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FEATURE ARTICLE
Biologic Agents forModerate-to-SeverePlaque PsoriasisMechanisms of Action and Treatment Considerations
Wendy Cantrell, Rhonda Kaler
ABSTRACT: Psoriasis is a chronic, inflammatory, immune-mediated skin disease that affects roughly 2% of adultsin the United States. The immunopathogenic pathwaysassociated with psoriasis are complex, and to effectivelytarget the underlying cytokine networks involved in dis-ease progression, drugs are needed that act on specificcomponents of the immune system. As understandingof the role of proinflammatory signaling molecules in thepsoriatic disease process has evolved, several biologicagents have been engineered to block key cytokinesassociated with psoriasis. Recently, improvements in theunderstanding of the pathogenesis have led to the de-velopment of agents that may target the mechanism ofdisease more directly. This review describes the immu-nopathogenesis of psoriasis and how targeting disease-specific mechanisms with biologic agents may improveclinical outcomes and potentially result in better safetyprofiles than conventional agents. Results from pivotal
clinical studies evaluating the efficacy and safety of ap-proved tumor necrosis factor-> antagonists (etanercept,infliximab, and adalimumab) and the interleukin-12/23inhibitor ustekinumab are summarized. In addition, we in-clude clinical findings to date evaluating a new class ofbiologics that neutralize interleukin-17A (secukinumab,ixekizumab) or act as an interleukin-17 receptor antago-nist (brodalumab). Finally, this review discusses efficacyand safety factors, as well as patient characteristics toconsider, when selecting a biologic agent for psoriasis dis-ease management.Keywords: Biologics, Efficacy, Pathogenesis, Psoriasis, Safety
Psoriasis is a chronic, inflammatory, immune-mediated skin disease affecting an estimated7.5 million Americans (approximately 2.2%of the population), making it the most prev-alent immune-mediated disease in the country
(National Psoriasis Foundation, 2012). The most common(980% of cases) manifestation of psoriasis is chronic plaquepsoriasis, which is characterized by distinctive, raised, redskin lesions that have an adherent, silvery, or silvery-whitescale (Ladizinski et al., 2013). These plaques, which typi-cally appear on the scalp, elbows, knees, and trunk, canpersist for months to years and cause symptoms of pain,itching, burning sensations, stinging, and bleeding in affectedareas (Ladizinski et al., 2013; Villasenor-Park, Wheeler, &Grandinetti, 2012). In addition to these physical symptoms,psoriasis can significantly impair patients’ quality of life, inpart because it is a visually apparent skin disease associatedwith social stigma. The psychological manifestations of pso-riasis can cause feelings of shame, embarrassment, andstress; interfere with personal relationships; create occupa-tional burdens (e.g., lost days of work, reduced productivity,
2.0Contact
Hours
178 Journal of the Dermatology Nurses’ Association
Wendy Cantrell, DNP, CRNP, UABDermatology, Birmingham, AL.Rhonda Kaler, RN, BSN, UAB Dermatology, Birmingham, AL.
WendyCantrell and RhondaKaler participated in an advisory boardand received honorarium from Novartis. The authors have partic-ipated as study staff for Novartis. Research funding is directed toUAB Dermatology and not the authors directly.The authors received no financial support or other form of com-pensation related to the development of this manuscript. Technicalassistance with copyediting and final styling of the manuscript wasprovided by Oxford PharmaGenesis, Inc., and this assistance wassupported by Novartis Pharmaceutical Corporation.
The authors declare no conflicts of interest.
Correspondence concerning this article should be addressed toWendy Cantrell, DNP, CRNP, UABDermatology, 2000 6th AvenueSouth, 3rd Floor, Birmingham, AL 35233.E-mail: [email protected]
DOI: 10.1097/JDN.0000000000000055
Copyright © 2014 Dermatology Nurses' Association. Unauthorized reproduction of this article is prohibited.
workplace discrimination); and increase the likelihood ofabusing alcohol and illicit substances (Feldman, Behnam,Behnam, &Koo, 2005; Hong, Koo, & Koo, 2008; Kimball,Jacobson, Weiss, Vreeland, & Wu, 2005; Young, 2005).Patients with psoriasis are also significantly more likely toreceive a diagnosis of depression, anxiety, or suicidality com-pared with control patients without psoriasis (Kurd, Troxel,Crits-Christoph, & Gelfand, 2010).
Comorbidities are also common in patients with psoria-sis. In a population-based, cross-sectional study, Yeung andcolleagues found that, compared with age- and practice-matched controls (n = 90,350), patients with psoriasis(n = 9035) were significantly more likely to have one ormore comorbidities, including diabetes, rheumatologic dis-ease, renal disease, diabetes with systemic complications,atherosclerotic outcomes (defined as the aggregate of cere-brovascular disease, myocardial infarction, and peripheralvascular disease), mild liver disease, chronic pulmonary dis-ease, peripheral vascular disease, myocardial infarction,or peptic ulcer disease (Yeung, Takeshita, et al., 2013). Theauthors also observed that the burdens of these comorbid-ities increased with increasing psoriasis severity (Yeung,Wan, et al., 2013). The link between psoriasis and thesecomorbidities supports the classification of psoriasis as asystemic inflammatory condition caused by the up-regulationof various cytokines, including tumor necrosis factor->(TNF>), interleukin-1" (IL-1"), and IL-17 (Villasenor-Parket al., 2012). In psoriasis, these cytokines are consequentlyassociated with inflammation and plaque formation; dis-ruption of insulin signaling and lipid metabolism; and in-creased atherosclerotic changes in coronary, cerebral, andperipheral arteries (Golden, McCormick, & Ward, 2013;Villasenor-Park et al., 2012).
As understanding of the role of proinflammatory sig-nalingmolecules in the psoriatic disease process has evolved,several therapies have been developed that inhibit selectcytokines and kinases associatedwith the disease (Schafer,2012; Sivamani et al., 2013). More recently, improvementsin the understanding of psoriasis pathogenesis have led tothe development of agents that may target the mechanismof disease more directly. This review describes the immu-nopathogenesis of psoriasis and how targeting psoriasis-specific disease mechanisms in themoderate-to-severe categorywith biologic agents may improve clinical outcomes andpotentially result in less treatment-related toxicity comparedwith conventional agents. In addition, this review will dis-cuss efficacy and safety factors to consider when selectingbiologic agents for disease management. Although othersystemic therapies are available, treatment has evolved withthe biologics.
PATHOGENESIS OF PSORIASISTriggers for the initiation of psoriasis may include bothchemical and physical insults, such as cutaneous injury,obesity, smoking, alcohol consumption, infection, stress,
pregnancy, hypocalcemia, and certain medications (e.g.,lithium, antimalarials, beta blockers, interferon; Villasenor-Park et al., 2012). In patients with a genetic predispositionfor psoriasis, these insults initiate a cascade that results inhyperproliferation of keratinocytes. This cascade startswhenstressed keratinocytes release self-DNA that forms com-plexes with the antimicrobial protein LL-37, thereby acti-vating dendritic cells (Nestle, Kaplan, & Barker, 2009).As shown in Figure 1 (Johnson-Huang, Lowes, & Krueger,2012), the activated dendritic cells release various cytokines(e.g., IL-12, IL-23, TNF>), which induce T helper 1 (Th1)cells to produce interferon-, and TNF>; Th17 cells to pro-duce IL-17, TNF>, and IL-22; and Th22 cells to produceIL-22 (Johnson-Huang et al., 2012). The increased pro-duction of these cytokines promotes formation and exac-erbation of psoriatic plaques through various mechanisms.Interferon-,, TNF>, and IL-17 induce chemokine expres-sion and production of antimicrobial peptides by keratino-cytes, which enhance local immune-cell recruitment andinflammation, and IL-22 production results in aberrantkeratinocyte proliferation and epidermal hyperplasia(Johnson-Huang et al., 2012).
An understanding of these cytokine pathways has con-tributed to the development and use of various biologicagents for the management of psoriasis. These biologicsare complex molecules that have been engineered to blockkey overproduced proinflammatory cytokines or their recep-tors (Focosi, Maggi, Pistello, Boggi, & Scatena, 2011).The first biologic agents to be used to treat moderate-to-severe psoriasis were TNF> antagonists. The therapeuticpotential of TNF> inhibition for the treatment of psoriasiswas discovered serendipitously when the monoclonal anti-body infliximab was found to improve the psoriatic plaquesof a patient being treated for Crohn’s disease (Oh, Das, &Gottlieb, 2000). Since this discovery, three biologics thattarget TNF> have been studied and approved for the treat-ment of moderate-to-severe (etanercept and adalimumab)or severe (infliximab) plaque psoriasis (AbbVie, 2013;Immunex Corporation, 2013; Janssen Biotech, 2013a).More recently, a fourth biologic agent with a novel mech-anism of action, ustekinumab, has also been approved fortreatingmoderate-to-severe plaque psoriasis (Janssen Biotech,2013b). Ustekinumab is a first-in-class monoclonal anti-body that binds and neutralizes the common p40 subunitof IL-12 and IL-23 (Benson et al., 2011), which, as de-scribed above and in Figure 1, are important cytokines inpsoriasis pathogenesis.
