Articles

Efficacy and safety of risankizumab in moderate-to-severe

plaque psoriasis (UltIMMa-1 and UltIMMa-2): results from
two double-blind, randomised, placebo-controlled and
ustekinumab-controlled phase 3 trials
Kenneth B Gordon, Bruce Strober, Mark Lebwohl, Matthias Augustin, Andrew Blauvelt, Yves Poulin, Kim A Papp, Howard Sofen, Lluís Puig,
Peter Foley, Mamitaro Ohtsuki, Mary Flack, Ziqian Geng, Yihua Gu, Joaquin M Valdes, Elizabeth H Z Thompson, Hervé Bachelez

Summary
Background Risankizumab is a humanised IgG1 monoclonal antibody that binds to the p19 subunit of interleukin-23, Published Online
inhibiting this key cytokine and its role in psoriatic inflammation. We aimed to assess the efficacy and safety of August 7, 2018
http://dx.doi.org/10.1016/
risankizumab compared with placebo or ustekinumab in patients with moderate-to-severe chronic plaque psoriasis. S0140-6736(18)31713-6
See Online/Comment
Methods UltIMMa-1 and UltIMMa-2 were replicate phase 3, randomised, double-blind, placebo-controlled and active http://dx.doi.org/10.1016/
comparator-controlled trials done at 139 sites in Australia, Austria, Belgium, Canada, Czech Republic, France, S0140-6736(18)31781-1
Germany, Japan, Mexico, Poland, Portugal, South Korea, Spain, and the USA. Eligible patients were 18 years or older, Medical College of Wisconsin,
with moderate-to-severe chronic plaque psoriasis. In each study, patients were stratified by weight and previous Milwaukee, WI, USA
(Prof K B Gordon MD);
exposure to tumour necrosis factor inhibitor and randomly assigned (3:1:1) by use of interactive response technology
University of Connecticut
to receive 150 mg risankizumab, 45 mg or 90 mg ustekinumab (weight-based per label), or placebo. Following the Health Center and Probity
16-week double-blind treatment period (part A), patients initially assigned to placebo switched to 150 mg risankizumab Medical Research, Farmington,
at week 16; other patients continued their originally randomised treatment (part B, double-blind, weeks 16–52). Study CT, USA (Prof B Strober MD);
Icahn School of Medicine at
drug was administered subcutaneously at weeks 0 and 4 during part A and at weeks 16, 28, and 40 during part B.
Mount Sinai, New York, NY,
Co-primary endpoints were proportions of patients achieving a 90% improvement in the Psoriasis Area Severity USA (Prof M Lebwohl MD);
Index (PASI 90) and a static Physician’s Global Assessment (sPGA) score of 0 or 1 at week 16 (non-responder University Medical Center
imputation). All efficacy analyses were done in the intention-to-treat population. These trials are registered with Hamburg-Eppendorf,
Hamburg, Germany
ClinicalTrials.gov, numbers NCT02684370 (UltIMMa-1) and NCT02684357 (UltIMMa-2), and have been completed.
(Prof M Augustin MD); Oregon
Medical Research Center,
Findings Between Feb 24, 2016, and Aug 31, 2016, 506 patients in UltIMMa-1 were randomly assigned to receive 150 mg Portland, OR, USA
risankizumab (n=304), 45 mg or 90 mg ustekinumab (n=100), or placebo (n=102). Between March 1, 2016, and Aug 30, 2016, (A Blauvelt MD); Centre
Dermatologique du Québec
491 patients in UltIMMa-2 were randomly assigned to receive 150 mg risankizumab (n=294), 45 mg or 90 mg ustekinumab
Métropolitain, Québec, QC,
(n=99), or placebo (n=98). Co-primary endpoints were met for both studies. At week 16 of UltIMMa-1, PASI 90 was Canada (Y Poulin MD); K Papp
achieved by 229 (75·3%) patients receiving risankizumab versus five (4·9%) receiving placebo (placebo-adjusted difference Clinical Research and Probity
70·3% [95% CI 64·0–76·7]) and 42 (42·0%) receiving ustekinumab (ustekinumab-adjusted difference 33·5% [22·7–44·3]; Medical Research, Waterloo,
ON, Canada (K A Papp MD);
p<0·0001 vs placebo and ustekinumab). At week 16 of UltIMMa-2, PASI 90 was achieved by 220 (74·8%) patients receiving University of California, Los
risankizumab versus two (2·0%) receiving placebo (placebo-adjusted difference 72·5% [95% CI 66·8–78·2]) and Angeles, School of Medicine,
47 (47·5%) receiving ustekinumab (ustekinumab-adjusted difference 27·6% [16·7–38·5]; p<0·0001 vs placebo and Los Angeles, CA, USA
ustekinumab). In UltIMMa-1, sPGA 0 or 1 at week 16 was achieved by 267 (87·8%) patients receiving risankizumab versus (H Sofen MD); Hospital de la
Santa Creu i Sant Pau,
eight (7·8%) receiving placebo (placebo-adjusted difference 79·9% [95% CI 73·5–86·3]) and 63 (63·0%) receiving Universitat Autònoma de
ustekinumab (ustekinumab-adjusted difference 25·1% [15·2–35·0]; p<0·0001 vs placebo and ustekinumab). In Barcelona, Barcelona, Spain
UltIMMa-2, 246 (83·7%) patients receiving risankizumab versus five (5·1%) receiving placebo (placebo-adjusted difference (Prof L Puig MD); University of
78·5% [95% CI 72·4–84·5]) and 61 (61·6%) receiving ustekinumab achieved sPGA 0 or 1 at week 16 (ustekinumab- Melbourne, Parkville, Skin &
Cancer Foundation Inc, Carlton,
adjusted difference 22·3% [12·0–32·5]; p<0·0001 vs placebo and ustekinumab). The frequency of treatment-emergent Probity Medical Research,
adverse events in UltIMMa-1 and UltIMMa-2 was similar across risankizumab (part A: 151 [49·7%] of 304 and 134 [45·6%] Carlton, and St Vincent’s
of 294; part B: 182 [61·3%] of 297 and 162 [55·7%] of 291), placebo (part A: 52 [51·0%] of 102 and 45 [45·9%] of 98), Hospital Melbourne, Fitzroy
ustekinumab (part A: 50 [50·0%] of 100 and 53 [53·5%] of 99; part B: 66 [66·7%] of 99 and 70 [74·5%] of 94), and placebo VIC, Australia (P Foley MD); Jichi
Medical University,
to risankizumab (part B: 65 [67·0%] of 97 and 61 [64·9%] of 94) treatment groups throughout the study duration. Shimotsuke, Japan
(Prof M Ohtsuki MD);
Interpretation Risankizumab showed superior efficacy to both placebo and ustekinumab in the treatment of moderate- Boehringer Ingelheim
to-severe plaque psoriasis. Treatment-emergent adverse event profiles were similar across treatment groups and there Pharmaceuticals, Ridgefield,
CT, USA (M Flack MD); AbbVie,
were no unexpected safety findings. North Chicago, IL, USA
(Z Geng PhD, Y Gu MS,
Funding AbbVie and Boehringer Ingelheim. J M Valdes MD); AbbVie,
Redwood City, CA, USA
(E H Z Thompson PhD); and
Copyright © 2018 Elsevier Ltd. All rights reserved.

www.thelancet.com Published online August 7, 2018 http://dx.doi.org/10.1016/S0140-6736(18)31713-6 1

