Guselkumab for the Treatment of Psoriasis
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BioDrugs
https://doi.org/10.1007/s40259-018-0265-6
REVIEW ARTICLE
Guselkumab for the Treatment of Psoriasis
Álvaro Machado1 • Tiago Torres1,2,3
Ó Springer International Publishing AG, part of Springer Nature 2018
Abstract Psoriasis is a common, chronic, immune-medi- adverse event was nasopharyngitis. Head-to-head studies
ated, inflammatory skin disease with systemic involvement comparing IL-23 inhibitors with agents in different classes,
and significant impact on patients’ quality of life. Several namely IL-17 inhibitors, will be crucial to establish the true
biologic treatments have been developed in recent decades, role of these agents in psoriasis treatment.
such as tumor necrosis factor (TNF)-a inhibitors, a non-
selective interleukin (IL)-23 inhibitor (ustekinumab, which
also inhibits IL-12), and—most recently—IL-17 inhibitors.
Key Points
Guselkumab is a novel biological therapy that selectively
targets IL-23 and is the first-in-class selective IL-23 inhi-
The interleukin (IL)-23/17 axis is currently
bitor approved to treat moderate-to-severe plaque psoriasis.
considered essential in the pathogenesis of psoriasis.
These inhibitors are expected to have some advantages
over the highly effective IL-17 inhibitors, as they do not Selective inhibition of IL-23 may have several
worsen inflammatory bowel disease and are not involved in advantages over the combined inhibition of IL-23
the development of candida infections. Additionally, and IL-12, as IL-12-dependent functions remain
selective inhibition of IL-23 may have additional benefits intact.
over ustekinumab as the IL-12-dependent cascades remain Guselkumab is the first in its class to be approved to
functional. These benefits include a decrease in IL-17A- treat moderate-to-severe plaque psoriasis and has a
producing T cells in the skin and the promotion of an anti- convenient dosing regimen and excellent safety
inflammatory effect through production of interferon-c and profile.
IL-10. In terms of efficacy, guselkumab showed promising
results in the treatment of psoriasis and psoriatic arthritis,
although it did not show significant clinical improvement
in rheumatoid arthritis. Studies in other inflammatory dis-
eases and Crohn’s disease are expected to begin soon.
Overall, guselkumab was well tolerated; the most common 1 Introduction
Psoriasis is a common, chronic, immune-mediated and
& Tiago Torres inflammatory skin disease with systemic involvement and
torres.tiago@outlook.com significant impact on patients’ quality of life [1, 2]. It has
1
Department of Dermatology, Centro Hospitalar do Porto, an estimated prevalence that ranges from 1 to 8.5% in the
Porto, Portugal population and an incidence between 78.9 and 230 per
2
Instituto de Ciências Biomédicas Abel Salazar, University of 100,000 person-years [2].
Porto, Porto, Portugal Psoriasis treatment evolved immensely over the last
3
Dermatology Research Unit, Centro Hospitalar do Porto, decades as knowledge about the disease’s pathophysiology
Porto, Portugal became clearer. In the 1950s, the treatment ofÁ. Machado, T. Torres
inflammatory dermatoses, including psoriasis, was rede- 23 is composed of two subunits—p40, shared with IL-12,
fined when hydrocortisone showed promising results [3]. and a unique p19 subunit. In fact, it has been shown that the
Later, cyclosporine proved to be an effective treatment for p40 subunit, but not the p35 subunit, which is exclusive of
psoriasis, emphasizing the importance of the immune IL-12, is increased in lesional psoriatic skin. Furthermore,
system, namely T cells. Thus, further studies focused on the IL-23/-17 axis has been reported to be essential in
the immune-mediated mechanisms that could be involved psoriasis pathogenesis, being involved in the differentiation
in psoriasis pathophysiology [4, 5]. of naive T cells into IL-17-producing T cells [24–26]
The development of biologic therapies completely (Fig. 1).
transformed the care of patients with moderate to severe Interestingly, inhibition of IL-12 may have a negative
psoriasis. The emergence of tumor necrosis factor (TNF)-a effect in psoriasis [27]. Several mechanisms have been
inhibitors was perhaps the first big step, as significantly suggested, including a regulatory function of IL-12
higher clinical responses were achieved. Additionally, the inhibiting the infiltration of IL-17A-producing cdT cells
success of this approach highlighted the importance of and inducting a protective transcriptional program in ker-
TNF-a in the physiopathogenesis of psoriasis. However, atinocytes, thus limiting skin inflammation, as demon-
some patients did not respond to such agents, which led to strated in an imiquimod murine model [28]. Also, mice
further investigation of additional and possibly more cru- lacking the IL-12-specific receptor subunit developed more
cial targets. Later, ustekinumab, an interleukin (IL)-12/23 severe lesions [27]. Additionally, IL-12 has an anti-in-
inhibitor that blocks the common p40 subunit of these flammatory effect through induction of expression of IL-10
cytokines, was developed after the p40 subunit was shown by type 1 T-helper (Th1) cells, in which interferon (IFN)-c
to be increased in psoriasis plaques [6]. Subsequent studies is a crucial mediator [29]. In fact, IL-10 plays a pivotal role
showed not only significant improvement in clinical in the maintenance of tolerance and limitation of immune-
responses [7] but also better responses than with TNF-a mediated processes, as shown in IL-10-deficient mice that
inhibitors [8]. Recently, new classes of agents have gained developed chronic intestinal inflammation due to an
increasing relevance—IL-17 receptor inhibitors (e.g., bro- uncontrolled immune reaction against intestinal flora [30].
