New and emerging biologic therapies for moderate-to-severe plaque psoriasis: Mechanistic rationales and recent clinical data for IL-17 and IL-23 inhibitors

Abstract

The development of effective and well-tolerated biologic therapies has advanced the management of psoriasis by enabling clinicians to treat underlying disease mechanisms. Biologics approved for the treatment of moderate-to-severe psoriasis include three tumor necrosis factor alpha inhibitors and an interleukin-12/interleukin-23 inhibitor. The establishment of the immunological basis of psoriasis has led to the development of biologic agents targeting specific downstream mediators in the psoriatic cascade. These drugs inhibit cytokines and cytokine signaling/transcription mediators like interleukin-17, which plays an important role in immunopathogenesis. Several interleukin-17 inhibitors are undergoing phase 3 clinical studies. In addition, biologics that selectively inhibit interleukin-23 have been assessed in phase 2 studies. This review describes how the dissection of pathways in the immunopathogenesis of psoriasis has led to the development of therapeutic agents and highlights the latest clinical efficacy, safety and tolerability data on new and emerging biologic therapies that selectively target interleukin-17 or interleukin-23.
© 2015 Wiley Periodicals, Inc.

Full text

REVIEW ARTICLE
New and emerging biologic
therapies for moderate-to-severe
plaque psoriasis: mechanistic
rationales and recent clinical
data for IL-17 and IL-23
inhibitors
Anthony A. Gaspari* & Stephen Tyring
†
*Department of Dermatology, University of Maryland Medical Center, Balti-
more, Maryland, and
†
Department of Dermatology, University of Texas Health Science Center,
Houston, Texas
ABSTRACT: The development of effective and well-tolerated biologic therapies has advanced the
management of psoriasis by enabling clinicians to treat underlying disease mechanisms. Biologics
approved for the treatment of moderate-to-severe psoriasis include three tumor necrosis factor alpha
inhibitors and an interleukin-12/interleukin-23 inhibitor. The establishment of the immunological
basis of psoriasis has led to the development of biologic agents targeting specific downstream
mediators in the psoriatic cascade. These drugs inhibit cytokines and cytokine signaling/
transcription mediators like interleukin-17, which plays an important role in immunopathogenesis.
Several interleukin-17 inhibitors are undergoing phase 3 clinical studies. In addition, biologics that
selectively inhibit interleukin-23 have been assessed in phase 2 studies. This review describes how the
dissection of pathways in the immunopathogenesis of psoriasis has led to the development of
therapeutic agents and highlights the latest clinical efficacy, safety and tolerability data on new and
emerging biologic therapies that selectively target interleukin-17 or interleukin-23.
KEYWORDS: biologic, interleukin-17, interleukin-23, psoriasis
Introduction
The development of new biologic drugs that target
specific mediators in the immunopathogenesis of
plaque psoriasis has transformed management of
the disease and has increased the range of options
beyond phototherapies and traditional immunosup-
pressants. Physicians in the Europe Union and Amer-
ica can now choose among five approved biologic
therapies that fall into three classes: the tumor necro-
sis factor alpha (TNF-a) inhibitors (etanercept, inflixi-
mab, adalimumab), the interleukin-12/interleukin-23
Address correspondence and reprint requests to: Anthony A.
Gaspari, MD, University of Maryland Medical Center, 419 W
Redwood St, Suite 240, Baltimore, MD 21201, or email:
agasp001@umaryland.edu.
V
C
2015 The Authors. Dermatologic Therapy published by Wiley Periodicals, Inc.
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(IL-12/23) inhibitors (ustekinumab), and an IL-
17 inhibitor (secukinumab). In the European
Union, all five biologics, including two recent
biosimilars of infliximab, are indicated in
patients with moderate-to-severe plaque psoria-
sis, generally for second-line use after immuno-
suppressants (cyclosporine and methotrexate) or
phototherapies. The TNF-a inhibitor etanercept
is also approved for use in children and adoles-
cents with chronic severe plaque psoriasis from
the age of 6 years. In America, the situation is
similar with biologics being approved for use in
patients that are unresponsive to other systemic
therapies, except secukinumab, which is indi-
cated for patients who are candidates for sys-
temic therapy or phototherapy. However,
etanercept has no pediatric indication in Amer-
ica. Treatment guidelines developed by derma-
tology societies in the European Union (1–7)
and North America (8,9) provide guidance to
physicians on selection of approved biologics
and treatment sequencing, as well as issues
such as use in patients with comorbidities.
Although outcomes for patients with plaque
psoriasis have improved since the introduction
of biologic therapies at the end of the 1990s,
safety concerns may limit their use, including
the risk of serious infections (e.g., tuberculosis),
and the potential for increased risk of malignan-
cies or major adverse cardiovascular events
(MACE). A greater understanding of the immune
pathways involved in psoriasis has led to the
identification of new therapeutic options (10).
Here, we briefly review the immunopathogenesis
of psoriasis, identify key mediators of psoriatic
plaques that are being targeted by new and
emerging biologic therapies, and highlight the
latest efficacy and safety data from trials of these
new agents.
Immunopathogenesis of psoriasis
Psoriasis is a disorder involving keratinocyte
hyperproliferation, which interferes with the
keratinocyte terminal differentiation program.
This results in poorly adhesive stratum corneum
and the formation of the characteristic plaques
seen in psoriasis (11–13). The psoriatic keratino-
cyte is now known to be driven by an immune-
mediated chronic inflammatory response.
Although the exact cause is unknown, the devel-
opment of psoriasis involves a complex interplay
between genetic and environmental factors (e.g.,
skin injury, infection, stress, certain prescription
drugs, smoking, alcohol, and obesity) (13,14).
More than 20 different susceptibility genes asso-
ciated with psoriasis have been identified
through several genome-wide association stud-
ies, indicating the heterogeneous nature of the
genetic susceptibility (15). Psoriasis genes fall
into five main functional categories: those asso-
ciated with acquired immunity (antigen presen-
tation and helper T cell [T
H
] 17 activation) and
those associated with innate immunity (nuclear
factor kappaB pathway signaling, type 1 inter-
feron induction, and skin barrier function) (16).
Initially, psoriasis was considered to be pri-
marily a keratinization disorder (11,17–19). Since
the 1970s, however, it has been established that
immune cells (particularly T cells and dendritic
cells) are present in psoriatic lesions and play a
pathologic role. Later research established that
the epidermal abnormalities are, in fact, T-cell
driven (11–13). The role played by various cyto-
kines in the immunopathogenesis of psoriasis is
shown in FIG. 1 (12,13,20).
Emerging immunotherapeutic
targets for psoriasis
Targeting IL-23 alone
Evidence is accumulating to suggest that IL-23
and its resulting T
H
17 pathway play a more
important role in psoriasis than IL-12 (21,22).
Thus, selective inhibition of IL-23 may be viewed
as a refinement on inhibition of both IL-12 and
IL-23 by ustekinumab. Both IL-12 and IL-23 are
composed of 2 subunits: IL-12 has p40 and p35
subunits, whereas IL-23 shares the p40 subunit
but has a distinct p19 subunit. Results of numer-
ous studies have indicated that levels of p19 and
p40 mRNA, but not p35 mRNA, are substantially
increased in psoriatic lesional skin compared
with psoriatic nonlesional skin (21,22). Immuno-
histochemical analyses show p40 and p19 pro-
tein expression in dermal dendritic cells and
keratinocytes within psoriatic lesions. Moreover,
correlations have been demonstrated between
reductions in IL-23 levels and clinical improve-
ments in psoriasis (21). Secretion of IL-23 by
dermal dendritic cells is believed to activate
T
H
17 cells to release proinflammatory cytokines
such as IL-17A, which in turn, drives and sus-
tains the psoriatic disease process (23).
The above findings, coupled with the role of
IL-12 in the T
H
1 response and host defense
against intracellular pathogens, suggest that
Gaspari and Tyring
180

