Bimekizumab versus ustekinumab for the treatment of moderate to severe plaque psoriasis (BE VIVID): efficacy and safety from a 52-week, multicentre, double-blind, active comparator and placebo controlled phase 3 trial
Kristian Reich, Kim A Papp, Andrew Blauvelt, Richard G Langley, April Armstrong, Richard B Warren, Kenneth B Gordon, Joseph F Merola, Yukari Okubo, Cynthia Madden, Maggie Wang, Christopher Cioffi, Veerle Vanvoorden, Mark Lebwohl
Summary
Background There is an unmet need for a treatment for psoriasis that results in complete skin clearance with a reliably quick response. Bimekizumab is a monoclonal IgG1 antibody that selectively inhibits interleukin (IL)-17F in addition to IL-17A. We aimed to compare the efficacy and safety of bimekizumab with placebo and ustekinumab in patients with moderate to severe plaque psoriasis over 52 weeks.
Methods BE VIVID was a multicentre, randomised, double-blind, active comparator and placebo controlled phase 3 trial done across 105 sites (clinics, hospitals, research units, and private practices) in 11 countries in Asia, Australia, Europe, and North America. Adults aged 18 years or older with moderate to severe plaque psoriasis (Psoriasis Area and Severity Index [PASI] score ≥12, ≥10% body surface area affected by psoriasis, and Investigator’s Global Assessment [IGA] score ≥3 on a five point scale) were included. Randomisation was stratified by geographical region and previous exposure to biologics; patients, investigators, and sponsors were masked to treatment assignment. Patients were randomly assigned (4:2:1) using an interactive response technology to bimekizumab 320 mg every 4 weeks, ustekinumab 45 mg or 90 mg (baseline weight-dependent dosing) at weeks 0 and 4, then every 12 weeks, or placebo every 4 weeks. At week 16, patients receiving placebo switched to bimekizumab 320 mg every 4 weeks. All study treatments were administered as two subcutaneous injections. Coprimary endpoints were the proportion of patients with 90% improvement in the PASI (PASI90) and the proportion of patients with an IGA response of clear or almost clear (score 0 or 1) at week 16 (non-responder imputation). Efficacy analyses included the intention-to-treat population; safety analysis included patients who received at least one dose of study treatment. This trial was registered at ClinicalTrials.gov, NCT03370133 (completed).
Findings Between Dec 6, 2017, and Dec 13, 2019, 735 patients were screened and 567 were enrolled and randomly assigned (bimekizumab 320 mg every 4 weeks n=321, ustekinumab 45 mg or 90 mg every 12 weeks n=163, placebo n=83). At week 16, 273 (85%) of 321 patients in the bimekizumab group had PASI90 versus 81 (50%) of 163 in the ustekinumab group (risk difference 35 [95% CI 27–43]; p<0·0001) and four (5%) of 83 in the placebo group (risk difference 80 [74–86]; p<0·0001). At week 16, 270 (84%) patients in the bimekizumab group had an IGA response versus 87 (53%) in the ustekinumab group (risk difference 30 [95% CI 22–39]; p<0·0001) and four (5%) in the placebo group (risk difference 79 [73–85]; p<0·0001). Over 52 weeks, serious treatment-emergent adverse events were reported in 24 (6%) of 395 patients in the bimekizumab group (including those who switched from placebo at week 16) and 13 (8%) of 163 in the ustekinumab group.
Interpretation Bimekizumab was more efficacious than ustekinumab and placebo in the treatment of moderate to severe plaque psoriasis. The bimekizumab safety profile was consistent with that observed in previous studies.
Funding UCB Pharma.
Copyright © 2021 Elsevier Ltd. All rights reserved.
