The n e w e ng l a n d j o u r na l of
Original Article
From Innovaderm Research, Montreal
(R.B.), McMaster University and Dermatri-
als Research, Hamilton, ON (R.V.), Alliance
Clinical Trials and Probity Medical Re-
search, Waterloo, ON (K.P.), and the Divi-
sion of Dermatology, Department of Medi-
cine, University of Toronto, Toronto (K.P.)
— all in Canada; Goethe University Frank-
furt, Frankfurt am Main (A.P.), and the
Center for Inflammatory Skin Diseases,
University Medical Center Schleswig–
Holstein Campus Kiel, Kiel (S.G.) — both
in Germany; the University of Pittsburgh,
Pittsburgh (L.K.F.), and Janssen Research
and Development, Spring House (M.M.,
Y.-K.S., A.K., S.L., C.D.) — both in Pennsyl-
vania; and Oregon Dermatology and Re-
search Center, Portland (P.R.). Dr. Bisson-
nette can be contacted at ­rbissonnette@​
­innovaderm​.­com or at Innovaderm Re-
search, 3530 Saint-Laurent Blvd., Ste. 300,
Montreal, QC H2X 2V1, Canada.
This article was updated on February 8,
2024, at NEJM.org.
N Engl J Med 2024;390:510-21.
DOI: 10.1056/NEJMoa2308713
Copyright © 2024 Massachusetts Medical Society.
510
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m e dic i n e
An Oral Interleukin-23–Receptor Antagonist
Peptide for Plaque Psoriasis
Robert Bissonnette, M.D., Andreas Pinter, M.D., Laura K. Ferris, M.D., Ph.D.,
Sascha Gerdes, M.D., Phoebe Rich, M.D., Ronald Vender, M.D.,
Megan Miller, M.P.H., Yaung‑Kaung Shen, Ph.D., Arun Kannan, Ph.D.,
Shu Li, Ph.D., Cynthia DeKlotz, M.D., and Kim Papp, M.D., Ph.D.​​
A BS T R AC T
BACKGROUND
The use of monoclonal antibodies has changed the treatment of several immune-
mediated inflammatory diseases, including psoriasis. However, these large proteins
must be administered by injection. JNJ-77242113 is a novel, orally administered
interleukin-23–receptor antagonist peptide that selectively blocks interleukin-23
signaling and downstream cytokine production.
METHODS
In this phase 2 dose-finding trial, we randomly assigned patients with moderate-
to-severe plaque psoriasis to receive JNJ-77242113 at a dose of 25 mg once daily,
25 mg twice daily, 50 mg once daily, 100 mg once daily, or 100 mg twice daily or
placebo for 16 weeks. The primary end point was a reduction from baseline of at
least 75% in the Psoriasis Area and Severity Index (PASI) score (PASI 75 response;
PASI scores range from 0 to 72, with higher scores indicating greater extent or sever-
ity of psoriasis) at week 16.
RESULTS
A total of 255 patients underwent randomization. The mean PASI score at baseline
was 19.1. The mean duration of psoriasis was 18.2 years, and 78% of the patients
across all the trial groups had previously received systemic treatments. At week 16,
the percentages of patients with a PASI 75 response were higher among those in
the JNJ-77242113 groups (37%, 51%, 58%, 65%, and 79% in the 25-mg once-daily,
25-mg twice-daily, 50-mg once-daily, 100-mg once-daily, and 100-mg twice-daily
groups, respectively) than among those in the placebo group (9%), a finding that
showed a significant dose–response relationship (P<0.001). The most common ad-
verse events included coronavirus disease 2019 (in 12% of the patients in the placebo
group and in 11% of those across the JNJ-77242113 dose groups) and nasopharyngitis
(in 5% and 7%, respectively). The percentages of patients who had at least one
adverse event were similar in the combined JNJ-77242113 dose group (52%) and the
placebo group (51%). There was no evidence of a dose-related increase in adverse
events across the JNJ-77242113 dose groups.
CONCLUSIONS
After 16 weeks of once- or twice-daily oral administration, treatment with the inter-
leukin-23–receptor antagonist peptide JNJ-77242113 showed greater efficacy than
placebo in patients with moderate-to-severe plaque psoriasis. (Funded by Janssen Re-
search and Development; FRONTIER 1 ClinicalTrials.gov number, NCT05223868.)
n engl j med 390;6 nejm.org February 8, 2024
The New England Journal of Medicine
 Interleukin-23–Receptor Antagonist for Plaque Psoriasis
T
he treatment of immune-mediated
inflammatory diseases has changed dra-
matically during the past 20 years owing
to the approval of several monoclonal antibod-
ies and fusion proteins that target inflammatory
cytokines or their receptors. Psoriasis is a multi-
systemic, immune-mediated inflammatory disease
that predominantly involves the skin and joints1
and is also a risk factor for atherosclerotic cardio-
vascular disease.2 Interleukin-23 plays a critical
role in pathogenic T-cell activation in psoriasis.3
