ORIGINAL ARTICLE
A Randomized, Double-Blind, Placebo-Controlled Phase 2a
Study of Tildrakizumab Efficacy and Safety in Patients
With Active Ankylosing Spondylitis
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Eric Peters, MD,* Richard C. Chou, MD, PhD,† Stephen J. Rozzo, PhD,‡
Siu-Long Yao, PhD,‡ and Ferran José García Fructuoso, MD§
Objective: Tildrakizumab is an anti-interleukin-23p19 monoclonal an-
tibody approved to treat moderate to severe plaque psoriasis. This study
evaluated the efficacy and safety of tildrakizumab in patients with
ankylosing spondylitis (AS).
Methods: In this randomized, double-blind, parallel-group, multinational
trial (clinicaltrials.gov NCT02980705), patients with active AS, according
to modified New York criteria and Bath Ankylosing Spondylitis Disease
Activity Index Score ≥4, were randomized 1:1 to tildrakizumab 200 mg
or placebo every 4 weeks until week 24. Thereafter, all patients received
tildrakizumab 200 mg every 4 weeks until week 48. The primary outcome
was proportion of patients achieving 20% improvement from baseline by
Assessment in SpondyloArthritis International Society criteria (ASAS20)
at week 24. This outcome was analyzed in subgroups defined by prior treat-
ment experience, weight, age, and sex using the full analysis set. Safety was
assessed through treatment-emergent adverse events.
Results: From December 5, 2017–September 3, 2019, 101 patients
(76.2% male, 97% White) enrolled and were randomized to treatment. At
week 24, the ASAS20 response rate was 74.0% in patients receiving
tildrakizumab 200 mg (n = 50) versus 80.4% in placebo-treated patients
(n = 51; treatment difference, −6.31%; 95% confidence interval, −22.34
to 9.71; p = 0.44). No difference in treatment effect by subgroups was ob-
served. Tildrakizumab treatment was generally well tolerated, with no un-
expected safety findings. The study was terminated after the week 24 in-
terim analysis due to lack of efficacy.
From the *Arizona Arthritis and Rheumatology Research, PLLC, Phoenix, AZ;
†Division of Allergy, Immunology, and Rheumatology, University at Buffalo
School of Medicine and Biomedical Sciences, Buffalo, NY; ‡Sun Pharma-
ceutical Industries, Inc, Princeton, NJ; and §Servicio de Reumatología, Hos-
pital CIMA Sanitas, Paseo Manuel Girona, Barcelona, Spain.
Contributors: All authors contributed to data interpretation and manuscript
development, critically reviewed each draft for intellectual content, and
approved the final version for submission.
Competing interests: E.P. has nothing to disclose; R.C.C. receives consultation fees
from Sun Pharma; S.J.R. and S.L.Y. are employees of Sun Pharmaceutical
Industries, Inc.; F.J.G.F. has received research grants, consulting fees, and/or
speaker fees from AbbVie, Eli Lilly, Gedeon Richter, MedImmune, Nichi-Iko,
Pfizer, Sanofi-Aventis, Takeda, and Union Chimique Belge.
Funding: The study was funded by Sun Pharma. Analyses and medical writing
support were funded by Sun Pharma, Princeton, NJ.
Ethics approval: The study protocol (online supplemental file) was approved by
Independent Ethics Committees or Institutional Review Boards at each site.
The trial was conducted in accordance with the Declaration of Helsinki and
the International Conference on Harmonisation Good Clinical Practice
guidelines.
Data availability statement: Data and other documents will be made available
after publication, with no end date, to anyone who submits a reasonable
request to the study sponsor.
Correspondence: Eric Peters, MD, Arizona Arthritis and Rheumatology
Associates PC, 4550 E Bell Rd Ste 170, Phoenix, AZ 85032. E‐mail:
Eric.Peters@azarthritis.com.
Supplemental digital content is available for this article. Direct URL citation
appears in the printed text and is provided in the HTML and PDF versions
of this article on the journal’s Web site (www.jclinrheum.com).
Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.
ISSN: 1076-1608
DOI: 10.1097/RHU.0000000000001973
JCR: Journal of Clinical Rheumatology • Volume 29, Number 5, August 2023
Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.
Conclusions: Tildrakizumab treatment was generally well tolerated but
did not improve ASAS20 response rate versus placebo in patients with AS.
Key Words: ankylosing spondylitis, IL-23, tildrakizumab, enthesitis, MRI
(J Clin Rheumatol 2023;29: 223–229)
A nkylosing spondylitis (AS) is a chronic inflammatory arthritis
affecting mainly the axial skeleton and sacroiliac joints. Avail-
able treatments for AS help to manage symptoms, but an unmet need
remains for more advanced treatment options. The interleukin
(IL)-23 and IL-17A signaling pathway is implicated in AS patho-
genesis,1,2 and inhibitors of both IL-17 and IL-23 have been assessed
as potential treatments for AS. Two IL-17 inhibitors, secukinumab
and ixekizumab, are approved in the United States for the treatment
of AS based on clinical trial efficacy but are associated with safety