Lancet 2021; 397: 487–98
This online publication has been corrected. The corrected version first appeared at thelancet.com on February 18, 2021
See Comment page 446
Center for Translational Research in Inflammatory Skin Diseases, Institute for Health Services Research in Dermatology and Nursing, University Medical Center Hamburg-Eppendorf,
Hamburg, Germany
(Prof K Reich MD); Probity Medical Research and K Papp Clinical Research, Waterloo, ON, Canada (K A Papp MD); Oregon Medical Research Center, Portland, OR, USA
(A Blauvelt MD); Division of Clinical Dermatology and Cutaneous Science, Dalhousie University, Halifax, NS, Canada (Prof R G Langley MD); Keck School of Medicine of USC, Dermatology, Los Angeles, CA, USA (Prof A Armstrong MD); The Dermatology Centre, Salford Royal NHS Foundation Trust, Manchester NIHR Biomedical Research Centre, University of Manchester,
Manchester, UK
(Prof R B Warren MD); Medical College of Wisconsin,
Milwaukee, WI, USA
(Prof K B Gordon MD); Department of Dermatology, Brigham and Women’s Hospital and Harvard Medical School,
Boston, MA, USA
(J F Merola MD); Department of Dermatology, Tokyo Medical University, Tokyo, Japan
Introduction
Plaque psoriasis is a chronic, immune-mediated, inflammatory skin disease with a high disease burden that substantially affects patient quality of life.1,2 Psoriasis might be associated with increased risk of several severe comorbidities, including cardiometabolic diseases, inflammatory bowel disease, malignancies, and depression.3
Multiple approved biologic therapies, including those inhibiting tumour necrosis factor (TNF), interleukin (IL)-12/23, IL-17, and IL-23, are effective treatments for moderate to severe psoriasis.4 However, a proportion of patients in pivotal phase 3 clinical trials and real-world studies do not have rapid and complete skin clearance that is maintained over time.5–9 Research investigating patient satisfaction with psoriasis treatment shows that
(Prof Y Okubo MD); UCB Pharma, Raleigh, NC, USA (C Madden MD, M Wang MS, C Cioffi PhD); UCB Pharma,
Brussels, Belgium
(V Vanvoorden MSc); Icahn School of Medicine, New York, NY, USA (Prof M Lebwohl MD)
Research in context
Evidence before this study classes of biologic agents to better inform benefit–risk decision On May 5, 2020, we searched the Cochrane Database of making in psoriasis disease management.
Systematic Reviews using the terms “psoriasis” or “psoria*” Added value of this study
with no language restrictions and identified 29 reviews on
treatments for plaque psoriasis published before To our knowledge, the BE VIVID study is the first phase 3 active
April 23, 2020. This included a network meta-analysis on comparator and placebo controlled trial comparing a novel dual
systemic pharmacological treatments for chronic plaque IL-17A and IL-17F inhibitor with the IL-12/23 inhibitor psoriasis. This network meta-analysis compared the efficacy ustekinumab for the treatment of moderate to severe plaque and safety of conventional systemic treatments, including psoriasis in adults. In this study, bimekizumab was superior to biologics, across 140 randomised controlled trials. Biologic placebo and ustekinumab, as shown by the significantly higher therapies including those inhibiting interleukin (IL)-12/23, response rates for all coprimary and ranked key secondary
IL-23, tumour necrosis factor (TNF)α, and IL-17 have been endpoints observed from week 4 through to the end of the
shown to be efficacious in the treatment of psoriasis. study at week 52.
The network meta-analysis found that, at 8–24 weeks after Implications of all the available evidence
treatment initiation, all of the anti-IL-17 biologics This study showed that bimekizumab had greater efficacy than (bimekizumab, brodalumab, ixekizumab, and secukinumab) ustekinumab, while maintaining a favourable safety profile. and some anti-IL-23 biologics (guselkumab and risankizumab) This suggests that IL-17A and IL-17F inhibition can provide were significantly more efficacious in reaching an more effective skin clearance than ustekinumab, improvement of 90% or more in Psoriasis Area and Severity an IL-12/23 inhibitor. The findings from this study support the
Index score than the anti-IL-12/23 biologic ustekinumab and rationale and value of dual inhibition of both IL-17A and IL-17F three anti-TNFα drugs (adalimumab, certolizumab pegol, and with bimekizumab. This and previously published studies might etanercept). However, results of the network meta-analysis help inform future clinician decision making in chronic disease highlighted a need for more direct comparisons between management of moderate to severe plaque psoriasis.
