THERAPY IN PRACTICE
Alem uzumab Use in Clinical P ac ice: Recommenda ions
om Eu opean Mul iple Scle osis Expe s
Thomas Be ge
1
•I ina Elo aa a
2
•S en F ed ikson
3
•Ch is McGuigan
4
•
Lucia Moiola
5
•Kjell-Mo en Myh
6
•Celia O eja-Gue a a
7
•Igo S olia o
8
•
Uwe K. Ze l
9
Published online: 23 No embe 2016
ÓThe Au ho (s) 2016. This a icle is published wi h open access a Sp inge link.com
Abs ac Alem uzumab (Lem ada
TM
) is a humanized
monoclonal an ibody app o ed in mo e han 50 coun ies.
Wi hin he Eu opean Union, alem uzumab is indica ed o
he ea men o adul pa ien s wi h elapsing- emi ing
mul iple scle osis (RRMS) wi h ac i e disease de ined by
clinical o imaging ea u es; in he USA, he indica ion
s a es ha alem uzumab should gene ally be ese ed o
he ea men o pa ien s wi h elapsing o ms o mul iple
scle osis who ha e had an inadequa e esponse o wo o
mo e disease-modi ying he apies (DMTs). In clinical i-
als, alem uzumab demons a ed e icacy in ea men -naı
¨ e
pa ien s wi h ac i e RRMS and hose elapsing on p io
DMTs, wi h a consis en and manageable sa e y and ol-
e abili y p o ile. The Eu opean Union indica ion p o ides
physicians wi h signi ican lexibili y ega ding ea men
decisions, a o ding he oppo uni y o indi idualized
ea men . Thus, alem uzumab may be an app op ia e
ea men choice ac oss a b oad ange o pa ien s wi h
RRMS, including, o example, ea men -naı
¨ e pa ien s
wi h ac i e disease, pa ien s wi h highly ac i e disease, o
o pa ien s elapsing on p io DMTs. The e a e se e al
p ac icali ies o conside when using alem uzumab,
including he unique dosing egimen, adminis e ed ia
in a enous in usion on 5 consecu i e days a baseline and
on 3 consecu i e days 12 mon hs la e , and as-needed
e ea men (3 consecu i e days a leas 12 mon hs a e he
las cou se) in cases o disease ecu ence. Addi ionally,
ou ine mon hly moni o ing is equi ed o up o 48 mon hs
a e he las in usion o p omp ly iden i y po en ially
se ious au oimmune ad e se e en s. Gi en hese consid-
e a ions, i is bene icial o gain insigh in o how alem-
uzumab is being used in he eal-wo ld clinical se ing.
He e, we epo ecommenda ions om Eu opean mul iple
scle osis expe s ega ding bes p ac ices o alem uzumab
ea men , including managemen o ad e se e en s and
compliance wi h ongoing sa e y moni o ing equi emen s.
&Thomas Be ge
[email p o ec ed]
1
Clinical Depa men o Neu ology, Medical Uni e si y o
Innsb uck, Innsb uck, Aus ia
2
Depa men o Neu ology and Rehabili a ion, Uni e si y o
Tampe e Medical School and Tampe e Uni e si y Hospi al,
Tampe e, Finland
3
Depa men o Clinical Neu oscience, Ka olinska Ins i u e,
S ockholm, Sweden
4
S Vincen ’s Uni e si y Hospi al, Dublin, I eland
5
San Ra aele Scien i ic Ins i u e, Milan, I aly
6
Haukeland Uni e si y Hospi al and Uni e si y o Be gen,
Be gen, No way
7
Hospi al Clı
´nico San Ca los, Mad id, Spain
8
Ins i u e o he Human B ain, Russian Academy o Sciences,
S . Pe e sbu g, Russia
9
Depa men o Neu ology, Neu oimmunological Sec ion,
Uni e si y o Ros ock, Ros ock, Ge many
CNS D ugs (2017) 31:33–50
DOI 10.1007/s40263-016-0394-8
Key Poin s
In he Eu opean Union (EU), alem uzumab is
indica ed o adul pa ien s wi h elapsing- emi ing
mul iple scle osis, wi h ac i e disease de ined by
clinical o imaging ea u es. I can be conside ed as
an ini ial he apeu ic o ea men -naı
¨ e pa ien s
wi h ac i e disease and o pa ien s elapsing on p io
disease-modi ying he apy.
Heal hca e p o ide s should adhe e o he
alem uzumab EU label, which gi es a b oad
de ini ion o pa ien eligibili y o ea men ;
alem uzumab is no sui able o pa ien s wi h
inac i e elapsing- emi ing mul iple scle osis, hose
s able on cu en he apy, o pa ien s wi h
p og essi e mul iple scle osis.
The Risk Managemen P og am in he EU and o he
coun ies in addi ion o he Risk E alua ion and
Mi iga ion S a egy in he USA a e c i ical o ensu e
ea ly de ec ion o po en ial ad e se e en s a ising
du ing and a e alem uzumab ea men and o
ensu e compliance wi h moni o ing equi emen s.
Da a om an ongoing ex ension s udy, om eal-
wo ld s udies, and om pos -ma ke ing sa e y da a
will also be impo an o es ablish long- e m sa e y
o alem uzumab ea men .