 Articles
Saint-Louis Hospital, AP-HP,
Sorbonne Paris Cité Université
Paris Diderot, INSERUM
UMR 1163, Institut Imagine,
Paris, France
(Prof H Bachelez MD)
Correspondence to:
Prof Kenneth B Gordon,
Department of Dermatology,
Medical College of Wisconsin,
Milwaukee, WI 53226, USA
kegordon@mcw.edu
or
Prof Hervé Bachelez,
Service de Dermatologie,
AP-HP Hôpital Saint-Louis,
75475 Paris cedex 10, France
herve.bachelez@aphp.fr
See Online for appendix
2 www.thelancet.com Published online August 7, 2018 http://dx.doi.org/10.1016/S0140-6736(18)31713-6
Research in context
Evidence before this study
We searched PubMed using the terms “psoriasis” and
“interleukin-23” with clinical trial as the article type to identify
phase 3 studies of interleukin-23 inhibitors in patients with
psoriasis published before May 16, 2018. We identified
30 articles, of which five described results from phase 3
randomised controlled trials of antibodies targeting the p40
subunit of interleukin-12 or interleukin-23, and three reported
results from phase 3 randomised controlled trials of antibodies
targeting the p19 subunit of interleukin-23. In phase 3
randomised placebo-controlled studies, interleukin-12 and
interleukin-23 inhibitors (ustekinumab and briakinumab;
targeting the p40 subunit) have shown efficacy in patients with
moderate-to-severe psoriasis. Selective interleukin-23p19
inhibitors (guselkumab and tildrakizumab; targeting the
p19 subunit) have shown efficacy in phase 3, randomised,
placebo-controlled and active-comparator-controlled trials in
patients with moderate-to-severe psoriasis (with tumour
necrosis factor inhibitors as the active comparators). Although
interleukin-12 and interleukin-23 inhibitors have been shown
to be efficacious in moderate-to-severe plaque psoriasis, recent
studies have suggested that some of the selective
interleukin-23p19 inhibitors might provide additional efficacy.
In a phase 2 trial, risankizumab showed superior efficacy over
ustekinumab, confirming the potential benefits of selective
interleukin-23p19 inhibition.
Introduction
Psoriasis is a common, chronic, immune-mediated, sys­
temic, inflammatory disease with prominent skin man­
ifestations, associated with a substantial disease burden
that affects quality of life.1–3 It is estimated to affect between
1% and 4% of the population in developed countries.4–6
Patients with psoriasis are at increased risk of developing
several comorbidities, including cardiovascular disease,
depression, metabolic syndrome, joint and entheseal
disease, and inflammatory bowel disease.7,8 Although the
introduction of biologics has improved treatment out­
comes, an unmet need remains for therapies that provide
predictable and durable skin clearance with convenient
dosing, thereby improving patients’ quality of life.9–12
Interleukin-23, a key regulator of multiple effector
cytokines, has a pivotal role in the pathogenesis of
psoriasis.13–16 Interleukin-23 is considered to drive the
development and maintenance of psoriasis by stimulating
the proliferation, differentiation, and maintenance of
T-helper-17 and innate immune cells, major sources of
pro-inflammatory cytokines, including interleukin-17.13,14
Ustekinumab, which blocks the p40 subunit shared by
both interleukin-12 and interleukin-23, has shown efficacy
and safety in treatment of psoriasis.17,18 Agents that
selectively target the p19 subunit, thereby inhibiting
interleukin-23, have shown efficacy in phase 3 studies
in psoriasis.19,20
Added value of this study
To our knowledge, this is the first report of two replicate
phase 3 head-to-head trials comparing a selective
interleukin-23p19 inhibitor versus a dual interleukin-12 and
interleukin-23 inhibitor. UltIMMa-1 and UltIMMa-2 assessed
the efficacy and safety of risankizumab compared with both
placebo and ustekinumab, an interleukin-12 plus
interleukin-23 inhibitor, in patients with moderate-to-severe
plaque psoriasis. Compared with recent phase 3 trials in
psoriasis, UltIMMa-1 and UltIMMa-2 included higher
proportions of patients with previous exposure to biologic
therapy (34–41%), indicative of a more treatment-refractory
patient population. Risankizumab provided consistently
superior efficacy compared with both placebo and
ustekinumab, as evidenced by significant improvements in
both co-primary endpoints and all ranked secondary
endpoints.
Implications of all the available evidence
Risankizumab, a selective interleukin-23p19 inhibitor dosed
every 12 weeks, was more efficacious than ustekinumab,
an antibody targeting interleukin-12 and interleukin-23.
The safety profile of risankizumab was similar to that of placebo
and ustekinumab, with no new safety findings. The data
presented here further support the therapeutic value of
risankizumab in patients with moderate-to-severe psoriasis.
Risankizumab is a humanised IgG1 monoclonal anti­
body that binds the p19 subunit of interleukin-23, thus
inhibiting this key cytokine and its role in psoriatic
inflammation.21–23 In a phase 1 study, a single dose of
risankizumab resulted in substantial and sustained skin
clearance.22 In a phase 2 study, risankizumab showed
superior efficacy with rapid and durable skin clearance
versus ustekinumab, highlighting the role of interleukin-23
in psoriasis.23
Two phase 3 studies were therefore done to assess the
efficacy and safety of risankizumab compared with placebo
or ustekinumab in patients with moderate-to-severe chro­
nic plaque psoriasis. Here, we report the efficacy and safety
results from the UltIMMa-1 and UltIMMa-2 studies.
Methods
Study design and patients
UltIMMa-1 and UltIMMa-2 were replicate phase 3,
randomised, double-blind, placebo-controlled and active
comparator-controlled trials done at 139 sites (including
hospitals, academic medical centres, clinical research
units, and private practices) in Australia, Austria, Belgium,
Canada, Czech Republic, France, Germany, Japan, Mexico,
Poland, Portugal, South Korea, Spain, and the USA. The
trial design is provided in the appendix.
Adult patients (aged ≥18 years) were eligible to partici­
pate if they had stable (≥6 months) moderate-to-severe

chronic plaque psoriasis (with or without psoriatic
arthritis) at both screening and baseline (randomisation)
with body surface area involvement 10% or greater,
Psoriasis Area Severity Index (PASI) 12 or greater, and
static Physician’s Global Assessment (sPGA) score 3 or
greater. Patients were required to be candidates for
systemic therapy or phototherapy and eligible for treatment
with ustekinumab. A complete list of inclusion and
exclusion criteria is provided in the appendix.
The studies were done in accordance with the study
protocol, International Council for Harmonisation of
Technical Requirements for Pharmaceuticals for Human
Use (ICH) guidelines, applicable local regulations, and
Good Clinical Practice guidelines governing clinical study
conduct, and ethical principles outlined in the Declaration
of Helsinki. All study-related documents (including the
study protocols) were approved by an institutional review
board or independent ethics committee at each study site,
and all patients provided written informed consent before
participation.
Randomisation and masking
In each study, patients were randomly assigned (3:1:1)
to receive risankizumab, ustekinumab, or matching
placebo (appendix). Randomisation was stratified by
weight (≤100 kg vs >100 kg) and previous exposure to
tumour necrosis factor (TNF) inhibitor (yes vs no); there
was no restriction on the number of patients with prior
TNF inhibitor exposure. Interactive response technology
was used for randomisation and allocation of double-blind
treatment to each patient. Patients, investigators, and
study personnel involved in the trial conduct or analyses
remained masked to treatment assignments until study
completion. To maintain blinding, the studies utilised a
double-dummy strategy wherein risankizumab and its
matching placebo or ustekinumab and its matching
placebo were identical in appearance.
Procedures
In UltIMMa-1 and UltIMMa-2, the screening period
(1–6 weeks) was followed by a 16-week double-blind
treatment period (part A). In part A, patients received
either 150 mg risankizumab, ustekinumab based on
weight per label (45 mg for patients with body weight
≤100 kg or 90 mg for patients with body weight >100 kg), or
placebo subcutaneously at weeks 0 and 4. In part B (double-
blind, weeks 16–52), patients initially assigned to placebo
switched to 150 mg risankizumab at week 16; other
patients continued their originally randomised treat­
ment. During part B, patients received the study drug
subcutaneously at weeks 16, 28, and 40. Efficacy outcomes
were assessed at weeks 4, 8, 12, 16, 22, 28, 34, 40, 46, and
52. Safety was monitored throughout the study.
Outcomes
The co-primary endpoints were the proportions of patients
achieving 90% improvement in PASI (PASI 90) and sPGA
www.thelancet.com Published online August 7, 2018 http://dx.doi.org/10.1016/S0140-6736(18)31713-6 3
Articles
0 or 1 (clear or almost clear) at week 16. Ranked secondary
endpoints included sPGA 0 (clear), PASI 100, Dermatology
Life Quality Index (DLQI) of 0 or 1, Psoriasis Symptom
Scale (PSS) score of 0, PASI 75, and change from baseline
in PSS total score at weeks 12, 16, or 52. The PSS is a
four-item, patient-reported outcome instrument used to
assess the severity of pain, redness, itching, and burning
symptoms due to psoriasis.24 A list of ranked secondary
endpoints in prespecified hierarchical order is provided in
the appendix. Additional endpoints included proportions
of patients achieving PASI 75, 90, or 100, sPGA 0 or 1, and
sPGA 0 at each study visit, percentage improvement from
baseline in PASI at each study visit, and maintenance of
PASI 90 responses at each study visit in part B among
PASI 90 responders at week 16.
Safety was evaluated according to reported adverse
events, including serious adverse events, laboratory values
(haematology, clinical chemistry, and urinalysis), phys­­
ical examination (vital signs and 12-lead electro­ cardio­
gram [ECG]), and local tolerability (swelling, induration,
heat, redness, pain, or other findings at injection site).
Treatment-emergent adverse events were defined as any
adverse events with an onset date on or after the first dose
of study drug and up to 105 days after the last dose of
study drug. Adverse events were coded with the
Medical Dictionary for Regulatory Activities (MedDRA,
version 20.0) and severity grading followed Rheumatology
Common Toxicity Criteria (RCTC). Any adverse event with
grade 3 or grade 4 on RCTC severity grading was considered
severe. Areas of safety interest included major adverse
cardiovascular events, serious infect­ ion, tuberculosis,
fungal and opportunistic infections (in­ cluding herpes
zoster), malignancies, hypersensitivity reactions, and
hepatic events. All observed cardiovascular, cerebrovascular,
and thrombotic events reported dur­ing the studies were
adjudicated by an independent adjudication committee.
Statistical analysis
For both UltIMMa-1 and UltIMMa-2 studies, efficacy
analyses were done in the intention-to-treat population (all
randomised patients). To assess the effect of protocol
deviations on co-primary endpoints, sensitivity analyses
were based on the per-protocol population (patients who
were most compliant with the protocol in ways that could
affect the efficacy endpoints). Safety analyses were done on
the safety analysis set (all patients who received at least one
dose of study drug). The UltIMMa-1 and UltIMMa-2
studies were powered to show benefit of risankizumab
over both placebo and ustekinumab in terms of achieving
PASI 90 and sPGA 0 or 1 at week 16. Based on response
rates in phase 1 and phase 2 trials, the PASI 90 response
rate at week 16 was assumed to be at least 65% for
risankizumab and at most 45% for ustekinumab; the
sPGA 0 or 1 response rate at week 16 was assumed
to be 85% for risankizumab and at most 67·5%
for ustekinumab. By use of a 3:1 randomisation scheme
(risankizumab to ustekinumab), we estimated that
 Articles