Correspondence to: Prof Kristian Reich, Center for Translational Research in Inflammatory Skin Diseases, Institute for Health Services Research in Dermatology and Nursing, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
[email protected]
rapid skin clearance is an important aspect of treatment.10 Consequently, an unmet need remains for a treatment that results in complete skin clearance with a reliably quick response.
IL-17A, along with its family member IL-17F, have been found to have a pivotal role in psoriasis pathogenesis,11 and both are overexpressed in psoriatic lesional skin and signal through the same IL-17RA/RC receptor complexes.11–13 IL-17A and IL-17F share approxi- mately 50% structural similarity and are able to form homodimers and heterodimers, with overlapping pro- inflammatory functions.14 Although IL-17A is more potent than IL-17F, recent data suggest regulation of IL-17A and IL-17F expression are distinct, because IL-17F is more abundantly expressed in lesional skin than IL-17A.15 Several biologic therapies have been developed specifically targeting the IL-17 pathway, including inhibition of IL-17A or its receptor subunit IL-17RA.6–8
Bimekizumab is a monoclonal IgG1 antibody that selectively inhibits IL-17F in addition to IL-17A.13,16 This novel mechanism of action allows for complete inhibition of IL-17A and IL-17F mediated biology through inhibition of IL-17A/A, IL-17A/F, and IL-17F/F isoforms using a single monoclonal antibody. Dual inhibition of IL-17A and IL-17F in human in vitro models led to a greater reduction in the production of pro-inflammatory cytokines, the expression of psoriasis-linked genes, and inflammatory cell migration, compared with inhibition of IL-17A alone.13,17 Previous bimekizumab phase 2 clinical studies have shown both rapid and durable clinical improvements
in skin clearance, with safety findings in line with those expected with the mechanism of action.18,19
We aimed to evaluate the efficacy and safety of bimekizumab in moderate to severe plaque psoriasis over 1 year compared with both placebo (first 16 weeks only) and the active comparator ustekinumab, an IL-12/IL-23 inhibitor and common treatment for plaque psoriasis.20,21 Data from other bimekizumab phase 3 clinical trials are reported elsewhere.22
Methods
Study design
BE VIVID was a multicentre, randomised, double-blind, active comparator and placebo controlled phase 3 trial done across 105 sites (clinics, hospitals, research units, and private practices) in 11 countries (Australia, Belgium, Canada, Germany, Hungary, Italy, Japan, Poland, Russia, the UK, and the USA). This study was done in accordance with the current version of the applicable regulatory and International Conference on Harmonisation Good Clinical Practice requirements, the ethical principles that have their origin in the principles of the Declaration of Helsinki, and the local laws of the countries involved. The study protocol, amendments, and patient written informed con- sent were reviewed by a national, regional, or independent ethics committee, or institutional review board.
Patients
Adults aged 18 years or older with moderate to severe plaque psoriasis (Psoriasis Area and Severity Index
[PASI] score ≥12, ≥10% body surface area affected by psoriasis, and Investigator’s Global Assessment [IGA] score ≥3 on a five point scale) for at least 6 months before screening were enrolled. All patients were can- didates for systemic psoriasis therapy, phototherapy, or both. Patients were excluded if they had previously received bimekizumab, ustekinumab, or both; had had primary failure (no response within the first 12 weeks of treatment) to any anti-IL-17 biologic or to more than one biologic other than an anti-IL-17 treatment; had psoriasis other than chronic plaque-type (eg, pustular, erythrodermic and guttate psoriasis, or drug-induced psoriasis); had a current, or history of, opportunistic, recurrent, or chronic infection; or had active Crohn’s disease or ulcerative colitis. Full details of inclusion and exclusion criteria are listed in the appendix (pp 2–5). Concomitant use of topical medications, such as topical moisturisers, and mild and low potency topical steroids limited to the face, axilla, and genitalia, was permitted provided they were not used 24 h before study visits. Stable doses of non-steroidal anti-inflammatory drugs, or analgesics as needed, were also permitted for psoriatic arthritis or symptoms of arthritis. All participants provided written informed consent.