preserving this cytokine may be beneficial and
have led to the development of specific anti-p19
monoclonal antibodies (22). The most advanced
of these agents are tildrakizumab and guselku-
mab, both of which have shown promising
results in phase 2 trials (Table 1) (24,25).
Tildrakizumab. Tildrakizumab is a humanized
immunoglobulin (Ig)G1k monoclonal anti-IL-
23p19 antibody that does not bind to IL-12 or
p40 (25). Phase 3 studies in moderate-to-severe
chronic plaque psoriasis are ongoing, and initial
results of a 52-week randomized, double-blind,
dose-finding, phase 2 study were reported
recently (25).
Efficacy. In the phase 2 study, the efficacy and
safety of four doses of tildrakizumab (5, 25, 100,
and 200 mg) administered by subcutaneous
injection at weeks 0 and 4 were compared with
placebo (25). The proportion of patients with a
75% improvement in psoriasis area-and-severity
index score (PASI 75) at week 16 (primary end-
point) was significantly higher in all four active
treatment groups compared with placebo (Table
1). Patients who achieved a PASI 75 response at
week 16 were eligible to receive treatment every
12 weeks for a further 40 weeks. Results have not
been reported in patients who continued to
receive the tildrakizumab 5-mg or 25-mg doses,
but the number of patients continuing to achieve
FIG. 1. Immunopathogenesis of psoriasis and sites of action of biologics. It is proposed that an initial trigger (e.g., injury,
infection, stress, etc.) precipitates a cascade of events that starts with the activation of innate immune cells (plasmacytoid
dendritic cells, natural killer cells, and keratinocytes). These activated cells secrete cytokines (e.g., interferon [IFN] a, tumor
necrosis factor [TNF] a, interleukin [IL]-1b, and IL-6), which in turn activate myeloid dendritic cells (DC). DC are central to
the immune system, providing a link between innate and adaptive responses. The activated myeloid DC enter the draining
lymph nodes, causing naive T cells (T-naive) to differentiate into helper type 17 (TH17) and type 1 (TH1) cells via the pre-
sentation of antigens and secretion of IL-12 and IL-23. These effector T cells then migrate into skin tissue, where they
secrete mediators (eg, IL-17A, IL-17F, and IL-22 from TH17/cytotoxic T17 [TC17] cells, and IFNc and TNFa from TH1/cyto-
toxic T1 [TC1] cells) that stimulate keratinocyte activation and proliferation, leading to plaque formation (12,13,20). Acti-
vated keratinocytes produce antimicrobial peptides, proinflammatory cytokines (IL-1b, TNF, and IL-6), and various
chemokines that feedback into the proinflammatory cycle. This feedback loop, as well as others involving fibroblasts and
endothelial cells, results in the continued immunopathologic progression of psoriasis.
Dermatologic Therapy
181

Table 1. Indirect comparison of key efficacy results from phase 2/3 studies of interleukin (IL)-23– and IL-17–targeted biologic therapies in
patients with moderate-to-severe chronic plaque psoriasis
IL-23–targeted therapies
Active therapy (trial design)
Trial acronym/lead author
(year) [primary outcome] Comparators n
Patients with a PASI
75 at week 16
(p value versus
placebo)
Patients with a PGA
score of 0 or 1 at
week 16 (p value
versus placebo)
Guselkumab subcutaneously
every 8 weeks (q8w), or on
weeks 0 and 4, then every
12 weeks (q12w)
(52-week randomized,
double-blind, dose-rang-
ing phase 2 trial)
X-PLORE (2014) (24) Guselkumab 5 mg q12w 41 43.9% (<0.001) 34.1% (=0.002)
[PGA score of 0 or
1 at week 16]
Guselkumab 15 mg q8w
Guselkumab 50 mg q12w
Guselkumab 100 mg q8w
Guselkumab 200 mg q12w
Adalimumab
a
Placebo
41
42
42
42
43
42
75.6% (<0.001)
81.0% (<0.001)
78.6% (<0.001)
81.0% (<0.001)
69.8% (<0.001)
4.8%
61.0% (<0.001)
78.6% (<0.001)
85.7% (<0.001)
83.3% (<0.001)
58.1% (<0.001)
7.1%
Tildrakizumab subcutane-
ously on weeks 0 and 4,
then every 12 weeks
(52-week randomized,
double-blind phase 2 trial)
Langley et al. (2014) (25)
[PASI 75 at week 16]
Tildrakizumab 5 mg
Tildrakizumab 25 mg
Tildrakizumab 100 mg
Tildrakizumab 200 mg
Placebo
42
92
89
86
46
33.3% (0.001)
64.4% (0.001)
66.3% (0.001)
74.4% (0.001)
4.4%
NR
b
NR
b
NR
b
NR
b
NR
b
IL-17–targeted therapies
Active therapy (trial
design)
Trial acronym/lead
author (year) [primary
outcome] Comparators n
c
Patients with improvement
in PASI score at week 12
(p value versus comparator)
Patients with a
PGA/IGA
d
score of
0 or 1 at week
12 (p value versus
comparator)PASI 75 PASI 90 PASI 100
Phase 3 trials
Secukinumab subcuta-
neously once weekly
for 5 weeks, then
every 4 weeks
e
FIXTURE (2014) (26) Secukinumab
300 mg
323 77.1%
(<0.001)
f
54.2%
(<0.001)
f
24.1%
(<0.001)
g
62.5%
(<0.001)
f
(5 randomized,
double-blind, phase
3 trials)
[Coprimary: PASI 75/
IGA score of 0 or 1 at
week 12]
Secukinumab
150 mg
327 67.0%
(<0.001)
f
41.9%
(<0.001)
f
14.4%
(<0.001)
g
51.1%
(<0.001)
f
Etanercept SC
50 mg
323 44.0% 20.7% 4.3% 27.2%
Placebo 324 4.9% 1.5% 0% 2.8%
ERASURE (2014) (26) Secukinumab
300 mg
245 81.6%
(<0.001)
59.2%
(<0.001)
28.6%
(<0.001)
65.3%
(<0.001)
[Coprimary: PASI 75/
IGA score of 0 or 1 at
week 12]
Secukinumab
150 mg
243 71.6%
(<0.001)
39.1%
(<0.001)
12.8%
(<0.001)
51.2%
(<0.001)
Placebo 246 4.5% 1.2% 0.8% 2.4%
Gaspari and Tyring
182