1 In oduc ion
Alem uzumab is a humanized monoclonal an ibody
app o ed in mo e han 50 coun ies [1], including he
Eu opean Union (EU) o he ea men o adul pa ien s
wi h ac i e elapsing- emi ing mul iple scle osis (RRMS)
de ined by clinical o imaging ea u es, and he USA o
he ea men o elapsing o ms o mul iple scle osis (MS)
[2,3]. In he USA, he indica ion o alem uzumab s a es
ha i should gene ally be ese ed o pa ien s who ha e
expe ienced an inadequa e esponse o wo o mo e dis-
ease-modi ying he apies (DMTs) [3].
Alem uzumab selec i ely a ge s CD52, a p o ein
exp essed a high le els on he su ace o T and B lym-
phocy es bu a lowe le els on na u al kille cells and o he
cell ypes in ol ed in inna e immuni y, leading o a
selec i e deple ion o ci cula ing T and B cells [4,5],
he eby dec easing in lamma o y MS disease ac i i y.
Following ea men wi h alem uzumab, T and B lympho-
cy es epopula e in a dis inc i e pa e n o e ime ha
esul s in a ebalancing o he immune sys em o e a pe iod
o 3–12 mon hs [5,6].
This mechanism allows o a unique dosing egimen o
12-mg in a enous in usions on 5 consecu i e days a
baseline and on 3 consecu i e days 12 mon hs la e and
may also accoun o he obse ed du able e icacy in he
absence o con inuous ea men , wi h mos pa ien s only
equi ing hese wo ini ial ea men cou ses [2,7,8].
The sa e y and e icacy o alem uzumab ha e been assessed
in phase II and III clinical ials in ea men -naı
¨ e pa ien s
(CAMMS223 [NCT00050778]; CARE-MS I [NCT0053034
8]), in pa ien s wi h ac i e disease despi e ea men wi h
ano he DMT (CARE-MS II [NCT00548405]) (Table 1), and
in ex ension (NCT00930553) and long- e m ollow-up s udies
(NCT02255656) ha include pa ien s om he phase II, III, and
IV ials. The phase II and III s udies all included an ac i e
compa a o a m in which pa ien s we e ea ed wi h subcu a-
neous (SC) in e e on b-1a (IFNb-1a), a DMT wi h an es ab-
lished e icacy ac oss s anda d endpoin s in RRMS [9–13]. In
CAMMS223 and CARE-MS II, wo doses (12 and 24 mg/day)
o alem uzumab we e e alua ed; howe e , discussion o da a in
his a icle will be es ic ed o he 12-mg dose as his is he
app o ed and comme cially a ailable dose [2,9,12].
2 Clinical T ial Expe ience wi h Alem uzumab
2.1 E icacy Da a om Clinical T ials
As discussed, in he h ee pi o al clinical ials, SC IFNb-
1a was included as an ac i e compa a o (Table 1); he e-
o e, all subsequen compa isons ela e o ou comes o
alem uzumab s. SC IFNb-1a. Ac oss he CAMMS223 and
CARE-MS I and II ials, alem uzumab signi ican ly
educed he annualized elapse a e (AAR) (co-p ima y
endpoin ) and was also associa ed wi h signi ican educ-
ions in 6-mon h con i med disabili y wo sening (CDW,
co-p ima y endpoin ) in CAMMS223 [9] and CARE-MS II
[12], and a non-signi ican 30% educ ion in CARE-MS I
[11].
In addi ion, in a ecen analysis o da a om he
CAMMS223 s udy, alem uzumab had g ea e e icacy han
SC IFNb-1a a mon h 36 in each o he unc ional sys ems
ha make up he Expanded Disabili y S a us Scale (EDSS)
sco e, wi h he g ea es e ec s being obse ed in he sen-
so y, py amidal, and ce ebella sys ems, which a e hough
o d i e CDW in RRMS [16]. Ac oss all ials, alem-
uzumab also demons a ed imp o emen s in se e al
magne ic esonance imaging (MRI) ou comes (lesion ol-
ume/load, and b ain a ophy) [9,11,12].
In CARE-MS I and II, alem uzumab- ea ed pa ien s
demons a ed a educed a e o b ain a ophy, as de e -
mined by median yea ly pe cen age change in b ain
34 T. Be ge e al.
pa enchymal ac ion o e 2 yea s [11,17], eaching sig-
ni icance in bo h CARE-MS I (42% educ ion, p 0.0001)
and CARE-MS II (24% educ ion, p= 0.0121) compa ed
wi h SC IFNb-1a a yea 2. Fu he mo e, du able e icacy
(AAR, disabili y, and MRI ou comes, including lesions and
b ain a ophy) was demons a ed h oughou he ex ension
s udies [7,8,13,17–19], wi h he majo i y o pa ien s
(68–94%) no equi ing e ea men wi h alem uzumab o
ano he DMT [17,20]. Key e icacy ou comes om he
clinical ial p og am ials a e summa ized in Table 2.
2.2 Sa e y Da a om Clinical T ials
Alem uzumab has a consis en and manageable sa e y and
ole abili y p o ile as demons a ed ac oss indi idual clin-
ical ials [9,11,12]), en olling a o al o 1694 pa ien s.
Fu he mo e, a simila sa e y and ole abili y p o ile was
also documen ed wi h a long- e m ollow-up (up o 5 yea s)
in he ex ension s udies [7,8,13].