concerns, including a risk of overall infections (not serious infections)
and potential risk for new-onset or exacerbation of inflammatory
bowel disease (IBD).1,3–6 On this basis, for patients with AS and
coexisting IBD, the American College of Rheumatology/Spondylitis
Association of America/SpondyloArthritis Research and Treatment
Network guidelines conditionally recommend treatment with tu-
mor necrosis factor (TNF) inhibitor monoclonal antibodies over
treatment with IL-17 inhibitors.5 Clinical trials targeting IL-23
signaling with either ustekinumab, an IL-12/IL-23 inhibitor, or
risankizumab, an anti–IL-23p19 antibody, failed to show clinical
efficacy in patients with AS.7,8
Tildrakizumab is a high-affinity,9–11 humanized, anti–IL-
23p19 monoclonal antibody approved for the treatment of moder-
ate to severe plaque psoriasis.12–14 Treatment with tildrakizumab
was more effective versus placebo across several measures of joint
and skin disease activity and physical function in a phase 2b trial
in patients with active psoriatic arthritis (PsA).15 The present
study investigated tildrakizumab efficacy and safety in patients
with AS.
MATERIALS AND METHODS
Study Design and Treatments
This was a 3-part, 72-week, multinational, randomized,
double-blind, placebo-controlled, phase 2a study that evaluated
the efficacy and safety of tildrakizumab in patients with AS
(clinicaltrials.gov NCT02980705). Race and ethnicity were iden-
tified at screening. The study consisted of a screening period (days
−28 to 0), a double-blind, placebo-controlled period (part 1, weeks
0–24), a 28-week treatment follow-up period (part 2, weeks
24–52), and a 20-week washout period (part 3, weeks 52–72). In
part 1, patients were randomized in a 1:1 ratio to receive
tildrakizumab 200 mg or placebo; the 200-mg dose was antici-
pated to provide robust suppression of IL-23 signaling with ac-
ceptable safety based on psoriasis studies.16 Randomization was
stratified by prior anti-TNF therapy use. The randomization
www.jclinrheum.com 223
 Peters et al JCR: Journal of Clinical Rheumatology • Volume 29, Number 5, August 2023
schedule was computer generated and implemented through an in-
teractive voice response system. The randomization code and
block size were known only to an unblinded study biostatistician.
Patients, investigators, and data analysts remained blinded to treat-
ment allocation from randomization until study completion.
During part 1, patients received tildrakizumab 200 mg or pla-
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cebo by subcutaneous injection at weeks 0, 4, 8, 12, 16, and 20. At
week 16, patients not achieving a minimal response to treatment
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(ie, without ≥10% improvement from baseline total back pain vi-
sual analog scale [VAS] 0 to 100 or ≥10% improvement in inflam-
mation assessed using the Bath Ankylosing Spondylitis Disease
Activity Index [BASDAI]) could have background medications
adjusted to the maximum permitted daily dose and continue the
study. Patients who received tildrakizumab during part 1 and
achieved ≥20% improvement from baseline by Assessment of
SpondyloArthritis International Society criteria (ASAS20)17 at
week 24 and all patients receiving placebo in part 1 continued to
part 2; tildrakizumab-treated patients who did not achieve
ASAS20 at week 24 discontinued treatment. In part 2, all patients
received tildrakizumab 200 mg every 4 weeks (Q4W) from week
24 to week 48. Part 3 is described in Supplemental Digital Con-
tent, http://links.lww.com/RHU/A556.
Ethics Statements
The study protocol and all amendments were approved by
the Independent Ethics Committee or Institutional Review Board
for each study site. The study was conducted in accordance with
the principles of the Declaration of Helsinki (2013). Safety data
were periodically reviewed by a Data Safety Monitoring Board.
All patients provided written informed consent before beginning
the study.
Patients
Patients ≥18 years with a diagnosis of AS based on the mod-
ified New York criteria (1984), symptoms for ≥3 months at
screening, active disease defined as BASDAI17 score ≥4, and a
VAS value ≥40 (0- to 100-mm scale) for overall level of AS neck,
back, or hip pain were eligible. Concomitant use of sulfasalazine
(up to 3 g/d), methotrexate (up to 25 mg/wk), prednisone/
prednisolone at a stable dose (for ≥4 weeks before baseline and
during the study) of up to 10 mg/d (or equivalent), and nonsteroi-
dal anti-inflammatory drugs at a stable dose (for ≥4 weeks before
baseline and throughout part 1, unless adjustment was required
due to toxicity) were permitted. Patients with radiographic evi-
dence of total ankylosis of the spine, history of malignancy and/
or infections, major chronic inflammatory or connective tissue
disease other than AS, or previous treatment with any biologic
for psoriasis or AS except as follows were excluded. Prior use of
