J Neurol (2007) 254:1473–1490DOI 10.1007/s00415-007-0684-7 REVIEW
Christoph KleinschnitzSven G. MeuthOlaf StüveBernd KieseierHeinz Wiendl
Multiple sclerosis therapy:
An update on recently finished trials
Introduction
Currently available immunomodulatory and immuno-suppressive substances have dramatically changed thetherapeutic perspectives for the treatment of multiplesclerosis (MS) during the last decade [61, 134, 159]. Al-though their beneficial effects on relapse rate and sur-rogate markers of disease activity on magnetic reso-nance imaging have clearly been demonstrated, theirimpact on disease progression is only modest. Problemswith the approved disease modifying drugs (DMD) in-clude unpleasant injection-related side effects, and theappearance of neutralizing antibodies (NAbs). Further-more, patient adherence and compliance have been sub-optimal [102]. These issues show that it is necessary tosearch for alternative treatment options.
As our understanding of MS immunopathogenesis
continues to evolve, selective or antigen-specific inter-ventions have gained increasing attention during recentyears [42, 60, 77]. MS heterogeneity at the clinical, im-munological and histopathological level introduces ahigh level of complexity in determining molecular treat-ment targets.
It is difficult to overlook the tremendous number ofpublications on MS therapy that increases significantlyevery year. In order to provide an overview on novel de-velopments that may be relevant for clinical practice, wesummarize the results from the most important studieson new substances published since 2004.Concerning ap-proved agents we are focusing on new insights regardingearly treatment, dosage modification regimens and at-tempts to implement oral substitutes (Table 1).
JON
2684
Received: 2 January 2007Received in revised form: 14 June 2007Accepted: 19 June 2007Published online: 15 November 2007
C. Kleinschnitz, MD · S. G. Meuth, MD, PhD ·H.Wiendl, MD (�)Dept. of NeurologyBayerische Julius-Maximilians-UniversitätWürzburgJosef-Schneider-Str. 1197080 Würzburg, GermanyTel.: +49-931/201-23755/-56Fax: +49-931/201-23488E-Mail:[emailprotected]
B. Kieseier, MDUniversity of DüsseldorfDept. of NeurologyDüsseldorf, Germany
optimize current therapies. The lat-ter includes modifications of dose,route of administration or the timepoint of treatment initiation. Inthis review, we provide an updateon the most important clinicalphase II/III trials on approved andnovel immunotherapeutic strate-gies in MS reported during the lasttwo years. Pharmacotherapies in-clude agents that target chemoat-traction, cell migration, chemo-therapies, and antigen-basedtherapies.
■ Key words multiple sclerosis ·therapy · disease modifying drugs ·trials · natalizumab
O. Stüve, MD, PhDUniversity of TexasDept. of NeurologySouthwestern Medical Center at DallasTX, U.S.A. and Neurology SectionVA North Texas Health Care SystemMedical Service
■ Abstract Six pharmacologicalagents are currently approved forthe treatment of multiple sclerosis(MS). However, all established sub-stances are only partially effectivein reducing disease progression orrelapse rates. In addition, they havepotentially serious side effects.Thus, significant efforts are beingmade to develop new agents or to
1473_1490_Kleinschnitz_JON_2684 08.11.2007 10:39 Uhr Seite 1473
1474
Tab
le1
Rece
ntly
pub
lishe
d m
ajor
MS
tria
ls
Agen
t(A
ssum
ed) M
echa
nism
Ch
arac
teris
tics/
Dise
ase
Outc
ome
MRI
Outc
ome
Furt
her/
ongo
ing
tria
lsRe
fere
nce
of a
ctio
nTr
ial d
esig
nco
urse
clin
ical
Appr
oved
/Est
ablis
hed
DMD IF
Nβ–1
bPl
eiot
ropi
c ant
i-inf
lam
mat
ory
250
μg s.
c. e
od in
CIS
: CI
SPo
sitiv
e, le
ss
Posit
ive,
less
Co
re st
udy
finish
ed69
and
imm
unom
odul
ator
y BE
NEFI
T st
udy
(cor
e co
nver
sion
to
conv
ersio
n to
pr
oper
ties
stud
y: 2
yea
rs),
phas
e III
McD
onal
d-CD
MS
(Pos
er)
posit
ive
MS
250
μg s.
c. e
od in
CIS
: CI
SPo
sitiv
e,
Posit
ive,
Ex
tens
ion
stud
y on
goin
g44
BENE
FIT
stud
y (3
yea
rs
sust
aine
d ef
ficac
y su
stai
ned
effic
acy
exte
nsio
n pe
riod)
, pha
se II
I(fi
rst y
ear)
(firs
t yea
r)IF
Nβ–1
b 25
0 μg
s.c.
eod
RR
-MS
No d
iffer
ence
No d
iffer
ence
Fini
shed
78ve
rsus
IFNβ
–1a
22 μ
g s.c
. ow
, hea
d-to
-hea
d de
sign,
pha
se II
/III
IFNβ
–1a
Plei
otro
pic a
nti-i
nfla
mm
ator
y 22
μg
s.c. v
ersu
s 44
μg
RR-M
SHi
gher
dos
e No
sign
ifica
nt
Fini
shed
104
and
imm
unom
odul
ator
y s.c
. ow
: OW
IMS
stud
y,
supe
rior
diffe
renc
epr
oper
ties
head
-to-
head
des
ign,
3
year
s ana
lysis
, pha
se II
IIF
Nβ–1
a 44
μg
s.c. t
tw
RR-M
SHi
gher
dos
e Hi
gher
dos
e Fi
nish
ed10
6, 1
24ve
rsus
IFNβ
–1a
i.m. o
w:
supe
rior
supe
rior
EVID
ENCE
stud
y,
(rela
pses
), no
he
ad-t
o-he
ad d
esig
n,
diffe
renc
e in
16
mon
ths e
xten
sion
EDSS
perio
d, p
hase
III
GAPl
eiot
ropi
c ant
i-inf
lam
mat
ory,
Do
se-c
ompa
rison
stud
y:
RR-M
S Ne
gativ
eNe
gativ
eFi
nish
ed41
imm
unom
odul
ator
y an
d 50
mg
or 5
mg
oral
ly o
d,
neur
opro
tect
ive
prop
ertie
sph
ase
III: C
ORAL
stud
yDo
se-c
ompa
rison
RR
-MS
High
er d
ose
High
er d
ose
Fini
shed
22, 1
19st
udy:
40
mg
vers
us 2
0m
g su
perio
rsu
perio
rs.c
. od:
900
6 st
udy,
ph
ase
III20
mg
s.c. o
d: P
ROM
iSe
PP-M
SNe
gativ
eNe
gativ
eFi
nish
ed15
5st
udy
in P
P-M
S,
phas
e III
Sequ
entia
l use
of G
A RR
-MS
Posit
ive
in b
oth
Posit
ive
in b
oth
Fini
shed
162
20m
g s.c
. od
in IF
Nβ
grou
ps (n
aïve
and
gr
oups
(naï
ve
pre-
trea
ted
and
IFNβ
pre
-tre
ated
)an
d IF
Nβ p
re-
trea
tmen
t-na
ïve
patie
nts
trea
ted)
Switc
h to
GA
20m
g s.c
. RR
-MS
Not i
nves
tigat
edPo
sitiv
eFi
nish
ed17
od fo
llow
ing
IFNβ
–1a
i.m.
ow tr
eatm
ent
IVIG
Plei
otro
pic a
nti-
2 g/
kg i.
v. lo
adin
g do
se,
CIS
Posit
ive
Posit
ive,
less
Fi
nish
ed2
infla
mm
ator
y an
d 0.
4 g/
kg b
oost
er
conv
ersio
n to
im
mun
omod
ulat
ory
infu
sions
eve
ry 6
wee
ks
CDM
S (P
oser
)pr
oper
ties
in C
IS, p
hase
III
Dose
-com
paris
on st
udy:
RR
-MS
Nega
tive
for
Nega
tive
for
Fini
shed
370.