Ne e heless, se e al ad e se e en s (AEs) o in e es
ha e been epo ed (Table 3). The mos equen ly epo ed
AEs in clinical ials we e in usion-associa ed eac ions
(IARs), expe ienced by [90% o pa ien s, which peaked
immedia ely ollowing he ini ial alem uzumab cou se and
hen dec eased wi h subsequen cou ses [21,22]. Few
(B3%) se ious IARs we e epo ed [9,11–13,21,23,24].
The incidence o in ec ions (which we e mainly mild o
mode a e in se e i y) was g ea es du ing he i s mon h
ollowing in usion in all h ee ials [25] bu was lowe in
he CAMMS223 and CARE-MS ex ensions compa ed wi h
he co e s udies, sugges ing a educ ion in in ec ion isk
o e ime [11–13,15].
Thy oid disease was he mos common au oimmune
e en ; howe e , 1% o pa ien s expe ienced se ious hy-
oid AEs [2,9,13,26,27]. Immune h ombocy openic
pu pu a (ITP) was iden i ied as a po en ial isk in he
CAMMS223 s udy, ini ially epo ed in six pa ien s,
including he a al index case in a pa ien ecei ing alem-
uzumab 24 mg [9,28,29]. Ac oss all clinical ials, ITP
incidence was 2% in pa ien s ecei ing alem uzumab 12 o
24 mg (1.6% in pa ien s ecei ing alem uzumab 12 mg)
[11–13,29].
In esponse o he index case and o he au oimmune
e en s, enhanced moni o ing and pa ien educa ion was
Table 1 Alem uzumab clinical ial p og am
CAMMS223
a
[2,9,14] CARE-MS I [2,11,14] CARE-MS II
a
[2,12,14]
Pa ien s wi h ac i e RRMS who we e ea men naı
¨ e Pa ien s wi h ac i e RRMS who elapsed on
p io DMT
S udy du a ion: 3 yea s S udy du a ion: 2 yea s S udy du a ion: 2 yea s
SC IFNb-1a
(44 lg TIW)
N= 111
Alem uzumab
(12 mg/day)
N= 112
SC IFNb-1a
(44 lg TIW)
N= 187
Alem uzumab
(12 mg/day)
N= 376
SC IFNb-1a
(44 lg TIW)
N= 202
Alem uzumab
(12 mg/day)
N= 426
MRI c i e ia: diagnosis pe McDonald 2001
c i e ia, including b ain MRI; C1Gd
?
lesion
on any o B4 b ain scans du ing B3-mon h
un-in pe iod (including baseline scan)
MRI c i e ia: diagnosis pe McDonald 2005
c i e ia; b ain MRI scan demons a ing whi e
ma e lesions a ibu able o MS (wi hin 5
yea s o sc eening)
MRI c i e ia: diagnosis pe McDonald 2005
c i e ia; whi e ma e lesions a ibu able o
MS and a leas one o he ollowing: C9T
2
lesions C3 mm, any axis; a Gd
?
lesion C3
mm, any axis, wi h C1 b ain T
2
lesion;
spinal co d lesion wi h C1 b ain T
2
lesion
Ac i e MS: C2 elapses in he p io 2 yea s
and C1Gd
?
MRI lesion a sc eening
Ac i e MS: C2 elapses in he p io 2 yea s,
wi h C1 elapse occu ing in he yea p io
o s udy en y
Ac i e MS: C2 elapses in he p io 2 yea s,
wi h C1 elapse occu ing in he yea p io
o s udy en y and C1 elapse occu ing
du ing p io ea men
b
Mean age: 32 yea s Mean age: 33 yea s Mean age: 35 yea s
EDSS ange: 0.0–3.0 (mean 2.0)
c
EDSS ange: 0.0–3.0 (mean 2.0)
d
EDSS ange: 0.0–5.0 (mean 2.7)
d
Mean/median ime since i s MS episode: 1.4/
1.3 yea s
Mean/median ime since i s MS episode: 2.0/
1.6 yea s
Mean/median ime since i s MS episode: 4.5/
3.8 yea s
Re ea men c i e ia o CAMMS223 (Sano i Genzyme, da a on ile) and CARE-MS ex ensions [15]: C1 elapse o C2 new o enla ging T
2
and/
o Gd
?
b ain o spinal lesions, C12 mon hs since he second alem uzumab cou se
DMT disease-modi ying he apy, EDSS Expanded Disabili y S a us Scale, Gd
?
gadolinium-enhancing, IFN in e e on, MRI magne ic esonance
imaging, MS mul iple scle osis, RRMS elapsing- emi ing mul iple scle osis, SC subcu aneous, TIW h ee imes pe week
a
A 24-mg/day ea men a m was included in hese s udies
b
T ea men wi h IFNbo gla i ame ace a e o C6 mon hs
c
A sc eening and baseline isi s
d
A sc eening
Recommenda ions o Alem uzumab Use in Clinical P ac ice 35
Table 2 O e iew o he key endpoin s om he alem uzumab clinical ial p og am
CAMMS223 ex ension
[13,20]
CARE-MS I
[8,11,17,18,33,34]
CARE-MS I ex ension
[8,17,18]
CARE-MS II
[7,12,17,19,35]
CARE-MS II ex ension
[7,19]
5-yea da a S udy du a ion: 2 yea s Yea 4 S udy du a ion: 2 yea s Yea 4
SC
IFNb-1a
44 lg
TIW
Alem uzumab
12 mg/day
SC
IFNb-1a
44 lg
TIW
Alem uzumab
12 mg/day
Alem uzumab
12 mg/day
SC
IFNb-1a
44 lg
TIW
Alem uzumab
12 mg/day
Alem uzumab
12 mg/day
Pa ien s en e ing s udy, N111 112 187 376 349 202 426 393
Clinical endpoin s
ARR 0.35 0.12 0.39 0.18 0.14 0.52 0.26 0.23
ARR ela i e educ ion (alem uzumab s. SC
IFNb-1a), %
66 (p 0.0001) 55 (p 0.0001) 49 (p 0.0001)
Relapse- ee pa ien s,
a
% 4168 5978(p
0.0001)
87 47 65 (p
0.0001)
79
Pa ien s wi h 6-mon h CDW,
a
% 38 16 11 8 17 (yea s 0-4) 21 13 24 (yea s 0-4)
CDW ela i e isk educ ion (alem uzumab s.