Thus, a number of biologic agents approved for
psoriasis affect interleukin-234; three target the
p19 subunit of interleukin-23,5-7 and one targets
the p40 subunit, which is present in both inter-
leukin-23 and interleukin-12.8 Modulation of the
interleukin-23 pathway with the use of monoclo-
nal antibodies has shown efficacy in the treatment
of psoriasis and is considered to be associated
with a more favorable safety profile than older
oral therapies (e.g., cyclosporine, acitretin, meth-
otrexate, and dimethyl fumarate).1
However, biologics have limitations, one of
which is that they require intravenous or subcu-
taneous administration.4,9 Many patients prefer
oral treatments over injections,10,11 and injections
are especially problematic among children and
among patients with a fear of needles.12 In the
past 10 years, two oral therapies — apremilast
(a phosphodiesterase 4 inhibitor) and deucra­va­
citinib (a tyrosine kinase 2 inhibitor) — were
approved for the treatment of psoriasis. However,
apremilast has modest efficacy relative to inject-
able biologics, and data on the long-term safety
of tyrosine kinase 2 inhibitors are limited.1,13,14
Thus, there is a need for efficacious targeted thera-
pies that can be administered orally.
JNJ-77242113 is an oral interleukin-23–recep-
tor antagonist peptide that selectively and potently
blocks interleukin-23 proximal signaling and the
production of downstream cytokines such as
interleukin-17.15 Here, we report the results of
FRONTIER 1, a phase 2 trial of JNJ-77242113 in
patients with moderate-to-severe plaque psoriasis.
Me thods
Trial Oversight
The FRONTIER 1 trial was conducted in accor-
dance with the Good Clinical Practice guidelines
of the International Council for Harmonisation
and the principles of the Declaration of Helsinki.
n engl j med 390;6
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Copyright © 2024 Massachusetts Medical Society. All rights reserved.
All the investigators received approval from an
ethics committee, and written informed consent
was obtained from all the patients. As part of the
informed consent process, patients were informed A Quick Take
is available at
that alternative treatments were available. NEJM.org
The sponsor (Janssen Research and Develop-
ment) designed the trial with input from external
medical experts (including the authors), provid-
ed JNJ-77242113 and placebo, and analyzed the
data with the participation of the authors. The
first author wrote the first draft of the manu-
script. All the authors had access to the data; par-
ticipated in the interpretation of the data; provided
critical review, revision, and approval of the manu-
script; and agreed to submit the manuscript for
publication. All the authors vouch for the com-
pleteness and accuracy of the data and for the
fidelity of the trial to the protocol, which is avail-
able with the full text of this article at NEJM.org.
Patients
Eligible adults (≥18 years of age) had moderate-
to-severe plaque psoriasis (as defined by an Inves-
tigator’s Global Assessment [IGA] score of ≥3, a
total body-surface area [BSA] of psoriasis involve-
ment of ≥10%, and a Psoriasis Area and Severity
Index [PASI] score of ≥12), had received a diag-
nosis of plaque psoriasis at least 6 months be-
fore receiving the first dose of JNJ-77242113 or
placebo, and were candidates for phototherapy
or systemic psoriasis treatment. IGA scores range
from 0 (clear skin) to 4 (severe disease). PASI scores
range from 0 to 72, with higher scores indicating
greater extent or severity of psoriasis. Patients
with nonplaque psoriasis or drug-induced psoria-
sis and those who had previously received a bio-
logic targeting interleukin-23 were excluded.
Patients who had previously received biologics
targeting interleukin-17 or both interleukin-23 and
interleukin-12, anti–tumor necrosis factor α ther-
apy, T-cell modulators, or an experimental anti-
body had to stop the treatment at least 12 weeks
or at least five half-lives before their first dose of
JNJ-77242113 or placebo. Patients had to have
discontinued phototherapy and systemic psoria-
sis treatments for at least 4 weeks before receiving
the first dose of JNJ-77242113 or placebo, live
vaccines for at least 12 weeks before receiving
the first dose (≥12 months for the bacille Calmette–
Guérin vaccine), and topical treatments for at least
2 weeks before receiving the first dose. Patients
were advised to avoid prolonged exposure to ultra-
nejm.org February 8, 2024 511
 512
Table 1. Demographic and Baseline Clinical Characteristics in the Full Analysis Set.*