2 g/
kg v
ersu
s 0.4
g/k
g i.v
., ei
ther
dos
eei
ther
dos
em
onth
ly in
terv
als:
PRIV
IG
stud
y, p
hase
III
1473_1490_Kleinschnitz_JON_2684 08.11.2007 10:39 Uhr Seite 1474
1475
Tab
le1
Cont
inue
d
Agen
t(A
ssum
ed) M
echa
nism
Ch
arac
teris
tics/
Dise
ase
Outc
ome
MRI
Outc
ome
Furt
her/
ongo
ing
tria
lsRe
fere
nce
of a
ctio
nTr
ial d
esig
nco
urse
clin
ical
1.0
g/kg
i.v.
, mon
thly
SP
-MS
Nega
tive
Nega
tive
Fini
shed
38, 6
2in
terv
als:
ESIM
S st
udy,
ph
ase
III
Adhe
sion/
Chem
otax
isNa
taliz
umab
α4β
1-in
tegr
in (V
LA-4
) 30
0m
g i.v
. eve
ry 2
8 RR
-MS
Posit
ive
Posit
ive
Fini
shed
113
anta
goni
st o
n le
ukoc
ytes
, da
ys: A
FFIR
M st
udy,
re
duce
s tra
nsm
igra
tion
of
phas
e III
auto
reac
tive
T ce
lls to
the
CNS
300
mg
i.v. e
very
28
days
RR
-MS
Posit
ive,
2 ca
ses
Posit
ive,
2 ca
ses
Fini
shed
121
alon
e or
in co
mbi
natio
n of
PM
Lof
PM
LSa
fety
/obs
erva
tiona
l w
ith IF
Nβ–1
a i.m
. onc
e st
udie
s ong
oing
wee
kly:
SEN
TINE
L st
udy,
pha
se II
ICC
R1 a
ntag
onist
Ch
emok
ine
rece
ptor
60
0m
g or
ally
thre
e RR
-MS
Nega
tive
Nega
tive
Fini
shed
160,
161
(BX-
471)
anta
goni
st, r
educ
es
times
per
day
, pha
se II
Tria
ls on
oth
er C
CR
tran
smig
ratio
n of
an
tago
nist
s (CC
R2,
auto
reac
tive
T ce
lls to
CC
R5) p
lann
ed/o
ngoi
ngth
e CN
S
Antig
en-/
Imm
une
cell-
base
d th
erap
yM
BP82
98In
duct
ion
of sy
stem
ic
500
mg
i.v. e
very
Ch
roni
c No
t inv
estig
ated
Posit
ive
(EDS
S Fi
nish
ed14
6im
mun
e to
lera
nce
via
6 m
onth
s, ph
ase
IIpr
ogre
ssiv
epr
ogre
ssio
n Ph
ase
II/III
stud
y st
imul
atio
n of
ant
igen
de
laye
d,
recr
uitin
gsp
ecifi
c reg
ulat
ory
cells
supp
ress
ion
of
anti-
MBP
au
toan
tibod
ies i
n th
e CS
F)DN
A va
ccin
atio
n In
duct
ion
of sy
stem
ic
Dose
-com
paris
on st
udy
RR-/
SP-M
SPe
ndin
gPe
ndin
g,
Ongo
ing
6(B
HT-3
009)
imm
une
tole
ranc
e vi
a (0
.5m
g, 1
.5m
g an
d 3.
0m
g)
redu
ctio
n of
MBP
-st
imul
atio
n of
ant
igen
in
com
bina
tion
with
sp
ecifi
c T ce
lls,
spec
ific r
egul
ator
y ce
llsat
orva
stat
in 8
0m
g od
, No
adv
erse
ph
ase
I/II
even
tsT
cell
vacc
inat
ion
Stim
ulat
ion
of
Thre
e va
ccin
atio
ns w
ith
Aggr
essiv
e No
t inv
estig
ated
Posit
ive
Fini
shed
142
endo
geno
us
MOG
-spe
cific
T ce
lls in
6
RR-M
SFu
rthe
r stu
dies
pla
nned
coun
terr
egul
ator
y to
8 w
eeks
inte
rval
s, im
mun
e m
echa
nism
sph
ase
I/II
T ce
ll de
plet
ion
Depl
etio
n of
pat
hoge
netic
Do
se-c
ompa
rison
stud
y RR
-MS
Posit
ive
Posit
ive,
Fini
shed
23(A
lem
tuzu
mab
; re
leva
nt T
cells
(12
mg/
d an
d 24
mg/
d 2
fata
l cas
es o
f Ph
ase
III st
udy
plan
ned
Cam
path
-1H)
i.v.),
hea
d-to
-hea
d IT
Pde
sign
vers
us IF
Nβ–1
a 44
μg
s.c. t
tw, p
hase
IIB
cell
depl
etio
n De
plet
ion
of p
atho
gene
tic
1000
mg
i.v. o
n da
ys 1
RR
-MS
Posit
ive
Posit
ive
Fini
shed
58(R
ituxi
mab
)re
leva
nt B
cells
, red
uced
an
d 15
, pha
se II
Furt
her s
tudi
es in
RR-
MS,
an
tibod
y fo
rmat
ion
PP-M
S, n
euro
mye
litis
optic
a on
goin
g/pl
anne
d
1473_1490_Kleinschnitz_JON_2684 08.11.2007 10:39 Uhr Seite 1475
1476
Tab
le1
Cont
inue
d
Agen
t(A
ssum
ed) M
echa
nism
Ch
arac
teris
tics/
Dise
ase
Outc
ome
MRI
Outc
ome
Furt
her/
ongo
ing
tria
lsRe
fere
nce
of a
ctio
nTr
ial d
esig
nco
urse
clin
ical
Nove
l im
mun
omod
ulat
ors
Fing
olim
od (F
TY72
0)In
crea
ses l
ymph
ocyt
e Do
se-c
ompa
rison
stud
y RR
-MS
Posit
ive
Posit
ive
Fini
shed
70ho
min
g to
seco
ndar
y (1
.25
mg
and
5.0
mg/
d Ph
ase
III st
udy
recr
uitin
gly
mph
atic
org
ans,
redu
ces
oral
ly),
FTY7
20 st
udy,
tr
ansm
igra
tion
of a
uto-
phas
e II
reac
tive
T ce
lls to
the
CNS
Dose
-com
paris
on st
udy
RR-M
SPo
sitiv
e,
Posit
ive,
Ex
tens
ion
stud
y on
goin
g10
1(1
.25
mg
and
5.0
mg/
d su
stai
ned
effic
acy
sust
aine
d ef
ficac
yor
ally
), FT
Y720
stud
y,
18 m
onth
s ext
ensio
n pe
riod,
pha
se II
Laqu
inim
odPl
eiot
ropi
c ant
i-inf
lam
mat
ory
Dose
-com
paris
on st
udy
RR-M
SPo
sitiv
e (0
.3m
g Ne
gativ
eFi
nish
ed11
1an
d im
mun
omod
ulat
ory
(0.1
mg
and
0.3
mg/
d gr
oup
only
)Ph
ase
II st
udy
recr
uitin
gpr
oper
ties
oral
ly),
phas
e II
Dose
-com
paris
on st
udy
RR-M
S Po
sitiv
e (0
.6m
g Ne
gativ
eFi
nish
ed25
(0.3
mg
and
0.6
mg/
d gr
oup
only
)Ph
ase
III st
udy
recr
uitin
gor
ally
), ph
ase
IITe
msir
olim
usIn
hibi
ts m
amm
alia
n Do
se-c
ompa
rison
stud
y RR
-/SP
-MS
Posit
ive
Posit
ive
Fini
shed
67(R
apam
ycin
)ta
rget
of r
apam
ycin
(2
.0m
g, 4
.0m
g or
8.0
mg
(mTO
R) k
inas
e,
od o
rally
), ph
ase
IIsu
ppre
sses
ant
igen
-m
edia
ted
prol
ifera
tion
of
T an
d B
cells
Fum
aric
aci
d es
ters
Plei
otro
pic a
nti-
Dose
-com
paris
on st
udy
RR-M
SPo
sitiv
e (7
20m
g Ne
gativ
eFi
nish
ed68
(BG1
2, fu
mar
ate)
infla
mm
ator
y an
d (1
20m
g, 3
60m
g, 7
20m
g gr
oup
only
)Ph
ase
III st
udy
recr
uitin
gim
mun
omod
ulat
ory
daily
ora
lly),
BG00
012
stud
y,
prop
ertie
s; TH
2 de
viat
ion
phas
e II
Stat
ins
Plei
otro
pic a
nti-
80m
g sim
vast
atin
od
RR-M
SPo
sitiv
eNo
t inv
estig
ated
Fini
shed
144
infla
mm
ator
y an
d or
ally
ove
r 6 m
onth
s, no
Ph
ase
III st
udy
(80
mg
imm
unom
odul
ator
y pl
aceb
o ar
m, p
hase
I/II
ator
vast
atin
/d) o
ngoi
ngpr
oper
ties:
inhi
bit T
and
Ph
ase
I/II c
ombi
natio
n B
cell
prol
ifera
tion
and
stud
y (a
torv
asta
tin+
IFNβ
-M
MP
secr
etio
n, in
duce
1a
s.c.
