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Managed Care &Healthcare Communications, LLC
Mltipl sclrosis (MS) is a ctral rvos systm
(CnS) disas caractrizd by imm activatio
wit dama to t CnS compots icldi
myli, axos, olioddrocyts, ad ros.1
T cors o MS is qit variabl. MS ca ra rom vry mild
to vry svr. T most commo cors o t disas i most
tratd patits ivolvs a rlapsi pattr, wic latr trasi-
tios to a slow, worsi prorssiv pattr i most tratdpatits.2 I iitial ost is prorssiv, disability will typically occr
mor rapidly ad wit ratr svrity.3
T ct o MS o lispa is also qit troos. T
priod rom symptom ost to dat as b stimatd to ra
rom 20 to 45 yars.4 ultimatly, t avra prso wit tratd
MS may b xpctd to los 5 to 10 yars o tir atral lispa.
Ost o MS rally occrs i yo ad arly middl-ad adlts,
wit pak ost btw t as o 20 ad 40 yars.5,6 Wom ar
at last 2 tims mor likly ta m to dvlop MS, ad tis trd
is icrasi.7
Pathophysiology of MS
MS is a croic disas distiisd by wavs o activity tat
dama t CnS. Disas activity is vidt o a macroscopic lvl
(i, dtctio o MS lsios si matic rsoac imai
[MRI]) ad a clllar lvl. T procss by wic MS lsios orm
is complx ad iclds mltipl actors (, cytokis, cmokis,
ad immoloblis). Tr is ocal brac o t blood-brai bar-
rir (BBB), ptratio o systmic imm clls, ad local imm
activatio ad rsposs ladi to dama o t CnS tiss.8,9
Microlial ad olioddrocyt cas may occr tat prim tis
imm rspos.
Prmability o t BBB allows mor T clls to tr ito
t CnS.9 Ts T clls prodc cytokis wic activat
macropaswit blood clls tat cosm otr clls tat
ty prciv to b ivasiv or arml. Rsidt macropas
i t brai ad spial cordcalld microlia cllsar activatd
ad attack t myli sat.10 T myli sat islats rv
ibrs (axos) ad spds p t implss tat travl alo ts
axos. As t microlia clls attack t myli sat, it radally
braks dow i a procss kow as dmyliatio. Aras wr
t myli sat ad srrodi tiss av b damad orm
T Rol o natalizmab i tTratmt o Mltipl Sclrosis
Patricia K. Coyle, MD
n report n
Abstract
Natalizumab is an 4-integrin antagonist,
the first in its class for the treatment of
multiple sclerosis (MS). Although multiple
mechanisms have been proposed for the
efficacy of natalizumab in MS, the most
likely explanation is that it interferes withthe migration of immune cells into the
central nervous system. It does this by
binding to the 4
subunit of4
1-integrin
and preventing leukocyte adhesion to
endothelial vascular cell adhesion mol-
ecule-1. The efficacy of natalizumab in
relapsing-remitting MS has been demon-
strated in several double-blind, placebo-
controlled trials. Natalizumab has been
shown to slow the progression of disability
in relapsing-remitting MS significantly bet-
ter than placebo, and to reduce the number
of new and enlarging T2 hyperintense andgadolinium-enhanced magnetic resonance
imaging lesions. In a post hoc analysis,
the proportion of patients with relapsing-
remitting MS free of disease activity was
significantly greater with natalizumab
compared with placebo. Due to the rare
risk of progressive multifocal leukoenceph-
alopathy as a complication, natalizumab
is primarily recommended in patients who
fail, or cannot tolerate, treatment with inter-
feron (IFN) beta or glatiramer acetate (GA).
Stratification of those patients most likely
to benefit from natalizumab treatmentsuch as those with highly active disease,
severe disease, or extensive functional loss,
or those who have failed or cannot tolerate
IFN beta or GA therapywould help define
natalizumabs appropriate place in therapy.
(Am J Manag Care. 2010;16:S164-S170)
For author inormation and disclosures, see end o text.
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lsios. Ts lsios ca b visalizd si MRI. Wil
rmyliatio procsss ar activatd to rpair t dama
to t myli sat, i MS, tis procss is iadqat.9 I
additio to t radal dmyliatio st dscribd, tr
is rodratio (dama to axos ad ros), wit
cosqt mrt symptoms.