TNF inhibitors (capped at 30%–40% of the total number of pa-
tients) was permitted with the following washout period: 4 weeks
for etanercept, 8 weeks for infliximab, and 3 months for all other
anti-TNF therapy. Full inclusion/exclusion criteria are provided in
Supplemental Digital Content, http://links.lww.com/RHU/A556.
Assessments
Physician Global Assessment of disease activity VAS,
patient-reported total back pain and nocturnal back pain VAS,
and Ankylosing Spondylitis Disease Activity Score including
C-reactive Protein (ASDAS-CRP) or Erythrocyte Sedimentation
Rate (ASDAS-ESR) were assessed, with blood collected for mea-
surement of high-sensitivity CRP (hsCRP) and ESR, at screening
(within 28 days); at baseline; Q4W through week 24; and at weeks
32, 40, 48, and 52 or end of treatment. Patient Global Assessment
of disease activity VAS was assessed at the same time points, except
224 www.jclinrheum.com
Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.
for screening. The Maastricht Ankylosing Spondylitis Enthesitis
Score (MASES),17 Tender Joint Count of 46 Joints (TJC46), and
Swollen Joint Count of 44 Joints (SJC44) were assessed at baseline;
Q4W through week 24; and at weeks 32, 40, 48, and 52 or end of
treatment. Radiographs of the spine and sacroiliac joints were ob-
tained at screening. Magnetic resonance imaging (MRI) of the spine
and sacroiliac joints was performed at screening, week 16, and week
52 or end of treatment, and Modified Berlin Ankylosing Spondylitis
Spine Magnetic Resonance Imaging activity (ASspiMRI)18 was
assessed at baseline, week 16, and week 52. Radiographs and MRI
data collected throughout the study were centrally reviewed and
scored to ensure consistent assessment across sites. Blood samples
were evaluated for plasma tildrakizumab concentrations, antidrug an-
tibodies, and laboratory abnormalities. Safety was assessed through-
out the trial via monitoring of adverse events (AEs), vital signs, clin-
ical laboratory parameters (blood chemistry, hematology, urinalysis,
lipid panel, and hsCRP level), and physical examinations.
Outcomes
The primary end point was the proportion of patients achiev-
ing an ASAS20 response at week 24. Secondary end points were
ASAS40 response rate at week 24, ASAS20 and ASAS40 re-
sponse rates at week 52, and proportion of patients who required
adjustment of background therapy at week 16. Exploratory end
points included ASAS20 and ASAS40 response rates at other time
points, change from baseline in TJC46, SJC44, ASDAS-CRP, and
ASDAS-ESR, and improvement from baseline in enthesitis based
on MASES through week 24, and the SpondyloArthritis Research
Consortium of Canada (SPARCC)19 MRI Indices of Disease Ac-
tivity (Sacroiliac Joints and Spine) and Modified Berlin ASspiMRI
at week 16. Safety end points included treatment-emergent AEs
(TEAEs), AEs of special or clinical interest (Supplemental Digital
Content, http://links.lww.com/RHU/A556), laboratory abnormali-
ties, and changes in vital signs and physical examination results.
Statistical Analysis
Assuming an ASAS20 response rate of 60% in tildrakizumab-
treated patients and 28% in placebo-treated patients1 and a 10%
dropout rate, 45 patients per treatment arm were estimated to pro-
vide 80% power to detect a difference between tildrakizumab
and placebo treatment in the primary end point using a 2-sided
Cochran-Mantel-Haenszel test at a significance level of 0.05.
The full analysis set (FAS) included all randomized patients who
received ≥1 dose of tildrakizumab or placebo. Demographic and
baseline characteristics and all primary and secondary efficacy
end points are reported in the FAS. Safety end points were evalu-
ated in the safety analysis set (all treated patients).
Differences in the binary end points through week 24 were
analyzed using a 2-sided Cochran-Mantel-Haenszel test stratified
by prior anti-TNF use. Efficacy results in part 2 were summarized
descriptively. For binary end points, missing values through week
24 were imputed as nonresponse. The primary end point was ex-
amined in subgroups defined by prior anti-TNF and methotrexate
use (yes/no), baseline weight (≤90 kg, >90 kg), age (<65, ≥65),
and sex to assess the consistency of results across factors of inter-
est; no formal hypothesis testing was performed, but an estimate
of the treatment difference with 95% confidence intervals (CIs)
was calculated.
Continuous end points were analyzed up to week 24 based on
a mixed model for repeated measure analysis that included fixed
effects of treatment, visit, treatment by visit interaction, and prior
anti-TNF use, with baseline value as a covariate, and summarized
descriptively thereafter. Missing data were not imputed for end
points summarized using descriptive statistics. For all secondary
© 2023 Wolters Kluwer Health, Inc. All rights reserved.
 JCR: Journal of Clinical Rheumatology • Volume 29, Number 5, August 2023 Tildrakizumab Efficacy and Safety in AS