JNJ-77242113 JNJ-77242113 JNJ-77242113 JNJ-77242113 JNJ-77242113

25 mg 25 mg 50 mg 100 mg 100 mg JNJ-77242113 Total,
Placebo Once Daily Twice Daily Once Daily Once Daily Twice Daily Dose Groups All Groups
Characteristic (N = 43) (N = 43) (N = 41) (N = 43) (N = 43) (N = 42) (N = 212) (N = 255)
Age — yr 43.9±14.70 44.5±12.72 45.7±11.91 45.1±11.08 44.7±14.11 42.0±11.34 44.4±12.24 44.3±12.65
Female sex — no. (%) 18 (42) 11 (26) 11 (27) 16 (37) 11 (26) 12 (29) 61 (29) 79 (31)
Race or ethnic group — no. (%)†
American Indian or Alaska Native 1 (2) 0 1 (2) 2 (5) 1 (2) 0 4 (2) 5 (2)
The

Asian 5 (12) 12 (28) 7 (17) 9 (21) 7 (16) 9 (21) 44 (21) 49 (19)

Black 0 0 3 (7) 0 0 2 (5) 5 (2) 5 (2)
Native Hawaiian or Pacific Islander 0 0 2 (5) 0 0 0 2 (1) 2 (1)
White 37 (86) 30 (70) 27 (66) 31 (72) 35 (81) 30 (71) 153 (72) 190 (75)
Not reported 0 1 (2) 1 (2) 1 (2) 0 1 (2) 4 (2) 4 (2)

n engl j med 390;6

Weight — kg 92.1±24.66 89.0±19.42 90.8±22.12 87.6±19.23 85.4±22.49 88.5±16.94 88.2±20.03 88.9±20.87
Body-mass index‡ 31.2±7.61 30.0±7.25 30.2±6.72 29.3±5.97 28.8±7.39 30.0±5.40 29.6±6.55 29.9±6.75
Duration of psoriasis — yr 17.9±14.37 15.5±11.76 18.1±11.82 21.5±11.16 19.5±13.34 16.7±13.78 18.3±12.48 18.2±12.79

nejm.org
PASI total score§ 18.99±5.34 18.90±5.27 18.46±5.84 19.23±5.08 18.42±6.87 20.33±6.51 19.07±5.94 19.05±5.83
n e w e ng l a n d j o u r na l

The New England Journal of Medicine

IGA score — no. (%)¶
of

3, Moderate psoriasis 38 (88) 30 (70) 33 (80) 36 (84) 35 (81) 30 (71) 164 (77) 202 (79)
4, Severe psoriasis 5 (12) 13 (30) 8 (20) 7 (16) 8 (19) 12 (29) 48 (23) 53 (21)

February 8, 2024
Percentage of affected body-surface 26.1±15.72 21.1±9.28 20.9±11.93 23.9±13.59 20.5±13.69 24.2±12.55 22.1±12.30 22.8±12.99

Copyright © 2024 Massachusetts Medical Society. All rights reserved.

area‖
m e dic i n e

Previous therapy — no. (%)

Phototherapy** 19 (44) 17 (40) 15 (37) 24 (56) 21 (49) 14 (33) 91 (43) 110 (43)
Conventional nonbiologic 17 (40) 20 (47) 20 (49) 21 (49) 24 (56) 20 (48) 105 (50) 122 (48)
systemic therapy††
Nonconventional nonbiologic sys- 4 (9) 5 (12) 2 (5) 2 (5) 2 (5) 3 (7) 14 (7) 18 (7)
temic therapy‡‡
Biologic therapy§§ 7 (16) 7 (16) 13 (32) 11 (26) 9 (21) 9 (21) 49 (23) 56 (22)
Systemic therapy¶¶ 34 (79) 33 (77) 33 (80) 35 (81) 34 (79) 31 (74) 166 (78) 200 (78)

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 Interleukin-23–Receptor Antagonist for Plaque Psoriasis

violet radiation. Additional details are provided in

¶¶ This category includes conventional nonbiologic systemic agents, nonconventional nonbiologic systemic agents, 1,25-dihydroxyvitamin D and analogues, phototherapy, and biologics.
§§ This category includes etanercept, infliximab, adalimumab, ustekinumab, briakinumab, secukinumab, ixekizumab, brodalumab, guselkumab, risankizumab, tildrakizumab, alefacept,
the protocol.
* Plus–minus values are means ±SD. The full analysis set included all the patients who had undergone randomization and received at least one dose of JNJ-77242113 or placebo.

Trial Design
Patients were enrolled at 60 sites across North
America, Europe, and Asia. The FRONTIER 1 trial
was a phase 2, dose-finding, double-blind, ran-
domized, placebo-controlled trial. With the use
of a dynamic central randomization system, pa-
tients were assigned to a trial group on the basis
of a minimization algorithm that was implement-
ed in an interactive Web-response system; details
§ Scores on the Psoriasis Area and Severity Index (PASI) range from 0 to 72, with higher scores indicating greater extent or severity of psoriasis.

are provided in the Supplemental Methods sec-

tion of the Supplementary Appendix, available at
NEJM.org. Patients were randomly assigned in a
1:1:1:1:1:1 ratio to receive JNJ-77242113 at a dose
of 25 mg once daily, 25 mg twice daily, 50 mg
‖ The percentage of affected body-surface area ranges from less than 3% (mild disease) to greater than 10% (severe disease).

once daily, 100 mg once daily, or 100 mg twice

daily or placebo for 16 weeks. All the patients
took two tablets in the morning and one in the
evening. Patients in all the trial groups received
the same number of tablets to maintain blinding.
The patients were instructed to take all the tablets
** This category includes psoralen and long-wave ultraviolet light (PUVA) and short-wave ultraviolet light.
¶ Scores on the Investigator’s Global Assessment (IGA) range from 0 (clear skin) to 4 (severe disease).

on an empty stomach (no food for ≥2 hours be-

fore taking the tablets and no food or liquid for
‡ The body-mass index is the weight in kilograms divided by the square of the height in meters.

≥30 minutes after taking the tablets) with ap-

proximately 240 ml of water. At week 16, patients
could enroll in a 36-week long-term extension
†† This category includes PUVA, methotrexate, cyclosporine, acitretin, and azathioprine.

phase (FRONTIER 2; ClinicalTrials.gov number,

NCT05364554). Patients who either were ineligi-
ble for participation in the FRONTIER 2 trial or
chose not to participate completed a final safety
follow-up visit 4 weeks after the final dose of
‡‡ This category includes apremilast, deucravacitinib, and tofacitinib.

JNJ-77242113 or placebo. Concomitant treatments

for psoriasis were prohibited, except for shampoos
containing salicylic acid and nonmedicated topi-
cal moisturizers.
Percentages may not total 100 because of rounding.
† Race and ethnic group were reported by the patient.

efalizumab, natalizumab, and cetolizumab pegol.

