most of the natalizumab-treated patients who
study (3b) developed PML have survived but exhibit varying levels of disability.
38
Mandatory No Yes No No
prescribing
A quantitative risk–benefit analysis demonstrated that the substantial
programme
benefits of natalizumab, particularly in patients with highly active
Observational No No Yes Yes
disease or those who do not respond to other DMTs, far outweigh the
programme
risk of PML.
44
At present, there are multiple long-term evaluation
Efficacy data Yes No No Yes
programmes in progress that are designed to further characterise the
collection
Safety data Yes Yes Yes Yes
long-term safety and efficacy of natalizumab (see Table 3). There are
collection
currently insufficient data on the efficacy and safety of natalizumab in
Number of 850 Unlimited 5,000 3,000
patients with progressive forms of MS to recommend the use of
patients natalizumab for primary or secondary progressive MS.
45
Duration 5 Unlimited 5 5
(years)
Discussion
STRATA = Safety of Tysabri Re-dosing And Treatment study; TOUCH = Tysabri Outreach: MS is a serious disease with devastating clinical and social
Unified Commitment to Health Prescribing Program; TYGRIS = Tysabri Global Observation
consequences for which there is a great need for more effective
Program in Safety observational cohort study; TOP = Tysabri Observational Program.
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