TABLE 1. Patient Demographics and Disease Characteristics at Baseline

Tildrakizumab 200 mg Placebo → Tildrakizumab

Characteristic (N = 50) 200 mg (N = 51)
Age, mean (SD), years 39.8 (9.2) 39.1 (11.0)
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Sex, male 39 (78.0) 38 (74.5)

Race
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White 48 (96.0) 50 (98.0)

Black or African American 0 1 (2.0)
Asian 1 (2.0) 0
Other 1 (2.0) 0
Ethnicity, not Hispanic/Latino 48 (96.0) 51 (100.0)
Height, mean (SD), cma 174.5 (10.3) 172.7 (8.2)
Weight, mean (SD), kg 80.9 (16.8) 81.2 (16.3)
BMI, mean (SD), kg/m2a 26.3 (4.4) 27.0 (5.2)
HLA-B27 at screening
Positive 40 (80.0) 43 (84.3)
Missing 0 2 (3.9)
MASES, mean (SD) 3.1 (3.4) 2.0 (2.7)
SPARCC MRI index of disease activity score of the SI joints, mean (SD)b 14.1 (15.6) 14.0 (14.5)
SPARCC MRI index of disease activity score of the spine, mean (SD)b 18.7 (17.7) 21.5 (20.5)
Modified Berlin ASspiMRI score, mean (SD)c 6.2 (5.9) 7.0 (7.8)
BASDAI (0–100 mm), mean (SD) 69.3 (12.1) 65.7 (13.5)
hsCRP, mean (SD), mg/L 14.2 (19.4) 13.0 (13.5)
Medical history of psoriasisd 3 (6.0) 1 (2.0)
Data shown as n (%), unless otherwise specified.
a
n = 49 patients randomized to tildrakizumab 200 mg and n = 50 patients randomized to placebo.
b
In the spine, the scoring system measured BMO of 6 of 23 DVUs, each unit representing the region between 2 imaginary lines drawn through the middle
of adjacent vertebrae. The 6 worst DVUs were selected for assessment. In the iliac and sacral bone marrow of the SI joints, the scoring system measured
BMO by assessing lesions in consecutive coronal slices through the synovial portion of the joint.
c
The volume of BMO in each DVU was scored on a scale of 0 to 3 (0 = no inflammation, 1 = 0% < BMO <25%; 2 = 25% < BMO <50%; 3 = BMO
>50%). The score was designed to evaluate MRIs of the total spine including 23 DVUs; score range 0 to 69.
d
Patients with psoriasis were not excluded per study protocol.
BMO, bone marrow edema; BMI, body mass index; DVU, discovertebral unit; HLA-B27, human leukocyte antigen B27; SD, standard deviation.

efficacy analyses, p values were not adjusted for multiplicity and
are presented as nominal.
Patient and Public Involvement
Patients and the public were not involved in study design, re-
cruitment, or dissemination of results, and patients were not asked
to assess the burden of study participation.
patients and AEs and withdrawal of consent for placebo-treated pa-
tients; the most frequent reason for discontinuation in part 2 was
sponsor decision (study termination). Demographic characteristics
and baseline disease activity were similar among treatment arms.
The majority of patients were male (76.2%) and White (97.0%;
Table 1; see Table S1 in Supplemental Digital Content, http://
links.lww.com/RHU/A556, prior medication use).