ttw
) ong
oing
anti-
infla
mm
ator
y Th
2 cy
toki
ne p
atte
rns
Hydr
olyt
ic e
nzym
esIn
crea
se th
e sp
ecifi
c Or
al d
rug
(90
mg
RR-M
SNe
gativ
eNe
gativ
eFi
nish
ed9
hydr
olyt
ic a
ctiv
ity o
n br
omel
ain
+48
mg
puta
tive
inge
sted
(aut
o)-
tryp
sin+
100
mg
antig
ens i
n th
e se
rum
ruto
sid),
phas
e III
Treo
sulfa
nIm
mun
osup
pres
sant
Op
en-la
bel,
no p
lace
bo
SP-M
SPo
sitiv
eSt
abili
zatio
n Fi
nish
ed15
4(a
lkyl
ans)
, inh
ibits
ar
m, 7
g/m
2i.v
. eve
ry 3
(re
laps
e ra
te,
Phas
e III
stud
y re
crui
ting
prol
ifera
ting
cells
m
onth
s ove
r 12
mon
ths,
EDSS
), w
ell
incl
udin
g pa
thog
enet
ic
phas
e I
tole
rate
dre
leva
nt im
mun
e ce
lls
CIS
clin
ical
ly is
olat
ed sy
ndro
me;
eod
ever
y ot
her d
ay; G
A gl
atira
mer
ace
tate
; IFN
inte
rfero
n; i.
min
tram
uscu
larly
; ITP
idio
path
ic th
rom
bocy
tope
nic p
urpu
ra; i
.v.i
ntra
veno
usly
; IVI
Gin
trav
enou
s im
mun
oglo
bulin
s; M
BPba
-sic
mye
lin p
rote
in; M
OGm
yelin
olig
oden
droc
yte
glyc
opro
tein
; od
once
dai
ly; o
w o
nce
wee
kly;
PM
Lpr
ogre
ssiv
e m
ultif
ocal
leuc
ence
phal
opat
hie;
PP-
MS
prim
ary
prog
ress
ive
mul
tiple
scle
rosis
; RR-
MS
rela
psin
g re
mitt
ing
mul
tiple
scle
rosis
; s.c.
subc
utan
eous
ly; S
P-M
Sse
cond
ary
prog
ress
ive
mul
tiple
scle
rosis
; ttw
thre
e tim
es w
eekl
y; V
LAve
ry la
te a
ntig
en
1473_1490_Kleinschnitz_JON_2684 08.11.2007 10:39 Uhr Seite 1476
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News from approved and established therapies
■ Interferon beta
Early treatment after clinically isolated syndrome
Two previous trials (CHAMPS and ETOMS) demon-strated the potency of interferon beta (IFNβ)-1a to delaythe conversion into clinically definite MS (CDMS) ac-cording to the Poser criteria when initiated after a firstdemyelinating episode (clinically isolated syndrome[CIS]) [26, 64, 114]. Recently, the 2-year results from theBENEFIT (Betaferon in Newly Emerging Multiple Scle-rosis For Initial Treatment) study testing the effect ofIFNβ-1b in CIS confirmed this principal finding andadded valuable information to this relevant topic [69].The multicenter, double-blind, randomised trial as-sessed the efficacy and safety of IFNβ-1b (Betaferon®)250 μg s.c. every other day in patients with CIS and MRIfindings suggestive of MS. Patients were randomised toIFNβ-1b (n = 292) or placebo (n = 176) and were treateduntil CDMS was diagnosed or they had been followedfor 2 years. Primary endpoints included the time toCDMS (second relapse) as well as time to diagnosis ofMS according to the McDonald criteria (disseminationin time by MRI criteria). After 2 years, IFNβ-1b therapyreduced the risk to convert to CDMS by 50 % and the riskto convert to McDonald MS by 46 %. The study also metthe secondary endpoints by significantly reducing thecumulative number of newly gadolinium (Gd) enhanc-ing lesions and T2-weighted (T2w) lesions under activetreatment [112]. In contrast to the CHAMPS trial sub-group analysis [100], the treatment effect was not supe-rior in patients with a high lesion load (> 9 T2 lesions)at the beginning. Moreover, patients who presented withmultifocal symptoms responded less well to therapythan patients with a monofocal presentation.
Despite increasing evidence supporting early therapyinitiation, the optimum time point for beginning an im-munomodulatory treatment is still under debate [117].Proponents of “early regimes”emphasize the positive ef-fects on subsequent disease progression [46] and under-line the risk of inflammatory axonal damage which al-ready occurs at the earliest stages of MS [13, 14, 63, 81].However, arguments against early initiation of therapyinclude heterogeneity of the disease course at the indi-vidual level, the existence of “benign” MS [32], and theimpossibility in predicting (or excluding) the future dis-ease course in individual patients. Furthermore, all cur-rently approved therapies are very expensive, and theirlong-term efficacy is unknown [110].
The BENEFIT study adds a new level of evidence tothis discussion. After 2 years, approximately 85 % of theCIS patients receiving placebo were diagnosed with MSaccording to the McDonald criteria. The ongoingprospective 3-year extension phase of the study in
which all participants switched to active treatment cur-rently analyzes if early IFNβ-1b therapy in MS may alsoexhibit long-term clinical effects on disability progres-sion. A recently presented analysis suggests that theearly treatment with IFNβ-1b exhibits a significant im-pact on disability, as measured by the EDSS [44]. How-ever, the full analysis after completion of this 5-yearstudy should be awaited before final conclusions can bedrawn.
Albeit the potency of IFNβ to delay the conversion toCDMS has clearly been demonstrated, it should be notedthat 24 months after starting treatment, approximately50 %–70 % of the patients receiving IFNβ-1a or IFNβ-1bshowed either clinical or MRI activity [26, 64, 69]. Thisillustrates that early administration of IFNβ is only par-tially effective and disease activity may neverthelesscontinue in many cases. The open extension of theCHAMPS (Controlled High Risk Subjects Avonex Multi-ple Sclerosis Prevention Study) study called CHAMPI-ONS (Controlled High Risk Avonex Multiple SclerosisPrevention Study in Ongoing Neurologic Surveillance)is the first study available that demonstrates a signifi-cant – though modest – long-term effect of early treat-ment initiation, both at the clinical as well as the MRIlevel [75].
Dose comparison trials with interferon beta preparations
Three different IFNβ products are currently approvedfor the therapy of relapsing-remitting (RR-)MS. For thesubcutaneous but not intramuscular preparations thereare accumulating data of a dose-response relationship.Latest evidence comes from the three-year analysis ofthe Once Weekly IFNβ-1a for MS Study (OWIMS) [104],which confirmed that IFNβ-1a 22 μg s.c. once weekly isless effective than 44 μg at least at the level of MRI activ-ity [45].