Randomisation and masking
Patients were randomly assigned (4:2:1) to receive bimekizumab, ustekinumab, or placebo, using an inter- active response technology, which assigned patients on the basis of a predetermined production randomisation or packaging schedule. Randomisation was stratified by geographical region (North America, western Europe, central and eastern Europe, and Asia and Australia) and previous exposure to biologics (yes or no). To maintain double-blinding, ustekinumab-treated patients received placebo to match the bimekizumab dosing regimen (appendix p 6). Throughout the study, patients, investi- gators, and sponsors remained masked to treatment assignment with the exception of specially designated, unmasked site staff responsible for the preparation and administration of study treatments, safety monitoring, or bioanalytical sample analysis.
Procedures
Following a 2–5-week screening period, the 52-week trial consisted of a 16-week placebo and active comparator- controlled initial treatment period and a 36-week active comparator-controlled maintenance treatment period (appendix p 6). During the initial treatment period, patients received either bimekizumab 320 mg every
4 weeks, ustekinumab 45 mg or 90 mg at weeks 0 and 4, then every 12 weeks, or placebo every 4 weeks. Ustekinumab dosing was based on patient bodyweight at baseline (45 mg for patients ≤100 kg or 90 mg for patients
>100 kg) and remained the same throughout the trial. After the initial treatment period, at week 16, patients in the placebo group received bimekizumab 320 mg every
4 weeks up to and including week 52. Patients in the other treatment groups continued to receive their original allocated treatment for the duration of the maintenance treatment period: bimekizumab 320 mg every 4 weeks or ustekinumab 45 mg or 90 mg every 12 weeks.
Bimekizumab was supplied in a 1 mL prefilled syringe at a concentration of 160 mg/mL, ustekinumab was supplied in a 0·5 mL prefilled syringe at a concentration of 45 mg/0·5 mL, and placebo was supplied as a 1 mL prefilled syringe of 0·9% sodium chloride aqueous solution. Study treatments were administered in the clinic as two subcutaneous injections by unmasked site staff not involved in study assessment.
Efficacy and safety assessments were made at baseline, weeks 1, 2, and 4, and then every 4 weeks thereafter up to and including week 52. Data from the Psoriasis Symptoms and Impacts Measure (P-SIM), a 14-item patient-reported outcome measure that assesses the severity of key signs, symptoms, and effects of psoriasis, were collected daily up to and including week 16 on an electronic device to record patient experience of each item within the past 24 h using an 11-point numeric rating scale.23 Dermatology Life Quality Index (DLQI), which assesses quality of life, was measured at baseline, week 1, 2, and 4, every 4 weeks to week 16, and then every 12 weeks thereafter up to and including week 52.
After completion of the 52 weeks, eligible patients could enter the BE BRIGHT (NCT03598790) 144-week, open-label extension study to assess the long-term safety, tolerability, and efficacy of bimekizumab. Those not enrolled on the open-label extension had a safety follow- up visit 20 weeks after the last dose of study treatment.
Outcomes
The coprimary efficacy endpoints were the proportion of patients with an improvement of 90% or more from baseline in PASI (PASI90) and the proportion of patients with an IGA response (score of 0 [clear skin] or 1 [almost clear skin] with at least a two-category improvement from baseline), both at week 16. The secondary effi- cacy endpoints were: the proportion of patients with 100% improvement from baseline in PASI (PASI100, complete skin clearance) at week 16; an IGA score of 0 (with at least a two-category improvement from baseline) at week 16; at least a 75% improvement from baseline in PASI (PASI75) at week 4; scalp IGA response at week 16 in patients with scalp psoriasis at baseline; PASI90 and an IGA response at weeks 12 and 52; and P-SIM responses for pain, itch, and scaling items at week 16. For each of the P-SIM items the response was defined as the proportion of patients with a prespecified point improvement at week 16. The threshold response for pain was 1·98, for itch was 2·39, and for scaling was 2·86, and analysis was limited to the patients with a baseline response at or above the threshold scores. Prespecified exploratory outcomes reported here are
See Online for appendix
Figure 1: Trial profile
*One patient was unable to comply with the upcoming visit schedule, two patients discontinued due to the site closing and the patient being unable to transfer. †Patient withdrew consent from study treatment, not from study procedures.
the proportion of patients reporting a DLQI total score of 0 or 1 from week 16 to week 52; the proportion of patients with PASI100 at week 52; the proportion of patients with PASI75 at week 52; and the proportion of patients with IGA 0 at week 52. Other prespecified exploratory endpoints are listed in the appendix (p 7) and will be reported elsewhere.