On the basis of evidence showing that some cytokinesof the IL-17 family are expressed at significantly higher levelsin lesional compared with nonlesional psoriatic skin, nu-merous studies have been conducted to elucidate the rolesof these cytokines in psoriasis (Cai et al., 2011; Chiricozziet al., 2011; Krueger et al., 2012). IL-17A has been iden-tified as a central driver in the pathogenesis of psoriasis;neutralization of this cytokine has been shown to rapidlyinhibit downstream cytokine and chemokine networks in
VOLUME 6 | NUMBER 4 | JULY/AUGUST 2014 179
Copyright © 2014 Dermatology Nurses' Association. Unauthorized reproduction of this article is prohibited.
the psoriatic cascade, resulting in near-complete reversalof the psoriatic phenotype (Hueber et al., 2010; Kruegeret al., 2012). Two biologics targeting IL-17A (secukinumaband ixekizumab) and one targeting the IL-17 receptor(brodalumab)are currentlyunder researchclinical development.
The next sections of this review discuss key findingsfrom randomized controlled trials (RCTs) of the approvedTNF> antagonists and IL-12/IL-23 inhibitor as well asinhibitors of the IL-17 family of cytokines. Tables 1 and 2provide a summary of each of the RCTs discussed. Severaloral medications are also in development for the treatmentof psoriasis, but this review focuses only on injectable bio-logic agents.
TNF> ANTAGONISTSTNF> antagonists are the current gold standard amongbiologic therapies for the treatment of psoriasis as wellas being treatment options for psoriatic arthritis, rheuma-toid arthritis, and Crohn’s disease (Tak & Kalden, 2011).However, because TNF> acts broadly to stimulate immuneresponses and induce other inflammatory cytokines, in-hibiting TNF> can potentially result in adverse events (AEs)such as infections, malignancies, neurologic complications,and autoimmune disorders (Silva, Ortigosa, & Benard,2010; Tak & Kalden, 2011). Key efficacy findings frompsoriasis RCTs of etanercept, infliximab, and adalimumabare presented here, followed by a discussion of safety andtolerability factors to consider when prescribing TNF>antagonists.
EtanerceptThe first biologic agent approved for the treatment ofmoderate-to-severe plaque psoriasis was etanercept, a re-combinant human TNF> receptor protein that inhibits bothsoluble and membrane-bound TNF> (Levy, Solomon, &Emer, 2012). Etanercept received United States Food andDrug Administration (FDA) approval for this indicationin 2004 (U.S. FDA, n.d.), with a recommended startingdose of 50 mg twice weekly for 3 months, followed bymaintenance dosing of 50 mg once weekly (Immunex Cor-poration, 2013). Etanercept is administered via subcuta-neous injection; with proper training, etanercept can beself-administered using prefilled syringes or autoinjectors(Immunex Corporation, 2013).
In a 24-week double-blind RCT in 652 patients withmoderate-to-severe plaque psoriasis, Psoriasis Area andSeverity Index (PASI) improvements of 75% or more (PASI75) from baseline were achieved at Week 12 (primary endpoint) by 49% of patients treated with etanercept 50 mgtwice weekly (high dose), 34% of patients treated withetanercept 25 mg twice weekly (medium dose), and 14%of patients treated with etanercept 25 mg once weekly(low dose), compared with 4% of patients receivingplacebo (all ps G .001; Leonardi et al., 2003). At the sametime point, PASI improvements of 90% or more (PASI 90)were achieved by 22%, 12%, and 3% of patients in theetanercept high-, medium-, and low-dose groups, respec-tively, compared with 1% in the placebo group (p G .001for the high- and medium-dose groups vs. placebo). After
FIGURE 1. Immunopathogenesis of psoriasis. Reprinted with permission from Johnson-Huang, L. M., Lowes, M. A., andKrueger, J. G. (2012).
180 Journal of the Dermatology Nurses’ Association
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TABLE
1.Su
mmaryofKey
Clinical
TrialsofBiologics
Approve
dfortheTrea
tmen
tofModerate-to-Sev
erePlaquePsoriasis
Stud
yn*
Stud
yDesign
Treatm
ent
Regim
ens
Effic
acyOutcomes
Safety
Outcomes
Etanercept
Leona
rdi
eta
l.,20
0365
224
-week
multicenter,
randomized
DBstudy
From
base
lineto
Week12
,patie
nts
were
randomized
toreceive:
&Etanercept,50
mgtw
ice/w
eek
&Etanercept,25
mgtw
ice/w
eek
&Etanercept,25
mgonce/w
eek
&Placebo
Week-24
PASI
75resp
onse
:&59
%with
50mgtw
ice/w
eek
&44
%with
25mgtw
ice/w
eek
&25
%with
25mgonce/w
eek
AEs
inQ10
%ofpatie
nts
inany
treatm
entgroup
atWeek24
included
injectio
n-site
reactio
ns,
headache,and
upper
resp
iratory
infectio
n.
Week-24
PASI
90resp
onse
:&30
%with
50mgtw
ice/w
eek
&20
%with
25mgtw
ice/w
eek
&6%
with
25mgonce/w
eek
Nocase
sofTB
oropportunistic
infectio
nswere
reported.
AtWeek12
,patie
nts
intheplacebo
group
were
switc
hed
toeta
nercept
25mgtw
ice/w
eek.
Pappet
al.,
2005
583
24-w
eek
multicenter,
randomized
DBstudy
From
base
lineto
Week12
,patie
nts
were
randomized
toreceive:
&Etanercept,50
mgtw
ice/w
eek
&Etanercept,25
mgtw
ice/w
eek
&Placebo
Week-24
PASI
75resp
onse
:&54
%ofpatie
nts
switc
hed
from
50mgtw
ice/w
eekto
25mg
twice/w
eek
&45
%with
contin
uouseta
nercept
25mgtw
ice/w
eek
&28
%ofpatie
nts
switc
hed
from
placeboto
eta
nercept
25mgtw
ice/w
eek
AEs
inQ10
%ofpatie
nts
inany
treatm
entgroup
from
base
lineto
Week12
orWeeks
13Y2
4included
injectio
n-site
reactio
ns,upper
resp
iratory
infectio
n,headache,
and
injectio
n-site
ecchym
osis.
AtWeek12
,allpatie
nts
were
switc
hed
toeta
nercept25
mgtw
ice/w
eek.
Twelvepatie
nts
exp
erie
nced
serio
usAEs,including
onese
rious
infectio
useve
nt.
Infliximab
EXPR
ESS
(Reich
etal.,
2005)
378
50-w
eek
multicenter,
randomized
DBstudy
From
base
lineto
Week24
,patie
nts
were
randomized
toreceiveinfusio
ns
atWeeks
0,2,
and
6and
theneve
ry8weeks
of:
&Infliximab,5mg/kg
&Placebo
AtWeek24
:&PA
SI75
wasachieve
dby82
%with
infliximab
versus4%
with
placebo(p
G.000
1)&PA
SI90
wasachieve
dby58
%with
infliximab
versus1%
with
placebo(p
G.000
1)
AEs
inQ10
%ofpatie
nts
inany
treatm
entgroup
from
base
lineto
Week24
includedupperresp
iratory
tractinfectio
nandhe
adache.
AtWeek24
,patie
nts
intheplacebo
group
switc
hed
toinfliximab
infusio
ns
atW
eeks
24,2
6,and30
andtheneve
ry8weeks
toWeek46
.
AtWeek50
:&PA
SI75
wasachieve
dby
61%
with
infliximab
versus
77%
with
placebo/infliximab
&PA
SI90
wasachieve
dby
45%
with
infliximab
versus50
%with
placebo/infliximab
Serio
usAEs
reported
by3%
with
placebove
rsus6%
with
infliximab.
(contin
ued)
VOLUME 6 | NUMBER 4 | JULY/AUGUST 2014 181
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TABLE
1.Su
mmaryofK
eyClin
icalTrialsofB
iologics
ApprovedfortheTreatm
ento
fModerate-to-SeverePlaquePsoriasis,C
ontin
ued
Stud
yn*
Stud
yDesign
Treatm
ent
Regim
ens
Effic
acyOutcomes
Safety
Outcomes
EXPR
ESSII
(Menter
etal.,
2007
)
835
50-w
eek
multicenter,
randomized
DBstudy
Atbase
line,patie
nts
were
randomized
toreceiveinfliximab
3or5mg/kg
orplacebo.
AtWeek14
,patie
nts
intheinfliximab
groupswere
rerandomized
tocontin
uous(e
very
8weeks)or
interm
ittent(a
s-needed)therapy.
Patie
ntsin
theplacebogroupsw
itched
toinfliximab
5mg/kgatWeeks
16,18
,and
22and
theneve
ry8weeks.
Week-26
PASI
75and
PASI
90:
&65
%and
33%
with
3mg/kgeve
ry8weeks
&42%and
20%with
3mg/kgasn
eeded
&78%and
56%with
5mg/kgev
ery
8wee
ks&58%and
24%with
5mg/kgasne
eded
Wee
k-50
PASI75
and
PASI90:
&44%and
25%with
3mg/kgev
ery
8wee
ks&25%and
10%with
3mg/kgasne
eded
&54%and
34%with
5mg/kgev
ery
8wee
ks&38%and
10%with
5mg/kgasne
eded
AEs
inQ10
%ofpatie
nts
inany
treatm
entgroup
from
base
lineto
Week14
includedupperresp
iratory
tractinfectio
n,h
eadache,a
ndinfusio
nreactio
n.
From
Weeks
0to
50,twocase
sofTB
and12
malig
nancieswere
reported.