The question as to which dose or frequency of IFNβis the most effective in MS has been discussed inten-sively during recent years. Results coming from two pre-vious class I/II head-to-head trials suggested that IFNβfollows a dose-response curve with higher doses and/orfrequencies of IFNβ, showing superiority in reducing re-lapse rate and MRI activity [31, 108]. Evaluation of theextension phase of the head-to-head EVIDENCE (Evi-dence of Interferon Dose-response: European NorthAmerican Comparative Efficacy) trial revealed superiorefficacy of 44 μg IFNβ-1a three times weekly comparedto IFNβ-1a i.m. once weekly on relapse rate and MRIactivity and differences sustained for at least 16 months[107, 125]. Changes in the EDSS did not differ signifi-cantly between the groups, probably reflecting the mod-est effect of IFNβ on disease progression in general.Overall adverse events were more common with thehigh-dose regime and were predominantly due to dif-ferences in injection-site reactions and hepatic and
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haematological laboratory abnormalities. Serious ad-verse events occurred to a similar extent [123].
For a number of reasons, some MS specialists havechallenged the true significance of dose-comparison or“switching” trials [7, 73, 89, 143]. Arguments includemethodological limitations and the unclear meaning ofa dose-relationship on long-term disease progression[120]. In contrast to the above mentioned evidence classI/II studies, several smaller trials could not confirm theobservation of a clinically relevant dose-response effectof IFNβ in MS [73, 89, 109, 143]. A recently publishedmulticenter, controlled, open-label study on Danish RR-MS patients compared the efficacy of IFNβ-1b 250 μgs.c. every other day (n = 158) to IFNβ-1a 22 μg s.c. onceweekly (n = 143) in a head-to-head randomized design[78] over 24 months. Owing to the different administra-tion schemes, blinding was restricted to the MRI end-points. No differences in the annualized relapse rate, thetime to first relapse (primary endpoints) or confirmeddisease progression as measured by EDSS (secondaryendpoint) were found in the two arms.There was a trendtowards decreased MRI activity and overall lesion loadin the high-dose group [78]. Both IFNβ-1b and IFNβ-1awere well tolerated and side effects did not occur morefrequently in either subgroup.
On the basis of class I and class II evidence it is con-sidered probable that there is a dose-response curveassociated with the use of IFNβ but one could state atpresent that potential differences between the IFNβ-preparations are small. Several trials are currently un-derway to further address this issue [30, 56].
■ Glatiramer acetate
Oral glatiramer acetate
Daily subcutaneous glatiramer acetate (GA) is approvedfor the treatment of RR-MS [27, 40, 66]. The double-blind, randomized, multicenter CORAL (Glatiramer ac-etate [Copaxone] administered orally in relapsing-re-mitting multiple sclerosis) study compared the effect oftwo different oral doses of GA (50 mg or 5 mg once daily)against placebo in 1644 patients with RR-MS over 14months [41]. The study outcome was negative: Neitherthe cumulative number of confirmed relapses (primaryendpoint), nor several secondary and tertiary clinicaland MRI parameters were different between eithergroup. Consequently, oral GA at the doses tested cannotbe recommended for the treatment of RR-MS. Severalpossible explanations for these disappointing resultswere offered: [1] the primary outcome power calcula-tions were incorrect [2], species-specific differences inthe gut-associated immune response could impair theefficacy of the oral formulation [55] and [3] an inade-quate dosage was chosen.
Dose comparison trials
The results from a nine month double-blind, parallel-group trial assessing the safety and efficacy of 40 mg ver-sus 20 mg GA given s.c.every day in patients with RR-MSwere recently presented [119]. The cumulative numberof Gd-enhancing lesions at month 9 was lower in the40 mg group compared to the group receiving 20 mg(38 % greater reduction) although the difference did notreach statistical significance (p = 0.0898). Compared tobaseline conditions, the risk of having active enhancingMRI lesions at months 7, 8 and 9 was significantly re-duced by 75 % in the high dose cohort (p < 0.001) and by65 % with the lower dose (p < 0.001). The time to first re-lapse was more delayed in the 40 mg than in the 20 mgsubgroup (213 days vs. 80, respectively; p = 0.0367). GA40 mg s. c. was well tolerated with a safety profile similarto the approved dose. A phase III trial is currently un-derway to validate these results in a larger patient sam-ple [22].
Comparison with interferon beta
A retrospective, open-label study by Hass and Firzlaff[57] on 308 patients with RR-MS reported a significantlyhigher reduction of relapses after 12 and 24 months forsubjects under GA compared to those receiving IFNβ. Inaddition, fewer patients injecting GA discontinuedtreatment. There are significant limitations of the studydesign (open-label, retrospective, single center). How-ever, the question of whether one of the available im-munomodulatory agents is superior to another is worthbeing further investigated, and several (larger) trials arecurrently recruiting patients to compare the safety andefficacy of GA against the approved IFNβ formulationsand vice versa [56].
Primary progressive MS
To date, no drug has been approved for the treatment ofprimary progressive (PP-) MS and very few trials existthat specifically address this disease course [84]. Themulticenter, double-blind, placebo-controlled PROMiSetrial was intended to analyze the effects and safety ofs. c. GA over 3 years in 943 patients with PP-MS againstplacebo [155]. An interim analysis revealed a possiblebenefit of GA for elderly male patients. However, thestudy was halted after 2 years because data at that timepoint indicated that treatment in the overall populationis ineffective. One possible drawback of the study wasthat the observed annual progression rate on EDSS wasonly 36 %, which is markedly lower than the 50 % annualprogression rate estimate used for determining size andstatistical power of the trial.
The results from the PROMiSe study are in line withthe unfortunate observation that modulation of the im-
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mune system is ineffective in halting disease progres-sion in PP-MS [84].
Sequential use of different disease-modifying drugs
Scarce data exist to indicate whether exposure to oneimmunomodulator would influence the response andadherence to a second immunomodulatory agent withdifferent modes of action. Both questions were ad-dressed by a recent prospective, open-label study evalu-ating the efficacy, safety and tolerability of GA in treat-ment-naïve RR-MS patients (n = 558) and in patientswho had previously received IFNβ (n = 247) [162]. Prior“IFN subjects” more often stayed on GA treatment thantreatment-naïve patients. There was no apparent differ-ence between the study cohorts in terms of reasons fordiscontinuation from the study. Adverse events weresimilar in type and frequency. The annual relapse ratehad declined by 75 % in both groups and median EDSSchanges were less than 0.5. The authors conclude thatIFNβ pre-treatment does not have a negative impact onefficacy or tolerability of subsequent GA administra-tion. In addition, patients who stop IFNβ therapy canbenefit from switching to GA.
Caon and colleagues [17] examined the clinicalcourse of 85 patients after switching disease modifyingtherapy from IFNβ-1a once weekly to GA. Therapy waschanged either because of persistent clinical disease ac-tivity (n = 62) or unacceptable toxicity/adverse effects(n = 23). Treatment with GA reduced the mean annualrelapse rate from 1.23 to 0.53 (p < 0.0001) compared to areduction from 1.41 to 1.23 (p = 0.005) under priorIFNβ-1a therapy. Interestingly, in patients who switchedto GA because of persistent toxicity the relapse fre-quency was not significantly altered. Therefore, clinicalobservations and tolerability may be used as criteria forswitching DMD in daily practice.
■ Intravenous immunoglobulins
Early treatment after CIS
IVIg have been suggested to exhibit beneficial effects inreducing relapses in patients with RR-MS [1, 36, 54, 88,128]. However, treatment protocols as well as responsesvaried considerably throughout the trials [52, 127] andthe true benefit of IVIg on disease activity and progres-sion remains controversial [39].