End Points
The primary end point was a reduction from base-
line of at least 75% in the PASI score16 (PASI 75
response) at week 16. PASI is a validated com-
posite outcome measure for psoriasis that takes
into consideration the percentage of affected BSA
and the severity of erythema, scaling, and indu-
ration in four body regions; as previously indi-
cated, scores range from 0 to 72, with higher
scores indicating greater extent or severity of pso-
riasis.17 Secondary end points included an IGA
score of 0 (clear skin) or 1 (minimal disease) at
week 16, a reduction from baseline of at least 90%
in the PASI score (PASI 90 response) at week 16,

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 The n e w e ng l a n d j o u r na l
a reduction from baseline of 100% in the PASI
score (PASI 100 response) at week 16, the change
from baseline in the PASI score at week 16, and
the change from baseline in BSA involvement at
week 16. Secondary end points evaluating patient-
reported outcomes at week 16 included a Derma-
tology Life Quality Index (DLQI) score18 of 0 or
1 (no effect or minimal effect, respectively, on
quality of life; scores range from 0 to 30, with
higher scores indicating a lower quality of life)
and the change from baseline in the score on the
Psoriasis Symptoms and Signs Diary (PSSD; scores
range from 0 to 100, with a higher score indicat-
ing greater severity of psoriasis).19 The investiga-
tors remained unaware of the trial-group assign-
ments during these evaluations.
The frequency and types of adverse events and
serious adverse events were assessed from the
time of informed consent through the last trial-
related procedure. Adverse events were coded ac-
cording to the Medical Dictionary for Regulatory Activi-
ties, version 25.1.
Biomarker Analysis
Blood samples were obtained through week 16 for
all the patients and at the safety follow-up visit
for patients not participating in the FRONTIER 2
trial. Low levels of the pharmacodynamic bio-
marker human β-defensin 2 (hBD-2) correlate
with clinical response and inhibition of the in-
terleukin-17–interleukin-23 axis in patients with
psoriasis.20-22 The hBD-2 protein concentrations
were measured by means of validated immuno-
assays that use an electrochemiluminescence-
based platform (Meso Scale Discovery). Concentra-
tion modifications were made to measured values
that were outside the empirically defined limits of
quantification.
Statistical Analysis
We determined that a trial population of 240 pa-
tients would provide adequate power to detect a
JNJ-77242113 dose–response signal with respect
to the percentage of patients with a PASI 75
response at week 16 using the Multiple Com-
parison Procedures with modeling techniques
(MCP-Mod) method; details are provided in the
Supplementary Appendix. A sample of 240 pa-
tients (40 patients per group) was estimated to
provide the trial with at least 90% power to de-
tect an absolute difference of 35 percentage points
between placebo and any of the dose levels of
514 n engl j med 390;6
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Copyright © 2024 Massachusetts Medical Society. All rights reserved.
of m e dic i n e
JNJ-77242113, assuming an incidence of PASI 75
response of 5 to 10% in the placebo group and
a two-sided alpha level of 0.05 on the basis of a
two-sample z test.
Patients who discontinued JNJ-77242113 or
placebo because of a lack of efficacy or worsen-
ing psoriasis, as well as those who began treat-
ment with a prohibited medication that could re-
duce psoriasis, were considered not to have had
a response after the occurrence with respect to
the binary end points and were assigned a result
of zero change from baseline for the continuous
end points. For patients who discontinued JNJ-
77242113 or placebo for other reasons, observed
data were used. For missing data, a status of no
response was assigned for binary end points, and
no imputation was performed for continuous end
points; a mixed model for repeated measures was
used to account for missing data.
Efficacy and safety were analyzed in the full
analysis set, which included all the patients who
had undergone randomization and received at
least one dose of JNJ-77242113 or placebo. To ad-
dress the primary objective of the trial, MCP-Mod
was used to determine the presence of a dose–
response relationship (as assessed by PASI 75
response at week 16) with JNJ-77242113 (primary
end point). Pairwise comparisons were not ad-
justed for multiplicity; therefore, any differences
between a JNJ-77242113 group and the placebo
group were reported with 95% confidence inter-
vals. Because the statistical analysis plan did not
include a provision for correcting for multiplicity
when performing tests for the secondary end
points, results are reported as point estimates and
95% confidence intervals. The widths of the con-
fidence intervals were not adjusted for multiplicity
and should not be used to infer definitive effects
of JNJ-77242113 for the secondary end points.
R e sult s
Patients
Patients were enrolled in the FRONTIER 1 trial
from February 2022 through July 2022. Among
the 255 patients who underwent randomization,
all received at least one dose of JNJ-77242113 or
placebo. Overall, 24 patients (9%) discontinued
treatment (7 [16%] in the placebo group and 17
[8%] across the JNJ-77242113 dose groups) (Fig.
S1 in the Supplementary Appendix). The most
common reason for discontinuation of JNJ-
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 Interleukin-23–Receptor Antagonist for Plaque Psoriasis

77242113 or placebo was withdrawal from the ously received conventional nonbiologic systemic
trial by the patient. No relationships between a therapy, 43% had received phototherapy, 22% had
JNJ-77242113 dose level and any reason for dis- received biologic therapy, and 7% had received
continuation were identified. nonconventional nonbiologic systemic therapy.
Demographic and baseline clinical character- The percentage of women, the baseline body
istics are shown in Table 1. A majority of the weight, and the baseline body-mass index were
patients were White (75%) and were men (69%). higher in the placebo group than in the JNJ-
The representativeness of the trial population is 77242113 dose groups. The percentage of patients
shown in Table S1. Overall, the mean (±SD) du- with severe psoriasis (as defined by an IGA score
ration of psoriasis was 18.2±12.79 years, and the of 4) at baseline was higher among those in the
mean PASI total score was 19.05±5.83. Across all JNJ-77242113 25-mg once-daily and 100-mg twice-
the trial groups, 48% of the patients had previ- daily groups than in the other groups.