Adalim
umab
Gordon
etal.,2006
147
12-w
eek
multicenter,
randomized
DBstudywith
48-w
eek
extensio
n
From
base
lineto
Week12
,patie
nts
were
randomized
toreceive:
&80
-mgadalim
umabatW
eeks
0and
1and
then40
mg/w
eekstarting
atW
eek2
&80
-mgadalim
umab
atWeek0and
then40
mgeow
startingatWeek1
&Placeboweekly
Patie
nts
whocompleted
12weeks
could
entera
48-w
eekextensio
n:
&Pa
tients
inadalim
umab
groups
contin
ued
theirassigned
dose
s&Pa
tients
onplacebosw
itched
toadalim
umab
80mgatWeek12
and
then40
mgeow
Week-24
PASI
75and
PASI
100:
&72
%and
24%
with
40mg/w
eek
&64
%and
13%
with
40mgeow
&55
%and
11%
with
placebo/40mgeow
Week-36
PASI
75and
PASI
100:
&68
%and
36%
with
40mg/w
eek
&62
%and
22%
with
40mgeow
&57
%and
19%
with
placebo/40mgeow
Week-60
PASI
75and
PASI
100:
&64
%and
26%
with
40mg/w
eek
&56
%and
16%
with
40mgeow
&45
%and
19%
with
placebo/40mgeow
AEs
inQ10
%ofpatie
nts
inany
treatm
entgroup
from
Weeks
12to
60included
naso
pharyngitis,upper
resp
iratory
tractinfectio
n,skin
papillo
ma,and
headache.
Fourteenpatie
nts
receiving
adalim
umab
exp
erie
nced
serio
us
AEs,including
twomalig
nant
melanomas,onesq
uamouscell
carcinoma,onebreast
carcinoma,
and
onegastric
adenocarcinoma.
Intheadalim
umab
groups,one
patie
ntwasdiagnose
dwith
coccidioidomyc
osis,and
one
patie
ntwasdiagnose
dwith
TB.
(contin
ued)
182 Journal of the Dermatology Nurses’ Association
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TABLE
1.Su
mmaryofK
eyClin
icalTrialsofB
iologics
ApprovedfortheTreatm
ento
fModerate-to-SeverePlaquePsoriasis,C
ontin
ued
Stud
yn*
Stud
yDesign
Treatm
ent
Regim
ens
Effic
acyOutcomes
Safety
Outcomes
REV
EAL
(Menter
eta
l.,20
08)
1,21
252
-week
multicenter,
randomized
DBstudy
From
base
lineto
Week15
,patie
nts
were
randomized
(2:1)to:
&Adalim
umab
80mgatWeek0
and
then40
mgeow
&Placebo-m
atching
adalim
umab
AtWeek24
,PA
SI75
and
PASI
90were
achieve
dby70
%and
49%
ofpatie
nts
inthepooled
adalim
umab
group.
AEs
inQ5%
ofpatie
nts
inany
treatm
entgroup
from
base
lineto
Week16
includedupperresp
iratory
tractinfectio
n,n
aso
pharyngitis,
andheadache
.
From
Weeks
17to
31,allpatie
nts
received
OLadalim
umab
40mgeow.
From
Weeks
33to
52,PA
SIresp
onse
fellbelow
50%
for
28%
ofpatie
nts
rerandomized
toplacebove
rsus5%
rerandomized
tocontin
ueadalim
umab
(pG.001
).
ThroughWeek16
,se
riousinfectio
ns
occurre
din
fourpatie
nts
(1%)with
placeboand
fivepatie
nts
(0.6%)
with
adalim
umab
(includingone
case
ofTB);m
alig
nanciesexc
luding
NMSC
occurre
din
0.3%
and
0.2%
,resp
ectiv
ely;a
ndNMSC
occurre
din
0.3%
and0.5%
,resp
ectiv
ely.
AtWeek33
,patie
nts
orig
inally
randomized
toactiv
etreatm
ent
whoachieve
dPA
SI75
were
rerandomize
dto
adalim
umab40
mg
eow
orp
lacebothroughWeek52
.
Ustekinumab
PHOEN
IX1
(Leona
rdi
eta
l.,20
08)
766
76-w
eek
multicenter,
randomized
DBstudy
From
base
lineto
Week12
,patie
nts
were
randomized
toreceive:
&Ustekinumab
45mgatWeeks
0and
4and
theneve
ry12
weeks
&Ustekinumab
90mgatWeeks
0and
4and
theneve
ry12
weeks
&PlaceboatWeeks
0and
4
Week-28
PASI
75and
PASI
90:
&71
%and
49%
with
ustekinumab
45mg
&79
%and
56%
with
ustekinumab
90mg
&66
%and
45%
with
placeboto
ustekinumab
45mg
&85
%and
62%
with
placeboto
ustekinumab
90mg
AEs
inQ5%
ofpatie
nts
inany
treatm
entgroup
(reported
from
Weeks
0Y12
,12
Y40,
and
40Y7
6)included
upperresp
iratory
tract
infectio
n,na
sopha
ryng
itis,arth
ralgia,
and
headache
.
AtWeek12
,placebogroup
switc
hed
toustekinumab
45or90
mgatWeeks
12and
16theneve
ry12
weeks.
AtWeek40
,PA
SI75
resp
onders
inthe
ustekinumab
groupswere
rerandomized
toplaceboor
contin
uoustherapy.
Among
patie
nts
rerandomized
at
Week40
,maintenanceofPA
SI75
wasbetterwith
maintenance
therapyve
rsuswith
drawal
from
therapythroughatleast
1ye
ar(p
G.000
1).Median
PASI
%im
prove
mentwasstable
toatleast
Week76
inthe
contin
uous-therapygroups.
Seve
nse
riousinfectio
ns,four
cuta
neouscancers,three
noncuta
neouscancers,and
four
cardiova
sculareve
nts
were
reported
across
treatm
entgroups
and
treatm
ent
pha
sesforinc
idenc
es
ofe
1.3%
,e1.2%
,e0.8%
,and
e0.8%
,resp
ectiv
ely.
(contin
ued)
VOLUME 6 | NUMBER 4 | JULY/AUGUST 2014 183
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TABLE
1.Su
mmaryofK
eyClin
icalTrialsofB
iologics
ApprovedfortheTreatm
ento
fModerate-to-SeverePlaquePsoriasis,C
ontin
ued
Stud
yn*
Stud
yDesign
Treatm
ent
Regim
ens
Effic
acyOutcomes
Safety
Outcomes
PHOEN
IX2(Papp
eta
l.,20
08)
1,23
052
-week
multicenter,
randomized
DBstudy
From
base
lineto
Week12
,patie
nts
were
randomized
toreceive:
&Ustekinumab
45mgatWeeks
0and
4and
theneve
ry12
weeks
&Ustekinumab
90mgatWeeks
0and
4and
theneve
ry12
weeks
&PlaceboatWeeks
0and
4
Week-28
PASI
75and
PASI
90:
&70
%and
45%
with
ustekinumab
45mg
&79
%and54
%with
ustekinumab
90mg
&70
%and42
%with
placeboto
ustekinumab45
mg
&79
%and52
%with
placeboto
ustekinumab90
mg
AEs
inQ5%
ofpatie
nts
inany
treatm
entgroup
(reported
from
Weeks
0Y12
,12
Y28,
and
28Y5
2)included
upperresp
iratory
tract
infectio
n,n
aso
pharyngitis,arthralgia,
headache,injectio
n-site
erythema,
and
cough.
Seve
nse
rious
infectio
ns,eight
cutane
ous
canc
ers,twono
ncutane
ous
cancers,a
ndonecardiova
scular
eve
ntwere
reportedacross
treatm
entg
roupsandtreatm
ent
phase
sforincidencesofe
1.2%
,e1.3%
,e1.3%
,ande0.2%
,resp
ectiv
ely.
AtWeek12
,theplacebogroup
switc
hed
toustekinumab
45or
90mgatWeeks
12and
16and
theneve
ry12
weeks.
AtWeek28
,partialresp
onders
(PASI
50to
G75
)to
ustekinumab
rerandomized
totreatm
enteve
ry8or12
weeks.
Dosin
gintensificatio
nforpartial
resp
onders
atWeek28
did
not
improve
resp
onse
inthe45
-mg
group.In
contrast,intensificatio
nin
the90
-mggroup
improve
doutcomes:PA
SI75
wasachieve
dby
69%
ofpatie
nts
dose
deve
ry8weeks
versus33
%dose
deve
ry12
weeks
(p=.004
).
ACCEP
T(G
riffiths
eta
l.,20
10)
903
64-w
eek
multicenter,
randomized
study
From
base
lineto
Week12
,patie
nts
were
randomized
toreceive:
&Ustekinu
mab45
mgatW
eeks
0and
4&Ustekinu
mab90
mgatW
eeks
0and
4&Etane
rcept5
0mgtw
ice/w
eek
throug
hWeek12
Afterbeing
switc
hed
toustekinum
ab90
mgfor1
2weeks,
PASI75
wasachieve
dby49
%and
PASI90
wasachieve
dby23
%of
patie
ntswhodid
notresp
ondto
etanerceptb
yWeek12
.
AEs
in910
%ofpatie
nts
inany
treatm
entgroup
(reported
from
Weeks
0Y12
and
0Y64
)included
naso
pharyngitis,upperresp
iratory
tractinfectio
n,headache,back
pain,and
injectio
n-site
reactio
n.
Treatm
ent
wasinterru
ptedatW
eek12
forresp
ond
ers.