Following the design of the recent IFNβ trials in CIS(see section Interferon beta), the efficacy of IVIg to de-lay the conversion into CDMS has also been investigated[2]. Ninety-one patients with CIS and abnormal brainMRI scans suggestive of MS [35] were randomized toIVIg therapy (2 g/kg loading dose) or placebo, withbooster infusions (0.4 g/kg) given once every 6 weeks
over 1 year. The results were as follows: [1] The cumula-tive probability of developing CDMS (primary end-point) was significantly lower in the treatment groupcompared to placebo (p = 0.03), [2] patients receivingIVIg showed a significant reduction in the volume(p = 0.01) and number (p = 0.01) of T2-w lesions and inthe volume of Gd-enhancing plaques (p = 0.03) (sec-ondary endpoint), [3] treatment was well tolerated with-out any differences in the frequency of adverse eventsbetween the groups.
Dose comparison trial in RR-MS
The objective of the multicenter, double-blind Preven-tion of Relapse with Intravenous Immunoglobulin(PRIVIG) study was to assess the safety and efficacy oftwo different doses of IVIg-C (10 %) in RR-MS [37]. 44and 42 patients were randomized to 0.2 g/kg and 0.4 g/kgIVIg, respectively and 41 subjects received placebo.Medication was infused at monthly intervals for 48weeks. The primary endpoint was the proportion of re-lapse-free patients at 48 weeks. Secondary and ex-ploratory endpoints comprised diverse MRI parame-ters, relapse rate, EDSS and MSFC. The study drug waswell tolerated and no differences in the rate of adverseevents were observed. However, in contrast to severalpositive studies on IVIg in RR-MS (see section Earlytreatment after CIS) neither the primary nor the sec-ondary endpoints were met and no differences wereseen between the different doses.
Albeit some possible explanations for this outcomewere offered (e.g. the low relapse rate in the placeboarm), the negative results of this well designed studyclearly question the role of IVIg in the treatment of RR-MS.
IVIg in secondary progressive MS
Treatment of secondary progressive (SP-) MS remainschallenging. For example, studies assessing the IFNβ-preparations in SP-MS revealed controversial results[21, 51, 131]. The European study on IVIg treatment inMultiple Sclerosis (ESIMS) was conducted to analyze theeffect of high-dose IVIg (1 g/kg per month) over 27months on disease progression as measured by EDSSagainst placebo [38, 62]. 321 SP-MS patients with clini-cally remaining disease activity were enrolled in thismulticenter, double-blind evidence class I study. No dif-ference was found between the groups in the primaryoutcome measure, which was the time of a confirmedtreatment failure defined as a 1.0 or 0.5 EDDS progres-sion depending on the initial EDSS score. In addition,analysis of the secondary outcome parameters (e.g. an-nual relapse-rate, lesion load on T2-w MRI) was alsonegative. Although the treatment was generally well tol-erated, drug-related adverse events such as headache,
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fever and chills occurred more frequently in the treat-ment group than in patients receiving placebo. Impor-tantly, deep venous thrombosis and pulmonary em-bolism were observed in six patients in the IVIg group.Against the background of the overall negative studyoutcome, the authors conclude that IVIg cannot be rec-ommended for patients with SP-MS and demur a poten-tial risk of thrombembolism which could be greater withhigh doses of IVIg.
In summary,recent evidence shed critical light on therole of IVIg in the treatment of MS patients since twowell designed studies in RR-MS and SP-MS (PRIVIG andESIMS) failed to demonstrate significant benefit.
■ Plasma exchange
The rationale to use plasma exchange (PE) in MS is that(auto)antibodies and complement are critically involvedin the pathogenesis of the disease in some patients [49,77, 85, 136]. Moreover, certain MS subtypes such as neu-romyelitis optica (NMO) and acute demyelinating en-cephalomyelitis (ADEM) are hallmarked by the pres-ence of humoral factors [87, 90] but earlier attempts toapply plasma exchange as continuous treatment in MSwere not convincing [85, 86, 99].
Several previous case reports as well as one placebo-controlled trial have demonstrated that patients suffer-ing from severe steroid-resistant relapses, NMO orADEM can benefit from subsequent PE [72, 91, 151].These findings were recently corroborated or extendedin some controlled observations: Ruprecht and co-workers reviewed a series of 10 consecutive patientstreated with PE for acute, severe optic neuritis unre-sponsive to prior high-dose steroid treatment [122]. Vi-sual acuity improved in 7 out of 10 patients and 5 pa-tients remained stable or continued to improve onfollow-up. The procedure was generally well toleratedwithout serious side effects.An uncontrolled open-labeltrial on 16 patients (13 adults and 3 pediatric cases) withsevere relapses, CIS or NMO revealed that 71 % of the in-dividuals had a good or very good outcome after PE fol-lowing unsuccessful steroid treatment.A better outcomeseemed to be associated with early initiation of PE ther-apy within one month after symptom onset [124]. Inter-estingly, most of the studies have demonstrated that re-sponse to PE seems to be an “all or nothing”phenomenon, which suggests that one (or few) commonpathophysiological parameter accounts for the varia-tion. Another trial including 19 subjects with fulminantidiopathic inflammatory demyelination retrospectivelycorrelated the response to PE to the immunopathologi-cal pattern of demyelination according to Lucchinettiet al. [71, 90].All patients with pattern II – characterizedby prominent immunoglobulin depositions and com-plement activation within the plaques – but none with
pattern I (macrophage-mediated demyelination) or pat-tern III (primary oligodendropathy), showed moderateto substantial improvement of neurological symptomsafter PE.
In summary, there is accumulating evidence that pa-tients with serious steroid-resistant relapses or certainmalignant subgroups of MS can profit from adjacent PE.The assumed probability to respond to PE under thegiven conditions is around 50 % – 70 %. Thereby, timelyinitiation (1–2 months) of PE after the onset of neuro-logical symptoms seems to critically determine the ther-apeutic effect.
News from novel therapies
■ Adhesion, chemotaxis and migration
Natalizumab
Most recently,natalizumab was (re)approved by the FDAand the EMEA as a monotherapy for the treatment of“active relapsing forms of MS”(see http//:www.FDA.gov,www.emea.eu.int). This monoclonal humanized anti-body (mAb) targets α4β1-integrin (VLA-4) on the sur-face of leukocytes. Natalizumab was designed to preventthe accumulation of encephalitogenic white blood cellsin the CNS [132]. Additional mechanisms acting on re-duced T cell reactivation and B cell proliferation are alsoconceivable [98, 138].
Since a previous phase II proof-of-concept study sug-gested remarkable clinical efficacy [95] two phase III tri-als on natalizumab in MS were initiated and recentlypublished [113, 121]. In the AFFIRM (NatalizumabSafety and Efficacy in Relapsing Remitting MultipleSclerosis) trial natalizumab was applied as a monother-apy (300 mg i.v. or placebo every 28 days for up to 28months) in 942 MS patients who had not received anyimmunotherapy in the preceding 6 months. 96 % of sub-jects in the treatment arm were devoid of new Gd-en-hancing lesions compared to 68 % in the placebo group.Relapse frequency was reduced by approximately two-thirds over year one and two and natalizumab also sig-nificantly delayed disease progression. The SENTINEL(Safety and Efficacy of Natalizumab in Combinationwith Interferon beta-1a in Patients with Relapsing Re-mitting Multiple Sclerosis) study tested the combinationof natalizumab with IFNβ-1a i.m. once-weekly againstIFNβ-1a alone. Subjects on IFNβ-1a were randomised toeither natalizumab 300 mg (n = 589) or placebo (n = 582)infusions every 28 days. Individuals receiving combina-tion therapy had a reduced relapse rate by 54 % overIFNβ-1a alone and significantly fewer MRI lesions. Fre-quent adverse events in both studies comprised anaphy-lactoid reactions, rash, arthralgia and headache.