Placebo JNJ-77242113, JNJ-77242113, JNJ-77242113, JNJ-77242113, JNJ-77242113,

(N=43) 25 mg once daily 25 mg twice daily 50 mg once daily 100 mg once daily 100 mg twice daily
(N=43) (N=41) (N=43) (N=43) (N=42)

A Patients with a PASI 75 Response B Patients with a PASI 90 Response C Patients with a PASI 100 Response
100 100 100
90 90 90
80 79 80 80
Percentage of Patients

Percentage of Patients

Percentage of Patients
70 70 70
65
60 58 60 60 60
50 51 50 51 50
47
40 40 40 40
37
30 30 27 30 26
26 23
20 20 20
12
10 9 10 10 10
0 0 2 0 0
12 4 8 12 16 12 4 8 12 16 12 4 8 12 16
Week Week Week

D Patients with an IGA Score of 0 or 1 E Patients with an IGA Score of 0 F Change in Serum Levels of hBD-2
100 100 1
Log2 Factor Change from Baseline

90 90
80 80 0
Percentage of Patients

Percentage of Patients

70 64 70
60 63 60 −1
58
50 51 50
45
40 40 40 −2
35
30 30 28
20 20 16 −3
12 15
10 10
0 0 0 −4
12 4 8 12 16 12 4 8 12 16 0 2 4 8 12 16
Week Week Week

Figure 1. Efficacy End Points According to Trial Group from Week 1 through Week 16.
Scores on the Psoriasis Area and Severity Index (PASI) range from 0 to 72, with higher scores indicating greater extent or severity of
psoriasis. PASI 75 response, PASI 90 response, and PASI 100 response refer to reductions from baseline of at least 75%, 90%, and
100%, respectively, in the PASI score. Scores on the Investigator’s Global Assessment (IGA) range from 0 (clear skin) to 4 (severe dis-
ease); a score of 1 indicates minimal disease. I bars denote 95% confidence intervals. For serum levels of human β-defensin 2 (hBD-2),
I bars indicate linear mixed-effect model–based 95% confidence intervals. The widths of the confidence intervals have not been adjusted
for multiplicity and should not be used to infer definitive effects of JNJ-77242113 for the secondary end points.

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 516
Table 2. Efficacy End Points at Week 16 According to Trial Group in the Full Analysis Set.*

JNJ-77242113 JNJ-77242113 JNJ-77242113 JNJ-77242113 JNJ-77242113

25 mg 25 mg 50 mg 100 mg 100 mg
Placebo Once Daily Twice Daily Once Daily Once Daily Twice Daily
End Point (N = 43) (N = 43) (N = 41) (N = 43) (N = 43) (N = 42)
Primary end point
PASI 75 response at wk 16 — no. (%)† 4 (9) 16 (37) 21 (51) 25 (58) 28 (65) 33 (79)
Difference vs. placebo — percentage points (95% — 28 42 49 56 69
CI)‡ (11 to 45) (24 to 59) (32 to 66) (39 to 72) (55 to 84)
Secondary end points
PASI 90 response at wk 16 — no. (%) 1 (2) 11 (26) 11 (27) 22 (51) 20 (47) 25 (60)
PASI 100 response at wk 16 — no. (%) 0 5 (12) 4 (10) 11 (26) 10 (23) 17 (40)
IGA score of 0 or 1 at wk 16 — no. (%) 5 (12) 17 (40) 21 (51) 25 (58) 27 (63) 27 (64)
The

IGA score of 0 at wk 16 — no. (%) 0 7 (16) 6 (15) 15 (35) 12 (28) 19 (45)

DLQI score of 0 or 1 at wk 16 — no. (%)§ 1 (2) 12 (28) 12 (30) 16 (37) 24 (56) 18 (44)
PSSD symptom score of 0 at wk 16 — no. (%)¶ 0 7 (16) 7 (17) 10 (24) 12 (28) 11 (26)
PSSD sign score of 0 at wk 16 — no. (%)¶ 0 1 (2) 4 (10) 6 (14) 7 (16) 6 (14)
PASI total score

n engl j med 390;6

Least-squares mean change from baseline at −3.7 −11.9 −12.9 −14.3 −14.3 −16.5
wk 16 (95% CI)‖ (−5.7 to −1.6) (−14.0 to −9.8) (−15.0 to −10.8) (−16.4 to −12.2) (−16.4 to −12.2) (−18.6 to −14.4)
Least-squares mean difference vs. placebo — −8.3 −9.2 −10.6 −10.7 −12.8
(95% CI)‖ (−11.2 to −5.3) (−12.2 to −6.3) (−13.6 to −7.7) (−13.6 to −7.7) (−15.8 to −9.9)

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Percentage of affected body-surface area
n e w e ng l a n d j o u r na l

The New England Journal of Medicine

Least-squares mean change from baseline at −0.8 −12.0 −14.2 −14.6 −16.1 −20.1
of

wk 16 (95% CI)‖ (−4.0 to 2.4) (−15.2 to −8.7) (−17.4 to −11.0) (−17.8 to −11.4) (−19.3 to −13.0) (−23.3 to −16.8)
Least-squares mean difference vs. placebo — −11.2 −13.4 −13.8 −15.3 −19.2
(95% CI)‖ (−15.7 to −6.6) (−18.0 to −8.8) (−18.3 to −9.3) (−19.9 to −10.8) (−23.8 to −14.7)