Patie
ntsin
ustekinumabgroupswere
retreatedifmoderate,m
arked,o
rse
vere
dise
ase
recurred.E
tane
rcept
nonrespon
derssw
itche
dto
ustekin
umab
90mgatW
eek
s16
and
20.
Ratesofmalig
nanciesotherthan
nonmelanoma
skin
cancerwere
e1.0%
;ratesofNMSC
were
e1.7%
.
Abbreviatio
ns:
AE=adve
rseeve
nt;DB=double-blind;eow
=eve
ryotherweek;
NMSC
=nonmelanoma
skin
cancer;OL=open-la
bel;PA
SI=Psoria
sisArea
and
Seve
rityIndex;
TB=tuberculosis.
*Numberrandomized
and
treated.
184 Journal of the Dermatology Nurses’ Association
Copyright © 2014 Dermatology Nurses' Association. Unauthorized reproduction of this article is prohibited.
TABLE
2.Su
mmaryofPreliminaryResultsorStudyDesignsforPhase3Clinical
TrialsofBiologics
inDev
elopmen
tforthe
Trea
tmen
tofModerate-to-Sev
erePlaquePsoriasis
Stud
yn
Stud
yDesign
Treatm
ent
Regim
ens
Effic
acyEn
dPo
ints/O
utcomes
Safety
EndPo
ints/O
utcomes
Secukinumab
FIXTURE
(NCT01358578;
Lang
ley
etal.,20
13)
1,30
652
-week
multicenter,
randomized
DB
studywith
8-week
follo
w-up
Patie
ntswere
rand
omize
dto
receive:
&Se
cuk
inum
ab15
0mgonc
ea
weekfor5
weeks
and
then15
0mg
onc
emonthly
&Se
cuk
inum
ab30
0mgonc
ea
weekfor5
weeks
and
then30
0mg
onc
emonthly
&Etane
rcept5
0mgtw
ice/w
eekfor
12weeks
and
thenonc
e/w
eek
&Placebo
Week-12
PASI
75and
IGA
mod
2011
0/1resp
onse
:&77
%and
63%
with
secuk
inum
ab
300mg
&44
%and
27%
with
etane
rcept
(both
ps=.025
0vs.secuk
inum
ab)
Naso
pharyngitisand
headachewere
themost
commonAEs.
Wee
k-16
PASI90
and
100respon
se:
&72
%and
37%
with
secukinum
ab
300mg
&~30
%and
G10
%with
etane
rcept
Serio
usAEs
exp
erie
nced
by
5.8%
,5.1%,a
nd6.2%
ofp
atie
nts
inthe30
0-mg-secukinum
ab,
150-mg-secukinumab,a
nd
etane
rcep
tgroup
s,respec
tively.
Resp
onsesto
secuk
inum
abwere
sustainedthroug
hWeek52
.
SCULPTUR
E(NCT01406938;
Mrowietz
etal.,20
13)
966
52-w
eek
multicenter,
randomized
DB
studywith
8-week
follo
w-up
Patie
ntswere
rand
omize
dto
receive:
&Se
cuk
inum
ab15
0mgonc
ea
weekfor5
weeks
&Se
cuk
inum
ab30
0mgonc
ea
weekfor5
weeks
Week-12
PASI
75,PA
SI90
,and
PASI
100resp
onse
:&90
%,64
%,and
26%
with
secukinumab
300mg
&84
%,49
%,and
16%
with
secukinumab
150mg
Naso
pharyngitis,upper
resp
iratory
tractinfectio
n,
and
headachewere
the
most
commonAEs.
AtWeek12
,patie
nts
with
PASI
75resp
onse
were
rerandomized
tothesa
medose
ofse
cukinumab
as
contin
uoustherapy(o
nce/m
onth)
orasneeded
forrelapse
.
Patie
ntswhoachieve
dPA
SI75
at
Week12
were
more
likelyto
maintain
theirresp
onseiftheyreceived
secuk
inum
abatfixe
dmonthlyintervals
comparedwith
as-ne
ededtre
atm
ent
at
thestartofrelapse
.
Serio
usAEs
exp
erie
nced
by6.5%
Y8.3%
and5.9%
Y6.4%
ofpatie
nts
inthe
300-mg-secukinumab
and
150-mg-secukinumab
groups,resp
ectiv
ely.
ERASURE
(NCT01365455;
Elewskie
tal.,
2013
)
738
52-w
eek
multicenter,
randomized
DB
studywith
8-week
follo
w-up
Patie
ntswere
rand
omize
dto
receive:
&Se
cuk
inum
ab15
0mgonc
ea
weekfor5
weeks
and
then15
0mg
onc
emonthly
&Se
cuk
inum
ab30
0mgonc
ea
weekfor5
weeks
and
then30
0mg
onc
emonthly
&Placebo
Secukinumab30
0mgwasmore
effectiv
ethan15
0mgforimproving
PASI75
(pG.01)
orIGA
mod
2011
0/1
(pG.002
)resp
onse
atWeek12
.
Naso
pharyngitis,upper
resp
iratory
tractinfectio
n,
and
headachewere
the
most
commonAEs.
Serio
usAEs
exp
erie
nced
by
5.4%
,5.4%,a
nd2.0%
ofp
atie
nts
inthe30
0-mg-secuk
inum
ab,
150-mg-secuk
inum
ab,a
ndplacebogroup
s,respectively.
(contin
ued)
VOLUME 6 | NUMBER 4 | JULY/AUGUST 2014 185
Copyright © 2014 Dermatology Nurses' Association. Unauthorized reproduction of this article is prohibited.
TABLE
2.Su
mmaryofPreliminaryResultsorStudyDesignsforPhase3Clinical
TrialsofBiologics
inDev
elopmen
tforthe
Trea
tmen
tofModerate-to-Sev
erePlaquePsoriasis,Continued
Stud
yn
Stud
yDesign
Treatm
ent
Regim
ens
Effic
acyEn
dPo
ints/O
utcomes
Safety
EndPo
ints/O
utcomes
Ixekizu
mab
UNCOVER
-3(NCT01646177)
1,22
5*12-w
eekmulticen
ter,
rand
omize
dDBstu
dy
with
amultiye
ar
extensio
n
Patie
nts
were
randomized
toreceive:
&Ixekizu
mab
2�
80mgatWeek0and
then1�
80mgperdosin
gregim
en
1to
Week12
and
thensw
itche
dto
dosin
gregim
en2
&Ixekizumab2�80
mgatW
eek0and
then
1�
80mgperd
osin
gregim
en2to
Week
264
&Etane
rcept5
0mgtw
iceaweekfro
mWeeks
0to
12and
thensw
itche
dto
dosin
gregim
en2
&Placebofro
mWeeks
0to
12and
then
switc
hedto
dosin
gregim
en2
Prim
ary
outcomesare
PASI
and
sPGA
atWeek12
.Sa
fety
outcomeswere
not
specified.
Estim
atedcompletio
ndate:A
pril20
19(p
rimary
end
point:
July20
14)
Secondary
outcomes
includePA
SI,sPGA,and
QoL
assessmentsatW
eek12
.
UNCOVER
-2(NCT01597245)
1,22
5*60
-weekmultic
enter,
rand
omize
d,D
Bstud
yPa
tients
randomized
toreceive:
&Ixekizu
mab
2�
80mgatWeek0and
then1�
80mgperdosin
gregim
en
1to
Week12
&Ixekizu
mab
2�
80mgatWeek0and
then1�
80mgperdosin
gregim
en
2to
Week12
&Etanercept50
mgtw
icea
week
from
Weeks
0to
12&Placebo
Prim
ary
outcomesare
PASI
and
sPGA
atWeek12
.Sa
fety
outcomeswere
not
specified.
Estim
atedcompletio
ndate:D
ecember
2018
(prim
ary
end
point:Se
ptember
2014
)
Secondary
outcomes
includePA
SI,sPGA,and
QoL
assessments
at
Week60
.
UNCOVER-A
(NCT01777191)
180*
12-w
eekRCTwith
optio
nal4
0-week
safety
extensio
n
Patie
nts
randomized
toreceive:
&Ixekizu
mab
80mgadministered
subcuta
neously
with
anautoinjector
&Ixekizu
mab
80mgadministered
subcuta
neously
with
aprefilled
syrin
ge
Prim
ary
outcomesare
PKproperties:C
maxfrom
Days
2to
14and
AUC
from
time0to
Day14
.
Safety
outcomeswere
not
specified.
Estim
atedcompletio
ndate:Janu
ary20
15Se
cond
ary
outcomesinclude
PASI,sPG
A,n
umbero
fdevice
failuresatW
eek12
,and
QoL
assessmentsatW
eek8.
(contin
ued)
186 Journal of the Dermatology Nurses’ Association
Copyright © 2014 Dermatology Nurses' Association. Unauthorized reproduction of this article is prohibited.
TABLE
2.Su
mmaryofPreliminaryResultsorStudyDesignsforPhase3Clinical
TrialsofBiologics
inDev
elopmen
tforthe
Trea
tmen
tofModerate-to-Sev
erePlaquePsoriasis,Continued
Stud
yn
Stud
yDesign
Treatm
ent
Regim
ens
Effic
acyEn
dPo
ints/O
utco
mes
Safety
EndPo
ints/O
utcomes
Brodalumab
AMAGINE-1
(NCT01708590)
600*
5-ye
armulticenter,
randomized
DBstudy
From
baselineto
Week12
,patie
nts
were
rand
omizedto
receive:
&sc
brodalumab
210mg
&sc
brodalumab14
0mg
&Placebo
Prim
ary
outcomesare
PASI
and
sPGA
atWeek12
.Sa
fety
tobeassessed
at12
weeks
and
5ye
ars,
includingAEs,A
Esofinterest,a
ndpresenc
eofa
ntibrodalumabantibodies.