Based on the positive interim analysis of both phase
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III trials, natalizumab was approved by the FDA for thetreatment of “relapsing forms of MS”in November 2004.However, in February 2005, the substance was with-drawn from the market because two patients receivingnatalizumab in combination with IFNβ-1a developedprogressive multifocal leukencephalopathy (PML) [76,83, 141].
As a consequence, an extensive re-examination of allpatients who had received natalizumab was performedcomprising various safety aspects [157]. Taken together,no additional cases of PML were identified in more than3000 patients exposed to the medication. Based on theseresults the FDA approved an application for resumedmarketing of natalizumab as a monotherapy in patientswith “relapsing forms of MS who have not respondedadequately to, or cannot tolerate other treatments” inJune 2006. To minimize the risk of further serious ad-verse events, a special restricted distribution programand the risk management plan TOUCH (Tysabri Out-reach Unified Commitment to Health) were imple-mented in the U.S. (see www.FDA.gov). In Europe, natal-izumab has been approved by the EMEA asmonotherapy for (i) patients with high disease activitydespite sufficient treatment with IFNβ as well as (ii) forpatients with initially high disease activity.
The advent of natalizumab for the treatment of MSopens a new era of immune-specific therapy. However,the current situation is unique since the high efficacy ofthis mAb is opposed by an uncertain safety profile, es-pecially with long-term application. Natalizumab inter-feres with a critical step in MS disease pathogenesis thatis the entry of encephalitogenic T cells to the CNS com-partment. Owing to its mechanism of action, the sub-stance may impede immune surveillance of the CNS. Itis unknown, however, whether the JC virus reactivation(or de novo infection) was caused by general immuno-suppression, or by a more specific effect related to theparticular mechanisms of drug action [115]. Balancingthe risk to benefit ratio of this class of agents, it is nec-essary to learn much more about JC virus infectionswithout delay [79].
Chemokine receptor 1 antagonism
Many experimental and clinical studies have stressedthe importance of chemokine/chemokine-receptor in-teractions in MS pathogenesis [5, 18, 48, 129]. Pharma-cological interference with the chemokine network hastherefore been regarded a promising therapeutic strat-egy [42].
The novel oral chemokine receptor 1 (CCR1) antago-nist BX-471 (ZK811752) showed positive results in pre-liminary phase I trials in autoimmune diseases includ-ing MS [33]. Consequently, a multicenter, randomized,double-blind phase II study was set up to test the safetyand efficacy of 600 mg ZK811752 given three times per
day against placebo in 90 patients with RR-MS over 16weeks [161]. Overall, the substance was well-toleratedbut failed to demonstrate significant efficacy on severalMRI parameters of disease activity (primary outcomemeasure).
Since the chemokine network is complex and redun-dant, it is difficult to predict to which extent the block-ade of a solitary chemokine mediates significant clinicaleffects. Several further studies addressing differentchemokine receptor antagonists (e.g. CCR2 and CCR5)are currently underway [18, 160].
■ Antigen-based immune therapy
Conceptually, antigen-specific therapy of autoimmunedisorders is still one of the most attractive therapeuticapproaches [60, 130, 133]. Under experimental condi-tions, antigen-specific tolerance can be elegantly in-duced by the oral application of putative autoantigenssuch as myelin basic protein (MBP) (“oral tolerance”).This induces antigen-specific regulatory T cells in theperiphery that can trigger bystander suppression afterrecognizing their antigen in the target organ [34,150]. Inaddition, numerous other attempts both at the experi-mental and clinical level, have been undertaken to im-plement antigen-specific therapy in MS [130].Albeit thisconcept has attracted considerable attention during lastyears, the clinical success in humans is limited as yet.
Administration of oral myelin led to impressive ame-lioration of EAE and suggested favourable effects in asmall phase I pilot study in MS patients [150]. However,a larger phase III multicenter trial testing oral myelin inMS showed no effect [43, 106, 153].
Clinical trials using altered peptide ligands (APLs)derived from immunodominant peptides of MBP werelikewise disappointing. One trial demonstrated that theMBP derived APL (amino acids 83–99; CGP77116) in-duced considerable disease exacerbation accompaniedby a drastic increase in the frequency of MBP-specific Tcells [11]. This suggests that APL can cross-stimulate en-cephalitogenic, MBP-specific T cells under certain cir-c*mstances [11, 74]. Furthermore, it must be taken intoaccount that the autoimmune reaction might eventuallyevade the effects of APL therapy, for example by epitopespreading.
Another approach is the repetitive application ofMBP8298, an MBP derived peptide containing residues85–96, which represent the minimal epitope for thedominant autoantibody response in the CSF of MS pa-tients. Residues 85–96 were found to represent the criti-cal contact site also for T-cell recognition as assessed bysystematic amino acid substitution. MBP8298 includesamino acid extensions at both ends which serve to opti-mize the interaction with T-cells. The assumed mecha-nism of action of the intravenously applied peptide is
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the induction of immunological tolerance [59, 103, 156].Data from subjects treated in open protocols (advanced,progressive MS) suggested that 500 mg MBP 8298 eitheras single or repeated injections induced long-lasting im-munological tolerance, confirmed by low or unde-tectable anti-MBP reactivity in the CSF of subjects withprogressive MS. Interestingly, HLA-DR haplotypes withhigh affinity to the administered peptide (DR2,DR4,andDR7) displayed more sustained tolerization effects[147]. A phase II study in chronic-progressive MSdemonstrated that fewer patients progressed on EDSSunder active treatment compared to those receivingplacebo. The effect of MBP was most impressive in thesubgroup of HLA-DR2 and/or DR4 individuals [146].Administration of MBP8298 suppressed anti-MBP au-toantibody levels in the CSF of most patients althoughthe extent of suppression was not predictive of clinicaloutcome. No serious adverse events occurred in eithergroup and the most frequent side effects included localinjection site reactions, occasional flush and mild hy-potension. A two-year phase II/III study in 553 patientswith SP-MS comprising stratification for DR2/4 is cur-rently recruiting in multiple centers in the United Statesand Europe.
The efficacy of antigen-induced tolerance might beimproved by employing DNA-derived immunizationtechniques [20, 145]. Vaccination using naked DNA en-coding self antigens protects from or even reverses es-tablished autoimmune disease in several animal models,including rheumatoid arthritis, insulin-dependent dia-betes mellitus, and MS. The convincing preclinical dataon the immunological effects of a plasmid encoding full-length MBP led to a phase I/II trial investigating the ef-fect of an MBP encoding plasmid (BHT-3009) in 30RR/SP-MS patients. The primary outcome measureswere safety and changes in the immune response. Intra-muscular plasmid injections of three different doses ofBHT-3009 (0.5 mg, 1.5 mg and 3.0 mg) at weeks 1, 3, 5,and 9 in combination with once-daily atorvastatin 80 mgwere tested against placebo. Preliminary analysis of 3patients demonstrated antigen-specific reduction inMBP reactive T cells. In general, BHT-3009 was well tol-erated and only mild to moderate adverse events wereobserved. Data on clinical efficacy are pending [6].
Although previous attempts toward antigen-specificimmunomodulation have often been disappointing, thedetailed analysis of this approach has renewed the in-terest in re-establishing tolerance to autoantigens at thelevel of either T cell- or antibody-mediated immune re-sponses. Such antigen-specific immunotherapies offerthe prospect of correcting pathological immune reactiv-ity in a highly specific manner without major side effects[130, 135]. There are, however, a number of caveats injudging the future perspectives of these approaches. TheT cell response in the human system towards differentCNS-candidate autoantigens is much more complex
than in the EAE model using inbred animal strains. Theheterogeneity of the TCR-repertoire implies that such aselective immune therapy might only work if it can be“individualized” or “tailored” for individual patientswith similar immunological features.