February 8, 2024
PSSD sign score

Copyright © 2024 Massachusetts Medical Society. All rights reserved.

m e dic i n e

Least-squares mean change from baseline at −7.8 −31.7 −40.9 −42.9 −45.3 −50.6
wk 16 (95% CI)‖ (−14.6 to −0.9) (−38.7 to −24.8) (−47.8 to −34.0) (−49.7 to −36.1) (−52.1 to −38.5) (−57.5 to −43.7)
Least-squares mean difference vs. placebo — −24.0 −33.1 −35.1 −37.5 −42.8
(95% CI)‖ (−33.7 to −14.2) (−42.8 to −23.4) (−44.8 to −25.5) (−47.2 to −27.9) (−52.6 to −33.1)
PSSD symptom score
Least-squares mean change from baseline at −4.2 −27.9 −32.6 −35.3 −36.7 −40.1
wk 16 (95% CI)‖ (−10.8 to 2.4) (−34.6 to −21.2) (−39.3 to −25.9) (−41.8 to −28.7) (−43.3 to −30.0) (−46.8 to −33.4)
Least-squares mean difference vs. placebo — −23.7 −28.4 −31.1 −32.5 −35.9
(95% CI)‖ (−33.2 to −14.2) (−37.8 to −19.0) (−40.4 to −21.7) (−41.8 to −23.1) (−45.4 to −26.5)

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 Interleukin-23–Receptor Antagonist for Plaque Psoriasis

Patients with a PASI 75 Response

greater than 1 at baseline. Four patients (two in the placebo group, one in the 25-mg twice-daily group, and one in the 100-mg twice-daily group) had a DLQI score of 1 or lower at base-

‖ Least-squares mean changes from baseline and least-squares mean differences as compared with placebo were based on a mixed model for repeated measures, with trial-group assign-
* PASI 75 response, PASI 90 response, and PASI 100 response refer to reductions from baseline of at least 75%, 90%, and 100%, respectively, in the PASI score. The widths of the confi-

of at least 1 at baseline. One patient in the 50-mg once-daily group had a PSSD symptoms score of 0 at baseline; therefore, the denominator used for this group, when calculating the
† Patients who discontinued JNJ-77242113 or placebo because of a lack of efficacy or because of worsening of psoriasis (reported as an adverse event) were assumed not to have had a

ment, visit, the interaction between trial-group assignment and visit, baseline weight category (≤90 kg vs. >90 kg), the interaction between baseline weight category and visit, baseline
‡ P<0.001 for all comparisons. Multiple Comparison Procedures with modeling techniques, also known as MCP-Mod, was used to determine the presence of a dose–response relation-
A significant dose–response signal for PASI 75

§ The score on the Dermatology Life Quality Index (DLQI) ranges from 0 to 30, with higher scores indicating a lower quality of life. This analysis included patients with a DLQI score of

¶ The score on the Psoriasis Symptoms and Signs Diary (PSSD) ranges from 0 to 100, with higher scores indicating greater severity. This analysis included patients with a PSSD score
response at week 16 was detected (P<0.001). At
week 16, the percentages of patients with a PASI
75 response were 37%, 51%, 58%, 65%, and 79%
in the JNJ-77242113 25-mg once-daily, 25-mg
twice-daily, 50-mg once-daily, 100-mg once-daily,
response. Observed data were used for patients who discontinued for any other reason. Patients with missing data were considered not to have had a response.

and 100-mg twice-daily groups, respectively, and

9% in the placebo group (Fig. 1A, Table 2, and
Table S2). The results of a sensitivity analysis in
dence intervals for the secondary end points have not been adjusted for multiplicity and should not be used to infer definitive effects of JNJ-77242113.

which a multiple imputation method was used

were consistent with these results (Table S3).

Secondary End Points

The percentages of patients with PASI and IGA
responses through week 16 are shown in Figure 1.
At week 16, a PASI 90 response had occurred in
26%, 27%, 51%, 47%, and 60% of the patients
in the JNJ-77242113 25-mg once-daily, 25-mg
twice-daily, 50-mg once-daily, 100-mg once-daily,
and 100-mg twice-daily groups, respectively, and
in 2% of the patients in the placebo group (Fig. 1B
and Table 2); the corresponding percentages of
patients with a PASI 100 response were 12%, 10%,
26%, 23%, 40%, and 0% (Fig. 1C and Table 2). The
changes from baseline to week 16 in the PASI
PASI total score, and the interaction between baseline PASI total score and visit as covariates.

total score and in the percentage of BSA involve-

line; therefore, the denominators used for these groups were 41, 40, and 41, respectively.

ment showed consistent response patterns (Ta-

ble 2). Similarly, at week 16, the percentages of
patients with an IGA score of 0 or 1 were 40%,
51%, 58%, 63%, and 64% in the JNJ-77242113
25-mg once-daily, 25-mg twice-daily, 50-mg once-
daily, 100-mg once-daily, and 100-mg twice-daily
groups, respectively, and 12% in the placebo
group (Fig. 1D and Table 2). The percentages of
patients with an IGA score of 0 at week 16 were
16%, 15%, 35%, 28%, and 45% in the JNJ-
77242113 25-mg once-daily, 25-mg twice-daily,
50-mg once-daily, 100-mg once-daily, and 100-mg
twice-daily groups, respectively, and 0% in the
placebo group (Fig. 1E and Table 2).