Table 1. Continued
IL-17–targeted therapies
Active therapy (trial
design)
Trial acronym/lead
author (year) [primary
outcome] Comparators n
c
Patients with improvement
in PASI score at week 12
(p value versus comparator)
Patients with a
PGA/IGA
d
score of
0 or 1 at week
12 (p value versus
comparator)PASI 75 PASI 90 PASI 100
FEATURE (2014) (27) Secukinumab
300 mg
58 75.9%
(<0.0001)
60.3%
(<0.0001)
43.1%
(<0.0001)
69.0%
(<0.0001)[Coprimary: PASI 75/
IGA score of 0 or 1 at
week 12]
Secukinumab
150 mg
59 69.5%
(<0.0001)
45.8%
(<0.0001)
8.5% (50.057) 52.5%
(<0.0001)
Placebo 59 0% 0% 0% 0%
JUNCTURE (2014) (28) Secukinumab
300 mg
60 86.7%
(<0.0001)
55.0%
(<0.0001)
26.7%
(<0.0001)
73.3%
(<0.001)[Coprimary: PASI 75/
IGA score of 0 or 1 at
week 12]
Secukinumab
150 mg
60 71.7%
(<0.0001)
40.0%
(<0.0001)
16.7%
(=0.0006)
53.3%
(<0.001)
Placebo 61 3.3% 0% 0% 0%
SCULPTURE
e
(2013)
(29)
Secukinumab
300 mg
483 90.1%
(NA)
64.2%
(NA)
25.7%
(NA)
76.0%
(NA)
[PASI 75 at week 12] Secukinumab
150 mg
482 84.4%
(NA)
49.3%
(NA)
16.2%
(NA)
62.8%
(NA)
Phase 2 trials
Secukinumab subcuta-
neously 150 mg at 1
of 3 induction regi-
mens and 2 mainte-
nance regimens
h
Rich et al. (2013) (30)
[PASI 75 at week 12]
Secukinumab
150 mg, single
dose
66 10.6%
(NS)
3.0%
(NS)
NA 4.5%
(NS)
Secukinumab
150 mg, monthly
dosing at weeks
0, 4, and 8
138 42.0%
(<0.001)
17.4%
(<0.001)
NA 22.6%
(= 0.003)
(32-week randomized,
double-blind, phase
2 trial)
Secukinumab
150 mg, early
dosing at weeks
0, 1, 2, 4, and 8
133 54.5%
(<0.001)
31.8%
(<0.001)
NA 37.1%
(<0.001)
Placebo 67 1.5% 1.5% NA 1.5%
Ixekizumab subcuta-
neously every other
week for 4 weeks,
then every 4 weeks
Leonardi et al. (2012)
(31)
Ixekizumab 10 mg 28 28.6%
(NS)
18.0%
(NS)
0%
(NS)
25.0%
(NS)
[PASI 75 at week 12] Ixekizumab 25 mg 30 76.7%
(0.001)
50.0%
(0.001)
16.7%
(NS)
70.0%
(NS)
Dermatologic Therapy
183

Table 1. Continued
IL-17–targeted therapies
Active therapy (trial
design)
Trial acronym/lead
author (year) [primary
outcome] Comparators n
c
Patients with improvement
in PASI score at week 12
(p value versus comparator)
Patients with a
PGA/IGA
d
score of
0 or 1 at week
12 (p value versus
comparator)PASI 75 PASI 90 PASI 100
(20-week randomized,
double-blind, phase
2 trial)
Ixekizumab 75 mg 29 83.0%
(0.001)
58.6%
(0.001)
37.9%
(0.001)
72.4%
(0.001)
Ixekizumab 150 mg 28 82.0%
(0.001)
71.4%
(0.001)
39.3%
(0.001)
71.4%
(0.001)
Placebo 26 7.7% 0% 0% 7.7%
Brodalumab subcuta-
neously every week
for 2 weeks, then
every 2 weeks for
the 70-mg, 140-mg,
or 210-mg doses, or
every 4 weeks for
the 280-mg dose
Papp et al. (2012) (32) Brodalumab 70 mg 39 33.3%
(<0.001)
18.0%
(<0.01)
10.3%
(<0.05)
26.0%
(<0.0.1)[Percentage change in
PASI score from base-
line to week 12]
Brodalumab
140 mg
39 77.0%
(<0.001)
71.8%
(<0.001)
38.5%
(<0.001)
84.6%
(<0.001)
Brodalumab
210 mg
40 82.5%
(<0.001)
75.0%
(<0.001)
62.5%
(<0.001)
80.0%
(<0.001)
(12-week randomized,
double-blind, phase
2 trial)
Brodalumab
280 mg
42 66.7%
(<0.001)
57.1%
(<0.001)
28.6%
(<0.001)
69.1%
(<0.001)
Placebo 38 0% 0% 0% 2.6%
a
Eighty milligram at week 0, 40 mg at week 1, then 40 mg once every 2 weeks.
b
Assessed as 1 of 2 secondary outcome measures, but not reported.
c
Efficacy evaluable population.
d
In the two trials of secukinumab, a more rigorous version of the PGA scale was used, which also required an a reduction in score from baseline of at least 2 points.
e
In the SCULPTURE trial, the treatment regimen changed after week 12; PASI 75 responders were rerandomized to receive secukinumab at the same dose, but with fixed-
interval, monthly dosing, or with retreatment as needed (dosing only at the start of a relapse) up to week 52.
f
Versus etanercept and versus placebo.
g
Versus etanercept; no comparison versus placebo was performed because no patient in the placebo group responded.
h
Results for the maintenance regimens are not shown in the table because this was assessed after week 12.
IGA: investigator global assessment; NA: not assessed; NR: not reported; NS: not significant; PASI: Psoriasis Area-and-Severity Index; PGA: Physician’s Global Assessment.
Gaspari and Tyring
184