RESULTS
Patients
From December 5, 2017 to September 3, 2019, 165 patients
were screened and 101 underwent randomization (tildrakizumab
200 mg, n = 50; placebo, n = 51) at 39 sites in 4 countries
(Poland, Spain, Hungary, and USA; see Fig. S1 in Supplemental
Digital Content, http://links.lww.com/RHU/A556, which shows
patient flow diagram through part 2). The study was terminated
early when an interim data analysis after the last patient's visit at
week 24 determined that the study was futile, and missing data af-
ter week 24 were not imputed. Overall, 68 (67.3%) patients
discontinued study drug, including 36 (72.0%) patients random-
ized to tildrakizumab 200 mg and 32 (62.7%) randomized to pla-
cebo. The most frequent reasons for discontinuation in part 1 were in-
sufficient response to treatment at week 24 for tildrakizumab-treated
Efficacy
At week 24, the ASAS20 response rate (standard error) was
numerically lower in patients treated with tildrakizumab 200 mg
(74.0% [6.2%]) versus placebo (80.4% [5.6%]; treatment differ-
ence, −6.3%; 95% CI, −22.3% to 9.7%; p = 0.44); the primary
end point was not met (Fig. 1, all time points; see Table S2 in Sup-
plemental Digital Content, http://links.lww.com/RHU/A556, for
ASAS20 response rates up to week 24 by cohort; see Table S3
in Supplemental Digital Content, http://links.lww.com/RHU/
A556, for change from baseline in domains of the assessment of
SpondyloArthritis International Society Improvement Criteria up
to week 24 by cohort). Subgroup analyses of ASAS20 response
rate by prior anti-TNF use, baseline weight, and sex showed no
significant difference between tildrakizumab 200 mg and placebo
(Fig. 2; see Table S4 in Supplemental Digital Content, http://links.
lww.com/RHU/A556, for ASAS20 response rate stratified by

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FIGURE 1. ASAS20 response rates through week 24. Error bars represent the SE. Baseline is defined as the last available value before the first
dose of the study drug. ASAS20 response rate analysis was performed using the FAS. Missing data were imputed as nonresponse. Plotted
data are available in Table S2, http://links.lww.com/RHU/A556. ASAS, Assessment of SpondyloArthritis International Society; SE, standard error.

prior anti-TNF use, baseline weight, and sex through week 24).
Subgroups stratified by methotrexate use and age are not reported
because there was only one patient treated with tildrakizumab
200 mg and 4 placebo-treated patients with methotrexate use,
and no patients were >65 years old.
At week 52, the ASAS20 response rate (95% CI; n/n) was
88.9% (78.6%–99.2%; 32/36) in patients continuously receiving
tildrakizumab 200 mg and 76.6% (64.5%–88.7%; 36/47) in pa-
tients who switched from placebo to tildrakizumab 200 mg at
week 24. The proportion of patients achieving ASAS40 response
at week 24 was 56.0% (95% CI, 42.2%–69.8%; 28/50) of patients
receiving continuous tildrakizumab 200 mg versus 53.1% (39.1%–
67.0%; 26/49) of those switched from placebo to tildrakizumab
200 mg at week 24 (treatment difference, 5.0%; 95% CI, −14.5 to
24.5; nominal p = 0.62). At week 52, 72.2% (95% CI, 57.6%–86.9%;
26/36) of patients receiving continuous tildrakizumab 200 mg versus
61.7% (47.8%–75.6%; 29/47) of those switched from placebo to
tildrakizumab 200 mg after week 24 achieved ASAS40 response
(Figs. 3A, B; see Table S5 in Supplemental Digital Content, http://
links.lww.com/RHU/A556, for ASAS20 and ASAS40 response rates
through week 52). Two (4.0%) patients in the tildrakizumab 200-mg
arm and no patient in the placebo arm required adjustment of back-
ground therapy at week 16 (see Table S6 in Supplemental Digital
Content, http://links.lww.com/RHU/A556, for proportion of pa-
tients who required adjustment of background therapy at week
16). The MASES (see Table S7 in Supplemental Digital Content,
http://links.lww.com/RHU/A556, for change from baseline in MASES
up to week 24 by cohort), ASDAS-CRP and ASDAS-ESR, TJC46 and
SJC44 (see Table S8 in Supplemental Digital Content, http://links.
lww.com/RHU/A556, for change from baseline in joint counts
and ASDAS-CRP and ASDAS-ESR up to week 24 by cohort),
SPARCC, and Modified Berlin ASspiMRI scores (see Table S9
in Supplemental Digital Content for change from baseline in
SPARCC MRI and Modified Berlin ASspiMRI scores at week
16 by cohort) decreased from baseline during part 1 but did not dif-
fer significantly between treatment arms at any of the time points an-
alyzed. Pharmacokinetic and antidrug antibodies (ADAs) data were
collected but were not analyzed due to early study termination.
Safety
The incidence of TEAEs was generally similar between treat-
ment arms (Table 2; see Table S10 in Supplemental Digital Con-
tent, http://links.lww.com/RHU/A556, for summary of all TEAEs
by study part through week 72). In part 1, 26 (52.0%) patients re-
ceiving tildrakizumab 200 mg and 27 (52.9%) receiving placebo