dalumab) and IL-17 inhibitors (secukinumab and ixek- Finally, IL-12 has been implicated in the protection against
izumab). These agents have been approved to treat bacterial and viral infections [31] and may have a role in
moderate to severe psoriasis [9–11] and have shown high tumor immune surveillance through regulation of both
levels of sustained efficacy and better clinical responses innate (natural killer cells) and adaptive (cytotoxic T
than TNF-a inhibitors [12, 13] and ustekinumab lymphocytes) immune responses [32, 33].
[10, 14, 15].
A new class of drugs is now being studied and devel-
oped in the treatment of psoriasis: IL-23 inhibitors. 3 Guselkumab
Guselkumab is a fully human immunoglobulin G1-lambda
(IgG1k) monoclonal antibody that selectively targets the 3.1 Pharmacokinetics
unique p19 subunit of human IL-23 without binding IL-12
[16–20] and was approved by the US FDA in July 2017 A phase I randomized study evaluated the pharmacoki-
[21] and by the European Medicines Agency in September netics, immunogenicity, safety, and tolerability of guselk-
2017 [22] for the treatment of moderate-to-severe plaque umab administered as a single intravenous (0.03–10 mg/
psoriasis. Tildrakizumab may also be available soon, kg) or subcutaneous (10–300 mg) dose [34]. Investigators
whereas risankizumab is in a late stage of development and observed that mean maximum serum concentration and
LY2525623 is still under investigation (NCT01018810) area under the zero-to-infinity serum concentration–time
[23]. curve values increased in an approximately dose-propor-
This article aims to review the current knowledge on tional manner. Mean clearance and volume of distribution
selective IL-23 inhibition in psoriasis, focusing on ranged from 3.62 to 6.03 ml/day/kg and from 99.38 to
guselkumab. 123.22 ml/kg, respectively. The mean half-life ranged from
12 to 19 days when administered intravenously and from
15 to 17 days following subcutaneous administration [34].
2 Advantages of Selective Inhibition of Interleukin A phase II study assessed the efficacy and safety of
(IL)-23 subcutaneous guselkumab (50 and 200 mg at weeks 0 and
4 and every 8 weeks, through week 28) with ustekinumab
Although ustekinumab proved effective in the treatment of in patients with rheumatoid arthritis [35] and reported that
psoriasis, evidence has suggested a more important role of median trough serum levels of guselkumab reached a
IL-23 in psoriasis pathogenesis compared with IL-12. IL-Guselkumab for Psoriasis
Fig. 1 Summarized schematic differences between IL-12/23, selec- IL-12/Th1 axis. IL-17A inhibitors such as secukinumab and ixek-
tive IL-23, and IL-17 inhibition. Non-selective IL-23 inhibitors such izumab also target the IL-23/IL-17 axis but via downstream blockade
as ustekinumab block IL-12 and IL-23 common subunit p40, of this pathway. DC dendritic cell, IL interleukin, KC keratinocyte, Th
inhibiting both the IL-23/T17 and the IL-12/Th1 pathways. Selective T-helper cell Adapted from Torres [5], with permission
IL-23 inhibitors such as guselkumab, tildrakizumab, and risankizu-
mab selectively block the IL-23/T17 pathway, avoiding effects on the
steady state by week 20 and were maintained through week normalization of psoriasis-related gene expression and
28. serum IL-17 levels were observed [36].