PASI 75 in the 100-mg and 200-mg groups
appeared to remain relatively constant during
weeks 16–52 and at a follow-up assessment 20
weeks after treatment discontinuation. In
patients who were rerandomized from 100 to
25 mg at week 16, there was a significant reduc-
tion on the proportion of patients achieving PASI
75 by week 52 (p 5 0.005) and Physician’s Global
Assessment (PGA) scores of 0 or 1 (p 5 0.02)
compared with those who continued to receive
the 100-mg dose (25). Together, these results
indicate that the two highest doses (100 and
200 mg) have promising efficacy and that a strat-
egy of reducing the dose below 100 mg may be
associated with deterioration in clinical
response.
Safety and tolerability. The overall incidence of
adverse events (AEs) and serious AEs (SAEs) dur-
ing the 52-week treatment phase of this study
have not been reported. However, the most fre-
quent AEs across the tildrakizumab groups were
nasopharyngitis, headache, hypertension, and
diarrhea (25). The SAEs that were considered to
be possibly related to tildrakizumab included
bacterial arthritis, lymphedema, melanoma,
stroke, epiglottitis, and knee infection. One death
of undetermined cause was reported (treatment
group unspecified), and malignancies (rectal
cancer, malignant melanoma and malignant
melanoma in situ), serious infections (sinusitis,
epiglottitis, and cellulitis), and ischemic stroke
were reported in one patient each. In the 20-
week posttreatment follow-up period, three
patients had serious infections (mycoplasma
pneumonia, pneumonia, and soft tissue infec-
tion) and one major cardiovascular event was
reported (thrombotic cerebral infarction) (25). At
present, it is unclear whether there was a rela-
tionship between the dose of tildrakizumab and
the incidence of AEs.
Guselkumab. Guselkumab is a human IgG1
monoclonal anti-IL-23 antibody (33,34). It is in a
similar stage of development as tildrakizumab:
phase 3 studies are ongoing and initial results of
a phase 2, dose-ranging study are available (24).
Efficacy. In the phase 2, double-blind study,
patients were randomized to receive subcutane-
ous injections of guselkumab 5, 50, or 200 mg
(at weeks 0 and 4, then every 12 weeks), guselku-
mab 15 or 100 mg (at weeks 0 and 8, then every
8 weeks), adalimumab (as indicated in the label),
or placebo for up to 52 weeks (24). At week 16,
proportionately more patients in all five guselku-
mab groups achieved PGA scores of 0 or 1 (pri-
mary endpoint) and PASI 75 (secondary
endpoint) than in the placebo group (Table 1).
The change in mean dermatology life quality
index (DLQI) scores from baseline to week 16
(secondary endpoint) also significantly favored
guselkumab over placebo (p  0.008, all compari-
sons) (24). A post hoc analysis indicated that the
proportions of patients achieving a response at
week 40 were higher with the guselkumab 50-
mg, 100-mg, and 200-mg dose groups than with
adalimumab (24).
Safety and tolerability. Safety findings have not
been reported in detail. However, it has been
reported that AEs and SAEs at week 16 were
experienced by 49 and 1.4% of patients, respec-
tively, in the guselkumab groups compared with
53.5 and 2.3% in the adalimumab group, and
50.0 and 2.4% in the placebo group (35). At week
52, the incidence of AEs and SAEs was 63.4 and
2.8%, respectively, in the guselkumab groups and
72.1 and 4.7% in the adalimumab group (24).
The most frequent AE was infection (36.6% of
patients in the guselkumab groups versus 41.9%
in the adalimumab group) of which three were
serious (lung abscess and appendicitis in the
guselkumab 50-mg group and pneumonia in
adalimumab group). MACE were reported in one
patient receiving guselkumab 5 mg (fatal myo-
cardial infarction) and two patients receiving the
100-mg dose (nonfatal myocardial infarction and
stroke). A grade III cervical intraepithelial neo-
plasia was reported in one patient who received
guselkumab 200 mg.
BI 655066. BI 655066 is a human IgG1 monoclo-
nal anti-IL-23A antibody (36). Phase 2 studies in
patients with moderate-to-severe chronic plaque
psoriasis are ongoing and results from a phase 1
single-rising-dose trial of 39 patients were
recently reported (36).
Efficacy. In the phase 1 study, the efficacy and
safety of a single dose of BI 655066 administered
intravenously (0.01, 0.05, 0.25, 1, 3, or 5 mg/kg)
or subcutaneously (0.25 or 1 mg/kg) was com-
pared with placebo (36). At week 12, PASI 75 was
achieved by 87% of patients receiving any dose
of BI 655066 (p <0.001 compared with placebo).
Similarly, 87% of patients treated with any dose
of BI 655066 achieved static physician global
assessment (sPGA) values of 0 or 1 at week 12.
Safety and tolerability. AEs were reported in 65%
of patients receiving any dose of BI 655066 over
Dermatologic Therapy
185