UltIMMa-1
560 patients assessed for eligibility
300 patients in the risankizumab group and 100 patients in
54 ineligible the ustekinumab group would provide 94% power for the
42 did not meet entry criteria
1 lost to follow-up PASI 90 endpoint and 95% power for the sPGA 0 or
9 withdrew 1 endpoint. Assuming a 5% placebo response rate for both
2 other
506 randomly assigned PASI 90 and sPGA 0 or 1 at week 16, 300 patients in the
risankizumab group and 100 patients in the placebo group
Part A would provide more than 99% power for both endpoints.
304 assigned to 150 mg 100 assigned to 45 mg or 102 assigned to placebo
For each study, multiplicity was controlled with a hier­
risankizumab 90 mg ustekinumab archical testing procedure for the primary and ranked
secondary endpoints (significant results for the com­
parison in the higher rank [primary followed by ranked
5 discontinued treatment 1 discontinued treatment 4 discontinued treatment
1 adverse event 1 lost to follow-up 2 disease worsening secondary endpoints] were necessary to initiate testing of
3 withdrawals 1 lost to follow-up the next comparison in the lower rank). All comparisons
1 other 1 withdrawal
were done with two-sided tests, with a type I error of 0·05.
Categorical variables were analysed with the Cochran-
299 completed part A 99 completed part A 98 completed part A Mantel-Haenszel risk differ­ ence estimate stratified by
baseline weight and previous exposure to TNF inhibitor.
Part B Change from baseline in PSS was analysed with a stratified
297 remained on 150 mg 99 remained on 45 mg or 97 crossed over to 150 mg van Elteren test. For other continuous variables, treatment
risankizumab 90 mg ustekinumab risankizumab groups were compared by use of ANCOVA with treatment
group, baseline value, and stratification factors in the
8 discontinued treatment 5 discontinued treatment 2 discontinued treatment model. Missing efficacy data for categor­ ical variables
1 adverse event 2 adverse events 1 lost to follow-up were handled with non-responder imput­ ation and for
5 lost to follow-up 2 lost to follow-up 1 withdrawal
2 withdrawals 1 withdrawal
continuous variables with last observation carried forward.

Role of the funding source

289 completed part B
UltIMMa-2
577 patients assessed for eligibility
491 randomly assigned
Part A
294 assigned to 150 mg
risankizumab
2 discontinued treatment
2 lost to follow-up
292 completed part A
Part B
291 remained on 150 mg
risankizumab
13 discontinued treatment
1 adverse event
7 lost to follow-up
4 withdrawals
1 other
278 completed part B
Figure 1: Trial profiles for UltIMMa-1 and UltIMMa-2
94 completed part B 95 completed part B Boehringer Ingelheim contributed to study design and
participated in data collection. AbbVie did the data
86 ineligible
analysis, and participated in data interpretation. AbbVie
2 adverse events and Boehringer Ingelheim participated in writing, review,
54 did not meet entry criteria and approval of the manuscript. All authors had full access
6 lost to follow up
20 withdrawals to the data from both studies, reviewed and approved the
4 other final version, and were responsible for the decision to
submit for publication. A medical writer, employed by
AbbVie, assisted with manuscript preparation under the
99 assigned to 45 mg or 98 assigned to placebo
authors’ direction.
90 mg ustekinumab
Results
3 discontinued treatment 4 discontinued treatment
Between Feb 24, 2016, and Aug 31, 2016, 506 patients in
2 lost to follow-up 1 disease worsening UltIMMa-1 were randomly assigned to receive 150 mg
1 other 3 withdrawals risankizumab (n=304), 45 mg or 90 mg ustekinumab
(n=100), or placebo (n=102); between March 1, 2016, and
96 completed part A 94 completed part A
Aug 30, 2016, 491 patients in UltIMMa-2 were randomly
assigned to receive 150 mg risankizumab (n=294), 45 mg
or 90 mg ustekinumab (n=99), or placebo (n=98; figure 1).
In UltIMMa-1, 496 patients (98%) completed part A and
94 remained on 45 mg or 94 crossed over to 150 mg
90 mg ustekinumab risankizumab 493 entered part B; 478 (97%) patients completed part B.
In UltIMMa-2, 482 patients (98%) completed part A and
479 entered part B; 459 (96%) completed part B (figure 1).
4 discontinued treatment 3 discontinued treatment
1 adverse event 1 adverse event Protocol deviations were reported in ten (2%) patients in
1 lost to follow-up 1 lost to follow-up UltIMMa-1 and in 15 (3%) in UltIMMa-2 (appendix).
2 withdrawals 1 other
Baseline patient demographics and disease character­
istics were generally balanced between treatment groups
and across studies, and were mostly consistent with
90 completed part B 91 completed part B those of recent trials in patients with psoriasis (table 1).
Most patients were men (71% in UltIMMa-1 and 68% in
UltIMMa-2), mean age was 48 (SD 13) years in UltIMMa-1

4 www.thelancet.com Published online August 7, 2018 http://dx.doi.org/10.1016/S0140-6736(18)31713-6

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UltIMMa-1 UltIMMa-2
Risankizumab (n=304) Ustekinumab (n=100) Placebo (n=102) Risankizumab (n=294) Ustekinumab (n=99) Placebo (n=98)
Sex
Men 212 (70%) 70 (70%) 79 (77%) 203 (69%) 66 (67%) 67 (68%)
Women 92 (30%) 30 (30%) 23 (23%) 91 (31%) 33 (33%) 31 (32%)
Age, years 48·3 (13·4) 46·5 (13·4) 49·3 (13·6) 46·2 (13·7) 48·6 (14·8) 46·3 (13·3)
Ethnic origin
White 200 (66%) 74 (74%) 71 (70%) 255 (87%) 91 (92%) 87 (89%)
Black or African American 0 (3%) 1 (1%) 1 (1%) 10 (3%) 2 (2%) 2 (2%)
Asian 86 (28%) 22 (22%) 28 (27%) 25 (9%) 4 (4%) 7 (7%)
Other 8 (3%) 3 (3·0%) 2 (2%) 4 (1%) 2 (2%) 2 (2%)
Weight, kg 87·8 (22·9) 88·9 (22·9) 88·8 (20·2) 92·2 (21·7) 91·9 (21·4) 92·2 (20·0)
≤100 kg* 226 (74%) 74 (74%) 76 (75%) 203 (69%) 69 (70%) 67 (68%)
>100 kg* 78 (26%) 26 (26%) 26 (25%) 91 (31%) 30 (30%) 31 (32%)
BMI, kg/m² 29·9 (6·9) 29·8 (6·9) 29·5 (6·4) 31·1 (7·1) 30·9 (6·8) 31·0 (5·8)
Psoriatic arthritis status (diagnosed or suspected) 85 (28%) 23 (23%) 36 (35%) 74 (25%) 27 (27%) 32 (33%)
PASI 20·6 (7·7) 20·1 (6·8) 20·5 (6·7) 20·5 (7·8) 18·2 (5·9) 18·9 (7·3)
sPGA
Moderate 256 (84%) 85 (85%) 86 (84%) 228 (78%) 81 (82%) 77 (79%)
Severe 48 (16%) 15 (15%) 16 (16%) 66 (22%) 18 (18%) 21 (21%)
BSA involvement 26·2% (15·4) 25·2% (14·7) 27·9% (17·2) 26·2% (15·9) 20·9% (12·1) 23·9% (15·7)
DLQI 13·0 (7·0) 13·6 (7·3) 12·3 (6·2) 13·5 (7·4) 11·7 (6·6) 12·9 (6·7)
Any previous biologic therapy 104 (34%) 30 (30%) 40 (39%) 118 (40%) 43 (43%) 42 (43%)
TNF inhibitor* 67 (22%) 19 (19%) 22 (22%) 67 (23%) 24 (24%) 26 (27%)
non-TNF inhibitor 54 (18%) 17 (17%) 24 (24%) 75 (26%) 31 (31%) 25 (26%)
Data are mean (SD) or n (%), unless otherwise specified. BMI=body-mass index. PASI=Psoriasis Area and Severity Index. sPGA=static Physician’s Global Assessment. BSA=body surface area. DLQI=Dermatology
Life Quality Index. TNF=tumour necrosis factor. *Stratification factors at randomisation.