SC IFNb-1a), %
69 (p= 0.0005) 30 (p= 0.22)
b
42 (p= 0.0084)
Pa ien s wi h 6-mon h CDI,
a
% N/A N/A 27
c
23
(p= 0.5192)
c
30
(yea s 0–4)
13 29
(p= 0.0002)
41 (yea s 0–4)
Mean change in EDSS sco e om baseline 0.46 -0.15
(p= 0.0056)
-0.14 -0.14 (p=
0.97)
-0.09
(yea s 0–4)
0.24 -0.17 (p
0.0001)
0.00 (yea s 0–4)
MRI endpoin s
Gd
?
lesion ee, % 81 93 (p
0.0001)
87 78 91 (p
0.0001)
89
New/enla ging T
2
lesion ee, % 60 78 (p
0.0001)
71 48 76 (p
0.0001)
70
New T
1
hypoin ense lesion ee, % 82 93 (p=
0.0001)
85 74 93 (p
0.0001)
86
MRI ac i i y ee,
d
%5977(p
0.0001)
70 47 76 (p
0.0001)
70
B ain olume change
Median BPF change, % (95% CI) –1.49 -0.87 (p
0.0001)
(yea s 0–2)
-1.134
c
(yea s 0–4)
–0.81 –0.62
(p= 0.0012)
(yea s 0–2)
-0.882
c
(yea s 0–4)
Reduc ion in a e o b ain olume loss, % 42 24
Disease- ee su i al
Pa ien s wi h NEDA,
e
% 273960 143255
36 T. Be ge e al.
Table 2 con inued
CAMMS223 ex ension
[13,20]
CARE-MS I
[8,11,17,18,33,34]
CARE-MS I ex ension
[8,17,18]
CARE-MS II
[7,12,17,19,35]
CARE-MS II ex ension
[7,19]
5-yea da a S udy du a ion: 2 yea s Yea 4 S udy du a ion: 2 yea s Yea 4
SC
IFNb-1a
44 lg
TIW
Alem uzumab
12 mg/day
SC
IFNb-1a
44 lg
TIW
Alem uzumab
12 mg/day
Alem uzumab
12 mg/day
SC
IFNb-1a
44 lg
TIW
Alem uzumab
12 mg/day
Alem uzumab
12 mg/day
Odds a io 1.75 (p= 0.006) 3.03 (p 0.0001) –
Re ea men
Pa ien s no equi ing e ea men , % N/A 94% N/A N/A 74 N/A N/A 68
ARR annualized elapse a e, BPF b ain pa enchymal ac ion, CI con idence in e al, CDI con i med disabili y imp o emen , CDW con i med disabili y wo sening, EDSS Expanded Disabili y
S a us Scale, Gd
?
gadolinium-enhancing, IFN in e e on, MRI magne ic esonance imaging, N/A no applicable, NEDA no e idence o disease ac i i y, SC subcu aneous, TIW h ee imes pe
week
a
Kaplan–Meie es ima es
b
When CAMMS223 and CARE-MS I da a we e pooled, a signi ican educ ion in isk o 6-mon h CDW (50%, p= 0.0029), as well as ARR (56%, p 0.0001) was obse ed, when compa ed
wi h SC IFNb-1a [36]
c
Sano i Genzyme, da a on ile
d
MRI ac i i y- ee was de ined as he absence o bo h Gd
?
lesions and new o enla ging T
2
-hype in ense lesions; clinical disease ac i i y- ee was de ined as he absence bo h o elapses and
6-mon h CDW [8]
e
P e-speci ied e ia y endpoin in CARE-MS I and II. NEDA was de ined as pa ien s who we e MRI and clinically disease ee [8]. NEDA alues a e pe yea . Fo CARE-MS II, he
denomina o o he pe cen age o pa ien s wi h each ype o e en is he o al numbe o pa ien s wi h MRIs pe o med a he gi en ime poin (Sano i Genzyme, da a on ile)
Recommenda ions o Alem uzumab Use in Clinical P ac ice 37

in oduced o ongoing ials, which esul ed in ea ly
iden i ica ion and managemen o ITP cases, as well as
o he au oimmune e en s ( hy oid dys unc ion and
glome uloneph opa hy) in he clinical ials and imp o ed
pa ien ou comes. Subsequen ly, a Risk Managemen P o-
g am (RMP) and a Risk E alua ion and Mi iga ion S a egy
(REMS) [30] we e implemen ed o ensu e ea ly de ec ion
o po en ial AEs in eal-wo ld clinical p ac ice. Ac oss he
clinical de elopmen p og am, he e we e ou epo ed
cases o immune neph opa hy, including one case o an i-
glome ula basemen memb ane (an i-GBM) disease (in
CAMMS223) epo ed 39 mon hs a e he second alem-
uzumab cou se [13,31].