Biomarker Analysis
PSSD symptoms score, was 42.

All the dose levels of JNJ-77242113 were associ-

ated with lower serum levels of hBD-2 than pla-
ship with JNJ-77242113.

cebo, as early as week 4 (Fig. 1F). The lowest hBD-

2 level was observed with the 100-mg twice-daily
dose. The correlation coefficients between the
change from baseline in the serum hBD-2 level
and the percent change from baseline in the PASI
score were −0.64, −0.55, −0.51, −0.54, and −0.58
in the JNJ-77242113 25-mg once-daily, 25-mg

n engl j med 390;6 nejm.org February 8, 2024 517

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 518
Table 3. Adverse Events after Initiation of JNJ-77242113 or Placebo in the Safety Analysis Set.*

JNJ-77242113 JNJ-77242113 JNJ-77242113 JNJ-77242113 JNJ-77242113

25 mg 25 mg 50 mg 100 mg 100 mg JNJ-77242113
Placebo Once Daily Twice Daily Once Daily Once Daily Twice Daily Dose Groups
Variable (N = 43) (N = 43) (N = 41) (N = 43) (N = 43) (N = 42) (N = 212)
Mean duration of follow-up — wk 15.0 15.7 16.2 15.8 16.1 15.8 15.9
Adverse events — no. (%)† 22 (51) 20 (47) 20 (49) 26 (60) 19 (44) 26 (62) 111 (52)
The

Infections and infestations 12 (28) 15 (35) 14 (34) 17 (40) 7 (16) 11 (26) 64 (30)
Covid-19 5 (12) 5 (12) 8 (20) 3 (7) 3 (7) 4 (10) 23 (11)
Nasopharyngitis 2 (5) 1 (2) 3 (7) 8 (19) 1 (2) 2 (5) 15 (7)
Upper respiratory tract infection 1 (2) 3 (7) 0 0 0 2 (5) 5 (2)

n engl j med 390;6

Gastrointestinal disorders 5 (12) 3 (7) 4 (10) 6 (14) 4 (9) 7 (17) 24 (11)
Diarrhea 1 (2) 2 (5) 2 (5) 4 (9) 1 (2) 1 (2) 10 (5)
Nervous system disorders 1 (2) 0 2 (5) 3 (7) 3 (7) 2 (5) 10 (5)

nejm.org
Headache 1 (2) 0 1 (2) 1 (2) 3 (7) 1 (2) 6 (3)
n e w e ng l a n d j o u r na l

Respiratory, thoracic, and mediastinal disorders 1 (2) 1 (2) 0 1 (2) 3 (7) 2 (5) 7 (3)

The New England Journal of Medicine

of

Cough 0 1 (2) 0 1 (2) 3 (7) 1 (2) 6 (3)

Serious adverse events — no. (%) 0 0 0 1 (2) 2 (5) 0 3 (1)
Infections and infestations 0 0 0 1 (2) 1 (2) 0 2 (1)

February 8, 2024
Covid-19 0 0 0 0 1 (2) 0 1 (<1)

Copyright © 2024 Massachusetts Medical Society. All rights reserved.

m e dic i n e

Infected cyst 0 0 0 1 (2) 0 0 1 (<1)

Psychiatric disorders 0 0 0 0 1 (2) 0 1 (<1)
Suicide attempt 0 0 0 0 1 (2) 0 1 (<1)

* The safety analysis set included the same patients as the full analysis set. Covid-19 denotes coronavirus disease 2019.
† Adverse events with an incidence of at least 5% (on the basis of the preferred term) in any trial group through the end of the trial are shown.

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 Interleukin-23–Receptor Antagonist for Plaque Psoriasis