■ T cell/T cell receptor vaccination and T cell depletion
The concept of T cell vaccination is based on the injec-tion of autoantigen specific T cell clones which are iso-lated from the prospective recipient, inactivated, andthen re-injected as a vaccine to stimulate endogenouscounterregulatory mechanisms [10, 65, 140]. Peptides ofthe antigen-specific TCR of autoreactive T cells can alsobe used for vaccination instead of whole T cells (TCRvaccination) [142]. Achiron and colleagues adminis-tered autologous MBP together with myelin oligoden-drocyte glycoprotein (MOG)-reactive T cells in 20 pa-tients with aggressive RR-MS [3]. Each patient received3 vaccinations at 6 to 8 weeks intervals. In this small trial,the authors found that the annualized relapse rate de-creased from 2.6 ± 1.6 to 1.1 ± 1.6 and progression onEDSS was delayed.
Thus far, available data on T cell and T cell receptorvaccination do not allow firm conclusions on the poten-tial of these strategies in clinical practice [60].
An alternative strategy is the complement-mediateddepletion of CD52+ T cells, which can be rapidly andpersistently obtained with the antibody alemtuzumab(Campath-1). In the last 15 years experience with thishumanized monoclonal antibody in patients with RR-MS as well as SP-MS has been gathered [24], revealing adramatic impact on the inflammatory activity, as deter-mined by MRI,and, in young RR-MS patients,promisingeffects on clinical disability. Recently the results of acomparative phase II trial,alemtuzumab versus IFNβ-1as. c. (Rebif® 44 μg three times weekly) were presented[23]: 111 patients were randomized to receive IFNβ-1a,113 to receive 5 infusions of 12 mg/d alemtuzumab i. v.and 110 to receive 5 infusions of 24 mg/d alemtuzumabi. v. in the first year, followed by 3 infusions in year 2. Af-ter two years, the annualized relapse rate was calculatedwith 0.35 (IFNβ-1a) versus 0.11 (alemtuzumab 12 mg/d)versus 0.07 (alemtuzumab 24 mg/d), which translatesinto a risk reduction of 87 %. However, evidence of se-vere toxicity (idiopathic thrombocytopenic purpura,ITP) including two cases of death still qualifies these im-pressive efficacy data. A phase III trial is currentlyplanned to underline the clinical safety and efficacy ofthis drug.
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■ B cell targeted therapy
Rituximab, an anti-CD20 antibody, effectively depletes Blymphocytes,and has been successfully used in the ther-apy of other immune-mediated disorders, such asrheumatoid arthritis, but also in those involving the pe-ripheral nervous system. A small recent study reporteda limited effect of rituximab on B cells in the cere-brospinal fluid compartment of patients with PP-MS[96]. In a case report Stuve and co-workers described apatient with therapy refractory RR-MS in whom ritux-imab monotherapy resulted in significant clinical im-provement. Inflammatory surrogate markers on MRIwere also reduced and B lymphocytes were depleted inthe cerebrospinal fluid as well as in the peripheral blood[137]. Rituximab was also studied as an add-on therapyin RR-MS with continuous clinical disease activity [29].In this phase II study B cells were found to be depletedfrom the cerebrospinal fluid at 24 weeks after initialtreatment. Promising results were also described in asmall trial with patients suffering from neuromyelitisoptica [28]. Recently, results of a larger phase II study inRR-MS were presented: 104 patients were randomized2:1 to receive either rituximab or placebo. After sixmonths, the total number of Gd-enhancing lesions wasreduced by 91 % (primary outcome measure), whereasthe relapse rate (secondary outcome measure) was re-duced by 58 % in those patients receiving the drug ver-sus placebo [58].
■ Novel immunomodulators and immunosuppressants
FTY720 (fingolimod)
FTY720 (fingolimod) is derived from the fungalmetabolite myriocin. Compared to established im-munomodulators this oral substance exhibits uniqueimmunoregulatory properties [15, 19]. Following in vivophosphorylation FTY720 acts as non-selective agonistof the sphingosine 1-phosphate receptor 1 (S1P1) thuspreventing lymphocyte egress from secondary lym-phatic organs (“entrapment hypothesis”) and subse-quent migration to sites of inflammation [92]. Addi-tional modes of action e.g. on dendritic cells are alsodiscussed (reviewed in [118]). FTY720 markedly de-creases peripheral lymphocyte counts but does notcause general immunosuppression since the activationof T cells and B cells or T cell memory function is not al-tered.
The efficacy of FTY720 has already been demon-strated in organ transplantation [16] and various animalmodels of MS [47, 148]. Very recently, the results of amulticenter, double-blind, placebo-controlled phase IIstudy in active RR-MS have been disclosed [70]. Two dif-ferent doses of oral FTY720 (1.25 mg/d or 5 mg/d, re-
spectively) were tested against placebo in 281 subjectsfor 6 months. At the end of the core study, several MRIparameters of disease activity including the total num-ber of Gd-enhancing MS lesions (primary outcome)were significantly improved in both dosage groups com-pared to placebo. In addition, a significantly higher pro-portion of patients under FTY720 remained relapse-freeand the overall relapse rate was reduced between 53 %and 55 %. 5 mg FTY/d were not superior to the lowerdose (1.25 mg/d) concerning clinical and paraclinicaloutcome parameters. Results of the 18 month extensionphase which included the switch of the placebo group toactive treatment confirmed sustained efficacy [101]. Ingeneral the substance was well tolerated and no seriousadverse events occurred in either of the groups. Themost common side effects comprised sinusitis, mildheadaches and gastrointestinal disorders and occurredmore frequently in the high dose arm. However, due tothe expression of the S1P1 in the cardiovascular system,changes in blood pressure and cardiac rhythm (brady-cardia) have to be monitored during FTY720 treatment.Two currently performed phase III studies will provewhether the substance is efficient and safe in a largernumber of patients.
FTY720 is clearly one of the most interesting novelimmunomodulatory agents currently under investiga-tion, both from an “immune-mechanistic” as well asfrom a practical point of view (oral drug).Phase III stud-ies will test whether the substance is able to documentlong-term efficacy and – even more important – safetyin larger numbers of patients.
Laquinimod
Laquinimod (ABR-215062, SAIK-MS) is a new, orally ac-tive immunomodulator that was shown to be approxi-mately twenty times more potent in EAE than its “an-cestor” roquinimex (linomide). The syntheticcompound has an excellent oral bioavailability andserves as an immunoregulatory drug without generalimmunosuppressive properties.
Two clinical phase I trials demonstrated that the drugis well tolerated by healthy volunteers and patients withMS. The results from a double-blind, randomized, mul-ticenter study testing two different doses of oral laquin-imod (0.1 mg/d and 0.3 mg/d) versus placebo in 180 pa-tients with RR-MS have recently been published [111].The study lasted 24 weeks and investigated the effect oflaquinimod on different MRI surrogate markers of dis-ease activity. Laquinimod reduced the mean cumulativenumber of Gd-enhancing lesions by 44 % at 0.3 mglaquinimod/d compared to those on placebo. Clinicaloutcome parameters (relapse rate, disability) were un-changed, which was probably due to the short observa-tion period of the study. No major safety concerns werenoted and importantly, undesired tissue inflammation
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as observed with linomide was absent.Very recently, theresults from another randomized, double-blind phaseIIb study testing 0.3 mg and 0.6 mg laquinimod/dayagainst placebo in 306 RR-MS patients have been an-nounced [25]. Patients were assessed clinically and byMRI scan at week –4, baseline, and monthly from weeks12 to 36. The primary outcome of the study was the cu-mulative number of Gd-enhancing lesions at weeks 24,28, 32 and 36. Secondary outcomes of the study includedadditional MRI metrics and confirmed relapse rate. Thelaquinimod 0.6 mg dose showed a significant reductioncompared with placebo in the cumulative number ofenhancing lesions per scan in the last four scans(p = 0.0048), while treatment with the 0.3 mg dose wasineffective. Significant differences in favour of the0.6 mg dose were found for most examined secondaryand exploratory MRI-based outcome measures. Trendsfavoured the group receiving the 0.6 mg dose on mea-sures of annual relapse rate (0.52 ± 0.92 vs. placebo0.77 ± 1.25; p = 0.21), relapse-free subjects (70.8 percentvs. 62.7 percent; p = 0.33) and time to first relapse(p = 0.14). Treatment with both 0.3 and 0.6 mg doses oflaquinimod were well tolerated with only some transientand dose-dependent increases in liver enzymes. Conse-quently, laquinimod is currently tested in a large phaseIII trial.