Table 1: Baseline demographics and disease characteristics of intention-to-treat population

and 47 (14) years in UltIMMa-2, and mean weight was
88 kg (22) in UltIMMa-1 and 92 kg (21) in UltIMMa-2.
Overall, mean PASI was 20 (SD 7) in both studies
and mean body surface area involvement was 26% (16)
in UltIMMa-1 and 25% (15) in UltIMMa-2. Previous
systemic therapy was reported in 70% of patients in
UltIMMa-1 and 67% of those in UltIMMa-2. Previous
non-biologic systemic therapy was reported in 52% of
patients in UltIMMa-1 and 47% of those in UltIMMa-2;
previous biologic therapy was reported in 34% in
UltIMMa-1 and 41% in UltIMMa-2.
In both studies, significantly greater proportions of
patients receiving risankizumab compared with those
receiving placebo achieved the co-primary endpoints of
PASI 90 and sPGA 0 or 1 at week 16 (p<0·0001 vs placebo;
table 2, figure 2). All 15 prespecified ranked secondary
endpoints were met in both studies (table 2). At week 16,
PASI 90 was achieved by 229 (75·3%) risankizumab-
treated patients compared with five (4·9%) placebo-
treated patients and 42 (42·0%) ustekinumab-treated
patients in UltIMMa-1, and in 220 (74·8%) risankizumab-
treated patients compared with two (2·0%) placebo-treated
patients and 47 (47·5%) ustekinumab-treated patients in
UltIMMa-2 (p<0·0001 vs placebo and ustekinumab for
both studies). sPGA 0 or 1 was achieved by 267 (87·8%)
patients receiving risankizumab versus eight (7·8%)
receiving placebo and 63 (63·0%) receiving ustekinumab
in UltIMMa-1, and by 246 (83·7%) patients receiving
risankizumab versus five (5·1%) receiving placebo and 61
(61·6%) receiving ustekinumab in UltIMMa-2 (p<0·0001
vs placebo and ustekinumab for both studies). Sens­
itivity analyses based on the per-protocol population
showed PASI 90 and sPGA 0 or 1 response rates
consistent with results in the intention-to-treat population
(appendix).
Complete clearance of psoriatic lesions (PASI 100 and
sPGA 0) was also achieved by significantly higher
proportions of risankizumab-treated patients compared
with those receiving placebo and ustekinumab at week 16
(table 2, figure 3). PASI 100 was achieved by 109 (35·9%)
patients receiving risankizumab compared with none
receiving placebo and 12 (12·0%) receiving ustekinumab
in UltIMMa-1, and by 149 (50·7%) patients receiving
risankizumab compared with two (2·0%) receiving
placebo and 24 (24·2%) receiving ustekinumab in
UltIMMa-2 (p<0·0001 vs placebo and ustekinumab for
both studies). In UltIMMa-1, sPGA 0 was achieved by
112 (36·8%) patients receiving risankizumab, compared
with two (2·0%) receiving placebo and 14 (14·0%)
receiving ustekinumab; in UltIMMa-2 it was achieved by

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Risankizumab Ustekinumab Placebo Placebo to Difference from Difference from

risankizumab ustekinumab (95% CI) Placebo (95% CI)
UltIMMa-1
Number of patients per group 304 100 102 97 .. ..
PASI 90 at week 16 229 (75·3%) 42 (42·0%) 5 (4·9%) NA 33·5% (22·7 to 44·3)* 70·3% (64·0 to 76·7)*
sPGA 0 or 1 at week 16 267 (87·8%) 63 (63·0%) 8 (7·8%) NA 25·1% (15·2 to 35·0)* 79·9% (73·5 to 86·3)*
sPGA 0 at week 16 112 (36·8%) 14 (14·0%) 2 (2·0%) NA 22·9% (14·3 to 31·6)* 34·7% (28·6 to 40·8)*
PASI 100 at week 16 109 (35·9%) 12 (12·0%) 0 NA 23·8% (15·5 to 32·1)* 35·5% (30·0 to 41·0)*
DLQI 0 or 1 at week 16 200 (65·8%) 43 (43·0%) 8 (7·8%) NA 23·0% (11·9 to 34·0)* 57·9% (50·4 to 65·3)*
PSS 0 at week 16 89 (29·3%) 15 (15·0%) 2 (2·0%) NA 14·3% (5·8 to 22·8)† 27·1% (21·2 to 32·9)*
PASI 90 at week 52 249 (81·9%) 44 (44·0%) NA 76 (78·4%) 38·3% (27·9 to 48·6)* NA
PASI 100 at week 52 171 (56·3%) 21 (21·0%) NA 53 (54·6%) 35·1% (25·7 to 44·6)* NA
sPGA 0 at week 52 175 (57·6%) 21 (21·0%) NA 53 (54·6%) 36·5% (27·0 to 45·9)* NA
PASI 75 at week 12 264 (86·8%) 70 (70·0%) 10 (9·8%) NA 17·0% (7·4 to 26·6)‡ 76·9% (70·1 to 83·8)*
sPGA 0 or 1 at week 12 250 (82·2%) 65 (65·0%) 9 (8·8%) NA 17·3% (7·3 to 27·3)§ 73·3% (66·4 to 80·3)*
Change in PSS at week 16 –5·6 (0·2) –4·4 (0·3) 0·2 (0·3) NA –1·2 (–1·9 to -0·4) –5·8 (–6·5 to -5·0)*
UltIMMa-2
Number of patients per group 294 99 98 94 .. ..
PASI 90 at week 16 220 (74·8%) 47 (47·5%) 2 (2·0%) NA 27·6% (16·7 to 38·5)* 72·5% (66·8 to 78·2)*
sPGA 0 or 1 at week 16 246 (83·7%) 61 (61·6%) 5 (5·1%) NA 22·3% (12·0 to 32·5)* 78·5% (72·4 to 84·5)*
sPGA 0 at week 16 150 (51·0%) 25 (25·3%) 3 (3·1%) NA 26·3% (16·1 to 36·4)* 47·5% (40·9 to 54·2)*
PASI 100 at week 16 149 (50·7%) 24 (24·2%) 2 (2·0%) NA 27·0% (17·0 to 37·0)* 48·2% (41·9 to 54·6)*
DLQI 0 or 1 at week 16 196 (66·7%) 46 (46·5%) 4 (4·1%) NA 20·2% (9·1 to 31·4)¶ 62·2% (55·5 to 68·9)*
PSS 0 at week 16 92 (31·3%) 15 (15·2%) 0 NA 16·1% (7·5 to 24·8)|| 31·2% (25·7 to 36·6)*
PASI 90 at week 52 237 (80·6%) 50 (50·5%) NA 80 (85·1%) 30·2% (19·6 to 40·9)* NA
PASI 100 at week 52 175 (59·5%) 30 (30·3%) NA 63 (67·0%) 29·5% (18·9 to 40·1)* NA
sPGA 0 at week 52 175 (59·5%) 30 (30·3%) NA 63 (67·0%) 29·5% (18·9 to 40·1)* NA
PASI 75 at week 12 261 (88·8%) 69 (69·7%) 8 (8·2%) NA 19·2% (9·5 to 28·8)* 80·2% (73·7 to 86·7)*
sPGA 0 or 1 at week 12 242 (82·3%) 64 (64·6%) 9 (9·2%) NA 18·0% (7·8 to 28·3)** 72·9% (65·7 to 80·0)*
Change in PSS at week 16 –6·4 (0·2) –5·6 (0·3) –0·0 (0·3) NA –0·8 (–1·6 to -0·1) –6·4 (–7·1 to –5·6)*
Data are least squares mean (SE), n (%), or % (95% CI). Categorical variables were analysed with the Cochran-Mantel-Haenszel risk difference estimate stratified by baseline
weight and previous exposure to tumour necrosis factor inhibitor. Continuous variable (change in PSS) was analysed with the stratified Van Elteren test. Missing data were
imputed as non-responders for categorical endpoints and by last observation carried forward for continuous endpoints. Multiplicity was controlled with a hierarchical test
procedure for primary and ranked secondary endpoints. PASI=Psoriasis Area and Severity Index. NA=not applicable. sPGA=static Physician’s Global Assessment.
DLQI=Dermatology Life Quality Index. PSS=Psoriasis Symptom Scale. *p<0·0001 compared with placebo and ustekinumab. †p=0·0010. ‡p=0·0005. §p=0·0007. ¶p=0·0004.
llp=0·0003. **p=0·0006 compared with ustekinumab.

Table 2: Co-primary, ranked secondary, and additional endpoints in UltIMMa-1 and UltIMMa-2

150 (51·0%) patients receiving risankizumab, compared
with three (3·1%) receiving placebo and 25 (25·3%)
receiving ustekinumab (p<0·0001 vs placebo and
ustekinumab for both studies).
PASI 90 responses were significantly higher in
risankizumab-treated patients starting at week 4 (at the
first measured timepoint) than in those treated with
placebo (UtlIMMa-1: p=0·0001; UltIMMa-2: p<0·0001)
and at week 8 versus those treated with ustekinumab
(UltIMMa-1 and UltIMMa-2: p<0·0001; figure 2). In
patients treated with risankizumab, sPGA 0 or 1 res­
ponses were significantly greater starting at week 4
than in those treated with placebo (UltIMMa-1 and
UltIMMa-2: p<0·0001) and those treated with ustekinumab
(UtlIMMa-1: p=0·0047; UltIMMa-2: p=0·0129). Patients
receiving risankizumab achieved a significantly higher
PASI 75 response at weeks 12 and 16 compared with
those receiving placebo (p<0·0001) and those receiving
ustekinumab (UltIMMa-1: week 12, p=0·0005; week 16,
p=0·0034; UltIMMa-2: p<0·0001, table 2, appendix).
In addition to clinical improvements, patient-reported
outcomes showed a positive impact of risankizumab
treatment at week 16. The proportion of patients
achieving DLQI 0 or 1 and PSS 0 was significantly higher
in the risankizumab group than in the placebo and
ustekinumab groups (figure 4). At week 16, 200 (65·8%)
risankizumab-treated patients achieved DLQI 0 or 1 in
UltIMMa-1 compared with eight (7·8%) placebo-treated
patients (p<0·0001) and 43 (43·0%) ustekinumab-treated
patients (p<0·0001); in UltIMMa-2, DLQI 0 or 1 was
achieved at week 16 in 196 (66·7%) risankizumab-treated
patients compared with four (4·1%) placebo-treated
patients (p<0·0001) and 46 (46·5%) ustekinumab-treated
patients (p=0·0004). PSS 0 at week 16 was achieved
by 89 (29·3%) risankizumab-treated patients versus
two (2·0%) placebo-treated patients (p<0·0001) and