the 24 weeks of the study; with the most com-
mon AEs being nasopharyngitis (13%), headache
(10%), and upper respiratory tract infection
(10%)(36). SAEs were reported in 13% of patients
treated with BI 655066 and consisted of a single
event of alcoholic pancreatitis, ischemic thalamic
stroke, transient ischemic attack, and polymyosi-
tis. None of the SAEs were considered related to
study treatment by the investigators. There were
no deaths during the study.
Targeting IL-17
Evidence is now emerging that IL-17 is a key
cytokine in the immunopathogenesis of psoriasis
at the keratinocyte level (37,38). IL-17 consists of
a family of six members (IL-17A–F), with the role
of IL-17A in psoriasis being the most extensively
researched. Because of new evidence supporting
a central role of IL-17A (and thus the IL-17A–
producing helper [T
H
17] and cytotoxic T cells
[T
C
17]), investigators have questioned the impor-
tance of T cells producing interferon c and TNF-a
in the pathogenesis of psoriasis (38). IL-17A has
proinflammatory effects on keratinocytes, macro-
phages, and endothelial cells and is responsible
for increased downstream production of cytokines
(20,39,40). IL-17A binds to receptors on keratino-
cytes and induces expression of neutrophil, T-cell,
and dendritic-cell chemokines that lead to the
migration of neutrophils, memory T cells, and
dendritic cells to psoriatic lesions (37). Neutro-
phils attracted to the skin by chemokines released
from IL-17A-stimulated keratinocytes can affect
the growth and differentiation of keratinocytes, in
addition to causing local tissue damage by pro-
ducing reactive oxygen species and proteolytic
enzymes (37).
Secukinumab, a monoclonal antibody that tar-
gets IL-17A, has been approved for the treatment
of moderate-to-severe psoriasis, and one other
monoclonal antibody that inhibits IL-17A (ixeki-
zumab) and one that blocks the IL-17 receptor
(brodalumab) are being researched for the treat-
ment of psoriasis (FIG. 2; 38,40–42). Key findings
from phase 2 and 3 trials of these agents in
patients with moderate-to-severe plaque psoriasis
are summarized in Tables 1 and 2
(26,29–32,43,44). RG7624, an antibody that targets
both IL-17A and IL-17F, is also being investigated
for the treatment of psoriasis but no clinical trial
results have been reported for this agent (45).
Secukinumab. Secukinumab is a fully human
IgG1j monoclonal anti–IL-17A antibody (38).
Results are available from five phase 3 studies:
the Full year Investigative eXamination of secu-
kinumab versus eTanercept Using 2 dosing Regi-
mens to determine Efficacy in psoriasis
FIG. 2. Targeting the interleukin (IL)-17 signaling pathway. IL-17RC and IL-17RA are subunits of the IL-17 receptor, which
is present on various cell types including keratinocytes, dendritic cells, dermal fibroblasts, and endothelial cells. Secukinu-
mab, a fully human immunoglobulin (Ig)G1j monoclonal antibody, and ixekizumab, a humanized IgG4 monoclonal anti-
body, target the cytokine IL-17A. These agents prevent inflammatory-mediated effects by neutralizing IL-17 and therefore
inhibit the binding of IL-17A to its receptor. Brodalumab is a human IgG2 monoclonal antibody that binds to IL-17RA,
thereby blocking signaling of IL-17 via its receptor. Another agent, RG7624, is a fully human IgG1 monoclonal antibody
against both IL-17A and IL-17F. All four agents are in clinical development for the treatment of psoriasis, with secukinumab
and ixekizumab being the furthest along (40–42). Reprinted by permission from Macmillan Publishers Ltd: Nat Rev Drug
Discov 12: 815–816,
V
C
2013.
Gaspari and Tyring
186

Table 2. Indirect comparison of the incidences of adverse events during the induction period (first
12–20 weeks) in phase 2/3 trials of interleukin (IL)-17–targeted biologic therapies; values are number
of patients (%)
Safety and tolerability over 12 weeks
Secukinumab
a
Phase 3 ERASURE study (26)
Secukinumab 300 mg
(n 5 245)
Secukinumab 150 mg
(n 5 245) Placebo (n 5 247)
Any AE 135 (55.1) 148 (60.4) 116 (47.0)
Any SAE 6 (2.4) 4 (1.6) 4 (1.6)
Death 0 0 0
Treatment discontinuation due to AE 3 (1.2) 5 (2.0) 4 (1.6)
Most common AEs
b
Nasopharyngitis 22 (9.0) 23 (9.4) 19 (7.7)
Headache 12 (4.9) 13 (5.3) 7 (2.8)
Infection or infestation 72 (29.4) 66 (26.9) 40 (16.2)
Other safety findings No cases of grade 3 or 4 neutropenia reported for the 12-week
induction period
Phase 3 FIXTURE study (26)
Secukinumab
300 mg
(n 5 326)
Secukinumab
150 mg
(n 5 327)
Etanercept
(n 5 323)
Placebo
(n 5 327)
Any AE 181 (55.5) 191 (58.4) 186 (57.6) 163 (49.8)
Any SAE 4 (1.2) 7 (2.1) 3 (0.9) 6 (1.8)
Death 0 0 0 0
Treatment discontinuation due to
AE
4 (1.2) 2 (0.6) 6 (1.9) 3 (0.9)
Most common AEs
b
Nasopharyngitis 35 (10.7) 45 (13.8) 36 (11.1) 26 (8.0)
Headache 30 (9.2) 16 (4.9) 23 (7.1) 23 (7.0)
Diarrhea 17 (5.2) 12 (3.7) 11 (3.4) 6 (1.8)
Infection or infestation 87 (26.7) 101 (30.9) 79 (24.5) 63 (19.3)
Phase 3 FEATURE study (27)
Secukinumab 300 mg
(n 5 59)
Secukinumab 150 mg
(n 5 59) Placebo (n 5 59)
Any AE 30 (50.8) 34 (57.6) 28 (47.5)
Any SAE 3 (5.1) 0 1 (1.7)
Death 0 0 0
Treatment discontinuation due to AE 1 (1.7) 0 1 (1.7)
Most common AEs
b
Diarrhea 5 (8.5) 2 (3.4) 1 (1.7)
Nasopharyngitis 3 (5.1) 3 (5.1) 5 (8.5)
Headache 0 4 (6.8) 3 (5.1)
Back pain 3 (5.1) 0 0
Nausea 3 (5.1) 0 1 (1.7)
Infection or infestation NR NR NR
Dermatologic Therapy
187