MS Lesions and Detection Using MRI
MRI is sd to visaliz ad dtrmi t caractristics
o MS lsios. T1-witd imai ad T2-witd ima-
i ar t most commo tciqs mployd to assss MS
lsios. Scarrd lsios ar vidt as wit, brit (i, ypr-
its) aras o T2 imas.11,12 T1 imas idtiy aras
wr rv ibrs av did; ts aras ar lss ds (i,
ypoits) ad ar commoly rrrd to as black ols.
gadoliim is sd as a cotrast at to idtiy aras o
activ disas; it will lak ito t brai tiss w tr
ar braks i t BBB.12 Ts aras will b yprits
o T1-witd imas, ad ar rrrd to as adoliim-
aci lsios.
Role of 4-integrin Antagonism in the
Treatment of MS
Alto t xact mcaism o actio o atali-
zmab i MS is kow, svral xplaatios av b
sstd. nw lsio dvlopmt ollows iiltratio o
activatd lympocyts tro t BBB, wic rqirs t
adsio o lympocyts to vasclar dotlial clls.9 Tis
procss ivolvs bidi o vasclar cll adsio molcl
(VCAM)-1 to 4
1-itri locatd o t lympocyts,
wic acilitats lympocytic ptratio o t BBB.13 It is
rally blivd tat t primary mcaistic xplaatio
or t icacy o atalizmab is tat it itrrs wit t
miratio o imm clls ito t CnS by bidi to t 4
sbit o4
1-itri, trby prvti lkocyt ad-
sio to dotlial VCAM-1.
A mri vrsio o atalizmab, An100226m, as b
sow to av a powrl limiti ct o lkocyt iil-
tratio ito t CnS o ia pis i a prcliical modl o
MS, xprimtal allric cpalomylitis (eAe).14 T
rapid clarac o lkocyts rom t CnS was associatd
wit a rdctio i disas prorssio ad a sbstatial
dcras i t icidc o dmyliatio. Similar rslts
av b obsrvd i stdis o eAe i rats.15
Svral otr cts o atalizmab av b ord as
xplaatios or its icacy i MS. O sc ct rlats
to t rol o ibrocti, a compot o t xtraclllar
matrix to wic 4
1-itri bids i t cors o mirat-
i to ilammatory sits as part o t imm rspos.
16
By
bidi to ibrocti, atalizmab itrrpts 4
1-itri
bidi, trby rdci t ilammatory rspos.17
Similarly, a rdctio i t ilammatory rspos appars
to rslt rom t bidi o atalizmab to ostopoti,
a proti ivolvd i dotlial cll ad lkocyt ad-
sio.17,18 ially, it as b sstd tat t cliical i-cacy o atalizmab i MS may b d to its ability to idc
apoptosis i T clls.19
Clinical Efficacy of Natalizumab
T cliical icacy o atalizmab was stablisd i
a dobl-blid, placbo-cotrolld trial: t natalizmab
Saty ad eicacy i Rlapsi-Rmitti Mltipl Sclrosis
stdy, kow as AIRM.20 AIRM was a 2-yar trial co-
dctd i 99 cliical ctrs i nort Amrica, erop, nw
Zalad, ad Astralia. A total o 942 patits btw t
as o 18 ad 50 yars (ma a, 36 yars), wit expadd
Disability Stats Scal (eDSS) scors rai rom 0 to 6
(ma scor, 2.3), wr radomizd i a 2:1 ratio to rciv
itr atalizmab 300 m ( = 627) or placbo ( = 315)
itravosly vry 4 wks.20 Patits wr valatd vry
12 wks.
T stdy dsi o AIRM icldd primary ad sc-
odary d poits at yars 1 ad 2. At yar 1, t primary
d poit was cliical rlaps rat, ad t scodary d
poits wr: (1) mbr o w or lari MRI-dtctd
yprits T2 lsios, (2) mbr o adoliim-acd
MRI lsios, ad (3) proportio o patits wo wr rlaps-
r.20 At yar 2, t primary d poit was t cmlativ
probability o sstaid disability prorssio ovr a 12-wk
priod. Disability prorssio was did as a icras o at
last 1.0 o t eDSS amo patits wit a basli eDSS
scor o at last 1.0. (Patits wit a basli eDSS scor o
0 wr did as xprici disability prorssio i tir
eDSS scor icrasd by at last 1.5.) At yar 2, scod-
ary d poits wr: (1) cliical rlaps rat, (2) volm
o T2-witd lsios, (3) mbr o w ypoits T1
lsios, ad (4) disability prorssio as masrd by t
Mltipl Sclrosis ctioal Composit (MSC).