3.2 Clinical Efficacy in Psoriasis 3.2.2 Phase II Studies
3.2.1 Phase I Studies A phase II 52-week, dose-ranging, randomized, double-
blind, placebo-controlled, active-comparator trial com-
A phase I first-in-human, randomized, double-blind, pla- pared guselkumab with adalimumab in patients with
cebo-controlled trial, which included 24 patients with moderate-to-severe psoriasis [18]. In total, 293 patients
moderate-to-severe plaque psoriasis, assessed the clinical were randomized to placebo, five guselkumab groups
response to and tolerability and safety of subcutaneous (5 mg at weeks 0 and 4 and every 12 weeks thereafter,
injections (10, 30, 100, and 300 mg) of guselkumab [36]. 15 mg every 8 weeks, 50 mg at weeks 0 and 4 and every
At week 12 (primary endpoint), Psoriasis Area and 12 weeks thereafter, 100 mg every 8 weeks, or 200 mg at
Severity Index (PASI) 75 was 50% for 10 mg, 60% for 30 weeks 0 and 4 and every 12 weeks thereafter) through
and 100 mg, and 100% for 300 mg. Additionally, at week week 40, or adalimumab in the standard psoriasis dosing
12, PASI 90 was achieved in 25, 40, 0, and 80% of patients regimen. At week 16, the proportion of patients achieving a
receiving 10, 30, 100, and 300 mg, respectively. These PGA score of 0 or 1 (primary endpoint) was significantly
PASI scores were generally maintained through week 24 in higher with all guselkumab doses than with placebo (34%
all treated groups, except those receiving 100 mg, in whom with 5 mg, 61% with 15 mg, 79% with 50 mg, 86% with
the initial high levels of response were lost over the follow- 100 mg, and 83% with 200 mg). Additionally, those
up. Physician Global Assessment (PGA) scores were gen- receiving guselkumab 50 mg, 100 mg, or 200 mg had
erally consistent with PASI responses over time. Investi- significantly higher PGA scores of 0 or 1 (p\0.05) than
gators also performed histologic and gene expression those in the adalimumab group. A dose-proportional
analysis and found a significant reduction in the epidermal response was noted for the lowest dose groups, whereas
thickness and in T cell and dendritic cell counts in results were similar between patients receiving 100 and
guselkumab-treated patients compared with those receiving 200 mg. PASI 75, 90, and 100 scores were significantly
placebo. Furthermore, significant reductions and higher in guselkumab-treated groups than in the placebo
group. Specifically, all guselkumab groups, except thoseÁ. Machado, T. Torres
receiving 5 mg, had PASI 75 scores of at least 75%. IGA, fingernail PGA (f-PGA), Nail Psoriasis Severity
Interestingly, clinical responses (PGA score of 0 or 1 and Index (NAPSI), and PGA of the hands and/or feet. At week
PASI 75) were observed as early as week 4. From week 16 16, a significantly higher proportion of guselkumab-treated
to week 40, an increased number of patients with a PGA patients achieved scalp-specific IGA 0/1 compared with
score of 0 or 1 was observed (maximum response at week placebo (83.4 vs. 14.5%) and at weeks 24 and 48 guselk-
20), and these responses were generally maintained from umab showed significantly better results than did adali-
week 24 to week 40. PASI scores showed a similar pattern mumab. Additionally, at week 16, a significantly higher
over time. Compared with those receiving adalimumab, proportion of guselkumab-treated patients had an f-PGA
guselkumab-treated groups (except for the 5-mg group) had 0/1 and percent improvement in NAPSI score compared
a higher proportion of patients achieving PGA scores of 0 with placebo. When compared with adalimumab, although
or 1, with significant differences observed in the 50-mg results in f-PGA were comparable at week 24, significant
(20% points), 100-mg (28% points), and 200-mg (25% differences were observed at week 48. On the other hand,
points) groups. These differences were also significant at NAPSI scores were comparable between guselkumab and
week 40: 71% for 50 mg, 77% for 100 mg, and 81% for adalimumab at weeks 24 and 48. The proportion of patients
200 mg versus 49% for adalimumab. At week 16, PASI 75 achieving PGA 0/1 of the hands and/or feet was signifi-
scores were achieved by 44% with 5 mg, 76% with 15 mg, cantly higher in guselkumab-treated patients than in those
81% with 50 mg, 79% with 100 mg, and 81% with receiving placebo at week 16 (73.3 vs. 14.0%), and
200 mg, whereas the response with adalimumab was 70%. responses were superior to adalimumab at weeks 24 (78.9
The statistical significance of these results was not vs. 56.8%; p\0.001) and 48 (75.6 vs. 62.1%; p\0.045).
reported. Finally, investigators also evaluated health-related quality
of life with patient-reported outcomes using the Derma-
3.2.3 Phase III Studies tology Life Quality Index (DLQI) and the Psoriasis
Symptoms and Signs Diary (PSSD). At week 16, signifi-
VOYAGE 1 was a phase III randomized, double-blind, cant differences were observed in the proportions of
placebo-controlled (from week 0 to week 16, after which guselkumab-treated patients with an improvement from
patients crossed over to receive guselkumab through week baseline DLQI and an achievement of DLQI score 0/1
48), active-controlled trial comparing guselkumab with compared with placebo. Additionally, at weeks 24 and 48,
adalimumab from week 0 to week 48 [16]. Patients were guselkumab showed significantly better results than did
randomized to guselkumab 100 mg at weeks 0, 4, 12, and adalimumab for both improvements from baseline DLQI
every 8 weeks through week 44; placebo at weeks 0, 4, and score and achievement of DLQI 0/1. Regarding PSSD, at
12 followed by guselkumab 100 mg at weeks 16 and 20, week 16, guselkumab showed significantly better results
and every 8 weeks through week 44; or adalimumab 80 mg versus placebo for both PSSD symptom score and mean
at week 0, 40 mg at week 1, and 40 mg every 2 weeks changes in PSSD sign score. Similarly, at weeks 24 and 48,
through week 47. Guselkumab was superior to placebo and mean changes in PSSD scores were significantly better for
adalimumab when assessing the proportion of patients guselkumab than for adalimumab.
