Bates_EU Neurology 10/03/2010 10:06 Page 59
Natalizumab (Tysabri
®
) – Re-defining Efficacy in Multiple Sclerosis
Table 1: Comparison of Efficacy of Two-year Clinical Trials of Current First-line
Disease-modifying Treatments in Multiple Sclerosis
Treatment Type n Dosage Annual Relapse Rate Disability Progression Reference
% Reduction p-value % Reduction p-value
IFNβ-1a 189 (560 total) 22µg SC 29 <0.005 23 <0.05 Galetta et al., 2002
21
3 times a week
IFNβ-1a 184 (560 total) 44µg SC 32 <0.005 30 <0.05 Galetta et al., 2002
21
3 times a week
IFNβ-1b 372 250µg SC 34 0.0001 29 NS IFNB, 1993
18
every other day
IFNβ-1a 301 30µg IM 32* 0.002 37 0.02 Jacobs et al., 1996
19
once a week
Glatiramer 251 20mg SC 29 0.007 12 NS Johnson et al., 1995
20
acetate daily
*Calculated for patients who completed at least 104 weeks on study. IFN = interferon; IM = intramuscular; SC = subcutaneous; NS = not significant.
expressed on endothelial cells and leukocytes. The current disease- Figure 1: Points Where Natalizumab Could Inhibit the
modifying treatments (DMTs) have multiple proposed mechanisms
Inflammatory Process in Multiple Sclerosis
of action, including a possible effect on the interaction of one
such adhesion molecule, α
4
β
1
integrin, with the ligand vascular cell
adhesion molecule 1 (VCAM-1). Some DMTs have been observed to
Circulation
1. Leukocyte migration
from blood to tissue
increase expression of VCAM-1 in active plaques in the brain and spinal
cord, which may bind activated T cells, preventing them from crossing
the blood–brain barrier.
14–16
The existing treatments include the
interferons beta IFNβ-1a (administered subcutaneously [SC], Rebif
®
or
Leukocyte
intramuscularly [IM], Avonex
®
) and IFNβ-1b (administered SC,
Betaferon
®
). The precise mode of action of glatiramer acetate, also
α
4
-integrin
known as copolymer 1 (Copaxone
®
), is unknown: it may act as an
Natalizumab
immunomodulator or as a decoy, given its structural similarity to myelin.
Blood–brain barrier VCAM-1
In clinical trials, all DMTs reduced the annualised relapse rate (ARR), but
Endothelial cells
only IFNβ-1a (IM and SC) significantly reduced disability progression as
determined by change in EDSS score compared with placebo
17–21
(see
Tissue
2. Leukocyte priming
and activation
Table 1). However, these treatments show only moderate efficacy and 3. Modulation of
Leukocyte
most patients still show disease progression. The majority (62–75%) of
leukocyte apoptosis
Parenchymal
patients relapse within two years, and 20–27% of patients worsen by ≥1
cell
point on EDSS within two years. Moreover, adherence to DMT treatment
Apoptosis
Natalizumab
is problematic, largely due to side effects, particularly injection-site
VCAM-1
reactions and influenza-like symptoms. A chart-based study in Ireland
Extracellular matrix
on 394 MS patients determined an overall IFNβ stopping rate of 28%
over five years.
22
The study also showed a significant difference between
VCAM = vascular cell adhesion molecule.
the IFNβ stopping rates for RRMS (14%) and SPMS (23%) after three years
(p=0.0003). Patients were shown to stop IFNβ due to side effects after a and the endothelial cell, thus disrupting the inflammatory cascade. It is
median of 13 months, and due to treatment failure after a median of 35 a humanised monoclonal antibody to α
4
β
1
-integrin derived from a
months (p=0.0004). Furthermore, many patients with MS have monoclonal antibody against human α
4
-integrin. Natalizumab has
breakthrough disease activity despite therapy with these agents, or are three putative modes of action (see Figure 1). It decreases leukocyte
unresponsive to treatment.
23
There is therefore a continuing and migration across the blood–brain barrier by blocking adhesion to
substantially unmet need for more effective treatments that limit endothelial cells and interaction with extracellular matrix (ECM)
relapses and disease progression within MS. proteins, e.g. fibronectin. It also limits leukocyte priming and activation
by blocking interaction with osteopontin and VCAM-1 expressed on
Natalizumab (Tysabri
®
) is a recently introduced recombinant humanised microglial cells and monocytes in the brain parenchyma, and
anti-α
4
-integrin antibody that is generally reserved for second-line use in modulates leukocyte apoptosis by blocking interaction of α
4
-integrin-
MS, although it can be used as a first-line agent in cases of rapidly expressing leukocytes with ECMs. After a 300mg intravenous
evolving severe RRMS.
24
The aim of this article is to review the infusion of natalizumab, the elimination half-life is six to nine days, but
broad spectrum of efficacy of natalizumab across traditional and α
4
-integrin receptors remain 80% saturated for approximately one
non-traditional outcomes from clinical trials and post-marketing studies. month; therefore, administration is by monthly infusion.
16
Mode of Action of Natalizumab Data from Clinical Trials Supporting
Natalizumab is the first α
4
-integrin antagonist in the class of selective Natalizumab Use in Multiple Sclerosis
adhesion molecule (SAM) inhibitors. It binds to α
4
-integrin on the Two key large phase III clinical studies evaluating the clinical use of
surface of activated T cells, preventing adhesion between the T cell natalizumab involved a total of 2,113 patients and 3,804 patient-years
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