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A B
UltlMMa-1 UltlMMa-2
Part A Part B Part A Part B
100

85%† 87%† 85%† 85% 85%

85%† 84%†
82%† 82%† 81%†
80 86%
75%*† 82%† 83% 84%†
80%† 74% 75%*† 81%†
79% 78%
Patients with PASI 90 (%)

68%*† 68%
62%*§ 67%
61%
60 55% 57%
52% 52% 54%
48% 47%*† 47%
45% 54%
44%*† 49% 47% 49% 51%
40 42% 44% 44%
32%
Risankizumab 24%
20 Placebo 26%
19% Ustekinumab
6%‡ 5% 3%
Placebo→risankizumab 6%*
5% 3% 2% 3% 2%
0% 5%
0 0%

C D
100
89%† 91% 89%† 91 %
88%*† 87%† 87%† 89% 87% 87%† 89% 87 %
87%†
82%* ** 88%† 82%*§§ 88%† 88%†
86% 86%† 86%† 84%*† 87 %
80 81%
85% 83%†
74%*||
Patients with sPGA 0 or 1 (%)

70% 70%*‡‡
65% 65% 64% 67 %
64% 62% 64%
60 63% 62%
61% 62% 60% 63%
59% 56%
54% 57 % 55%
54%

40 33%*††
34%*¶

20 20% 21 %
9% 9%
6% 5%
3% 8% 1% 5%
0
0 4 8 12 16 22 28 34 40 46 52 0 4 8 12 16 22 28 34 40 46 52
Time (weeks) Time (weeks)

Figure 2: Proportions of patients (non-responder imputation) achieving PASI 90 and sPGA 0 or 1 through to week 52 in UltIMMa-1 and UltIMMa-2
(A) Patients with PASI 90 in UltIMMa-1. (B) Patients with PASI 90 in UltIMMa-2. (C) Patients with sPGA 0 or 1 in UltIMMa-1. (D) Patients with sPGA 0 or 1 in UltIMMa-2. Dotted lines indicate dosing
schedule. PASI=Psoriasis Area and Severity Index. sPGA=static Physician’s Global Assessment. *p values for comparison vs placebo: p<0·0001. p values for comparison vs ustekinumab: †p<0·0001;
‡p=0·0001; §p=0·0107; ¶p=0·0047; ||p=0·0004; **p=0·0007; ††p=0·0129; ‡‡p=0·0065; §§p=0·0006.

A B
UltlMMa-1 UltlMMa-2
Part A Part B Part A Part B
100 PASI 100 sPGA 0
Risankizumab Risankizumab
Placebo Placebo
Patients with PASI 100 or sPGA 0 (%)

80 Ustekinumab Ustekinumab
Placebo→risankizumab Placebo→risankizumab
67%
58%†
60 56%†
51%*† 60%†
55%
37%*†
40 36%*†
30%
25%
20 14% 24%
21%
12% 3%
2% 2%
0
0 4 8 12 16 22 28 34 40 46 52 0 4 8 12 16 22 28 34 40 46 52
Time (weeks) Time (weeks)

Figure 3: Proportions of patients (non-responder imputation) achieving PASI 100 and sPGA 0 through to week 52 in UltIMMa-1 (A) and UltIMMa-2 (B)
Dotted lines indicate dosing schedule. PASI=Psoriasis Area and Severity Index. sPGA=static Physician’s Global Assessment. *p values for comparison vs placebo: p<0·0001. †p values for comparison vs
ustekinumab: p<0·0001.

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receiving risankizumab versus 0·2 (0·3) in those

A
Risankizumab Placebo Ustekinumab Placebo→risankizumab
receiving placebo in UltIMMa-1, and –6·4 (0·2) in
100 Week 16 Week 52 patients receiving risankizumab versus 0·0 (0·3) in
†
† those receiving placebo in UltIMMa-2 (p<0·0001 for both
*† *‡
studies; table 2).
Patients with DLQI 0 or 1 (%)

80 75%
71% 68%
66% 67%
62%
The proportions of patients achieving PASI and sPGA
60 responses continued to increase after week 16 in patients
46% 47%
43% 44% initially assigned to receive risankizumab (figures 2, 3;
40 appendix). PASI 75, PASI 90, PASI 100, sPGA 0 or 1,
sPGA 0, DLQI 0 or 1, and PSS 0 response rates at week 52
20
8% were significantly higher for risankizumab-treated pat­
4%
ients than for ustekinumab-treated patients (table 2,
0
figures 2, 3, 4; appendix). At week 52, 249 (81·9%) patients
B on continuous risankizumab achieved PASI 90 compared
100 with 44 (44·0%) on ustekinumab in UltIMMa-1, as did
237 (80·6%) patients on continuous risankizumab versus
80
† 50 (50·5%) on ustekinumab in UltIMMa-2 (p<0·0001 vs
Patients with PSS 0 (%)

†
57% ustekinumab for both studies; table 2, figure 2). PASI 100
60 54%
51% 48% at week 52 was achieved by 171 (56·3%) patients on
*§ *¶
40 continuous risankizumab compared with 21 (21·0%)
31% 30% 30%
29% ustekinumab-treated patients in UltIMMa-1, and in
20 15% 15% 175 (59·5%) patients on continuous risankizumab com­
pared with 30 (30·3%) ustekinumab-treated patients in
2% 0%
0 UltIMMa-2 (p<0·0001 for both studies). In UltIMMa-1,
UltlMMa-1 UltlMMa-2 UltlMMa-1 UltlMMa-2
sPGA 0 at week 52 was achieved by 175 (57·6%) patients
Figure 4: Proportions of patients (non-responder imputation) achieving DLQI 0 or 1 (A) and PSS 0 (B) at continuing risankizumab versus 21 (21·0%) ustekinumab-
weeks 16 and 52 in UltIMMa-1 and UltIMMa-2 treated patients (p<0·0001), while in UltIMMa-2 it
DLQI=Dermatology Life Quality Index. PSS=Psoriasis Symptom Scale. p values for comparison vs placebo: *p<0·0001.
was achieved by 175 (59·5%) patients continuing
p values for comparison vs ustekinumab: †p<0·0001; ‡p=0·0004; §p=0·0010; ¶p=0·0003.
risankizumab versus 30 (30·3%) ustekinumab-treated
patients (p<0·0001). In patients initially assigned to
100 96%* 95%‡ 94%§
placebo switching to risankizumab at week 16, response
92%† 91%¶
88%|| rates for PASI, sPGA, DLQI and PSS at week 52
90%
80
were similar to those in patients initially assigned to
75% 81% 83%
78% 79% risankizumab (table 2, figure 2, 3, 4; appendix).
Patients with PASI 90 (%)

73%
The percentage improvement from baseline in PASI
60
was significantly increased in risankizumab-treated
45% patients starting at week 4 through to week 16 compared
40 with placebo-treated patients and, through to week 52,
compared with ustekinumab-treated patients (appendix).
Risankizumab Among patients who achieved PASI 90 at week 16 across
20 (n=450)
Ustekinumab both studies, a significantly greater proportion of those
(n=90) continuing risankizumab maintained their PASI 90
0
Risankizumab Ustekinumab Entry into 22 28 34 40 46 52 response through to week 52 than did ustekinumab-
(n=598) (n=199) part B treated patients (figure 5). At week 52, 398 (88·4%) of
Entry into part B Time (weeks) 450 patients on continuous risankizumab maintained
Figure 5: Maintenance of PASI 90 response (non-responder imputation) from entry of part B through to their PASI 90 response compared with 66 (73·3%) of 90
week 52 integrated across UltIMMa-1 and UltIMMa-2 on ustekinumab (p=0·0009).
Dotted lines indicate dosing schedule. PASI=Psoriasis Area and Severity Index. p values for comparison vs The proportions of patients with treatment-emergent
ustekinumab: *p=0·0476; †p=0·0015; ‡p=0·0007; §p<0·0001; ¶p=0·0012; ||p=0·0009. adverse events were similar across treatment groups
throughout the study duration in both UltIMMa-1 and
15 (15·0%) ustekinumab-treated patients (p=0·0010) in UltIMMa-2. In part A of UltIMMa-1, adverse events
UltIMMa-1, and by 92 (31·3%) risankizumab-treated occurred in 151 (49·7%) patients on risankizumab, in
patients versus no placebo-treated patients (p<0·0001) 52 (51·0%) on placebo, and 50 (50·0%) on ustekinumab,
and 15 (15·2%) ustekinumab-treated patients (p=0·0003) and in part A of UltIMMa-2 in 134 (45·6%) patients on
in UltIMMa-2. The mean change from baseline in PSS risankizumab, 45 (45·9%) on placebo, and 53 (53·5%)
total score (minimal clinically important difference 2·0, on ustekinumab (table 3). Serious adverse events were
unpublished results) was –5·6 (SD 0·2) in patients reported in seven (2·3%) patients on risankizumab,