Temsirolimus
Temsirolimus (rapamycin) is a macrocyclic immuno-suppressant which specifically inhibits the mammaliantarget of rapamycin (mTOR) kinase. This enzyme is re-quired in the control of the cell cycle, and thus, tem-sirolimus suppresses antigen-mediated proliferation ofT and B cells [126].
The agent is approved for the treatment of renal can-cer and its application in 296 individuals with RR-MSand active SP-MS has recently been investigated withthree different doses against placebo for a period of 9months [67]. In summary, patients receiving the highestdose of temsirolimus had significantly less Gd-enhanc-ing MRI lesions and 51 % fewer relapses compared tothose on placebo. Side effects were dose-dependent andincluded menstrual dysfunction, mouth ulceration, hy-perlipidemia and rashes. The side effect profile and theestimated critical risk-benefit ratio of temsirolimushave so far prevented further development of the MSprogramme by the company.
Fumaric acid
Fumaric acid is an immunomodulator which is used forthe treatment of psoriasis. Due to its side effect profile,novel fumaric acid esters (FAE; BG12, fumarate) withbetter tolerability have recently been developed.
Kappos and colleagues recently presented the results
from a larger randomized, double-blind, placebo-con-trolled trial in 257 RR-MS patients treated with threedifferent doses of FAE (BG00012) [68]. Subjects in thetreatment group either received 120 mg, 360 mg or720 mg BG00012 per day over 24 weeks.The highest doseof BG00012 (720 mg/d) significantly reduced the meannumber of new Gd-enhancing lesions on MRI (primaryend point) compared to placebo. The most common ad-verse effects comprised flushing, headache, na-sopharyngitis and nausea with no significant differencebetween the treatment and placebo arm [50]. The au-thors conclude that BG00012 is safe and effective in RR-MS at least over 24 weeks and support further long-termstudies. A large phase III study on BG00012 in RR-MS iscurrently recruiting.
Statins
Approved for the therapy of dyslipidaemia statins act onthe enzyme 3-hydroxy-3-methylglutaryl coenzyme A(HMG-CoA), thereby influencing cholesterol biosynthe-sis. However, compelling evidence now exists that thissubstance class also has extensive immunomodulatoryand anti-inflammatory properties that operate indepen-dently from lipid lowering [53, 82, 94]. For example, oraltreatment with statins was beneficial in different EAEmodels [4, 105, 158] and potential mechanisms of ac-tions include the inhibition of T and B cell proliferation,blockade of matrix metalloproteinase (MMP) secretionand the induction of an anti-inflammatory Th2 cytokinepattern [116, 149].
Based on these findings and their favourable safetyprofile a small multicenter trial including 28 patientswith RR-MS was conducted to analyze the effect of dailyoral simvastatin (80 mg) over 6 months. Although sim-vastatin treatment significantly reduced the numberand volume of Gd-enhancing lesions on brain MRI[144], the lack of a placebo arm in this study markedlylimits data interpretation. Currently, a larger placebo-controlled trial including 152 patients with CIS is beingperformed in 14 centers in North America.Here, the oralapplication of 80 mg atorvastatin is tested over 12months against placebo. Due to their pharmacologicalprofile and assumed mechanisms of action, statins werealso investigated in different studies on combinationtherapy: In an animal model of MS atorvastatin com-bined with GA displayed synergistic immunomodula-tory effects and a clinical trial using this combination inRR-MS is currently planned [139, 149]. In vitro, the com-bination of IFNβ and statins resulted in an enhanced in-hibition of T cell activation compared to IFNβ alone[97]. Accordingly, a small clinical trial was set up to an-alyze the combination of high-dose IFNβ-1a (44 μg threetimes a week) with atorvastatin in RR-MS but results arestill pending [12].
Despite a very limited number of patients from pre-
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liminary trials, a plethora of reviews have been pub-lished on the potential use of statins in MS.Although ex-perimental results and safety data are encouraging, fur-ther larger studies are clearly warranted to finallyappraise the role of statins in human autoimmune andinflammatory disorders.
Hydrolytic enzymes
Hydrolytic enzymes such as Phlogenzym® which con-sists of bromelain, trypsin and the anti-oxidant rutopsidhave been empirically used for the treatment of variousautoimmune disorders including MS for a long time [8,80]. Mechanistically, these substances are thought to in-crease the specific hydrolytic activity on putative in-gested (auto)antigens in the serum.However,a currentlypublished randomized, double-blind, placebo con-trolled trial of oral hydrolytic enzymes in 301 patientswith RR-MS was negative for both clinical and MRI pa-rameters [9].
Treosulfan
Treosulfan (L-threitol-1,4-bis(methanesulfonate)) is abifunctional alkylating agent approved for the treatmentof advanced ovarian cancer. Patient tolerability is goodand acute and long-term toxicity is favourable com-pared, e. g. to cyclophosphamide [93]. Treosulfan was al-ready successfully applied in MOG-induced EAE both ina prophylactic and therapeutic approach [152]. In addi-tion, the substance induced concentration-dependentapoptosis in human peripheral blood lymphocytes invitro [152].Recently, the safety and efficacy of treosulfanin active SP-MS was tested in a non-randomized, openlabel pilot study [154]. Eleven patients with active sec-ondary progressive MS that failed to or did not qualifyfor approved disease modifying drugs received intra-venous treosulfan infusions of 7 g/m2 body surface areaevery 4 weeks for 3 months (cycles 1–4, induction phase)with a predefined one-step dose escalation, thereafterevery 3 months for the following 9 months (cycles 5–7,maintenance phase). Taken together, treatment with tre-osulfan was safe and well tolerated. Nine out of 11 pa-tients remained on study drug over the whole treatmentperiod and showed clinical stabilisation or improve-
ment on EDSS. No relapses occurred during the treat-ment period and the median number of annual relapseswas significantly reduced compared to pre-study. Ther-apy with treosulfan led to a clear reduction of MRI ac-tivity as revealed by a reduced number of Gd+ enhanc-ing lesions on T1 weighted images.As a consequence, thefurther development of this agent is currently pursuedin a planned phase II clinical trial.
Summary
Numerous trials on approved and novel agents for thetreatment of MS have recently been finished or are cur-rently being performed. Certainly, the most significantinnovation in MS treatment in 2006 is the (re)approvalof natalizumab as monotherapy for active RR-MS. How-ever, due to an unknown long-term risk of PML, the truerisk-benefit ratio of this agent will not be known formany years.
At present it is not possible to foresee which, if any, ofthe new treatment strategies will supersede or comple-ment the currently approved therapies in the near fu-ture. One has to realistically consider that few successfulstudies face a large number of therapeutic disappoint-ments [153]. Prominent recent examples include IVIg ornovel agents like the CCR1 antagonist. The reasons forthese backstrokes are multifaceted and point out the dif-ficulties that are associated with the development of newtreatments for MS.
Although established and novel substances have im-proved MS therapy, the ultimate goal to halt disease pro-gression still appears elusive.
■ Acknowledgement We thank Ms Anke Bauer (Wuerzburg) forediting the manuscript.
■ Disclosures CK received honoraria for lecturing and travel ex-penses for attending meetings from Biogen Idec/Elan, Schering,Serono, Bayer and Sanofi-Aventis. BCK and HW received honorariafor lecturing and travel expenses for attending meetings, and finan-cial research support from Bayer, Biogen Idec/Elan, Sanofi-Aventis,Schering, Serono, and Teva Pharmaceuticals. HW and BCK haveserved or serve as consultants for Serono, Medac and Schering. SGMreceived honoraria and travel expenses for attending meetings fromSerono and Biogen Idec/Elan. OS reported no conflict of interest.
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