FIGURE 2. ASAS20 response rate stratified by prior anti-TNF use, baseline weight, and sex through week 24. Error bars represent the SE.
Baseline is defined as the last available value before the first dose of the study drug. ASAS20 response rate analysis was performed using the
FAS. Missing data were imputed as nonresponse. Plotted data are available in Table S4, http://links.lww.com/RHU/A556. ASAS, Assessment of
SpondyloArthritis International Society; SE, standard error; TIL, tildrakizumab.

226 www.jclinrheum.com © 2023 Wolters Kluwer Health, Inc. All rights reserved.

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 JCR: Journal of Clinical Rheumatology • Volume 29, Number 5, August 2023 Tildrakizumab Efficacy and Safety in AS
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FIGURE 3. ASAS20 (A) and ASAS40 (B) response rates through week 52. Error bars represent the SE. At week 24, patients receiving placebo
were switched to tildrakizumab 200 mg treatment. Patients receiving tildrakizumab during part 1 who did not achieve ASAS20 at week 24
discontinued study drug and entered the washout period per protocol. Week 24 assessments for patients who discontinued study drug were
recorded at week 52/EOT. These assessments were reported as part of the week 24 visit. Missing data through week 24 were imputed as
nonresponse; missing data after week 24 were not imputed. Plotted data are available in Table S5, http://links.lww.com/RHU/A556. ASAS,
Assessment of SpondyloArthritis International Society; EOT, end of trial; SE, standard error; TIL, tildrakizumab.

experienced TEAEs. Treatment-related TEAEs occurred in 7
(14.0%) patients receiving tildrakizumab 200 mg and 7 (13.7%)
receiving placebo. Most TEAEs were mild or moderate in severity,
and the most frequent were upper respiratory tract infection,
nasopharyngitis, increased blood creatine phosphokinase, hy-
pertension, and diarrhea. No patient experienced a serious TEAE
or an AE of special or clinical interest during part 1. Similar find-
ings were observed throughout the remainder of the study, in-
cluding in patients switched from placebo to tildrakizumab after
week 24. The majority of TEAEs were mild or moderate in sever-
ity, and no deaths were reported during the study (Table 2, see
Table S9 in Supplemental Digital Content, http://links.lww.
com/RHU/A556). No consistent pattern of abnormalities be-
tween treatments was observed for the majority of laboratory
assessments.
DISCUSSION
The present study investigated tildrakizumab efficacy and
safety in patients with AS. Although tildrakizumab treatment is asso-
ciated with improvement in skin and joint manifestations of psoriatic
disease, there was no significant difference in ASAS20 or ASAS40
response rate at week 24 ( p = 0.44 and p = 0.61, respectively) in
patients with AS receiving tildrakizumab 200 mg versus placebo.
Changes in ASDAS-CRP, ASDAS-ESR, TJC46, and SJC44 were
also similar between treatment arms. Our findings are consistent
with similar studies in which anti–IL-23 agents provided no clin-
ical benefit in patients with AS.7,8 These findings were confirmed
by the lack of improvement in the sacroiliac joints and axial spine
by MRI; change from baseline in MASES, SPARCC, and Modi-
fied Berlin ASspiMRI scores designed to measure active inflam-
mation were similar between treatment arms throughout the study.
Subgroup analyses did not identify any factors that might explain the
negative result for the primary end point. Overall, tildrakizumab was
well tolerated, and no new or unexpected safety findings or deaths
were observed in patients with AS.
The activation of the proinflammatory IL-23/IL-17 signaling
pathway is critical to the development of rheumatic diseases, in-
cluding psoriasis, PsA, AS, and IBD.2 The anti–IL-17 antibodies
secukinumab and ixekizumab were efficacious for AS treatment
in several phase 3 clinical trials. In MEASURE 1 and MEASURE
2, 2 double-blind trials evaluating the IL-17A inhibitor secukinumab
(75 mg and 150 mg) in patients with active AS, efficacy compared
with placebo was apparent as early as week 16.1 The benefit of