Occurrence of treatment-emergent adverse events and serious treatment-emergent adverse events was evaluated. Treatment-emergent adverse events were defined as any adverse events with an onset on or after the first dose of study treatment and up to 140 days after the final dose. Serious treatment-emergent adverse events were defined as meeting at least one of the following criteria: death; life- threatening; clinically significant or persistent disability or incapacity; congenital anomaly or birth defect; an impor- tant medical event that might jeopardise the patient and require medical or surgical intervention; and initial
inpatient hospitalisation or prolongation of hospitalisation. Treatment-emergent adverse events and serious treatment- emergent adverse events were coded according to the Medical Dictionary for Regulatory Activities version 19.0. Prespecified areas of safety interest included: infections (serious infectious events, opportunistic infections, fungal infections, and tuberculosis); neutropenia; hypersen- sitivity; suicidal ideation and behaviour; depression; major adverse cardiovascular events (defined as cardiovascular death, non-fatal myocardial infarction, and stroke); hepatic events; malignancies; and inflammatory bowel diseases. Suicidal ideation and behaviour events and major adverse cardiovascular events were adjudicated by an external committee.
Statistical analysis
The primary objective was to show statistical superiority of bimekizumab compared with placebo for PASI90 and
Placebo (n=83) Bimekizumab 320 mg every
4 weeks (n=321) Ustekinumab (n=163) All patients* (n=567)
Age, years 49·7 (13·6) 45·2 (14·0) 46·0 (13·6) 46·1 (13·9)
Sex
Male 60 (72%) 229 (71%) 117 (72%) 406 (72%)
Female 23 (28%) 92 (29%) 46 (28%) 161 (28%)
Bodyweight, kg 89·1 (26·4) 88·7 (23·1) 87·2 (21·1) 88·4 (23·0)
Body-mass index, kg/m² 30·0 (7·6) 29·6 (7·0) 29·4 (6·4) 29·6 (6·9)
Race or ethnicity
White 63 (76%) 237 (74%) 120 (74%) 420 (74%)
American Indian or Alaskan 0
native 1 (<1%) 1 (1%) 2 (<1%)
Asian 20 (24%) 71 (22%) 36 (22%) 127 (22%)
Black 0 9 (3%) 3 (2%) 12 (2%)
Native Hawaiian or other 0 0 0 0
IGA response at week 16. Based on data from previous trials evaluating bimekizumab and ustekinumab in patients with psoriasis,18,24 assumed responder rates for PASI90 at week 16 were 75% for bimekizumab, 58% for ustekinumab, and 2% for placebo; assumed responder rates for an IGA response at week 16 were 85% for bimekizumab, 68% for ustekinumab, and 5% for placebo. Using these assumptions, it was determined that power provided by a sample size of 560 (320 bimekizumab; 160 ustekinumab; 80 placebo) to show statistical superi- ority of bimekizumab relative to placebo for the coprimary endpoints was more than 99%. The power to detect a statistically significant difference between bimekizumab and ustekinumab at a two-sided significance level of 0·05 is 95% for PASI90 response and 98% for an IGA response. For the assessment of non-inferiority, a non-inferiority
margin of 10% was used because this represented the Pacific Islander
largest loss of effect relative to the comparator that was Other or mixed race 0 3 (1%) 3 (2%) 6 (1%)
considered to be clinically acceptable.25 Region
Efficacy analyses included all randomly assigned Asia or Australia 18 (22%) 69 (22%) 35 (22%) 122 (22%)
patients (intention-to-treat population). Safety analyses Central or eastern Europe 27 (33%) 108 (34%) 54 (33%) 189 (33%)
included all patients who received at least one dose of North America 26 (31%) 100 (31%) 51 (31%) 177 (31%)
study treatment. Multiplicity and type I errors were controlled for the coprimary and ranked secondary efficacy endpoints by using a sequential testing procedure approach. The evaluation of statistical significance for each comparison in the sequence was dependent on the previous comparison reaching a statistical significance with a two-sided α level of 0·05. The testing hierarchy is detailed in the appendix (p 8). The testing sequence was designed such that both coprimary efficacy endpoints needed to be significant at a two-sided α level of 0·05 for the testing procedure to proceed. For coprimary and secondary efficacy endpoints, comparisons between treatment groups were done using the stratified Cochran-Mantel-Haenszel test, using geographical region and previous biologic exposure as stratification variables. Preplanned sensitivity analyses (including on the full analysis set and per-protocol set) were done to support the robustness of the main analysis of the coprimary endpoints. For the binary variables reported here, non-responder imputation was used to account for missing data. All analyses were done using SAS version 9·3. This trial is registered with ClinicalTrials.gov, NCT03370133.
