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S164 n www.amc.com n june 2010

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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VOL. 16, nO. 6 n The AMeRICAn jOuRnAL O MAnAgeD CARe n S165

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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