Estim
ated
completio
ndate:Se
ptember20
18(p
rimary
end
point:
March20
14)
AtWeek12
,patie
nts
inthe
brodalumab
groups
rerandomized
toplaceboor
contin
ued
treatm
ent.
Secondary
outcomesare
PASI,sPGA,and
patie
nt
symptom
scoresatWeeks
12and
52.
AMAGINE-2
(NCT01708603)
1,80
0*5-ye
armulticenter,
randomized
DBstudy
From
baselineto
Week12
,patie
nts
were
rand
omizedto
receive:
&sc
brodalumab21
0mg
&sc
brodalumab14
0mg
&sc
ustekinum
abaccording
tolabel
&Placebo
Prim
ary
outcomesare
PASI
and
sPGA
atWeek12
.Sa
fety
tobeassessed
at12
weeks
and
5ye
ars,
includingAEs,A
Esofinterest,a
ndpresenc
eofa
ntibrodalumabantibodies.
Estim
ated
completio
ndate,Se
ptember20
18(p
rimary
end
point
August
2014
)
AtWeek12
,patie
nts
inthe
brodalumab
groupswere
rerandomized
tooneoffour
dosin
gsc
hedules.
Secondary
outcomesare
PASI,sPGA,and
patie
nt
symptom
scoresatWeeks
12and
52.
AMAGINE-3
(NCT017
0862
9)1,88
1*5-ye
armulticenter,
randomized
DBstudy
From
baselineto
Week12
,patie
nts
were
rand
omizedto
receive:
&sc
brodalumab21
0mg
&sc
brodalumab14
0mg
&sc
ustekinum
abaccording
tolabel
&Placebo
Prim
ary
outcomesare
PASI
and
sPGA
atWeek12
.Sa
fety
tobeassessed
at12
weeks
and
5ye
ars,including
AEs,AEs
ofinterest,
and
prese
nceofantib
rodalumab
antib
odies.
Estim
ated
completio
ndate:October20
18(p
rimary
end
point:
September20
14)
AtWeek12
,patie
nts
inthe
brodalumab
groupswere
rerandomized
tooneoffour
dosin
gsc
hedules.
Secondary
outcomesare
PASI,sPGA,and
patie
nt
symptom
scoresatWeeks
12and
52.
Abbreviatio
ns:AE=adve
rseeve
nt;AUC
=areaundertheconcentratio
n-tim
ecurve;C
max=maximum
plasm
aconcentratio
n;DB=double-blind;IG
Amod20
11=Inve
stigator’sGlobalA
ssessment
modified
2011
;PA
SI=Psoria
sisArea
and
Seve
rityIndex;
PK=pharm
acokinetic
;QoL=qualityoflife;sc
=subcuta
neous;sPGA
=static
Physician’s
GlobalA
ssessment.
*Estim
ated
enrollm
ent.
VOLUME 6 | NUMBER 4 | JULY/AUGUST 2014 187
Copyright © 2014 Dermatology Nurses' Association. Unauthorized reproduction of this article is prohibited.
12 weeks, patients in the placebo group were switched todouble-blind etanercept 25 mg twice weekly. FromWeeks12 to 24, PASI responses were generally maintained in adose-dependent manner (Table 1; Leonardi et al., 2003).
Subsequently, Papp and colleagues conducted a 24-weekRCT to further assess the efficacy and safety of etanerceptin patients with clinically stable moderate-to-severe plaquepsoriasis (Papp et al., 2005). In this study, 583 patientswere randomized (1:1:1) to receive double-blind etanercept25 or 50 mg twice weekly or placebo for 12 weeks; there-after, all patients received open-label etanercept 25 mgtwice weekly throughWeek 24. At theWeek-12 primaryend point, PASI 75was achieved by 49%of patients in thehigher dose group, 34% in the lower dose group, and 3% inthe placebo group (both ps G .0001 vs. placebo), and PASI90 was achieved by 21%, 11%, and 1%, respectively (bothps G .0001 vs. placebo). PASI responses were generally main-tained throughWeek 24,with no apparent decrease observedin patients who underwent a dose reduction at Week 12(Table 1; Papp et al., 2005).
InfliximabInfliximab, a chimeric immunoglobulin (Ig)G1 antibodythat neutralizes TNF> by binding to both its solubleand transmembrane forms (Levy et al., 2012), receivedFDA approval in 2006 for the treatment of severe plaquepsoriasis (U.S. FDA, n.d.). Infliximab is administered byintravenous infusion, with a recommended starting dose of5 mg/kg at 0, 2, and 6 weeks, followed by a maintenanceregimen of 5 mg/kg every 8 weeks thereafter (JanssenBiotech, 2013a).
In the 50-week double-blind European Infliximab forPsoriasis (Remicade) Efficacy and Safety Study (EXPRESS),378 patients withmoderate-to-severe plaque psoriasis wererandomized (4:1) to receive infusions of infliximab 5mg/kgor placebo at Weeks 0, 2, and 6 and then every 8 weeks toWeek 46. At Week 24, patients in the placebo group wereswitched to infliximab (Reich et al., 2005). At the Week-10primary end point, PASI 75 was achieved by 80% of pa-tients in the infliximab group and 3% of patients in theplacebo group (p G .0001), and PASI 90 was achieved by57% and 1%, respectively (p G .0001). PASI improvementswere maintained throughWeek 24, and more than half ofall patients achieved PASI 75 at Week 50 (Table 1; Reichet al., 2005).
The subsequent double-blind Evaluation of Infliximabfor Psoriasis in a Remicade Efficacy and Safety Study wasconducted to compare the efficacy and safety of infliximab3 or 5 mg/kg administered to 835 patients at Weeks 0, 2,and 6, followed by either continuous (every 8 weeks) orintermittent (as needed) maintenance infusions throughWeek 50 (Menter et al., 2007). At the Week-10 primaryend point, PASI 75 was achieved by 70% of patients inthe lower dose group, 76% of the higher dose group, and2% of the placebo group (both ps G .001 vs. placebo), andPASI 90 was achieved by 37%, 45%, and 0.5%, respec-
tively (both ps G .001 vs. placebo). At Week 50, PASI scoreswere better maintained with continuous versus intermittenttherapywithin each group andwith the higher versus lowerdose (Table 1; Menter et al., 2007).
AdalimumabAdalimumab was the first fully human IgG1 monoclonalantibody to TNF> approved for the treatment of moderate-to-severe plaque psoriasis (Levy et al., 2012). Adalimumabreceived FDA approval for this indication in 2008 (U.S.FDA, n.d.), with recommended subcutaneous administra-tion at an initial dose of 80 mg, followed by 40 mg everyother week (eow) starting 1 week after the initial dose(AbbVie, 2013). With proper training, adalimumab canbe self-administeredwith single-use pens or prefilled syringes(AbbVie, 2013).
In a 60-week double-blind RCT in 147 patients withmoderate-to-severe plaque psoriasis, patients were random-ized (1:1:1) to receive adalimumab 80mg atWeeks 0 and 1,then adalimumab 40 mg every week; adalimumab 80 mgat Week 0, and then adalimumab 40 mg eow; or placebofor 12 weeks. At Week 12, patients taking adalimumabcould continue taking their assigned dose for a 48-weekextension, and patients in the placebo group were switchedto adalimumab 80 mg at Week 12 and then adalimumab40 mg eow (Gordon et al., 2006). For the primary endpoint, PASI 75 was achieved at Week 12 by 80% of pa-tients taking adalimumab once weekly, 53% of those takingadalimumab eow, and 4% of the placebo group (both ps G.001 vs. placebo); PASI 90was achieved by 48%and 24%of patients in the active groups, respectively (PASI 90 datanot provided for placebo group), and PASI 100was achievedby 26%, 11%, and 0%, respectively (both ps G .001 vs.placebo). PASI responses were sustained through 60 weeksof treatment for most patients (Table 1; Gordon et al.,2006).
In the randomized controlled evaluation of adalimumabevery other week in moderate-to-severe psoriasis, Menterand colleagues evaluated the short- and long-term efficacyand safety of adalimumab as a continuous or interruptedtherapy (Menter et al., 2008). Patients (n = 1,212) wererandomized (2:1) to receive an initial dose of adalimumab80 mg at Week 0 followed by adalimumab 40 mg eow orplacebo for 15 weeks in a double-blind fashion. FromWeeks 17 to 31, all patients received open-label adalimumabof 40mg eow. Patients whowere originally randomized toactive treatment and who achieved PASI 75 at Week 33were rerandomized to adalimumabof 40mg eowor placebothrough Week 52. At the Week-16 primary end point, PASI75was achieved by 71% of the adalimumab group and 7%of the placebo group (p G .001), and PASI 90 was achievedby 45%and2%, respectively (p G .001). BetweenWeeks 33and 52, PASI improvements were lost in 28% of patientsrerandomized to placebo compared with 5% of patientswho received continuous adalimumab (p G .001; Table 1;Menter et al., 2008).
188 Journal of the Dermatology Nurses’ Association
Copyright © 2014 Dermatology Nurses' Association. Unauthorized reproduction of this article is prohibited.