achieving an Investigator’s Global Assessment (IGA) score In VOYAGE 2, a complementary study of VOYAGE 1,
of 0/1 and PASI 90 (coprimary endpoints) and all major investigators assessed the efficacy and safety of interrupted
secondary endpoints. At week 16, significantly higher treatment in responders (patients who achieved at least
proportions of patients achieved IGA 0/1 (85.1 vs. 6.9% in PASI 90), which included a randomized withdrawal and
the placebo group) and PASI 90 (73.3 vs. 2.9% in the retreatment period from weeks 28 to 72 (data only from
placebo group). In addition, significantly higher propor- weeks 28 to 48 were shown) [20]. VOYAGE 2 confirmed
tions of patients achieving IGA, PASI 75, and PASI 100 the results of VOYAGE 1 relating to efficacy of guselk-
were also observed (Table 1). When compared with adal- umab versus both placebo and adalimumab, as similar
imumab at week 16, guselkumab-treated patients also had results were observed. Concerning the randomized and
significantly higher IGA 0/1 (85.1 vs. 65.9%), PASI 90 retreatment period, PASI 90 responses were better main-
(73.3 vs. 49.7%), and PASI 75 (91.2 vs. 73.1%) scores. tained in patients continuing guselkumab than in respon-
Responses were still significantly different at week 24 ders re-randomized to placebo. Through week 48, a total of
(IGA 0/1 for 84.2 vs. 61.7%; PASI 90 for 80.2 vs. 53%) 88.6% of patients continuing guselkumab sustained a PASI
and at week 48 (IGA 0/1 for 80.5 vs. 55.4%; PASI 90 for 90 response compared with 36.8% in the withdrawal group.
76.3 vs. 47.9%). After initiating guselkumab, at week 16, Similar results were observed in improvements in DLQI
patients in the placebo cross-over group achieved similar and PSSD scores. Lastly, when assessing adalimumab
responses to those in the guselkumab group. In this study, nonresponders who switched to guselkumab, PASI 90 and
regional psoriasis was also assessed using scalp-specificGuselkumab for Psoriasis
Table 1 Summary of key results from clinical trials of guselkumab
Clinical trial Dosing regimen Proportion of pts achieving
PASI 75 PASI 90 PASI 100 IGA 0/1
VOYAGE 1 100 mg at wk 0, 4 and every 8 wk At wk 16: GUS At wk 16: GUS At wk 16: GUS At wk 16: GUS
91.2%, ADA 73.3%, ADA 37.4%, ADA 85.1%, ADA
73.1%, PL 5.7% 49.7%, PL 2.9% 17.1%, PL 0.6% 65.9%, PL 6.9%
At wk 24: GUS At wk 24: GUS At wk 24: GUS At wk 24: GUS
91.2%, ADA 80.2%, ADA 44.4%, ADA 84.2%, ADA
72.2% 53.0% 24.9% 61.7%
At wk 48: GUS At wk 48: GUS At wk 48: GUS At wk 48: GUS
87.8%, ADA 76.3%, ADA 47.4%, ADA 80.5%, ADA
62.6% 47.9% 23.4% 55.4%
(all p\0.001) (all p\0.001) (all p\0.001) (all p\0.001)
VOYAGE 2 At wk 16: GUS At wk 16: GUS At wk 16: GUS At wk 16: GUS
86.3%, ADA 70.0%, ADA 34.1%, ADA 84.1%, ADA
68.5%, PL 8.1% 46.8%, PL 2.4% 20.6%, PL 0.8% 67.7%, PL 8.5%
At wk 24: GUS At wk 24: GUS At wk 24: GUS At wk 24: GUS
89.1%, ADA 75.2%, ADA 44.2%, ADA 83.5%, ADA
71.0% 54.8% 26.6% 64.9%
(all p\0.001) (all p\0.001) (all p\0.001) (all p\0.001)
NAVIGATE In pts with inadequate response to NR At wk 28: GUS At wk 28: NR At wk 28: GUS
UST: 100 mg at wk 0, 4 and 48.1%, UST 22.6% At wk 52: GUS 31.1%, UST 14.3%
every 8 wk (p\0.001) 20.0%, UST 7.5% (p = 0.001)
At wk 52: GUS (p = 0.003) At wk 52: GUS
51.1%, UST 24.1% 36.3%, UST 17.3%
(p\0.001) (p\0.001)
Non-responder imputation was used to assess binary endpoint missing data
ADA adalimumab, GUS guselkumab, NR not reported, PL placebo, pts patient(s), UST ustekinumab, wk week(s)
PASI 100 response rates were higher after switching, at The primary endpoint was the number of visits at which
66.1 and 28.6%, respectively, at week 48. randomized patients achieved IGA 0/1 and C 2-grade
Recently, a study evaluated the consistency of efficacy improvement relative to week 16 from week 28 through
of guselkumab across several subpopulations of patients week 40. PASI 90, PASI 100, and DLQI of 0/1 were also
with psoriasis using pooled data from VOYAGE 1 and evaluated. The mean number of visits at which patients had
VOYAGE 2 trials [37]. Subgroups were defined by base- an IGA 0/1 and C 2-grade improvement (week 28–40) was
line demographics, psoriasis disease characteristics, and significantly greater in the guselkumab group than in the
previous psoriasis treatments. Guselkumab provided sig- randomized ustekinumab group. Additionally, significantly
nificant benefit across almost all subpopulations, as greater more patients achieved IGA 0/1 and C 2-grade improve-
proportions of patients achieved IGA 0/1 compared with ment at week 28 and week 52. Finally, greater proportions