Phase 3 JUNCTURE study (28)
Secukinumab 300 mg
(n 5 60)
Secukinumab 150 mg
(n 5 61) Placebo (n 5 61)
Any AE 42 (70.0) 39 (63.9) 33 (54.1)
Any SAE 1 (1.7) 3 (4.9) 1 (1.6)
Death 0 0 0
Treatment discontinuation due
to AE
0 0 1 (1.6)
Most common AEs
b
Nasopharyngitis 19 (31.7) 14 (23.0) 10 (16.4)
Headache 3 (5.0) 5 (8.2) 3 (4.9)
Pruritus 5 (8.3) 1 (1.6) 2 (3.3)
Sinusitis 3 (5.0) 1 (1.6) 0
Cough 3 (5.0) 0 2 (3.3)
Infection or infestation NR NR NR
Phase 2 study (30)
Single dose
Secukinumab
150 mg
(n 5 66)
Monthly dosing
Secukinumab
150 mg
(n 5 138)
Early dosing
Secukinumab
150 mg
(n 5 133)
Placebo
(n 5 67)
Any AE 41 (62.1) 91 (65.9) 89 (66.9) 47 (70.1)
Any SAE 3 (4.5) 3 (2.2) 6 (4.5) 1 (1.5)
Death 0 0 0 0
Treatment discontinuation due to AE 1 (1.5) 0 3 (2.3) 1 (1.5)
Most common AEs
b
Nasopharyngitis 8 (12.1) 31 (22.5) 30 (22.6) 12 (17.9)
Headache 6 (9.1) 8 (5.8) 11 (8.3) 3 (4.5)
Psoriasis
c
6 (9.1) 8 (5.8) 4 (3.0) 7 (10.4)
Infection or infestation 14 (21.2) 56 (40.6) 45 (33.8) 26 (38.8)
Other safety findings No injection-site reactions or antibodies to secukinumab detected
No cases of grade 3 or 4 neutropeni
a
Brodalumab
Phase 2 study (32)
Brodalumab
70 mg
(n 5 38)
Brodalumab
140 mg
(n 5 39)
Brodalumab
210 mg
(n 5 40)
Brodalumab
280 mg
(n 5 41)
Placebo
(n 5 37)
Any AE 26 (68) 27 (69) 33 (82) 30 (73) 23 (62)
Any SAE 1 (3) 0 1 (2) 0 1 (3)
Death 0 0 0 0 0
Treatment discontinuation due to AE 0 0 2 (5) 1 (2) 1 (3)
Most common AEs
b
Nasopharyngitis 6 (16) 1 (3) 4 (10) 2 (5) 3 (8)
Upper respiratory tract infection 3 (8) 3 (8) 2 (5) 5 (12) 2 (5)
Arthralgia 1 (3) 2 (5) 0 4 (10) 1 (3)
Injection site erythema 1 (3) 1 (3) 3 (8) 4 (10) 1 (3)
Pain in extremity 1 (3) 0 3 (8) 4 (10) 0
Nausea 4 (11) 1 (3) 1 (2) 0 1 (3)
Infection or infestation NR NR NR NR NR
Other safety findings Approximately 6% of patients had injection-site erythema 5% to 10% of
patients developed antibodies to brodalumab (none neutralizing) 2 Cases
of grade 3 neutropenia (210-mg group)
Gaspari and Tyring
188

(FIXTURE; 26), Efficacy of Response And Safety
of two fixed secUkinumab REgimens in psoriasis
(ERASURE; 26), Study Comparing secukinumab
Use in Long-term Psoriasis maintenance therapy:
fixed regimens versus retreatment Upon start of
Relapse (SCULPTURE; 29), First study of sEcuki-
numAb in pre-filled syringes in subjecTs with
chronic plaqUe-type psoriasis: RE sponse at 12
weeks (FEATURE; 27), and Judging the efficacy
of secUkinumab in patients with psoriasis using
autoiNjector: a Clinical Trial evalUating treat-
ment REsults (JUNCTURE; 28).
Efficacy. FIXTURE and ERASURE were both 1-
year randomized, double-blind studies that had
the same coprimary endpoint and assessed secu-
kinumab at doses of 150 and 300 mg. Secukinu-
mab was compared with placebo (FIXTURE and
ERASURE) and with etanercept (FIXTURE only).
A nonresponder imputation analysis was used to
evaluate both trials. Both studies met the copri-
mary endpoint at week 12, with significantly
higher proportions of secukinumab-treated
patients achieving PASI 75 and scores of 0 (clear
skin) or 1 (almost clear skin) with an improve-
ment from baseline of at least two points on the
static Investigator’s Global Assessment (IGA
modified 2011) of overall psoriasis severity than
those receiving placebo or etanercept (p < 0.001,
all comparisons; Table 1). All secondary end-
points were also met in both studies. Signifi-
cantly higher proportions of patients in the
secukinumab groups achieved PASI score
improvements of 90% (PASI 90; almost clear
skin) and 100% (PASI 100; completely clear skin)
than those receiving either etanercept or placebo
(p < 0.001, all comparisons; Table 1). Improve-
ments in PASI score became evident as early as
week 2, with a significantly shorter median time
to 50% reduction in mean PASI score from base-
line with secukinumab 300 mg (3.0 weeks) and
150 mg (3.9 weeks) than with etanercept in the
FIXTURE study (7.0 weeks; p < 0.001, both com-
parisons)(26). Importantly, the improvements
were also maintained at 1 year in significantly
higher proportions of secukinumab-treated
patients than those receiving etanercept; 82–84%
of patients receiving secukinumab maintained a
Safety and tolerability over 20 weeks
Ixekizumab
Phase 2 study (31)
Ixekizumab
10 mg
(n 5 28)
Ixekizumab
25 mg
(n 5 30)
Ixekizumab
75 mg
(n 5 29)
Ixekizumab
150 mg
(n 5 28)
Placebo
(n 5 27)
Any AE 21 (75) 21 (70) 17 (59) 13 (46) 17 (63)
AnySAE 00000
Death 00000
Treatment discontinuation
due to AE
NR NR NR NR NR
Most common AEs
b
Nasopharyngitis 3 (11) 3 (10) 3 (10) 4 (14) 5 (19)
Upper respiratory
tract infection
1 (4) 3 (10) 1 (3) 1 (4) 1 (4)
Injection-site reaction 0 3 (10) 1 (3) 2 (7) 0
Headache 4 (14) 4 (13) 1 (3) 1 (4) 1 (4)
Allergy or hypersensitivity 1 (4) 1 (3) 2 (7) 1 (4) 2 (7)
Infection or infestation 12 (43) 9 (30) 9 (31) 8 (29) 7 (26)
Other safety findings 0% to 10% of patients had injection-site reactions Incidence of antibodies
to ixekizumab not reported No cases of grade 3 or 4 neutropenia
a
The phase 3 SCULPTURE study of secukinumab has not been included because results at week 12 have not yet been
reported.
b
Reported in more than 5% of patients in any active treatment group.
c
Indicates worsening of psoriasis; the protocol suggested that psoriasis, being the studied indication, was not to be reported
as an AE by the investigators.
AE: adverse event; NR: not reported; SAE: serious adverse event.
Dermatologic Therapy
189