A single a al case o p og essi e mul i ocal leukoen-
cephalopa hy (PML) has been epo ed in a pa ien who
swi ched om na alizumab o alem uzumab. The PML
diagnosis was no made un il a e he pa ien had ecei ed
he i s cou se o alem uzumab; howe e , e ospec i e
analysis o he MRI da a showed ha he onse o PML
p eda ed alem uzumab ea men and, he e o e, was
a ibu ed o na alizumab ea men (Sano i Genzyme, da a
on ile). The e icacy and sa e y ou comes om he alem-
uzumab clinical ials ha e also been ex ensi ely epo ed
in he li e a u e; o u he in o ma ion, we e e he eade
o hese publica ions [9,11–13,32].
2.3 Addi ional Long-Te m Expe ience
wi h Alem uzumab
A long- e m, in es iga o -led, obse a ional coho s udy
has also demons a ed he long- e m e icacy and sa e y o
alem uzumab in pa ien s wi h ac i e RRMS [37]. In his
s udy, 87 pa ien s (39% ha ing ecei ed a p io DMT) we e
ollowed o up o 12 yea s (median ollow-up 7 yea s).
The majo i y o pa ien s (68%) expe ienced an imp o e-
men o s abiliza ion o disabili y (based upon 6-mon h
CDW) compa ed wi h baseline. Re ea men was pe mi ed
in he e en o a elapse wi h 52% o pa ien s ecei ing
only he ini ial wo cou ses, wi h he emainde ecei ing
h ee (36%), ou (8%), o i e (1%) cou ses. The
emaining pa ien s (3%) ecei ed only a single ea men
cou se [37].
3 Use o Alem uzumab in a Real-Wo ld Clinical
Se ing
Real-wo ld da a indica e ha , in he majo i y o pa ien s
wi h ac i e o highly ac i e RRMS, alem uzumab ea -
men is associa ed wi h disease s abiliza ion [37,38]. The e
is, howe e , some deba e ega ding which pa ien s would
bene i mos om alem uzumab ea men . The ollowing
sec ions o his a icle p esen he opinions and ecom-
menda ions o Eu opean MS expe s wi h ega d o iden-
i ying he mos app op ia e pa ien s o alem uzumab
ea men and bes p ac ices o ea men and moni o ing.
3.1 Alem uzumab Indica ion
The EU indica ion o alem uzumab s a es ha alem-
uzumab is sui able o ‘‘adul pa ien s wi h RRMS wi h
ac i e disease de ined by clinical o imaging ea u es’’ [2].
This ep esen s an appa en shi om p e ious egula o y
labeling on he eligibili y o pa ien s o a pa icula DMT
and po en ially allows physicians o use alem uzumab as a
i s -line ea men choice in app op ia e pa ien s. EU
indica ions o o he DMTs (e.g., ingolimod, na alizumab)
a e mo e es ic i e, equi ing e idence o a speci ied le el
o MRI ac i i y, in addi ion o clinical ac i i y be o e
ea men ini ia ion. Fingolimod and na alizumab a e
he e o e ecommended o use in pa ien s wi h highly
ac i e disease who ha e b eak h ough disease ac i i y on a
Table 3 Mos common AEs
obse ed in clinical ials o
alem uzumab 12 mg
CAMMS223
[9,10]
N= 108
CARE-MS I
[11]
N= 376
CARE-MS II
[12]
N= 435
AEs occu ing in [10% o pa ien s, n(%)
In usion-associa ed eac ions 106 (98) 338 (90) 393 (90)
In ec ion 71 (66) 253 (67) 334 (77)
Uppe espi a o y ac 48 (44) 57 (15) 71 (16)
U ina y ac 10 (9) 64 (17) 93 (21)
Au oimmuni y
Any au oimmune hy oid-associa ed e en 28 (26) 68 (18) 69 (16)
Blood and lympha ic sys em diso de s NR 66 (18) 59 (14)
Lymphopenia NR 26 (7) 23 (5)
Leukopenia NR 11 (3) NR
AEs ad e se e en s, NR no epo ed
38 T. Be ge e al.
p e ious DMT (i.e., as a second-line he apy) o in hose
wi h mo e apidly e ol ing se e e RRMS [39,40].
3.2 Is The e a Requi emen o Speci ic Pa ien
P o iles?
The EU indica ion o alem uzumab may p o ide p e-
sc ibing physicians wi h ce ain challenges when deciding
which pa ien s a e mos sui able o ea men , al hough i
also p o ides physicians wi h lexibili y, allowing hem o
use hei own clinical expe ience and judgmen o make an
in o med decision ega ding wha cons i u es ac i e disease
and o p o ide indi idualized ea men choices in collab-
o a ion wi h hei pa ien s. Clinical expe ience may be
mo e aluable han igid ea men guidelines, which
a emp o de ine speci ic pa ien p o iles o ea men
eligibili y. Fu he mo e, de ining a single speci ic pa ien
p o ile o alem uzumab may no be help ul as his may
unin en ionally es ic he use o alem uzumab in ce ain
pa ien s, pa icula ly gi en ha alem uzumab e icacy has
been demons a ed in a b oad ange o pa ien s and ha
subg oup analyses ha e shown ha he e ec s o alem-
uzumab emain consis en ac oss mos demog aphic and
disease cha ac e is ic subg oups [41–43].