natalizmab was siicatly mor ctiv ta pla-
cbo. At yar 1, 77% o patits iv atalizmab wr
rlaps r compard wit 56% o tos iv placbo; at
yar 2, t proportios wr 67% ad 41%, rspctivlya
rdctio o 59% ovr 2 yars (P
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placbo (0.23 vs 0.73, rspctivly; P
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(9); (4) prsc o adoliim-aci
lsios (0, >1); (5) a (40 yars); (6) ad
sx.22 Compard wit placbo, atalizmab was as-
sociatd wit a siicat rdctio i t risk o
disability prorssio i most sbrops, wit t
xcptio o t ollowi: patits wit 2 rlapssprior to t start o t stdy, tos wit a basli
eDSS scor o mor ta 3.5 (37 iv placbo, 79
iv atalizmab), patits wit lss ta 9 T2
lsios (15 iv placbo, 29 iv atalizmab),
mals, ad tos 40 yars or oldr.22 T aalizd
rlaps rat was lowr wit atalizmab trapy i
vry sbrop ad aild to mt statistical sii-
cac oly i t small sbrop o patits wit
wr ta 9 T2 lsios at basli. A raso or
tis mit b t small mbr o patits i tis
sbrop (52 iv placbo, 67 iv atalizmab).
htciso t al also codctd a post oc
aalysis o otcoms i patits wit ily activ
disas, dd as at last 2 rlapss dri t yar prior
to stdy try ad at last 1 adoliim-aci lsio
at stdy try.22 Ovr t cors o t 2-yar stdy, t c-
mlativ probability o sstaid disability prorssio or
12 wks was 29% wit placbo compard wit 14% wit
atalizmab, rprsti a 53% rdctio i risk (P
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n Table. Adverse Events Occurring in the AFFIRM Trial
Adverse Reactions (Preferred Term)
Tysabri (N = 627)Percentage
Placebo (N = 312)Percentage
General
Headache 38 33
Fatigue 27 21Arthralgia 19 14
Chest discomort 5 3
Acute hypersensitivity reactionsa 4
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i AIRM xpricd som dr o brai atropy at yar
1, bt at t d o 2 yars, brai atropy was siicatly
lss amo patits iv atalizmab compard wit tos
rcivi placbo.12
Tak totr, ts data corm t cacy o ata-
lizmab i rlapsi-rmitti MS basd o bot cliicalad radioloic critria. T AIRM data ar otworty
bcas across cliical masrmts, icldi rlaps
rat, disability prorssio, ad proportio o patits wo
wr rlaps-r, patits iv atalizmab cosisttly
acivd siicatly bttr rslts ta tos iv plac-
bo. T MRI data wr similarly rmarkabl, as atalizmab
was cosisttly associatd wit a siicat rdctio i
t mbr o adoliim-aci ad T2 lsios. O
itrst is tat t stdy dsi o AIRM did ot allow
cormatio o disability prorssio witi 4 wks o ii-
tiatio o a rlaps, trby costitti a ir trsold
or t acivmt o cacy ta tat o otr cliical
trials.28-31
Safety of Natalizumab in AFFIRM
Saty rslts rom AIRM wr similar btw ata-
lizmab ad placbo. narly all patits i bot rops x-
pricd som typ o advrs vt (Ae); owvr, oly
ati (atalizmab 27% vs placbo 21%; P = .048) ad al-
lric ractio (atalizmab 9% vs placbo 4%; P = .012)
wr siicatly dirt.20 T icidc o srios Aes
was similar btw atalizmab ad placbo (19% vs 24%,
rspctivly; P = .06).20 T tabl provids a ll list o Aes
occrri i t AIRM trial. T most commo srios
Ae was rlapsi MS (6% wit atalizmab, 13% wit pla-
cbo; P
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Address correspondence to: Patricia K. Coyl, MD, Dpartmt onroloy, hSC T-12 20, Stat uivrsity o nw York, Stoy Brook, nY
11794-8121. e-mail: [email protected].
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