TABLE 2. Summary of TEAEs by Cohort and Study Part Through Week 72

Part 1 Part 2 Part 3

TIL 200 mg PBO → TIL TIL 200 mg PBO → TIL TIL 200 mg PBO → TIL
Patients, n (%) (N = 50) 200 mg (N = 51) (N = 50) 200 mg (N = 51) (N = 50) 200 mg (N = 51)
Any TEAE 26 (52.0) 27 (52.9) 23 (46.0) 22 (43.1) 18 (36.0) 13 (25.5)
Any serious TEAE 0 0 0 1 (2.0) 0 3 (5.9)
Any treatment-related TEAE 7 (14.0) 7 (13.7) 7 (14.0) 5 (9.8) 1 (2.0) 0
Discontinued due to TEAE 0 0 0 0 0 1 (0.2)
Death due to TEAE 0 0 0 0 0 0
Most frequent TEAEs (≥5%)
Nasopharyngitis 1 (2.0) 4 (7.8) 4 (8.0) 4 (7.8) 1 (2.0) 1 (2.0)
Upper respiratory tract infection 3 (6.0) 3 (5.9) 2 (4.0) 3 (5.9) 4 (8.0) 1 (2.0)
AS NA NA NA NA 3 (6.0) 0
All values are n (%) unless otherwise noted. N, number of patients in the treatment group analysis set; n, number of patients in the specified category with
nonmissing values. Percentage (%) based on number of patients in the row category/N within the column category. All preferred terms shown occurred in
≥5% of patients in any treatment arm. TEAE in part 1 is defined with the event start date on/after the first dose but before week 24 dosing date of IMP or on/
before the last dose date of IMP if the patient discontinued before week 24. TEAE in part 2 is defined with the event start date on/after week 24 dosing date
but on/before the last dose date of IMP. TEAE in part 3 is defined with the event start date after the last dose date of IMP. Patients in placebo group at part 1
switched to tildrakizumab 200 mg at part 2.
IMP, investigational medicinal product; PBO, placebo; TIL, tildrakizumab.

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Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.