twice-daily, 50-mg once-daily, 100-mg once-daily, once-daily group), an infected cyst (JNJ-77242113
and 100-mg twice-daily groups, respectively. 50-mg once-daily group), and a suicide attempt
(JNJ-77242113 100-mg once-daily group). Details
Patient-Reported Outcomes are provided in the Supplemental Results section
The least-squares mean changes from baseline at of the Supplementary Appendix; all three events
week 16 in the PSSD sign scores were −31.7, −40.9, were determined by the principal investigator and
−42.9, −45.3, and −50.6 in the JNJ-77242113 25-mg the sponsor to be unrelated to JNJ-77242113. No
once-daily, 25-mg twice-daily, 50-mg once-daily, relationship between JNJ-77242113 dose group
100-mg once-daily, and 100-mg twice-daily groups, and the occurrence of adverse events or serious
respectively, as compared with −7.8 in the pla- adverse events was observed. No deaths, major
cebo group (Table 2 and Fig. S2A); corresponding adverse cardiovascular events, or cancers were re-
least-squares mean changes from baseline in the ported during the trial.
PSSD symptom scores were −27.9, −32.6, −35.3,
−36.7, −40.1, and −4.2 (Table 2 and Fig. S2B). Discussion
Among the patients with a baseline DLQI score
of greater than 1, the percentages of patients who JNJ-77242113 is an oral interleukin-23–receptor
had a DLQI score of 0 or 1 at week 16 were 28%, antagonist that offers a novel approach to block-
30%, 37%, 56%, and 44% in the JNJ-77242113 ing the pathogenic effects of interleukin-23 in
25-mg once-daily, 25-mg twice-daily, 50-mg once- patients with psoriasis. Owing to its potency and
daily, 100-mg once-daily, and 100-mg twice-daily stability in the gastrointestinal tract, this pep-
groups, respectively, and 2% in the placebo group tide is able to provide systemic interleukin-23
(Table 2 and Fig. S2C). pathway blockade through oral administration.15
JNJ-77242113 showed a significant dose–response
Safety relationship with respect to the primary end point
In the FRONTIER 1 trial, the mean duration of (PASI 75 response at week 16). At the highest
follow-up was 15.9 weeks in the combined JNJ- dose of JNJ-77242113, 100 mg twice daily, 79%
77242113 group (in which the data from the five of patients had a PASI 75 response, as compared
dose groups were pooled) and 15.0 weeks in the with 9% of patients who had received placebo.
placebo group. Adverse events that occurred af- The results for the secondary end points and
ter receipt of the first dose of JNJ-77242113 or patient-reported outcomes were generally con-
placebo were reported in 20 patients (47%), 20 sistent with those for the primary end point.
patients (49%), 26 patients (60%), 19 patients The level of reduction of psoriasis that was
(44%), and 26 patients (62%) in the JNJ-77242113 observed with higher doses of JNJ-77242113 at
25-mg once-daily, 25-mg twice-daily, 50-mg once- week 16 was similar in magnitude to the re-
daily, 100-mg once-daily, and 100-mg twice-daily sponses seen with several of the injectable biolog-
groups, respectively, and in 22 patients (51%) in ics that are currently approved for psoriasis.13,14,23
the placebo group (Table 3). The most common The percentage of patients who had a PASI 90
adverse events (incidence of ≥5% in any trial group) response with JNJ-77242113 100 mg twice daily
were coronavirus disease 2019 (Covid-19), naso- at week 16 was 60%. In contrast, phase 3 trials
pharyngitis, upper respiratory tract infection, di- of other available oral treatments showed that
arrhea, headache, and cough. The incidence of 27 to 36% of patients had a PASI 90 response
adverse events was generally similar in the com- after 16 weeks of treatment with deucravacitinib,
bined JNJ-77242113 group and the placebo group and 18 to 20% of patients had a PASI 90 response
(Table 3). The incidence of diarrhea was 5% in with apremilast at week 16.24,25 However, without
the combined JNJ-77242113 group and 2% in the head-to-head trials, no conclusions can be drawn
placebo group; the incidence of diarrhea did not about the comparative efficacy of JNJ-77242113.
appear to increase with higher JNJ-77242113 doses. Results from the FRONTIER 2 trial, as well as
Nervous system disorders occurred in 5% of the from phase 3 trials, will clarify the magnitude
patients in the combined JNJ-77242113 group and and durability of the clinical response to JNJ-
in 2% of those in the placebo group. 77242113.
Three serious adverse events (in 3 patients) were The serum level of the pharmacodynamic
reported: a case of Covid-19 (JNJ-77242113 100-mg biomarker hBD-2 was lower with all the doses of

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Copyright © 2024 Massachusetts Medical Society. All rights reserved.
 The n e w e ng l a n d j o u r na l of m e dic i n e

JNJ-77242113 than with placebo. These data are
consistent with the role of JNJ-77242113 as an
interleukin-23–receptor antagonist and reflect
its inhibition of downstream effectors, such as
interleukin-17. As was observed in previous stud-
ies,20-22 a reduction in hBD-2 occurred in conjunc-
tion with a clinical response in the FRONTIER 1
trial. Taken together, these data corroborate an
important mechanistic link between the phar-
macodynamic activity of JNJ-77242113 and clini-
cal outcomes. Evaluation of other systemic and
skin biomarkers of psoriasis could further char-
acterize the activity of JNJ-77242113 relative to
other interleukin-23 pathway inhibitors.
Through week 16, the percentage of patients
who had an adverse event was similar in the com-
bined JNJ-77242113 group and the placebo group;
no dose relationship was observed between in-
creasing doses of JNJ-77242113 and the incidence
of adverse events or serious adverse events. The
incidence of diarrhea was higher in the combined
JNJ-77242113 group than in the placebo group,
but the incidence among patients who received
the highest doses was similar to the incidence
among those who received placebo; this observa-
tion may reflect the variation that can occur with
a small sample size. No major adverse cardiovas-
cular events, cancers, or deaths were reported
during the trial. However, larger and longer trials
will be needed to assess the occurrence of any
infrequent adverse events.
The data from this trial are limited by the
small number of patients in each trial group and
the short duration of treatment. In addition, no
corrections for multiplicity were made, so defini-
tive effects of JNJ-77242113 for particular dose
groups or for secondary end points cannot be
inferred.
In this phase 2 trial, JNJ-77242113, an oral in-
terleukin-23–receptor antagonist peptide, showed
a dose–response relationship and greater efficacy
than placebo, as measured by the PASI 75 response
at week 16, in patients with moderate-to-severe
plaque psoriasis. Overall, there was no evidence
of a relationship between the JNJ-77242113 dose
and the incidence of adverse events.
Supported by Janssen Research and Development.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
A data sharing statement provided by the authors is available
with the full text of this article at NEJM.org.
We thank the patients and the trial personnel who made this
phase 2 trial successful; David Strawn, B.S., and Dylan Rich-
ards, Ph.D., of Janssen, Immunology Translational Sciences, for
hBD-2 data generation and analysis; and Erica Chevalier-Larsen,
Ph.D., of Janssen Scientific Affairs, under the direction of the
authors, for medical writing assistance with an earlier version
of the manuscript. JNJ-77242113 was jointly developed by Pro-
tagonist and Janssen.

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