The e o e, u he s udies a e equi ed o elucida e he
a iabili y and du abili y o esponse in pa ien s ea ed
wi h alem uzumab o iden i y eliable bioma ke s o clin-
ical cha ac e is ics ha can assis in he managemen o MS
and u he in o m ea men decisions. Recen ly, se e al
g oups ha e in es iga ed he p ognos ic alue o pe iphe al
CD4
?
lymphocy e cell coun eco e y as a po en ial bio-
ma ke o iden i y pa ien s who migh bene i om
e ea men wi h an addi ional cou se o alem uzumab,
al hough he e idence is con lic ing in his ega d [44–46].
3.3 Pe sonal Expe ience wi h Alem uzumab
in Rou ine Clinical P ac ice
In he absence o speci ic pa ien p o iles and alida ed
bioma ke s, pe sonal clinical expe ience will ine i ably
in luence alem uzumab- ela ed ea men decisions. Col-
lec i ely, we ha e ea ed 181 pa ien s wi h alem uzumab,
ei he as a i s -line o as an escala ion he apy in pa ien s
wi h b eak h ough disease ac i i y on a p e ious DMT
(Table 4).
Mos o ou pa ien s ini ia ed ea men wi h alem-
uzumab owing o b eak h ough disease (i.e., ha ing only a
pa ial esponse o, o no esponding o, o he he apies).
In gene al, hese pa ien s had expe ienced one o mo e
elapses wi hin he p e ious 12 mon hs and demons a ed
ecen in lamma o y disease ac i i y (as e idenced ei he
by gadolinium enhancemen (Gd
?
) o by an ob ious
inc ease in T
2
lesion load) on a b ain MRI. Thus, alem-
uzumab use in his g oup o pa ien s was consis en wi h a
ea men escala ion pa adigm. The e was a consensus ha
mo e a o able ea men ou comes a e ypically obse ed
in hese pa ien s i alem uzumab ea men can be ini ia ed
ea ly on in he disease cou se, pa icula ly in pa ien s who
a e younge , ha e highly ac i e disease, and ha e low
le els o disabili y a he s a o ea men . Ne e heless, in
clinical p ac ice, we ha e also ound alem uzumab is e i-
cacious in pa ien s wi h al eady accumula ing disabili y,
pa icula ly when used as a escue he apy o s abilize
disease and p e en u he disabili y wo sening i in lam-
ma o y disease ac i i y (ei he clinically o on MRI) is s ill
o e . We, he e o e, ecommend he use o alem uzumab
in pa ien s wi h ac i e RRMS, ega dless o hei le el o
disabili y.
Howe e , 15% o ou pa ien s ep esen ed a e y
impo an ea men g oup, namely hose who we e ea -
men naı
¨ e bu who p esen ed wi h ea ly, highly ac i e
disease. Compa ed wi h pa ien s ecei ing alem uzumab as
an escala ion he apy, hese pa ien s we e gene ally
younge and had a sho e , bu mo e ac i e disease cou se,
usually wi h wo o mo e elapses in he p eceding 3–6
mon hs (clus e o elapses). We eel ha alem uzumab
may ep esen an e ec i e ea men op ion in ea men -
naı
¨ e pa ien s wi h apidly e ol ing MS (o a clinical
elapse accompanied by an inc ease in he numbe o T
2
lesions and/o ongoing e idence o Gd
?
T
1
lesions), and, as
expe ience g ows and he a o able ou comes associa ed
wi h ea ly in e en ion wi h alem uzumab become e iden ,
alem uzumab use in his pa ien popula ion will inc ease. In
CARE-MS I, alem uzumab signi ican ly educed he a e o
Table 4 Summa y o au ho
expe iences wi h alem uzumab Na ional app o al/ eimbu semen pe iod Sep embe 2013–May 2015
Pa ien s ea ed, N181
Female, n(%) 129 (71)
Age, mean ( ange), yea s 35 (17–66)
Alem uzumab as:
Fi s -line he apy, n(%) 27 (15)
Escala ion he apy, n(%) 154 (85)
Da a p o ided cou esy o he au ho s and ep esen s a summa y o he expe iences in Aus ia, Finland,
Ge many, I eland, I aly, No way, and Spain
Recommenda ions o Alem uzumab Use in Clinical P ac ice 39
b ain olume loss in ea men -naı
¨ e pa ien s wi h MS by
42% compa ed wi h SC IFNb-1a [34], and, gi en he
co ela ion be ween b ain olume loss and disabili y and
cogni i e wo sening [47,48], ea ly ea men wi h alem-
uzumab may be mo e a o able han delaying ea men
(discussed in Sec . 3.4). Indeed, we eel ha ini ia ing
alem uzumab in ea men -naı
¨ e pa ien s may be ad an a-
geous, as lymphocy e le els ha e no been a ec ed by use
o p io DMTs.
In ou expe ience, alem uzumab has a place in ou ine
clinical p ac ice o he ea men o pa ien s elapsing on
p io ea men s, as well as hose who a e ea men naı
¨ e.
Pos poning ea men in a o o escala ing pa ien s
h ough al e na i e DMTs, in e ec e aining alem uzumab
as a las eso , is no ad ised, and we eel ha ini ia ing
alem uzumab as soon as possible, pa icula ly in pa ien s
wi h low le els o disabili y, will be associa ed wi h he
mos a o able ou comes.