PASI 75 response between weeks 12 and 52 com-
pared with 73% in the etanercept group
(p < 0.01, both comparisons) and a similar trend
was observed for maintenance of a PASI 90
response between weeks 16 and 52 (26). In ERA-
SURE, the benefits were similar, with further
increases in the response rates for PASI 75, PASI
90, PASI 100, and modified IGA scores of 0 or 1
from week 12 to week 16 in both secukinumab
groups, which were then maintained to 52 weeks
(26). In both studies, a significantly higher pro-
portion of patients reported no impact of dis-
ease on their quality of life (as indicated by a
DLQI score of 0 or 1) in both secukinumab
groups (300 mg, 57–59%; 150 mg, 46–51%) than
in the placebo groups (7–10%; p < 0.001, all
comparisons); in the FIXTURE study the differ-
ence was also significant versus etanercept
(35%; p < 0.001, both doses). These DLQI
response rates were maintained at 1 year with
both doses of secukinumab (300 mg, 66–70%;
150 mg, 49–56%).
Initial results have also been reported for the
1-year SCULPTURE study, which assessed the
maintenance of efficacy of secukinumab (300 and
150 mg) when administered at fixed, monthly
intervals versus retreatment as needed (i.e., only
at the start of a relapse) after an initial induction
period of 12 weeks (29). At the end of the induc-
tion period, the proportions of patients achieving
PASI 75, PASI 90, PASI 100, or modified IGA
scores of 0 or 1 were numerically similar to those
reported in FIXTURE and ERASURE (Table 1).
Patients who initially achieved PASI 75 or PASI 90
at week 12 were more likely to maintain their
response at 1 year if they received secukinumab
at fixed, monthly intervals compared with treat-
ment only at start of relapse. The secukinumab
300-mg dose was considered to be more effective
than the 150-mg dose (29). Similar efficacy was
observed at week 12 in the FEATURE and JUNC-
TURE trials which evaluated self-administration
of secukinumab by pre-filled syringe or autoinjec-
tor, respectively (27,28). In both trials, patients
reported high levels of device usability.
Safety and tolerability. In the FIXTURE study, the
overall exposure-adjusted incidence rates over 52
weeks for AEs and SAEs were similar with secuki-
numab 300 mg (252 and 6.8 events per 100
patient-years, respectively), secukinumab 150 mg
(236 and 6.0 events per 100 patient-years) and
etanercept (243 and 7.0 events per 100 patient-
years)(26). In the placebo group, the equivalent
rates were slightly higher (330 and 8.3 events per
100 patient-years). The incidence rates of AEs
and SAEs in ERASURE were consistent with those
of FIXTURE (26). There were no clinically
apparent differences in the types of SAEs among
the study groups in either study and no deaths
occurred during the treatment period in either
study. In both studies, the most common AEs in
the secukinumab groups (reported in more than
5% of patients) during the induction period and
the entire treatment period were nasopharyngitis
and headache; in FIXTURE, diarrhea was also
reported in more than 5% of patients. Across
both studies, there were no apparent dose-
related effects in AEs between the secukinumab
groups, with the exception of nonserious Can-
dida infections, which were reported in a higher
proportion of patients in the 300-mg groups
(FIXTURE, 4.7%; ERASURE, 2.0%) compared with
the 150-mg groups (FIXTURE, 2.3%; ERASURE,
0.8%); all Candida infections were mild or mod-
erate in severity, localized, and resolved sponta-
neously or with standard therapy, without the
need to discontinue secukinumab. AEs in the sys-
tem organ class infections and infestations were
more frequent in both studies in the secukinu-
mab groups than in the placebo groups during
the entire 52-week treatment period (secukinu-
mab, 92–105 events per 100 patient-years; pla-
cebo 84–90 events per 100 patient-years). Across
both studies and over 52 weeks, serious infec-
tions (n 5 13), malignant or unspecified tumors
(n 5 12) and MACE (n 5 6) were reported in < 1%
of patients with either secukinumab dose. Two
patients in 300-mg group had MACE (one patient
had two myocardial infarction events and one
patient had a cerebrovascular infarction); the
remaining four MACE occurred in the secukinu-
mab 150-mg group (ischemic stroke, moyamoya
disease, cerebrovascular accident, and myocardial
infarction). Evaluation by a blinded adjudication
committee determined that the moyamoya dis-
ease event did not meet MACE adjudication cri-
teria. Grade 3 neutropenia was reported in 10
patients treated with secukinumab in FIXTURE
or ERASURE; grade 4 neutropenia was not
reported in any patient receiving secukinumab
across both studies. In FIXTURE, injection-site
reactions were 15-fold less frequent with secuki-
numab (0.7%) than with etanercept (11.1%).
Development of antibodies to secukinumab was
uncommon: 0.4% of patients in the FIXTURE
study (none were neutralizing) and 0.3% in ERA-
SURE (classified as neutralizing in 1 patient; 26).
Ixekizumab. Ixekizumab is a humanized IgG4
monoclonal antibody that neutralizes IL-17A.
Gaspari and Tyring
190