 Peters et al JCR: Journal of Clinical Rheumatology • Volume 29, Number 5, August 2023
targeting IL-17A in AS was later corroborated by 2 randomized con-
trolled trials, COAST-Vand COAST-W, in which ixekizumab 80 mg,
administrated either every 2 weeks or Q4W, resulted in significantly
greater improvement compared with placebo for measures of disease
activity in patients with active radiographic axial spondyloarthritis up
to week 52, with a favorable safety profile.3
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Despite initial genetic, preclinical, and clinical data supporting
a role for IL-23 in AS pathology, its clinical relevance remains
wCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8KKGKV0Ymy+78= on 10/11/2023
unclear.20–22 Although several single nucleotide polymorphisms
related to IL-23 have been linked to AS and other conditions that
respond to IL-23 inhibition—including PsA, psoriasis, and IBD
(both Crohn disease and ulcerative colitis)23–28—the relative risk
associated with these polymorphisms seems moderate at best.22
As in the present study, the anti–IL-12/23p40 antibody ustekinumab
and the specific anti–IL-23p19 antibody risankizumab were not
efficacious in patients with AS.7,8 In contrast to the present study,
where tildrakizumab treatment did not result in improvements in
SPARCC scores or MASES versus placebo, a limited impact of
risankizumab on SPARCC total spine score was observed at week
24, which could suggest a distinct role for IL-23 in spinal and pe-
ripheral entheses.7 There is evidence that IL-23 alone drives
enthesitis in vivo and promotes IL-17 and IL-22 expression by
entheseal cells.29 Overexpression of IL-23 in hepatocytes resulted
in peripheral enthesitis and polyarticular joint destruction in B10.
RIII mice, an experimental autoimmune encephalomyelitis model,
but induced entheseal inflammation, sacroiliitis, and aortic root in-
flammation in wild-type mice even in the absence of T-helper-17
cells.29,30 However, studies in the experimental spondyloarthritis
model induced in human leukocyte antigen B27/Huβ2m trans-
genic rats showed no effect of IL-23 blockade on fully established
arthritis, which could explain the lack of improvement observed
in this and other studies.31 Therefore, although no safety issues
were identified, the failure of IL-23p19 inhibitors to show clinical
efficacy in AS clinical trials has prompted revisitation of the role
of IL-23 in the pathophysiology of this disease.
The ASAS20 response is largely patient reported and was de-
signed to distinguish nonsteroidal anti-inflammatory drug treat-
ment from placebo.32 Placebo effects can be particularly strong
in studies where subjective patient-reported outcomes, such as
pain and fatigue, are primary end points.33 The advent of effective
disease-modifying therapies for AS has likely increased patients'
and physicians' expectations, which could influence ASAS20 re-
sponse rates in clinical trial populations. Placebo response rates
may be generally increasing over time, and this effect seems not
limited to AS. In an analysis of clinical trials of drugs for neuro-
pathic pain conducted from 1990 to 2013, placebo response rates
increased while treatment responses remained similar.34 A rise in
the placebo response rate in rheumatoid arthritis clinical trials over
time was recently analyzed by Bechman et al.35 The study identi-
fied changes in trial design and geographical distribution of trial
sites among possible factors contributing to the observed trend.35
To our knowledge, this is the first study reporting such a high
ASAS20 placebo response rate (80.4%) compared with results of
previous trials assessing efficacy of biologics in AS (20%–
40%).36–38 However, our MRI findings confirm the lack of re-
sponse in patients treated with tildrakizumab versus placebo.
Subgroup analyses did not identify any explanatory variable, in-
cluding baseline demographics and/or clinical characteristics,
which could account for the observed ASAS20 response rates, al-
though the ability to draw conclusions from subgroup analyses re-
garding possible confounding factors was itself limited due to the
sample size. Therefore, it is plausible that the high placebo re-
sponse rate in the present study represents an incidental outcome
due to the limitation of reporting the ASAS20 and diverse geo-
graphic locations of trial sites. The ASAS40 response rates and
228 www.jclinrheum.com
Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.
—more convincingly—MRI results support the conclusion that
tildrakizumab is not efficacious for treatment of AS. Therefore,
the choice of ASAS20 as the primary end point is not likely to
have affected the outcome. However, our results should alert pa-
tients, physicians, drug developers, and regulatory authorities that
the ASAS20 response may be losing utility and that more rigorous
end point measures—as well as the need for careful selection of
study populations with attention to potential confounders, particu-
larly in relatively small phase 2 trials—should be considered dur-
ing study design.
Although observations from animal models and human sys-
tems suggested IL-23 as central to the pathophysiology of AS,
treatment with tildrakizumab—as in previous studies of ustekinumab
and risankizumab—did not reduce AS disease activity or improve
MRI findings in the spine and sacroiliac joints. Further studies
are needed to explore the possibility that AS is regulated by
IL-23–dependent and IL-23–independent pathways in specific
tissues or at different times.
KEY POINTS
• The IL-23/IL-17A signaling pathway is implicated in AS
pathogenesis.
• Although no safety issues were identified, tildrakizumab treat-
ment did not reduce AS disease activity or improve MRI find-
ings in the spine and sacroiliac joints. Subgroup analyses did
not identify any factors that might explain the negative result
for the primary end point.
• The failure of tildrakizumab to show clinical efficacy in AS fur-
ther confirmed results in previous studies of ustekinumab
and risankizumab.
• In light of these findings, the role of IL-23 in the pathophysiology
of this disease should be revisited to explore the possibility that
AS is regulated by IL-23–dependent and IL-23–independent
pathways in specific tissues or at different times.
ACKNOWLEDGMENTS
We thank the patients and investigators for their participation
in the study. Medical writing and editorial support were provided
by Elisabetta Lauretti, PhD, of AlphaBioCom, LLC, and funded by
Sun Pharma.
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