Safety and Tolerability of TNF> AntagonistsOverall, the RCTs summarized in Table 1 showed thatetanercept, infliximab, and adalimumab are generally safeand well tolerated, with similar AE profiles. However, anumber of rare but serious safety issues have been ob-served in large patient registries and in longer-term safetyevaluations, including demyelination, infections, tubercu-losis, reactivation of hepatitis B,malignancies, lymphoma,and major adverse cardiovascular events (MACE; Papp,Dekoven, et al., 2012; Rustin, 2012). Black-box warningsrelated to these safety concerns as well as other warningsand precautions, contraindications, required monitoring,andknowndrugYdrug interactions are summarized inTable 3.
Case reports ofworsening or new-onset congestive heartfailure (CHF) have been reported with TNF> antagonists;thus, it is recommended that these agents be used withcaution in patients with a history of CHF, and infliximab95 mg/kg is contraindicated in patients with moderate-to-severe CHF (Papp, Dekoven, et al., 2012). However, itshould be noted that a meta-analysis of 22 RCTs involvingmore than 10,000 patients treatedwith biologics for plaquepsoriasis failed to show an association between use of bio-logic agents and MACE rates (Ryan et al., 2011). In ad-dition to the broadwarnings about the risk for malignancieslisted in Table 3, periodic skin examinations should beconsidered for all patients, especially those with otherrisk factors for skin cancer, such as prior treatment withpsoralen plus ultraviolet A light or cyclosporine (Kamangar,Neuhaus, & Koo, 2012). Patients taking infliximab oradalimumab should also bemonitored for the developmentof antidrug antibodies, as these can lower drug-serum con-centrations and reduce clinical efficacy (Hsu, Snodgrass, &Armstrong, 2014). Antidrug antibodies have also been ob-served in clinical studies of etanercept, but these antibodiesare nonneutralizing and are not associated with any ap-parent changes in clinical response (Hsu et al., 2014).
IL-12/IL-23 INHIBITORUstekinumab is a fully humanized IgG1 monoclonal anti-body specific for the common p40 subunit of IL-12 andIL-23, which prevents interaction between these cytokinesand their receptor and inhibits T-cell differentiation (Levyet al., 2012). Ustekinumab was approved by the FDA in2009 for the treatment of moderate-to-severe plaque pso-riasis (U.S. FDA, n.d.), with recommended subcutaneousinjections atWeeks 0 and 4 and then every 12weeks (JanssenBiotech, 2013b). The recommended ustekinumab dose is45 mg for patients weighing e100 kg (220 lbs) and 90 mgfor patients weighing 9100 kg (220 lbs; Janssen Biotech,2013b). With proper training, ustekinumab can be self-administered with single-use prefilled syringes (JanssenBiotech, 2013b).
The double-blind Psoriasis followed by long-termextension-1 (PHOENIX 1, n = 766; Leonardi et al., 2008)and Extension-2 (PHOENIX 2, n = 1,230; Papp et al.,
2008) RCTs evaluated the efficacy and safety ofustekinumab (45 or 90 mg) administered at Weeks 0 and4 and then every 12 weeks, compared with placebo givenat Weeks 0 and 4 with crossover to ustekinumab at Week12. At the Week-12 primary end point in PHOENIX 1(Leonardi et al., 2008), PASI 75 was achieved by 67% ofthe 45-mg group, 66% of the 90-mg group, and 3% ofthe placebo group (both ps G .0001 vs. placebo), and PASI90 was achieved by 42%, 37%, and 2% of patients,respectively (both ps G .0001 vs. placebo). Then, PASI 75responders receiving ustekinumab were rerandomized atWeek 40 to their current treatment or placebo. Over thecourse of this 76-week study, patients who received con-tinuous ustekinumab therapy maintained their PASI im-provements better than those who were withdrawn fromtreatment at Week 40 (Table 1; Leonardi et al., 2008).
Similarly, in PHOENIX 2, at the Week-12 primary endpoint, PASI 75 was achieved by 67% of the 45-mg group,76% of the 90-mg group, and 4% of the placebo group(both ps G .0001 vs. placebo), and PASI 90 was achievedby 42%, 51%, and 1%, respectively (both ps G .0001 vs.placebo; Papp et al., 2008). At Week 28, ustekinumabpartial responders (PASI 50 to G75) were rerandomizedto continue receiving the same dose every 12 weeks orto receive intensified therapy with the same dose every8 weeks through Week 52. Results indicated that doseintensification to 90 mg every 8 weeks may elicit a fullresponse in patients who only partially respond to initialtherapy (Table 1; Papp et al., 2008).
The first head-to-head trial of biologic agents for thetreatment of moderate-to-severe psoriasis was the 64-weekActive Comparator (CNTO 1275/Enbrel) Psoriasis Trial,which compared ustekinumab 45 or 90mg atWeeks 0 and4 versus etanercept 50 mg twice weekly for 12 weeks in903 patients (Griffiths et al., 2010). At Week 12, PASI 75was achieved by 67%of patients treatedwith ustekinumab45 mg and 74% of patients treated with ustekinumab90mg, comparedwith 57%of thosewho received etanercept50 mg (p = .01 and p G .001, respectively); PASI 90 wasachieved by 36%, 45%, and 23% of patients, respectively(both ps G .001 vs. etanercept). At Week 12, patients inthe etanercept group who did not have a response (i.e.,still had moderate, marked, or severe psoriasis) receivedustekinumabatWeeks 16 and20. Switching from etanerceptto ustekinumab resulted in achievement of PASI 75 by49% of patients (Table 1; Griffiths et al., 2010).
Safety and Tolerability of the IL-12/IL-23 InhibitorThe PHOENIX 1 and 2 trials, as well as long-term safetystudies, have shown that ustekinumab is generally safe andwell tolerated (Table 1); the most common AEs withustekinumab are similar to those observed with TNF>antagonists (e.g., nasopharyngitis, upper respiratory infec-tion, headache, injection-site reactions, arthralgias; Leonardiet al., 2008; Papp et al., 2008; Papp, Griffiths, et al., 2013;
VOLUME 6 | NUMBER 4 | JULY/AUGUST 2014 189
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TABLE
3.Sa
fety
Warnings
andConsiderationsAssociated
WithApprove
dBiologicAge
nts(AbbVie,2013;Im
munex
Corporation,2013;Janssen
Biotech
,2013a,
2013b)
Safety
Issu
eEtane
rcept
Infliximab
Adalim
umab
Ustekinu
mab
Black-boxwarnings
&Se
riousinfectio
ns(i.e.,TB,bacteria
lse
psis,inva
sivefungalinfectio
ns,
otheropportunistic
pathogens)
&Se
riousinfectio
ns(i.e.,TB,bacteria
lse
psis,inva
sivefungalinfectio
ns,
otheropportunistic
pathogens)
&Se
rious
infectio
ns(i.e.,TB,b
acteria
lsepsis,inv
asiv
efung
alinfectio
ns,
othero
pportu
nistic
pathogens)
&None
&Lympho
maand
otherm
alig
nancies
&Lymphoma
and
other
malig
nancies
&Lympho
maand
other
maligna
ncies
&Hepatosp
lenic
T-celllymphoma
inpatie
nts
receiving
aza
thioprin
eor
6-mercaptopurin
e
&Hepatosp
lenic
T-celllymphoma
inpatie
ntsreceivingaza
thioprin
eor6
-mercaptopurin
e
Otherwarnings
&Demye
linatin
gdise
ase
exa
cerbatio
norn
ew
onset
&Demye
linatin
gdise
ase
exa
cerbatio
nornew
onse
t&Demye
linatin
gdise
ase
exa
cerbatio
nornew
onse
t&Se
riousinfectio
ns
(e.g.,myc
obacteria
,sa
lmonella
,BC
Gva
ccinatio
n,TB)
&CHFworsening
ornew
onse
t&CHFworsening
ornew
onse
t&CHFworsening
ornew
onse
t
&Malig
nancies
&Pa
ncytopenia
oraplastic
anemia
&Cytopenias
&Cytopenias,pancytopenia
&Ana
phylaxisorserio
us
alle
rgic
reactio
n
&Ana
phy
laxis
orserious
allergic
reactio
n&Hyp
ersensitivity
,se
riousinfusio
nreactio
ns,anaphylaxis,se
rum
sickn
ess
&Anaphylaxisorse
riousalle
rgic
reactio
n
&Reve
rsible
posterio
rleuk
oenc
epha
lopathy
synd
rome
&Autoantib
odiesrarely
associated
with
deve
lopmentoflupus-like
syndromeorautoim
mune
hepatitis
&Autoantib
odiesrarely
associated
with
deve
lopmentoflupus-like
syndrome
&Autoantibodiesrarelyassociated
with
deve
lopmento
flup
us-like
syndrome
&Hepatotoxicity
Contraindicatio
ns
&Se
psis
&Dose
s95mg/kgin
patie
nts
with
moderate-to-seve
reHF
&None
&None
Precautio
ns
&Pregnancycategory
B&Pregnancycategory
B&Pregnancycategory
B&Pregna
ncycategory
B
&Avo
idin
patie
nts
with
Wegener’s
granulomatosis
&Use
with
cautio
nin
patie
nts
with
mod
erate-to
-seve
realcoho
liche
patitis
Recommended
monito
ring
&TB
(eve
nifinitiallatenttest
isnegativ
e)
&TB
(eve
nifinitiallatenttest
isnegativ
e)
&TB
(eve
nifinitiallatenttest
isnegativ
e)
&Ev
aluate
forTBbefore
initiatin
gtherapy
&Infectio
ns
&Infectio
ns
&Infectio
ns
&Infectio
ns
&Reactiv
atio
nofhepatitisB
&Reactiv
atio
nofhepatitisB
&Reactiv
atio
nofhepatitisB
&Ja
undiceore
leva
tedlivere
nzymes
&Eleva
ted
liverenzymes
(contin
ued)
190 Journal of the Dermatology Nurses’ Association
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Wu et al., 2012). Analyses of safety data from more than3,000 patients treated with ustekinumab for up to 5 yearsshowed no dose-related or accumulated toxicities and lowrates of antidrug antibody formation (Papp, Griffiths, et al.,2013; Wu et al., 2012). In the Active Comparator (CNTO1275/Enbrel) Psoriasis Trial study, the safety profile ofustekinumab was similar to that of etanercept; the mostnotable disparity was the reported rates of injection-sitereactionAEs (4%withustekinumabvs. 25%with etanercept;Griffiths et al., 2010). As with the TNF> antagonists, seriousinfections and malignancies have been observed as rarebut potentially serious side effects of ustekinumab; how-ever, unlike the TNF> antagonists, ustekinumab has noblack-box warnings (Table 3; Janssen Biotech, 2013b).Although studies to date support that ustekinumab is gen-erally safe andwell tolerated, themost current (2009) guide-lines from theBritishAssociation ofDermatology recommendustekinumab as a second-line biologic therapy because thelong-term safety profiles of the TNF> antagonists are betterestablished (Smith et al., 2009). Furthermore, increasedMACErateswereobserved in early-stage trials ofustekinumaband briakinumab (an IL-12/IL-23 inhibitor that was in de-velopment but was withdrawn in 2011) compared withplacebo,which prompted concern about the cardiovascularsafety of targeting these cytokines (Ryan et al., 2011). How-ever, recent studies have failed to show an increased riskfor MACEwith ustekinumab relative to placebo or TNF>antagonists (Papp, Griffiths, et al., 2013; Ryan et al., 2011).