Phase 3 studies, including head-to-head compar-
isons with etanercept and adalimumab, are
ongoing and the results of a phase 2, double-
blind, placebo-controlled trial have been
reported (31).
Efficacy. In the phase 2 study, patients were
randomized to receive ixekizumab 10, 25, 75, or
150 mg, or placebo (31). At 12 weeks, signifi-
cantly higher proportions of patients in the
ixekizumab 25-mg, 75-mg, and 150-mg groups,
but not the 10-mg group, achieved PASI 75 (pri-
mary endpoint) or PASI 90 (secondary endpoint)
than in the placebo group (p  0.001, all compari-
sons; Table 1). Differences in the proportions of
patients achieving PASI 100 (secondary endpoint)
were significant versus placebo for the ixekizu-
mab 75-mg and 150-mg groups only (p  0.001,
both comparisons). Static PGA scores of 0 or 1
were achieved by proportionately more patients
at week 12 in the three highest dose groups (25,
75, and 150 mg) compared with placebo (Table
1). With the two highest doses, the differences in
response rates for PASI 75 and PGA scores of 0 or
1 were observed at week 1 (p values not reported)
and were maintained through week 20 (p < 0.05 at
all assessments from week 6 onwards; 31). Changes
in score from baseline to week 12 favored the high-
est doses of ixekizumab over placebo for Nail Psori-
asis Severity Index (75-mg and 150-mg doses),
Psoriasis Scalp Severity Index (25-mg, 75-mg, and
150-mg doses), and a joint pain visual analogue
scale (150-mg dose; p  0.05, all comparisons). In
addition, changes in mean DLQI scores and an
itch severity score at weeks 8 and 16 favored the
25-mg, 75-mg, and 150-mg doses of ixekizumab
over placebo (p < 0.001, all comparisons).
Safety and tolerability. Over 20 weeks, the overall
incidence of AEs was similar to placebo when all
doses of ixekizumab were combined (Table
2)(31). No SAEs or deaths were reported. Infec-
tion or infestation AEs, including nasopharyngitis
and upper respiratory infections, were the most
common AEs. No grades 3 or 4 neutropenia was
reported. Injection-site reactions were reported
in 5.2% of patients receiving ixekizumab.
Brodalumab. Brodalumab is a human IgG2
monoclonal antibody that binds to and blocks
IL-17R, the receptor subunit shared by IL-17A,
IL-17F, and IL-17A/F heterodimer ligands (38).
Phase 3 studies in plaque psoriasis (140-mg or
210-mg doses) are ongoing and the results of a
phase 2, double-blind, placebo-controlled, dose-
ranging study have been reported (32).
Efficacy. In the phase 2 study, patients were
randomized to receive subcutaneous brodalu-
mab 70, 140, 210 (at day 1 and weeks 1, 2, 4, 6,
8, and 10), or 280 mg (once monthly), or placebo
(32). Mean percentage improvement in PASI
score from baseline to week 12 (primary end-
point) favored brodalumab over placebo
(p < 0.001, all comparisons). PASI 50, 75, 90, and
100, and PGA scores of 0 or 1 at week 12 (sec-
ondary endpoints) were also reached in propor-
tionately more patients in the brodalumab
groups than in the placebo group (p  0.05, all
comparisons; Table 1). At week 12, brodalumab
also reduced the mean body surface area
affected and was associated with lower mean
DLQI scores than placebo (p  0.01, all compari-
sons). The brodalumab 280-mg regimen did not
appear to confer any additional benefits over the
210-mg or 140-mg doses (32).
Safety and tolerability. The overall incidence of AEs
was higher with the 210-mg dose of brodalumab
(82%) than with the other three doses (68–73%;
32). Although the overall incidence of infections
and infestations was not reported, nasopharyngitis
and upper respiratory tract infections were the
most frequent AEs, followed by arthralgia,
injection-site erythema, extremity pain, and nau-
sea (all reported in more than 5% of patients in
any group). In the brodalumab groups, one case
of renal colic (in the 70-mg group) and one case
of grade 3 neutropenia (in the 210-mg group)
were reported as SAEs. Grade 3 neutropenia was
reported in two patients in the brodalumab 210-
mg group; in one of these patients who re-
initiated brodalumab after normalization of neu-
trophil counts, neutropenia returned, and treat-
ment was discontinued. Antibodies to brodalumab
were detected in 5–10% of patients (none were
classified as neutralizing antibodies)(32).
Summary
Based on evidence from clinical studies, IL-23
and IL-17 appear to be suitable targets for
moderate-to-severe psoriasis. Emerging biologic
therapies that selectively inhibit either IL-23 or
IL-17 significantly reduced the severity of
moderate-to-severe plaque psoriasis during 12–
16 weeks of treatment. Initial results from the
phase 2 studies of the selective IL-23 inhibitors
indicate that this efficacy may be maintained for
up to 40 weeks (guselkumab) or 52 weeks (tildra-
kizumab). However, full results from these stud-
ies and further phase 3 studies are awaited. The
Dermatologic Therapy
191

three selective IL-17 inhibitors have also all
shown convincing efficacy over 12 weeks,
although the 1-year results of large-scale phase 3
studies have only been reported for secukinu-
mab. In these studies, the efficacy of secukinu-
mab was not only superior to placebo, but also
to etanercept. In addition, the PASI and IGA
modified 2011 response rates were maintained
up to 52 weeks, with numerically higher rates
than in patients treated with etanercept.
Whether selective inhibition of IL-23 or IL-17
will result in similar or improved safety profiles
compared with TNF-a or IL-12/23 inhibition,
remains to be established from long-term studies
and real-world evidence because, although piv-
otal trials are powered to evaluate efficacy and
common AEs, AEs of special interest require
broader patient populations and longer time
periods to detect. However, these new biologic
therapies show great promise and, if approved,
would increase the range of options for patients
with plaque psoriasis.
ACKNOWLEDGMENTS
Technical assistance with editing and styling of the
manuscript for submission was provided by
Oxford PharmaGenesis Inc, Newtown, PA. Funding
sources: Novartis Pharmaceuticals Corporation
(East Hanover, NJ, USA) provided funding for edit-
ing and styling of the manuscript. The authors
were fully responsible for all content and editorial
decisions and received no financial support or
other form of compensation related to the devel-
opment of this manuscript. Dr Gaspari has partici-
pated in Data Monitoring Committee activities for
Johnson & Johnson (New Brunswick, NJ) and has
served on the Novartis (East Hanover, NJ) Advisory
Board for secukinumab. Dr Tyring’s institution has
received grants from the manufacturers of etaner-
cept, adalimumab, secukinumab, guselkumab,
ixekizumab, brodalumab, and tildrakizumab for
clinical studies of these drugs in the treatment of
psoriasis. In addition, Dr Tyring is a speaker for the
manufacturers of etanercept and adalimumab and
is a consultant for the manufacturers of adalimu-
mab and secukinumab.
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