placebo at week 16 and compared with adalimumab at of patients in the guselkumab group achieved PASI 90,
week 24. Of note, guselkumab showed a more consistent PASI 100, and DLQI 0/1 compared with ustekinumab-
response among lighter and heavier patients when com- treated patients at week 52 (Table 1). To conclude, in
paring with adalimumab. NAVIGATE, patients with inadequate response to ustek-
Finally, NAVIGATE was a phase III, randomized, inumab significantly benefited from switching to
double-blind study assessing the clinical efficacy of guselkumab.
guselkumab in patients with moderate to severe psoriasis
and inadequate response to ustekinumab. A total of 871 3.3 Clinical Efficacy in Psoriatic Arthritis
patients received ustekinumab (45 or 90 mg) at weeks 0
and 4 [19]. At week 16, patients with inadequate response Psoriatic arthritis (PsA), a psoriasis-related spondy-
to ustekinumab (IGA C 2) were randomized to guselkumab loarthropathy, may develop in 20–30% of patients with
100 mg at weeks 16, 20, and every 8 weeks or to continue psoriasis [38]. The utility of guselkumab in the treatment of
ustekinumab at week 16 and every 12 weeks thereafter. patients with PsA was also evaluated. In a phase IIaÁ. Machado, T. Torres
randomized, double-blind, placebo-controlled multicentre guselkumab 5-mg group and two patients in the 100-mg
study, all primary and all secondary endpoints were met, as group experienced nonfatal myocardial infarction and
guselkumab demonstrated significant improvement in joint stroke. Lastly, one case of cancer (grade 3 cervical
symptoms, physical function, enthesitis, dactylitis, and intraepithelial neoplasia) was reported in a patient receiv-
quality of life [39]. Two phase III trials are underway to ing guselkumab. Throughout the whole study, there was no
investigate the efficacy and safety of guselkumab in evidence of a relationship between the dose and the rate of
patients with PsA, one of them including patients previ- AEs among the guselkumab groups.
ously treated with TNF-a inhibitors (NCT03158285; In the phase II study assessing the efficacy and safety of
NCT03162796). guselkumab with ustekinumab in patients with rheumatoid
arthritis [35], the proportions of patients with at least one
3.4 Clinical Efficacy in Other Indications AE were comparable among the treatment groups. Infec-
tions were the most common AE, and no evident differ-
The efficacy of guselkumab was also evaluated in patients ences were observed between treatment groups. No cases
with rheumatoid arthritis in a phase II randomized, double- of tuberculosis or opportunistic infections were observed.
blind, placebo-controlled trial investigating the efficacy All serious AEs reported were isolated and no association
and safety of guselkumab and ustekinumab in patients with between the events and the active treatments was noted.
active rheumatoid arthritis despite treatment with VOYAGE 1 investigators also reported comparable AEs
methotrexate [37]. Guselkumab and ustekinumab did not between treatment groups and throughout the study. The
significantly reduce the signs and symptoms of rheumatoid most frequent events were nasopharyngitis and upper res-
arthritis, as there were no statistically significant differ- piratory tract infection [16]. Treatment withdrawal due to
ences in the proportions of patients achieving an American AEs was infrequent and similar between the groups. Iso-
College of Rheumatology (ACR)-20 response between lated events also occurred: at week 16, one case of basal
guselkumab and ustekinumab groups compared with the cell carcinoma in the guselkumab group and two MACEs
placebo group [37]. Currently, there are no ongoing studies (one in each of the guselkumab and adalimumab groups).
evaluating guselkumab in patients with rheumatoid From week 16 to week 48, two serious infections were
arthritis. reported in the guselkumab group (thigh abscess and cel-
To date, no studies are evaluating guselkumab in lulitis) and another two in the adalimumab group (ab-
Crohn’s disease. However, given the efficacy of ustek- dominal abscess and a fatal staphylococcal pneumonia).
inumab in these patients, guselkumab will likely enter Additionally, two other basal cell carcinomas were repor-
clinical trials soon [40]. ted, one each in the guselkumab and adalimumab groups,
and two malignancies—prostate and breast—in the
3.5 Safety and Tolerability guselkumab group. Of note, the incidence of candidiasis
and neutropenia was low and comparable between groups.