IL-17 INHIBITORSAs discussed in the previous sections, several recent studieshave identified IL-17A as a central driver of the direct acti-vation of keratinocytes in psoriasis, and three biologic agents(secukinumab, ixekizumab, and brodalumab) that targetmembers of the IL-17 family or their receptors are cur-rently in research clinical development for the manage-ment of moderate-to-severe plaque psoriasis (Chiricozziet al., 2011; Chiricozzi & Krueger, 2013; Krueger et al.,2012). Unlike the other cytokines implicated in the patho-genic psoriasis pathway, it is hypothesized that IL-17A is adownstream cytokine, meaning that altering its levels mayhave fewer adverse effects on other biologic processes thanalterations in TNF> or IL-12/IL-23 levels (Girolomoni,Mrowietz, & Paul, 2012).
SecukinumabSecukinumab (AIN457) is a fully human IgG1. monoclonalantibody that selectively binds to and neutralizes IL-17A(Rich et al., 2013). Several phase 3 studies are evaluatingthe efficacy and safety of subcutaneous secukinumab forthe treatment of plaque psoriasis (Table 2). The pivotal Fullyear Investigative eXamination of secukinumab versuseTanercept Using 2 dosing Regimens to determine Efficacyin psoriasis (FIXTURE) study consisted of four periods:
TABLE
3.Sa
fety
Warnings
andConsiderationsAssociated
WithApprove
dBiologicAge
nts(AbbVie,2013;Im
munex
Corporation,2013;Janssen
Biotech
,2013a,
2013b),Continued
Safety
Issu
eEtane
rcept
Infliximab
Adalim
umab
Ustekinu
mab
Drug
interactio
ns
&Live
vaccines
&Live
vaccines
&Live
vaccines
&Live
vaccines
&Anakinra
&Anakinra
&Anakinra
&Abata
cept
&Abata
cept
&Abata
cept
&Cyc
lophosp
hamide
&To
ciliz
umab
Antid
rug
antib
odies
&~6%
ofpatie
nts
deve
lop
no
neutralizing
antib
odiesto
eta
nercept
&Deve
lopmentofanti-infliximab
antib
odiesreportedin
upto
51%
of
patie
nts
with
pso
riasis
&~8%
ofpatie
nts
deve
lop
antib
odiesto
adalim
umab
&~6%
ofpatie
nts
deve
lop
antibodiesto
ustekinum
ab
Abbreviatio
ns:
BCG
=bacillu
sCalm
etteYG
uerin
;CHF=congestiveheartfailure;TB
=tuberculosis.
VOLUME 6 | NUMBER 4 | JULY/AUGUST 2014 191
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screening, induction (of 12 weeks), maintenance (of40 weeks), and follow-up (of 8 weeks; Langley et al.,2013). Patients (n = 1,306) were randomized to receivesecukinumab 150 or 300 mg once weekly for 5 weeksfollowed by once-monthly dosing thereafter, etanercept50mg twice weekly for 12weeks followed by 50mg onceweekly thereafter, or placebo. Overall, it was observedthat patients’ skin cleared faster, and improvements weremaintained longer with secukinumab compared withetanercept. At Week 12, assessment of the coprimary endpoints of PASI 75 and Investigator’s Global Assessmentshowed that the efficacy of secukinumab was superior toplacebo (p G .0001) and to etanercept (p = .0250; Langleyet al., 2013). In the Study Comparing secukinumab Usein Long-term Psoriasis maintenance therapy: fixed regi-mens vs reTreatment Upon start of RElapse (SCULPTURE),966 patients received secukinumab 150 or 300 mg onceweekly for 5 weeks (Mrowietz et al., 2013). Those whoachieved PASI 75 were rerandomized at Week 8 to thesame doses at either once-monthly intervals or as neededin response to psoriasis relapse. Patients who achieved PASI75 atWeek 12 were more likely to maintain their responseif they received secukinumab at fixed monthly intervalscompared with as-needed treatment at the start of re-lapse (Mrowietz et al., 2013). Results from SCULPTURE(Mrowietz et al., 2013) and the Efficacy of Response andSafety of 2 Fixed Secukinumab Regimens in Psoriasisstudy showed that secukinumab of 300 mg was moreeffective than secukinumab 150 mg (Table 2; Elewskiet al., 2013). The most common AEs across these phase3 studieswere nasopharyngitis (exposure-adjusted incidencerates: 18.1%Y31.1%, secukinumab 150mg; 18.5%Y35.2%,secukinumab 300 mg; 35.7% of etanercept; and30.8%Y32.8% of placebo), upper respiratory tract infec-tion (5.8%Y12.7%, 6.6%Y11.1%, 6.4%, and 3.0%Y3.5%,respectively), and headache (7.5%Y12.4%, 5.0%Y15.7%,15.2%, and15.1%Y29.6%, respectively; Elewski et al., 2013;Langley et al., 2013; Mrowietz et al., 2013). Serious AE rateswere 5.1%Y6.4% with secukinumab 150 mg, 5.4%Y8.3%with secukinumab 300 mg, 6.2% with etanercept, and2.0%Y2.1% with placebo.
In a regimen-finding, phase 2 study, patients (n = 404)were randomized to receive either a single injection ofsecukinumab 150 mg at Week 0; ‘‘early’’ secukinumab150mg atWeeks 0, 1, 2, and 4; once-monthly secukinumab150 mg at Weeks 0, 4, and 8; or placebo (Rich et al.,2013). At Week 12, PASI 75 was achieved by 11% witha single injection, 54.5% with early treatment, and 42%with once-monthly treatment, compared with 1.5% withplacebo (p G .001 for early and once-monthly regimens vs.placebo); PASI 90 was achieved by 3%, 32%, 17%, and1.5%of patients, respectively (p G .001 for early and once-monthly regimens vs. placebo; Rich et al., 2013). In asecond regimen-finding, phase 2 study (n = 125), PASI75 was achieved at Week 12 by 82% of patients whoreceived secukinumab 150 mg three times and 57% of
patients who received secukinumab 75 mg three times (atWeeks 0, 4, and 8), compared with 9% with placebo(p G .001 and p = .002, respectively; Papp, Langley, et al.,2013). The types and frequencies of AEs, as well as ratesof serious AEs, in the phase 2 studies (Papp, Langley, et al.,2013; Rich et al., 2013) were similar to those reported inthe abovementioned phase 3 studies.
IxekizumabIxekizumab (LY2439821) is a humanized IgG4 monoclo-nal antibody that binds and neutralizes IL-17A. In a phase2 RCT, 142 patients with moderate-to-severe plaque pso-riasis were randomized to receive subcutaneous ixekizumab(10, 25, 75, or 150 mg) or placebo at Weeks 0, 2, 4, 8, 12,and 16, with follow-up through 20 weeks (Leonardi et al.,2012). At the Week-12 primary end point, PASI 75 wasachieved by 82%, 83%, 77%, and 29%of patients treatedwith ixekizumab 150, 75, 25, and 10 mg, respectively,compared with 8% with placebo (p G .001 for all dosesexcept 10 mg); PASI 90 was achieved at the same timepoint by71%,59%,50%,and18%with the four ixekizumabdoses, respectively, compared with no patient with placebo(p G .001 for all doses except 10 mg). The most commonAEs included nasopharyngitis (ixekizumab, 10%Y14%;placebo, 19%), upper respiratory infection (3%Y10% and4%), injection-site reaction (0%Y10% and 0%), and head-ache (3%Y14% and 4%). The AEs did not appear to bedose related, and no serious AEs were reported (Leonardiet al., 2012).