Role of the funding source
The funder contributed to study design, participated in data collection, completed the data analysis, and partici- pated in data interpretation. The funder participated in writing, review, and approval of the report. A medical writing agency employed by the funder assisted with manuscript preparation under the authors’ direction.
Results
Between Dec 6, 2017, and Dec 13, 2019, 735 patients were screened and 567 were randomly assigned to receive
Western Europe
Baseline disease characteristics Disease duration, years
PASI score 12 (15%)
19·7 (13·8)
20·1 (6·8) 44 (14%)
16·0 (11·6)
22·0 (8·6) 23 (14%)
17·8 (11·6)
21·3 (8·3) 79 (14%)
17·1 (12·0)
21·5 (8·3)
IGA score
3 (moderate) 54 (65%) 201 (63%) 96 (59%) 351 (62%)
4 (severe) 28 (34%) 119 (37%) 66 (41%) 213 (38%)
BSA 27·0% (16·3) 29·0% (17·1) 27·3% (16·7) 28·2% (16·9)
DLQI score 10·0 (6·8) 9·9 (6·3) 11·0 (6·9) 10·2 (6·6)
Previous biologic therapy 33 (40%) 125 (39%) 63 (39%) 221 (39%)
Anti-TNF 16 (19%) 51 (16%) 24 (15%) 91 (16%)
Anti-IL-17 18 (22%) 76 (24%) 38 (23%) 132 (23%)
Anti-IL-23 5 (6%) 16 (5%) 6 (4%) 27 (5%)
Previous systemic therapy 64 (77%) 267 (83%) 132 (81%) 463 (82%)
either bimekizumab 320 mg every 4 weeks (n=321), ustekinumab 45 mg or 90 mg every 12 weeks (n=163), or placebo (n=83; figure 1). Discontinuation rates were low in all treatment groups: 537 (95%) patients completed the trial to week 16, and of those, 493 (92%) completed the trial to week 52 (figure 1). Important protocol deviations that could have affected study conduct or primary efficacy and key safety outcomes were reported in 17 (3%) patients and were similar in all treatment groups (appendix p 9).
Demographics and baseline disease characteristics were similar across all treatment groups and consistent with the wider population with moderate to severe psoriasis (table 1).
Proportion of patients with PASI100 (%)
Proportion of patients with PASI90 (%)
Proportion of patients with an IGA score of 0 (%)
Proportion of patients with IGA response (%)
Proportion of patients with a DLQI score of 0 or 1 (%)
Figure 2: Week 16 responses for the non-responder imputation
(A) PASI90 response at week 16. (B) IGA response at week 16. (C) PASI100 response at week 16. (D) IGA score of 0 at week 16. (E) DLQI score of 0 or 1 at week 16. DLQI=Dermatology Life Quality Index. IGA=Investigator’s Global Assessment. IGA response=Investigator’s Global Assessment score of 0 or 1 with at least a two-category improvement relative to baseline. PASI90=at least a 90% improvement from baseline in Psoriasis Area and Severity Index. PASI100=100% improvement from baseline in Psoriasis Area and Severity Index. *p value considered nominal and not controlled for multiplicity. p values for the comparison of treatment groups were based on the Cochran-Mantel-Haenszel test from the general association. Proportions were calculated using
non-responder imputation.