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UltIMMA-1 UltIMMA-2
Risankizumab (n=304) Ustekinumab (n=100) Placebo (n=102) Risankizumab (n=294) Ustekinumab (n=99) Placebo (n=98)
Any adverse event 151 (49·7%) 50 (50·0%) 52 (51·0%) 134 (45·6%) 53 (53·5%) 45 (45·9%)
Serious adverse events 7 (2·3%) 8 (8·0%) 3 (2·9%) 6 (2·0%) 3 (3·0%) 1 (1·0%)
Severe adverse events 6 (2·0%) 3 (3·0%) 5 (4·9%) 7 (2·4%) 6 (6·1%) 1 (1·0%)
Adverse event leading to drug discontinuation 2 (0·7%) 2 (2·0%) 4 (3·9%) 1 (0·3%) 0 1 (1·0%)
Infections 75 (24·7%) 20 (20·0%) 17 (16·7%) 56 (19·0%) 20 (20·2%) 9 (9·2%)
Serious infections 1 (0·3%) 3 (3·0%) 0 3 (1·0%) 1 (1·0%) 0
Active tuberculosis 0 0 0 0 0 0
Latent tuberculosis 0 0 0 0 0 0
Adjudicated major adverse cardiovascular event 0 0 0 0 0 0
Malignancies 1 (0·3%) 0 1 (1·0%) 1 (0·3%) 0 0
Malignancies excluding non-melanoma skin 0 0 0 0 0 0
cancer
Serious hypersensitivity 0 0 0 0 0 0
Deaths (including non-treatment emergent) 0 0 0 1 (0·3%)* 0 0

Any adverse event with grade 3 or grade 4 on Rheumatology Common Toxicity Criteria severity grading was considered severe. *One non-treatment emergent death of unknown cause on study day 189
occurred 161 days after last dose of study drug and fell outside of the treatment-emergent window.

Table 3: Treatment-emergent adverse events during part A in UltIMMa-1 and UltIMMa-2

three (2·9%) on placebo, and eight (8·0%) on ustekinumab
in UltIMMa-1, and in six (2·0%) patients on risankiz­
umab, one (1·0%) on placebo, and three (3·0%) on
ustekinumab in UltIMMa-2. The most frequently reported
adverse events (occurring in ≥5% of patients in any
treatment group) in part A of either study were viral upper
respiratory tract infection, upper respiratory tract infection,
psoriasis, and diarrhoea (appendix). During part A, serious
infections occurred in one (0·3%) patient on risankizumab
and three (3·0%) on ustekinumab in UltIMMa-1 and in
three (1·0%) on risankizumab and one (1·0%) on
ustekinumab in UltIMMa-2.
During part B of UltIMMa-1, adverse events occurred in
182 (61·3%) patients continuing on risankizumab, in
66 (66·7%) on ustekinumab, and in 65 (67·0%) patients
switching from placebo to risankizumab, and during part
B of UltIMMa-2 in 162 (55·7%) patients continuing on
risankizumab, in 70 (74·5%) on ustekinumab, and in
61 (64·9%) switching from placebo to risankizumab
(table 4). In UltIMMa-1, serious adverse events were
reported in 16 (5·4%) patients on risankizumab,
four (4·0%) on ustekinumab, and three (3·1%) switching
from placebo to risankizumab, and in UltIMMa-2 in
13 (4·5%) patients on risankizumab, four (4·3%) on
ustekinumab, and three (3·2%) switching from placebo
to risankizumab. The most frequently reported adverse
events in part B of either study were viral upper respiratory
tract infection, upper respiratory tract infection, urinary
tract infec­tion, influenza, and headache (appendix).
During part B, serious infections occurred in two (0·7%)
patients each in the risankizumab treatment group of
UltIMMa-1 and UltIMMa-2, and in one (1·0%) patient
each in the placebo-to-risankizumab and ustekinumab
treatment groups of UltIMMa-1.
During part A, there were no events of tuberculosis,
opportunistic infections, adjudicated major adverse
cardiovascular events, or serious hypersensitivity across
both studies (table 3). Through to week 16, malignancy
was reported in two patients on risankizumab (squamous
cell carcinoma in UltIMMa-1; basal cell carcinoma in
UltIMMa-2) and in one patient in the placebo treatment
group (squamous cell carcinoma in UltIMMa-1;
appendix). One patient in the risankizumab treatment
group died of unknown cause on study day 189 (161 days
after the last dose, outside of the treatment-emergent
window of 105 days).
During part B, no events of serious hypersensitivity
were observed across both studies. Two cases of latent
tuberculosis were reported in the risankizumab treatment
group; both patients had a negative QuantiFERON TB
Gold test (Qiagen, Germantown, USA) at baseline. In
part B, no clinically relevant opportunistic infections
were reported. Through to week 52, two patients on
risankizumab had major adverse cardiovascular events,
including one patient with cardiovascular death and one
patient with type 1 myocardial infarction (appendix).
During part B, malignancy was reported in one patient on
continuous risankizumab (basal cell carcinoma in
UltIMMa-2), in one on ustekinumab (prostate cancer
in UltIMMa-2), and in two switching from placebo to
risankizumab (one patient with both basal cell and
squamous cell carcinoma in in UltIMMa-1; one patient
with breast cancer in UltIMMa-2; appendix).
Discussion
Findings from these two phase 3 randomised, double-
blind, controlled clinical studies show that risankizumab
was highly effective in treatment of patients with moderate-

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UltIMMA-1 UltIMMA-2
Risankizumab Ustekinumab Placebo to Risankizumab Ustekinumab Placebo to
(n=297) (n=99) risankizumab (n=97) (n=291) (n=94) risankizumab (n=94)
Any adverse event 182 (61·3%) 66 (66·7%) 65 (67·0%) 162 (55·7%) 70 (74·5%) 61 (64·9%)
Serious adverse events 16 (5·4%) 4 (4·0%) 3 (3·1%) 13 (4·5%) 4 (4·3%) 3 (3·2%)
Severe adverse events 13 (4·4%) 1 (1·0%) 1 (1·0%) 5 (1·7%) 1 (1·1%) 5 (5·3%)
Adverse event leading to drug discontinuation 0 0 0 2 (0·7%) 2 (2·1%) 2 (2·1%)
Infections 112 (37·7%) 41 (41·4%) 34 (35·1%) 101 (34·7%) 46 (48·9%) 34 (36·2%)
Serious infections 2 (0·7%) 1 (1·0%) 1 (1·0%) 2 (0·7%) 0 0
Active tuberculosis 0 0 0 0 0 0
Latent tuberculosis 1 (0·3%)* 0 0 1 (0·3%)† 0 0
Adjudicated major adverse cardiovascular event 0 0 0 2 (0·7%)‡§ 0 0
Malignancies 0 0 1 (1·0%) 1 (0·3%) 1 (1·1%) 1 (1·1%)
Malignancies excluding non-melanoma skin cancer 0 0 0 0 1 (1·1%) 1 (1·1%)
Serious hypersensitivity 0 0 0 0 0 0
Deaths (including non-treatment emergent) 0 0 0 1 (0·3%)‡ 0 0
Any adverse event with grade 3 or grade 4 on Rheumatology Common Toxicity Criteria severity grading was considered severe. *One patient with latent tuberculosis reported on study day 365, treated with
rifampicin. †One patient with seroconversion without evidence of active disease reported during annual TB screening. ‡One patient with sudden cardiac death on study day 385 (101 days after last dose of study
drug; event was not considered to be related to study drug by investigator). §One patient with type 1 myocardial infarction on study day 168 (event was not considered to be related to study drug by investigator).