3.4 Alem uzumab Ea ly in Mul iple Scle osis
The impo ance o ea ing MS ea ly in he disease cou se
o p e en in lamma o y p ocesses ha lead o i e e sible
b ain loss is well es ablished [49–52]. T adi ionally, he
ea men pa adigm is one o escala ion he apy, du ing
which d ugs wi h g ea e e icacy (o en wi h dis inc
mechanisms o ac ion) bu wi h inc easing isk a e used
as disease p og esses, wi h he mos e icacious d ugs
(e.g., na alizumab, o en conside ed ollowing ailu e o
one o mo e DMTs [53,54]) used as he las line o
he apy. Howe e , da a om alem uzumab clinical s udies
[9,11–13], coupled wi h i s indica ion in he EU [2],
a o d physicians he oppo uni y o s a alem uzumab
ea men in pa ien s wi h ac i e MS ea ly in he disease
cou se o p e en po en ially a oidable CNS damage and
p o ide he pa ien wi h he bes oppo uni y o a o able
ea men ou comes. This may be pa icula ly impo an
o pa ien s wi h ac i e MS wi h poo p ognos ic signs,
o example, pa ien s p esen ing wi h mo o , ce ebella , o
sphinc e in ol emen a onse o hose expe iencing
equen elapses wi h poo eco e y du ing he ea ly
yea s o hei disease [55,56]. The bene i s o ea ly
in e en ion wi h o he DMTs ha e been widely epo ed;
o example, in he pi o al 2-yea SC IFNb-1a s udy
(PRISMS) and i s 2-yea ex ension (PRISMS-4), pa ien s
who s a ed ea men ea ly had imp o ed clinical ou -
comes compa ed wi h pa ien s whose ea men was
delayed [57,58]. These obse a ions ha e been con i med
in long- e m ollow-up s udies [59–61]. Ea ly in e en ion
is hough o add ess he in lamma o y componen o he
disease, he eby educing de elopmen o u he CNS
pa hology [53,62]. Agg essi e he apy ea ly on in he
disease cou se may p o oke an immunological ese and
may, he e o e, a o ably a ec long- e m disease p o-
g ession [53].
Howe e , he concep o ea ly ea men o ac i e dis-
ease wi h an immunomodula o y d ug such as alem-
uzumab, belie ed o ebalance he immune sys em, is no
ye ully es ablished and would ep esen a signi ican
change in mindse o some physicians. In some Eu opean
specialis MS cen e s, pa ien s wi h highly ac i e o apidly
e ol ing se e e RRMS a e al eady conside ed o i s -line
ea men wi h ingolimod o na alizumab (bo h conside ed
ypically second-line he apies in he EU), and, as no ed
abo e, alem uzumab was used as a i s -line he apy in 15%
o all alem uzumab- ea ed pa ien s in ou expe ience
(Table 4). These obse a ions pe haps indica e ha MS
ea men may be mo ing in o a new e a, away om he
escala ion pa adigm and owa d mo e obus ea ly ea -
men o ac i e disease.
3.5 Swi ching o Alem uzumab om P io Disease-
Modi ying The apies
The e icacy o alem uzumab in pa ien s wi h ac i e disease
who had elapsed on p io DMTs is o pa icula clinical
ele ance; in such cases, swi ching he apies should be
conside ed u gen ly o b ing MS ac i i y unde con ol. As
discussed b ie ly abo e (Sec . 2.1, Table 2), he CARE-MS
II s udy demons a ed supe io e icacy wi h alem uzumab
s. SC IFNb-1a in pa ien s wi h ac i e disease who had
elapsed on p io DMTs [12]. The oppo uni y o swi ch
he apies may be pa icula ly impo an o ce ain pa ien
subg oups. Fo example, pa ien s ecei ing na alizumab
he apy o o e 2 yea s and/o who a e posi i e o an i-
John Cunningham i us (an i-JCV) an ibodies, as well as
hose ha ing p e iously ecei ed o he immunosupp essi e
medica ions, a e a inc eased isk o de eloping PML and
may equi e an al e na i e DMT [63]. He e, oo, alem-
uzumab may p o ide a ea men al e na i e op ion.
Howe e , ansi ioning om one pa icula DMT o
ano he can be complex, and a washou pe iod may be
equi ed in ce ain ci cums ances. T ea men cessa ion
guidelines and ecommended washou pe iods a e some-
imes p o ided wi hin he espec i e label o each DMT
(Table 5), al hough he e a e cu en ly no ecommenda-
ions o ansi ioning o alem uzumab om hese indi-
idual DMTs. Howe e , in he CARE-MS II ex ension,
pa ien s who swi ched om SC IFNb-1a o alem uzumab
we e no equi ed o unde go a washou pe iod. The e o e,
i is o en unclea o which ea men ansi ions a washou
pe iod is equi ed, how long i should be, o wha long- e m
sa e y su eillance p ocedu es should be implemen ed [53].
Ne e heless, as wi h o he immunomodula o y he apies,
concomi an ea men , including ini ia ion o alem-
uzumab wi hin he washou pe iod o he p e ious DMT,
40 T. Be ge e al.
is no ad isable, owing o he po en ial isk o ca y-o e
PML om p e ious ea men and addi i e e ec s on he
immune sys em [2]. Consequen ly, i is impo an o con-
side he hal -li e as well as he mechanism o ac ion
(MoA) o he p e ious DMT when ansi ioning o alem-
uzumab [53].