A phase I study reported comparable adverse event (AE) No Crohn’s disease-related events were noted. Laboratory
rates between guselkumab and placebo groups (65 vs. 50%, abnormalities were low and similar between groups.
respectively) and reported no serious AEs [36]. VOYAGE 2 confirmed the results of VOYAGE 1, as the
In a phase II study, at week 16, the incidence of AEs proportions of patients with AEs, AEs leading to discon-
was similar between groups (50% in the guselkumab tinuation, and serious AEs were comparable in the first
groups, 56% in the adalimumab group, and 52% in the 16 weeks of the study (placebo-controlled period) [20].
placebo group) [18]. Specifically, the most commonly Headache was added to the list of the most common events,
reported AE was infection, with rates of 20% in the along with nasopharyngitis and upper respiratory tract
guselkumab groups, 12% in the adalimumab group, and infection. Unlike in VOYAGE 1, no malignancies or
14% in the placebo group. A serous AE was reported in nonmelanoma skin cancers (NMSCs) were observed in this
two patients in the guselkumab 50 mg group (lung abscess period. One case of MACE occurred in the adalimumab
and appendicitis). From week 16 to 52, the AE rates in the group. In the active-comparator period (weeks 0–28), the
guselkumab groups was 49% compared with 61% in the pattern of AEs observed was similar to that in the placebo-
adalimumab group. As in the first 16 weeks, the most controlled period. Three serious infections were observed
frequent AE was infection, which was observed in roughly in the guselkumab group (bronchitis, erysipelas, and soft-
30% of patients. No infection-related serious AEs were tissue infection), and another three were reported in the
reported in the guselkumab groups. Of note, no cases of adalimumab group (two cases of tuberculosis and one
tuberculosis or opportunistic infections were reported. injection-site abscess). One malignancy (prostate cancer)
Major adverse cardiac events (MACEs) were also reported, and two NMSCs (one squamous cell carcinoma in the
as one patient died from myocardial infarction in the guselkumab group and one basal cell carcinoma in theGuselkumab for Psoriasis
placebo/guselkumab group) were reported. Two cases of that 62% of the patients receiving 200 mg and 64% of
MACE were observed, one each in the guselkumab and the those receiving 100 mg achieved PASI 75 compared with
adalimumab group. In the randomized withdrawal and re- 6% receiving placebo and that 59% of those receiving
treatment period (weeks 28–48), one serious infection was 200 mg and 58% of those receiving 100 mg achieved PGA
reported (appendicitis) in the maintenance group. From responses compared with 7% receiving placebo. In reSU-
weeks 28 to 48, one case of MACE was reported in the FARCE 2, 66% in the 200-mg group and 61% in the
placebo–guselkumab group, and, through week 48, one 100-mg group achieved PASI 75 compared with 48% in
basal cell carcinoma and one squamous cell carcinoma the etanercept group and 6% in the placebo group. Fur-
were also reported in the placebo–guselkumab group. No thermore, 59% of patients in the 200-mg group and 55% in
other events were observed. Finally, as in VOYAGE 1, the 100-mg group achieved PGA responses compared with
laboratory abnormalities were low and comparable 4% in the placebo group and 48% in the etanercept group
between groups. [42]. In terms of safety and tolerability, tildrakizumab was
In terms of the safety profile in patients with psoriatic well tolerated overall, with the most common adverse
arthritis and rheumatoid arthritis, guselkumab was also event being nasopharyngitis. Treatment-related discontin-
well tolerated, and no new AEs were observed. uations were infrequent [42].