Table 4: Treatment-emergent adverse events during part B in UltIMMa-1 and UltIMMa-2

to-severe plaque psoriasis. Risankizumab showed superior
efficacy to both placebo and ustekinumab, as evidenced by
the achievement of co-primary endpoints and supported
by all ranked secondary endpoints.
Treatment with risankizumab resulted in rapid onset of
clinical response, which improved with continuous
treatment every 3 months, and was maintained through to
52 weeks. Within 16 weeks, PASI 90 and sPGA 0 or 1
responses were achieved by more patients on risankizumab
than those on ustekinumab. Furthermore, complete
resolution of psoriatic lesions (PASI 100 or sPGA 0) at
week 16 was achieved by more patients on risankizumab
than those on ustekinumab.
In risankizumab-treated patients, PASI and sPGA
response rates continued to increase after week 16,
especially at the highest levels of response. At week 52,
a greater proportion of patients continuing on
risankizumab achieved PASI 90 and sPGA 0 or 1
responses compared with those treated with ustekinumab.
At week 52, a greater proportion of patients continuing
risankizumab maintained PASI 90 response compared
with those treated with ustekinumab. Complete clearance
(PASI 100 or sPGA 0) at week 52 was also achieved by up
to 60% of patients on continuous risankizumab compared
with 21–30% of those on ustekinumab. In patients
switching from placebo to risankizumab at week 16, PASI
and sPGA response rates were comparable to those of
patients on continuous risankizumab by week 52. In
general, every 12-week dosing is considered to be
convenient from patients’ perspectives, but it might be
associated with fluctuations in efficacy between dosing.
Efficacy was better maintained between doses in patients
on risankizumab than in those on ustekinumab. Thus,
the absence of fluctuations in efficacy between dosing in
risankizumab-treated patients confirms the appropriate­
ness of the 12-week dosing interval.
With the emergence of new, improved therapies for
psoriasis, complete and durable skin clearance is inc­
reasingly considered as a treatment target, because of the
impact of residual disease on patients’ quality of life.12,25–28
Skin clearance achieved following risankizumab treat­
ment correlated with improvements in patient-reported
quality of life. By week 16, two thirds of patients on
risankizumab achieved a DLQI response of 0 or 1,
indicative of no impact of psoriasis on quality of life,
compared with 43–46% of patients on ustekinumab;
29–31% of risankizumab-treated patients achieved a PSS
of 0 compared with 15% of those on ustekinumab. At
week 52, DLQI 0 or 1 response rates improved up to 75%
and PSS 0 response rates up to 57%, in patients
continuing on risankizumab compared with 44–47% and
30% in patients on ustekinumab. More than half of
patients on risankizumab reported complete resolution
of itching, pain, burning, and redness by week 52
compared with a third of those on ustekinumab. Itching
is frequently reported as the most burdensome symptom
in psoriasis.5,24
Overall, the safety profiles were similar across
risankizumab, ustekinumab, and placebo treatment
groups. Across both studies, infections were more
frequently reported in patients receiving risankizumab
or ustekinumab compared with those receiving placebo.
Through to week 16 in both studies, no meaningful
differences were observed in the rates of adverse events,
serious adverse events, severe adverse events, and
adverse events leading to discontinuation of study drug
between risankizumab, placebo, and ustekinumab
treatment groups. During the initial 16 weeks of both

10 www.thelancet.com Published online August 7, 2018 http://dx.doi.org/10.1016/S0140-6736(18)31713-6