Despi e he absence o speci ic guidance o swi ching o
alem uzumab om he DMTs lis ed in Table 5, he e a e
some conside a ions ha may help guide swi ching in
clinical p ac ice. The p oposed MoA o ingolimod (p e-
en ing lymphocy e eg ess om pe iphe al lymphoid
o gans) esul s in low le els o ci cula ing lymphocy es
[69]. The e o e, i may be ad isable o wai un il lym-
phocy e coun s begin o eco e be o e ini ia ing ea men
wi h a DMT, such as alem uzumab, pa icula ly gi en ha
he p oposed MoA o alem uzumab in MS equi es e ec-
i e a ge ing o ci cula ing T and B cells, leading o hei
deple ion and subsequen epopula ion [4,5,64]. Indeed, a
ecen epo demons a ed clinical and MRI disease
ac i i y in alem uzumab- ea ed pa ien s who had swi ched
om ingolimod bu o whom a po en ially insu icien
washou pe iod ollowing ingolimod cessa ion had been
used, esul ing in lymphocy e coun s below no mal le els
a he ime o alem uzumab ea men . The au ho s
hypo hesized ha he seques a ion o lymphocy es in
lymph nodes, owing o he mechanism o ac ion o in-
golimod, coupled wi h an inadequa e washou pe iod
(median 6 weeks, ange 4–10 weeks) may ha e educed he
e ec i eness o alem uzumab [70].
By con as , he p oposed MoA o dime hyl uma a e
(DMF) (ac i a ion o he nuclea ac o e y h oid 2- ela ed
ac o 2) would gene ally no p edic any issues wi h apid
ansi ion o ano he he apy, al hough DMF has also been
shown o ha e a lymphopenic e ec in ce ain pa ien
popula ions. Thus, as o ingolimod, a washou pe iod
migh be ad isable when ansi ioning o alem uzumab
[64,71]. Un o una ely, o bo h ingolimod and DMF, he
ime pe iod o e which lymphocy es e u n o no mal is
a iable and can ake many weeks, du ing which ime he
pa ien is a isk o elapse [64].
Te i lunomide is also associa ed wi h a educ ion
(*15%, mean wi hin no mal limi s) in lymphocy es and
neu ophil coun s wi hin he i s 3 mon hs ollowing
ea men ; mean lymphocy e and neu ophil coun s hen
emain wi hin he no mal ange o whi e blood cell coun s
(3.8–10.7 910
9
/L) du ing ea men [72]. Pa ien s ecei -
ing e i lunomide ha e he oppo uni y o unde go an
accele a ed elimina ion p ocedu e, which can educe
plasma le els by [96% in 11 days [66,73], po en ially
allowing he ini ia ion o alem uzumab ela i ely quickly
a e s opping e i lunomide.
By con as , na alizumab does no educe ci cula ing
lymphocy e coun s, a he i blocks hei en y o he CNS
esul ing in only mild lymphocy osis [64,74], and he e
may be limi ed bene i in delaying ini ia ing ea men wi h
ano he DMT ollowing na alizumab discon inua ion [64].
In ac , i has been sugges ed ha s a ing a new ea men
immedia ely a e s opping na alizumab (i.e., no a washou
pe iod) may be p e e able because he isk o de eloping
PML, e en in an i-JCV an ibody-posi i e pa ien s, is lowe
han he isk o a se e e elapse [75,76]. In CARE-MS II,
pa ien s p e iously ea ed wi h na alizumab (3%) unde -
wen a 6-mon h washou pe iod be o e s a ing alem-
uzumab [12]. In eal-wo ld clinical se ings, and, in
Table 5 Gene al guidance o he apy cessa ion o common DMTs
In e e ons, gla i ame
ace a e
No speci ic guidance o cessa ion o he apy
a
No washou pe iod ecommended based upon he mechanism o ac ion [64]
Te i lunomide An AEP is a ailable i apid emo al o e i lunomide om he ci cula ion is desi ed [65]
AEP will educe plasma concen a ions o 0.02 mg/L in 11 days. Comple e elimina ion equi es 8 mon hs o 2 yea s in
he absence o AEP [65,66]
Dime hyl uma a e No speci ic guidance o cessa ion o he apy o equi emen o washou [67]
Fingolimod A 6-week ea men - ee pe iod is equi ed o clea ingolimod om ci cula ion [39]
Na alizumab A washou pe iod migh be app op ia e as he pha macodynamic e ec s o na alizumab las o app oxima ely 12
weeks ollowing he las dose [40]
Daclizumab Washou pe iod o 4 weeks is ecommended
b
[68]
Ri uximab/oc elizumab
c
Washou pe iod o 6 mon hs is ecommended
b
[68]
AEP accele a ed elimina ion p ocedu e, DMTs disease-modi ying he apies, EU Eu opean Union, FACS luo escence-ac i a ed cell so ing, IFN
in e e on, MS mul iple scle osis, SC subcu aneous
a
In CARE-MS II [12], no washou pe iod was equi ed o pa ien s swi ching om SC IFNb-1a o alem uzumab
b
Washou guidance is based on ci ed sou ces along wi h he expe opinion o he au ho s
c
Oc elizumab is no ye app o ed o he ea men o MS in he EU
In all cases, he immune compe ence (including FACS analysis o B cells in he case o i uximab/oc elizumab) should be con i med be o e
ini ia ing alem uzumab
Recommenda ions o Alem uzumab Use in Clinical P ac ice 41
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