3.6 Immunogenicity 4.2 Risankizumab
Gordon et al. [18] reported antibodies to guselkumab in 6% Risankizumab is an IgG1j monoclonal antibody that
of patients, albeit non-neutralizing and with low titers. In showed promising results in a phase II dose-ranging ran-
the phase II study comparing guselkumab and ustekinumab domized trial. The study investigated risankizumab com-
in patients with rheumatoid arthritis [35], 11.3% of pared with ustekinumab in 166 patients with moderate-to-
guselkumab-treated patients had positive antibodies to severe psoriasis [43]. Patients were randomly assigned to
guselkumab, but again, they were non-neutralizing as the risankizumab (single 18-mg dose at week 0 or doses of
serum guselkumab concentrations were similar between 90 mg or 180 mg at weeks 0, 4, and 16) or ustekinumab
patients who tested positive and those who tested negative (45 or 90 mg, according to body weight, at weeks 0, 4, and
for antibodies. In part 2 of the study by Zhuang et al. [34], 16). Risankizumab was superior to ustekinumab: 77% of
which included patients with psoriasis, 1 of 20 patients patients receiving risankizumab (90 and 180 mg pooled)
(5.0%) had positive antibodies to guselkumab. Information achieved a PASI 90 or greater response at week 12 (pri-
about guselkumab clearance and elimination half-life (t) mary endpoint) compared with 40% of ustekinumab-trea-
was not reported [34]. VOYAGE 1 and 2 reported rates of ted patients. Additionally, at week 12, totals of 63, 98, and
antibody development of 5.3% through week 44 and 6.6% 88% of patients receiving risankizumab achieved PASI 75
through week 48, respectively. No association between in the 18-, 90-, and 180-mg dose groups, respectively,
antibody incidence and reduced efficacy was noted compared with 72% of ustekinumab-treated patients. PASI
[16, 20]. 100 responses were observed in 14, 41, and 48% of those
receiving risankizumab 18, 90, and 180 mg, respectively,
compared with 18% of the ustekinumab group. Further-
4 Other p19 Inhibitors more, at week 24, the proportion of patients who achieved
a PASI 75 response was 53, 90, and 88% in those receiving
4.1 Tildrakizumab risankizumab 18, 90, and 180 mg, respectively, compared
with 70% of the ustekinumab group. Additionally, 28, 63,
Tildrakizumab is an IgG1j monoclonal antibody, the and 81% of risankizumab-treated patients (18, 90, and
efficacy of which in treating moderate to severe plaque 180 mg, respectively) achieved PASI 90 at week 24 com-
psoriasis has been shown in phase II and III studies pared with 55% of those in the ustekinumab group. Inter-
[41, 42]. In reSURFACE 1, a phase III RCT, patients were estingly, improvements in PASI score were observed as
randomized to tildrakizumab 200 mg (n = 308), tildrak- early as week 2. Risankizumab was also well tolerated:
izumab 100 mg (n = 309), or placebo (n = 155). In the rates of reported side effects were similar in the treatment
second phase III RCT, reSURFACE 2, patients were ran- and placebo groups. The most common AE was
domized to tildrakizumab 200 mg (n = 314), tildrak- nasopharyngitis [43].
izumab 100 mg (n = 307), etanercept 50 mg (n = 313), or Recently, a press release has revealed promising results
placebo (n = 156). Tildrakizumab was administered at from phase III clinical trials with 12-week dosing regi-
baseline and week 4 and subsequently every 12 weeks in mens. Results of two replicate studies—ultIMMa-1 and
both trials. Week 12 results from reSURFACE 1 showed ultIMMa-2—showed that risankizumab achievedÁ. Machado, T. Torres
significantly greater responses of clear or almost clear skin 12 weeks—compared with guselkumab, which is admin-
(static PGA [sPGA] 0/1) than did ustekinumab and adali- istered every 8 weeks, in the maintenance period. Although
mumab, with rates ranging from 84 to 88% at week 16. guselkumab is administered more often, we believe the
Also, at 1 year, 56 and 60% of patients treated with dosing regimen is still convenient; if guselkumab proves
risankizumab achieved PASI 100 compared with 21 and the most effective in the class, administration frequency
30% with ustekinumab [44]. Peer reviewed study results may become less important. Safety and immunogenicity
are expected soon. results were similar: Overall, all three agents were well-
Finally, in a recent phase II study in patients with active tolerated, and AEs were mild to moderate, with infec-
Crohn’s disease, risankizumab was more effective than tions—namely nasopharyngitis—being the most common.
placebo at inducing clinical remission. Thus, selective Future studies with more patients and longer follow-up
inhibition of IL-23 might be a viable therapeutic approach periods will help establish a more complete safety profile
in these patients [5, 45]. for these agents.
As discussed, guselkumab has not been studied in pop-
ulations with Crohn’s disease. However, given the efficacy
5 Discussion of risankizumab in this disease [5, 45], guselkumab is
expected to enter clinical trials assessing its efficacy in this
Currently, the IL-23/IL-17 axis is widely considered the regard soon.