studies, no adjudicated major adverse cardiovascular
event was reported in any treatment group. Two cases of
non-melanoma skin cancers were reported in the
risankizumab treatment group; one was reported in the
placebo group. One death, after the treatment-emergent
period, in the risankizumab treatment group of
UltIMMa-2 was of an unknown cause.
In both studies, rates of adverse events through to week
52 were similar between continuous risankizumab and
ustekinumab treatment groups. Two major adverse
cardiovascular events were reported in the risankizumab
treatment group of UltIMMa-2, including one patient
with sudden cardiac death. Both patients with major
adverse cardiovascular events had several cardiovascular
risk factors and the events were not considered by the
investigator to be related to the study drug. One patient
had a pre-existing history of myocardial infarction,
hypertension, and smoking. In the other case of major
adverse cardiovascular events, the investigator considered
the patient to be at increased risk of sudden death
because of a history of coronary artery disease,
hypertension, chronic obstructive pulmonary disease,
and obesity. One case of breast cancer was reported in a
patient on placebo switching to risankizumab, and one
case of prostate cancer was reported in the ustekinumab
treatment group.
The chosen placebo-controlled period was sufficient to
meet the study objectives while avoiding long periods
with suboptimal disease control; however, this approach
precluded placebo-controlled assessment of outcomes
for up to 1 year. Since psoriasis is a chronic disease,
further studies are needed to evaluate longer-term
outcomes. Additionally, as has been typical of studies
in moderate-to-severe plaque psoriasis, patients in
both trials were predominantly white and male. Some
strengths of these studies were inclusion of an active
biologic comparator that is used often in the clinic,29 with
sufficient power to allow superiority comparisons with
both placebo and ustekinumab, and inclusion of patients
from several geographical locations permitting gen­
eralisation to a larger population. Although previous
treatment with dual interleukin-12 and interleukin-23
inhibitors (ustekinumab) or interleukin-23 inhibitors
was disallowed, 34–41% of patients had previous
exposure to biologic therapy. Moreover, validation of
efficacy and safety results in two independent replicate
trials provides further confidence in the benefit–risk
profile of risankizumab.
In summary, selective blockade of the p19 subunit of
interleukin-23 with risankizumab was superior to dual
inhibition of interleukin-12 and interleukin-23 by
ustekinumab in providing substantial skin clearance
with a rapid onset and durable maintenance, supporting
the strategy of a more targeted approach. The overall
safety profile of risankizumab was similar to that of the
placebo and ustekinumab treatment groups throughout
the duration of both studies.
www.thelancet.com Published online August 7, 2018 http://dx.doi.org/10.1016/S0140-6736(18)31713-6 11
Articles
Contributors
KBG was coordinating investigator for UltIMMa-1 and HB was
coordinating investigator for UltIMMa-2; both contributed equally to
the conduct of the studies. MF was involved in designing the studies.
KBG, BS, ML, MA, AB, YP, KAP, HS, LP, PF, MO, and HB collected the
data. ZG, YG, JMV, and EHZT did or supervised data analyses. All
authors were involved in the interpretation of the data, preparation and
critical review of the manuscript, and approved the final version of the
manuscript.
Declaration of interests
KBG has received honoraria for serving as a consultant and/or grants as
an investigator from AbbVie, Almirall, Amgen, Boehringer Ingelheim,
Bristol-Myers Squibb, Celgene, Dermira, Eli Lilly, GlaxoSmithKline,
Janssen, Leo Pharma, Novartis, Pfizer, Regeneron, Sanofi-Aventis, Sun,
and UCB. BS has received honoraria as a consultant for AbbVie,
Almirall, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene,
Dermavant, Dermira, Eli Lilly, Galderma, GlaxoSmithKline, Janssen,
Leo Pharma, Medac, Meiji Seika Pharma, Menlo Therapeutics, Merck,
Novartis, Ortho Dermatologics/Valeant, Pfizer, Regeneron,
Sanofi Genzyme, Sebela, Sienna, Sirtris, Sun Pharma, and UCB pharma,
and as scientific director for the CORRONA-NPF Psoriasis Registry. He
is an investigator for AbbVie, Boehringer Ingelheim, Celgene, Eli Lilly,
Galderma, GlaxoSmithKline, Janssen, Merck, Pfizer, and Sienna. ML has
received grants as an investigator from AbbVie, Amgen, Boehringer
Ingelheim, Celgene, Eli Lilly, Janssen Research & Development,
Kadmon, Leo Pharma, Novartis, Pfizer, and ViDac and has received
honoraria for serving as a consultant for Allergan, Aqua, Boehringer
Ingelheim, Leo Pharma, Menlo, and Promius. MA has received
honoraria or fees for serving on advisory boards, as a speaker, and as a
consultant; and grants as an investigator from AbbVie, Amgen, Biogen,
Boehringer Ingelheim, Celgene, Centocor, Hexal, Janssen, Leo Pharma,
Eli Lilly, Medac, Mundipharma, MSD, Novartis, Pfizer, Sandoz, UCB,
and Xenoport. AB has received honoraria or fees for serving on advisory
boards, as a speaker, and as a consultant; and grants as an investigator
from AbbVie, Aclaris, Akros, Allergan, Almirall, Amgen, Boehringer
Ingelheim, Celgene, Dermavant, Dermira, Eli Lilly, Genentech/Roche,
GlaxoSmithKline, Janssen, Leo Pharma, Meiji, Merck Sharp & Dohme,
Novartis, Pfizer, Purdue Pharma, Regeneron, Sandoz, Sanofi Genzyme,
Sienna pharmaceuticals, UCB, Valeant, and Vidac. YP has received
honoraria or fees for serving on advisory boards, as a speaker, and as a
consultant, and grants as an investigator from AbbVie, Amgen, Baxalta,
Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Dermira, Eli Lilly,
Galderma, GlaxoSmithKline, Incyte, Janssen/Centocor, Leo Pharma,
MedImmune, Merck, Novartis, Pfizer, Regeneron, Roche,
Sanofi-Genzyme, Sun Pharma, Takeda, Valeant, and UCB. KAP has
received honoraria or fees for serving on advisory boards, as a speaker,
as a consultant, or as a steering committee member or grants as an
investigator from AbbVie, Akros, Allergan, Amgen, Anacor, Arcutis,
Astellas, AstraZeneca, Baxalta, Baxter, Boehringer Ingelheim,
Bristol-Myers Squibb, CanFite, Celgene, Coherus, Dermira, Eli Lilly,
Forward Pharma, Galderma, Genentech, GlaxoSmithKline, Janssen,
Kyowa-Hakko Kirin, Leo Pharma, MedImmune, Meiji Seika Pharma,
Merck (MSD), Merck-Serono, Mitsubishi Pharma, Novartis, Pfizer,
Regeneron, Roche, Sanofi Genzyme, Takeda, UCB, and Valeant. HS has
received honoraria or fees for serving on advisory boards, as a speaker,
and as a consultant, and grants as an investigator from AbbVie, Amgen,
Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novartis, and Pfizer.
LP has received honoraria or fees for serving on advisory boards, as a
speaker, and as a consultant, and grants as an investigator from AbbVie,
Amgen, Baxalta, Biogen, Boehringer Ingelheim, Eli Lilly, Janssen,
Leo Pharma, Merck-Serono, MSD, Novartis, Pfizer, Regeneron, Roche;
Sandoz, and Sanofi Genzyme. PF has received honoraria and/or
research grants from and/or served as an investigator and/or advisory
board member for AbbVie, Amgen, Boehringer Ingelheim, Bristol-
Myers Squibb, Celgene, Celtaxsys, CSL, Cutanea, Dermira, Galderma,
Genentech, GSK, iNova, Janssen, Leo Pharma, Lilly, Merck, Novartis,
Pfizer, Regeneron Pharmaceuticals, Roche, Sanofi, Sun Pharma, UCB
Pharma, and Valeant. MO has received honoraria or fees for serving on
advisory boards, as a speaker, and as a consultant, and grants as an
investigator from AbbVie, Actelion, Astellas, Bayer, Boehringer
Ingelheim, Bristol-Myers Squibb, Celgene, Eisai, Eli Lilly and Company,
 Articles
Galderma, Janssen, Kaken, Kyowa-Kirin, Leo Pharma, Maruho, Mochida,
Nichi-Iko, Nippon Kayaku, Nippon Zoki, Novartis, Ono, Ohtsuka,
Pola Pharma, Pfizer, Sanofi, Shionogi, Taiho, Tanabe-Mitsubishi, Teijin,
and Torii. MF is a full-time employee of Boehringer Ingelheim. ZG, YG,
and JMV are full-time employees of AbbVie and own stock or options.
EHZT, a former employee of AbbVie, currently owns stock. HB has
received honoraria or fees for serving on advisory boards, as a speaker,
and as a consultant, and grants as an investigator from AbbVie, Almirall,
Amgen, Bayer, Baxalta, Biocad, Boehringer Ingelheim, Celgene,
Dermavant, Eli Lilly, Janssen, Leo Pharma, Menarini, MSD, Novartis,
Pfizer, Pierre Fabre, Sandoz, Sun Pharmaceuticals, and UCB.
Data sharing
These clinical trial data can be requested by any qualified researchers who
engage in rigorous, independent scientific research, and will be provided
following review and approval of a research proposal and statistical
analysis plan and execution of a Data Sharing Agreement. Data requests
can be submitted at any time and the data will be accessible for 12 months,
with possible extensions considered. For more information on the process,
or to submit a request, visit the following link: https://www.abbvie.com/
our-science/clinical-trials/clinical-trials-data-and-information-sharing/data-
and-information-sharing-with-qualified-researchers.html.
Acknowledgments
AbbVie and Boehringer Ingelheim funded the UltIMMa-1
(NCT02684370) and UltIMMa-2 (NCT02684357) studies; Boehringer
Ingelheim contributed to its design and participated in data collection,
AbbVie did the data analysis, and participated in interpretation of the
data, and both funders participated in writing, review, and approval of
the publication. AbbVie, Boehringer Ingelheim, and the authors thank
all study investigators for their contributions and the patients who
participated in these studies. Joseph Scherer of Boehringer Ingelheim
was involved in designing the studies. Statistical support was provided
by Xin Huang and medical writing support was provided by
Deepa Venkitaramani, both from AbbVie.
References
1 Di Meglio P, Villanova F, Nestle FO. Psoriasis.
Cold Spring Harb Perspect Med 2014; 4: a015354.
2 Boehncke W-H, Schön MP. Psoriasis. Lancet 2015; 386: 983–94.
3 Goff KL, Karimkhani C, Boyers LN, et al. The global burden of
psoriatic skin disease. Br J Dermatol 2015; 172: 1665–68.
4 Parisi R, Symmons DP, Griffiths CE, et al. Global epidemiology of
psoriasis: a systematic review of incidence and prevalence.
J Invest Dermatol 2013; 133: 377–85.
5 Lebwohl MG, Bachelez H, Barker J, et al. Patient perspectives in the
management of psoriasis: results from the population-based
Multinational Assessment of Psoriasis and Psoriatic Arthritis
Survey. J Am Acad Dermatol 2014; 70: 871–81.e30.
6 Chandran V, Raychaudhuri SP. Geoepidemiology and environmental
factors of psoriasis and psoriatic arthritis. J Autoimmun 2010;
34: J314–21.
7 Takeshita J, Grewal S, Langan SM, et al. Psoriasis and comorbid
diseases: epidemiology. J Am Acad Dermatol 2017; 76: 377–90.
8 Yeung H, Takeshita J, Mehta NN, et al. Psoriasis severity and the
prevalence of major medical comorbidity: a population-based study.
JAMA Dermatol 2013; 149: 1173–79.
9 de Carvalho AV, Duquia RP, Horta BL, Bonamigo RR. Efficacy of
immunobiologic and small molecule inhibitor drugs for psoriasis:
a systematic review and meta-analysis of randomized clinical trials.
Drugs R D 2017; 17: 29–51.
10 Lebwohl M. Do we need more psoriasis therapies? Lancet 2015;
386: 512–14.
11 Boehncke WH, Brembilla NC. Unmet needs in the field of
psoriasis: pathogenesis and treatment. Clin Rev Allergy Immunol
2017; published online Aug 6. DOI:10.1007/s12016-017-8634-3.
12 www.thelancet.com Published online August 7, 2018 http://dx.doi.org/10.1016/S0140-6736(18)31713-6
12 Puig L, Thom H, Mollon P, Tian H, Ramakrishna GS. Clear or
almost clear skin improves the quality of life in patients with
moderate-to-severe psoriasis: a systematic review and meta-analysis.
J Eur Acad Dermatol Venereol 2017; 31: 213–20.
13 Gaffen SL, Jain R, Garg AV, Cua DJ. The IL-23-IL-17 immune axis:
from mechanisms to therapeutic testing. Nat Rev Immunol 2014;
14: 585–600.
14 Puig L. The role of IL 23 in the treatment of psoriasis.
Expert Rev Clin Immunol 2017; 13: 525–34.
15 Bachelez H. Interleukin 23 inhibitors for psoriasis: not just another
number. Lancet 2017; 390: 208–10.
16 Gooderham MJ, Papp KA, Lynde CW. Shifting the focus—the primary
role of IL-23 in psoriasis and other inflammatory disorders.
J Eur Acad Dermatol Venereol 2018; 32: 1111–19.
17 Leonardi CL, Kimball AB, Papp KA, et al. Efficacy and safety of
ustekinumab, a human interleukin-12/23 monoclonal antibody,
in patients with psoriasis: 76-week results from a randomised,
double-blind, placebo-controlled trial (PHOENIX 1). Lancet 2008;
371: 1665–74.
18 Papp KA, Langley RG, Lebwohl M, et al. Efficacy and safety of
ustekinumab, a human interleukin-12/23 monoclonal antibody,
in patients with psoriasis: 52-week results from a randomised,
double-blind, placebo-controlled trial (PHOENIX 2). Lancet 2008;
371: 1675–84.
19 Blauvelt A, Papp KA, Griffiths CE, et al. Efficacy and safety of
guselkumab, an anti-interleukin-23 monoclonal antibody, compared
with adalimumab for 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 Dermatol 2017; 76: 405–17.
20 Reich K, Papp KA, Blauvelt A, et al. Tildrakizumab versus placebo
or etanercept for chronic plaque psoriasis (reSURFACE 1 and
reSURFACE 2): results from two randomised controlled, phase 3
trials. Lancet 2017; 390: 276–88.
21 Singh S, Kroe-Barrett RR, Canada KA, et al. Selective targeting of
the IL23 pathway: Generation and characterization of a novel
high-affinity humanized anti-IL23A antibody. MAbs 2015;
7: 778–91.
22 Krueger JG, Ferris LK, Menter A, et al. Anti-IL-23A mAb BI 655066
for treatment of moderate-to-severe psoriasis: safety, efficacy,
pharmacokinetics, and biomarker results of a single-rising-dose,
randomized, double-blind, placebo-controlled trial.
J Allergy Clin Immunol 2015; 136: 116–24.e7.
23 Papp KA, Blauvelt A, Bukhalo M, et al. Risankizumab versus
ustekinumab for moderate-to-severe plaque psoriasis. N Engl J Med
2017; 376: 1551–60.
24 Rentz AM, Skalicky AM, Burslem K, et al. The content validity of
the PSS in patients with plaque psoriasis. J Patient Rep Outcomes
2017; 1: 4.
25 Puig L. PASI90 response: the new standard in therapeutic efficacy
for psoriasis. J Eur Acad Dermatol Venereol 2015; 29: 645–48.
26 Strober B, Papp KA, Lebwohl M, et al. Clinical meaningfulness of
complete skin clearance in psoriasis. J Am Acad Dermatol 2016;
75: 77–82.e7.
27 Armstrong AW, Siegel MP, Bagel J, et al. From the Medical Board of
the National Psoriasis Foundation: treatment targets for plaque
psoriasis. J Am Acad Dermatol 2017; 76: 290–98.
28 Gladman DD, Poulin Y, Adams K, et al. Treating psoriasis and
psoriatic arthritis: position paper on applying the treat-to-target
concept to Canadian daily practice. J Rheumatol 2017; 44: 519–34.
29 Sbidian E, Giboin C, Bachelez H, et al. Factors associated with the
choice of the first biologic in psoriasis: real-life analysis from the
Psobioteq cohort. J Eur Acad Dermatol Venereol 2017; 31: 2046–54.