Several phase 3 studies of ixekizumab are ongoing. Thestudy designs for these trials are summarized in Table 2.
BrodalumabBrodalumab (AMG 827) is a human IgG2 monoclonalantibody that binds to and blocks IL-17RA, the receptorsubunit shared by IL-17A, IL-17F, and IL-17A/F heterodimerligands. In a phase 2 RCT, 198 patients with moderate-to-severe plaque psoriasis were randomized to receive sub-cutaneous brodalumab (70, 140, 210, or 280mg) or placeboon Day 1 and at Weeks 1, 2, 4, 6, 8, and 10 (280 mg wasonly given onDay 1 and atWeeks 4 and 8),with a follow-upassessment at 12 weeks (Papp, Leonardi, et al., 2012). Atthe Week-12 primary end point, mean PASI improvementfrom baseline was 45%, 86%, 86%, and 76% amongpatients treated with brodalumab 70, 140, 210, and280 mg, respectively, compared with 16% in the placebogroup (all ps G .001). At the same time point, PASI 75 wasachieved by 33%, 77%, 82%, and 67% of patients in thebrodalumab groups, respectively, compared with no pa-tients who received placebo (all ps G 0.001); PASI 90 wasachieved by 18%, 72%, 75%, and 57% of patients inthe four brodalumab groups, respectively, and by zero pa-tients in the placebo group (all ps G .01). The most com-mon AEs included nasopharyngitis (brodalumab, 8%;placebo, 8%), upper respiratory infection (8% and 5%),
192 Journal of the Dermatology Nurses’ Association
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injection-site erythema (6% and 3%), arthralgia (4% and3%), pain in extremity (5% and 0%), and nausea (4%and3%).With the exception of nasopharyngitis and nausea,these events were most common in the high-dose group.Across the brodalumab groups, serious AEswere reportedby two patients (renal colic and grade 3 neutropenia; Papp,Leonardi, et al., 2012).
Several phase 3 studies of brodalumab are ongoing. Thestudy designs for these trials are summarized in Table 2.
TREATMENT CONSIDERATIONSIn terms of efficacy, available biologic therapies can be ex-pected to provide good PASI responses in patients withmoderate-to-severe plaque psoriasis; however, efficacydifferences exist between the various agents. Althoughhead-to-head data are limited, data suggest that ustekinumaband infliximab may provide better efficacy than etanerceptand adalimumab (Bansback et al., 2009; Griffiths et al.,2010; Lin, Ringold, & Devine, 2012; Reich, Burden,Eaton, & Hawkins, 2012) and that secukinumab maybe superior to etanercept (Langley et al., 2013). Resultsfrom ongoing head-to-head studies (e.g., ixekizumab vs.etanercept [NCT01597245] andbrodalumabvs. ustekinumab[NCT01708603 and NCT01708629]) may further iden-tify differences among the biologic therapies and help de-fine a treatment hierarchy formanaging patientswith plaquepsoriasis.
Available evidence suggests that the IL-17 inhibitorsmayprovide an alternative approach to achieving targeted effi-cacy. As described herein, in clinical studies to date, a sub-stantial proportion of patients have reported near-completepsoriasis clearance with IL-17A inhibitors, with mainte-nance of these improvements for up to 1 year (e.g., onestudy showed up to approximately two thirds of patientsachieving PASI 90 at 1 year; Langley et al., 2013). This isa very relevant observation, as lack of efficacy and loss ofefficacy over time are the most commonly cited reasonspatients have given for discontinuing treatment with TNF>antagonists; for example, in a survey of over 1,000 patientswho discontinued their psoriasis treatment regimen, lackof efficacywas themain reason patients discontinued TNF>therapy (reported by up to 34% of patients), followed byloss of efficacy over time (reported by up to 32% of pa-tients; Yeung, Wan, et al., 2013).
For patients who do not achieve an adequate responsewith conventional systemic therapy or a previous biologictherapy, switching to a different biologic agent is a validtreatment strategy (Gottlieb et al., 2012; Strober et al.,2011). For example, in one study, roughly two thirds ofpatients who had an inadequate response to etanerceptachieved cleared or minimal disease 10 weeks after switch-ing to infliximab (Gottlieb et al., 2012). Similarly, a studyby Strober and colleagues showed that more than half ofpatients who switched to adalimumab achieved cleared orminimal disease after having an inadequate response to
etanercept, methotrexate, or narrow-band ultraviolet Btherapy.
Safety and tolerability are also important factors whenchoosing psoriasis treatments. In a survey of expert Europeandermatologists, long-term safety was identified as the mostimportant attribute these physicians consider when select-ing a biologic agent to treat psoriasis (Guibal, Iversen, Puig,Strohal, & Williams, 2009). Because available biologicsare all generally well tolerated, with similar long-term safetyprofiles and low reported rates of serious AEs, the choice oftherapy is usually based on each patient’s underlying riskfactors for serious infection and malignancy. For instance,TNF> antagonists should be used with caution in patientswith CHF or risk factors for developing this condition(AbbVie, 2013; Immunex Corporation, 2013; JanssenBiotech, 2013a). Weight gain is also a potentially undesir-able side effect that has been observed in patients takingTNF> inhibitors but not the IL-12/IL23 inhibitor ustekinumab(Gisondi et al., 2013), so it may be advisable to avoid theseagents when obesity or weight gain are significant con-cerns. Early cardiovascular safety concerns with IL-12/IL-23inhibitors (Ryan et al., 2011) may warrant caution whenusing ustekinumab until larger-scale, longer-term data areavailable on these risks. Although the long-term safety pro-files of IL-17 inhibitors have yet to be confirmed, it has beenhypothesized that, by providingmore downstream-targetedtherapy than existing biologics, these agentsmayhave amorefavorable AE profile, offering a new variant in the optionsfor patients with psoriasis (Girolomoni et al., 2012).
Dosing frequency and route of administration may af-fect patient and physician preferences for one biologic agentover another, with less-frequent dosing often the preferredoption for both providers and patients (Richter, Anton,Koch,&Dennett, 2003). Of the approved agents, ustekinumabhas the most convenient dosing schedule, with adminis-tration required every 12 weeks after the initial dosing pe-riod (Sivamani et al., 2013). Many patients may also preferself-administration over intravenous infusion, which maymake infliximab a less desirable choice than the other avail-able biologics that can all be self-administered by subcuta-neous injection (Scarpato et al., 2010). Some biologic agentscurrently in development may be available as oral formu-lations (e.g., apremilast, tofacitinib), which may be moreappealing than injectables tomany patients (Schafer, 2012).
Patient-reported outcomes (e.g., improving quality oflife and reducing feelings of frustration, self-consciousness,and depression) are an area of growing interest and shouldalso be considered when deciding on the best treatmentapproach (Heller et al., 2012). Speaking with patientsabout their treatment goals, life circumstances, and pre-ferred approach to disease management may help health-care professionals decide which options are most suitablefor different individuals (Uhlenhake & Mehregan, 2012).Noncompliance with therapy may be a sign that a patient’stherapy choice is not right for him or her, and understand-ing the causes of noncompliance may assist in providing
VOLUME 6 | NUMBER 4 | JULY/AUGUST 2014 193
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better guidance for an alternative choice (Uhlenhake &Mehregan, 2012).
Special consideration is also required when decidingwhether to use biologic agents to treat children with pso-riasis. No biologic agents are currently approved in theUnited States to treat pediatric psoriasis, and data are limitedin this population. However, etanercept and adalimumabare approved in the United States to treat juvenile idio-pathic arthritis, and infliximab is approved to treat pedi-atric Crohn’s disease and ulcerative colitis (AbbVie, 2013;Immunex Corporation, 2013; Janssen Biotech, 2013a).The TNF> inhibitors are also approved to treat pediatricpsoriasis in the EuropeanUnion andBrazil (Luu & Cordoro,2013). One RCT of etanercept (Paller et al., 2008) andnumerous case studies of TNF> antagonists support theirefficacy in the treatment of pediatric patients withmoderate-to-severe psoriasis (Luu & Cordoro, 2013). Data are ex-tremely limited on the use of ustekinumab in pediatricpatients, but a phase 3 study with this agent is ongoingin adolescents with moderate-to-severe plaque psoriasis(NCT01090427). By far, the greatest concern with usingbiologics in pediatric patients is the lack of long-term safetydata in this population; given this limitation, biologic agentsshould be used with caution in children.
CONCLUSIONSBiologic agents used for the management of moderate-to-severe plaque psoriasis are generally well-tolerated andeffective treatment options that may result in clinical im-provements. Not all agents work in all patients; therefore,it is critical to be aware of the multiple treatment options,many with different mechanisms of action. New agents indevelopment may provide alternative options to existingbiologic therapies for the achievement of rapid and sus-tained clearance of psoriatic lesions. h
AcknowledgmentsTechnical assistance with editing and styling of the manu-script for submissionwas provided byOxford PharmaGenesis,Inc., and was funded by Novartis Pharmaceuticals Corpo-ration. The authors were fully responsible for all contentand editorial decisions and received no financial support orother form of compensation related to the development ofthis manuscript. The opinions expressed in the manuscriptare those of the authors, andNovartis Pharmaceuticals hadno influence on the contents.
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