most important pathogenic pathway in psoriasis. The A recent Cochrane meta-analysis showed that, compared
clinical efficacy of IL-23p19 and IL-17 inhibitors reinforce with placebo, the biologics ixekizumab, secukinumab,
this concept. Although some IL-23p19 inhibitors are in a brodalumab, guselkumab, certolizumab, and ustekinumab
late stage of development, IL-17 inhibitors are already are the best choices for achieving PASI 90 in people with
approved and used to treat moderate-to-severe psoriasis. moderate to severe psoriasis, although head-to-head trials
These two drug classes differ in some aspects. Specifically, are essential to establish the true role of these agents in
IL-17 inhibitors were ineffective in the treatment of psoriasis treatment [49]. Interestingly, the first study to
inflammatory bowel disease, with a tendency to worsen the compare guselkumab with an agent from a different
disease [46, 47]. Furthermore, IL-17 is crucial in the class—secukinumab, an IL-17A inhibitor—is ongoing
immune response against Candida infections. However, (ECLIPSE—NCT03090100). Furthermore, two ongoing
although Candida infections have been reported, the studies are assessing the efficacy of guselkumab in the
majority were mild to moderate in severity and resolved treatment of generalized pustular psoriasis or erythroder-
with conventional therapy, and some experts do not con- mic psoriasis (NCT02343744) and palmoplantar pustulosis
sider these infections a reason to discontinue IL-17 inhi- (NCT02641730).
bitor treatment [48]. Guselkumab may also be an option in specific situations.
Selective IL-23 inhibition may prove to have great Results from NAVIGATE were interesting, with guselk-
benefit, as IL-12-dependent funtions remain intact. In fact, umab being effective in patients with an inadequate
IL-12 has been associated with inhibition of infiltration of response to ustekinumab. Although why remains unclear,
IL-17A-producing cdT cells in the skin, which is a key potential reasons include a more potent blockade of IL-23
cytokine in psoriasis pathogenesis [27]. IL-12 may also with guselkumab and/or increased Th17 responses with
have anti-inflammatory properties that increase the ustekinumab [19]. Finally, guselkumab might be a good
expression of IL-10 through IFN-c, which may result in a alternative in patients who do not respond to TNF-a inhi-
synergic effect in decreasing psoriasis inflammation [29]. bitors and ustekinumab, as shown in VOYAGE 2 and
Guselkumab is the first in its class to be approved to NAVIGATE [19, 20].
treat moderate-to-severe plaque psoriasis [21]. Tildrak- Real-world results will be crucial in unveiling the role of
izumab may also be available soon. Although no head-to- guselkumab in psoriasis treatment, as the disease is often
head comparison has been performed, tildrakizumab difficult to treat and has frequently already been treated
appears to show numerically inferior efficacy. Results of with multiple biological drugs.
only phase II studies are available for risankizumab;
although these were promising and better than for guselk-
umab and tildrakizumab, phase III studies will establish the 6 Conclusion
true efficacy of this agent. Dosing regimen is also impor-
tant and can be a decisive factor since recent treatment Guselkumab is a monoclonal antibody that selectively
options tend to be highly effective, with most patients targets IL-23 and is the first in its class to be approved to
achieving almost clear or clear skin. The dosing regimens treat moderate-to-severe plaque psoriasis. Its very effective
of tildrakizumab and risankizumab are similar—every and safe profile combined with a convenient dosingGuselkumab for Psoriasis
regimen could see it soon considered as first-line treatment 13. Griffiths CEM, Reich K, Lebwohl M, Van De Kerkhof P, Paul C,
for moderate-to-severe psoriasis. Menter A, et al. Comparison of ixekizumab with etanercept or
placebo in moderate-to-severe psoriasis (UNCOVER-2 and
UNCOVER-3): results from two phase 3 randomised trials.
Lancet. 2015;386(9993):541–51.
Funding No sources of funding were used to conduct this study or 14. Reich K, Pinter A, Lacour JP, Ferrandiz C, Micali G, French LE,
prepare this manuscript. et al. Comparison of ixekizumab with ustekinumab in moderate-
to-severe psoriasis: 24-week results from IXORA-S, a phase III
Compliance with ethical standards study. Br J Dermatol. 2017;177(4):1014–23.
15. Lebwohl M, Strober B, Menter A, Gordon K, Weglowska J, Puig
Conflicts of interest Álvaro Machado has no conflicts of interest. L, et al. Phase 3 studies comparing brodalumab with ustekinumab
Tiago Torres has participated in clinical trials sponsored by AbbVie, in psoriasis. N Engl J Med. 2015;373(14):1318–28.
Amgen, and Novartis and has received honoraria for acting as a 16. Blauvelt A, Papp KA, Griffiths CEM, Randazzo B, Wasfi Y, Shen
consultant and/or as a speaker at events sponsored by AbbVie, Y-K, et al. Efficacy and safety of guselkumab, an anti-inter-
Boehringer Ingelheim, Celgene, Janssen, Leo-Pharma, Lilly-Eli, leukin-23 monoclonal antibody, compared with adalimumab for
MSD, Novartis, and Pfizer. the continuous treatment of patients with moderate to severe
psoriasis: results from the phase III, double-blinded, placebo- and
active comparator-controlled VOYAGE 1 trial. J Am Acad
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