A greater proportion of patients receiving bimekizumab than those receiving ustekinumab and placebo had PASI90 and an IGA response at week 16. 273 (85%) of 321 patients in the bimekizumab treatment group had PASI90 at week 16, compared with 81 (50%) of 163 in the
ustekinumab group (risk difference 35 [95% CI 27–43]; p<0·0001), and four (5%) of 83 in the placebo group (risk difference 80 [74–86]; p<0·0001; figure 2A; table 2).
270 (84%) of 321 patients receiving bimekizumab had an IGA response at week 16, compared with 87 (53%) of 163 receiving ustekinumab (risk difference 30 [95% CI 22–39]; p<0·0001) and four (5%) of 83 receiving placebo (risk difference 79 [73–85]; p<0·0001; figure 2B; table 2). Sensitivity analyses were supportive of these results (appendix p 10).
Significantly more patients receiving bimekizumab had complete skin clearance (PASI100) at week 16 than patients receiving ustekinumab (nominal p<0·0001) or placebo (p<0·0001; figure 2C; table 2). Likewise, significantly more patients receiving bimekizumab had an IGA score of 0 at week 16 than patients in the ustekinumab group (nominal p<0·0001) or the placebo group (p<0·0001; figure 2D; table 2). At week 16, significantly more patients in the bimekizumab group with a scalp IGA score at baseline of 2 or more had a scalp IGA response than patients in the ustekinumab group (nominal p=0·0004) or the placebo group (p<0·0001; table 2).
The response with bimekizumab was greater and more rapid than with ustekinumab or placebo as early as week 4, after only one dose of bimekizumab. At week 4, significantly more patients treated with bimekizumab had PASI75 than patients treated with ustekinumab or placebo (p<0·0001 for both comparisons; figure 3A; table 2).
Responses were maintained up to and including week 52 with bimekizumab treatment. At week 52, a higher proportion of patients receiving bimekizumab had PASI90 than patients receiving ustekinumab (p<0·0001; figure 3B; table 2), and more patients had an IGA response in the bimekizumab group than in the ustekinumab group (p<0·0001; figure 3D; table 2). At week 52, 207 (65%) of 321 patients in the bimekizumab group had PASI100 compared with 62 (38%) of 163 in the ustekinumab group (nominal p<0·0001; figure 3C). PASI75 and IGA 0 also remained high in patients originally assigned to bimekizumab (figure 3A, E).
Patients who switched from placebo to bimekizumab at week 16 showed rapid improvement after receiving bimekizumab and had responses in all efficacy outcomes at week 52 that were similar to patients initially assigned to receive bimekizumab (figure 3).
Patients treated with bimekizumab had greater improvements in patient-reported outcomes measuring core psoriasis symptoms and effect of psoriasis on quality of life compared with patients in both the placebo and ustekinumab groups. Patients assigned to
Placebo (n=83) Bimekizumab 320 mg every Ustekinumab (n=163) Odds ratio vs
placebo (95% CI) Odds ratio vs
ustekinumab Risk difference
vs placebo Risk difference vs
ustekinumab
4 weeks (n=321) (95% CI) (95% CI) (95% CI)
PASI90 at week 16 4 (5%) 273 (85%) 81 (50%) 99·9 (34·0–293·2)* 6·1 (3·9–9·5)* 80 (74–86) 35 (27–43)
IGA response at week 16 4 (5%) 270 (84%) 87 (53%) 118·8 (36·7–384·3)* 4·8 (3·1–7·5)* 79 (73–85) 30 (22–39)
PASI100 at week 16 0 188 (59%) 34 (21%) 25·6 (9·1–72·3)* 5·7 (3·6–8·9)† 59 (53–64) 38 (30–46)
IGA 0 at week 16 0 188 (59%) 36 (22%) 25·5 (9·0–71·9)* 5·2 (3·4–8·1)† 59 (53–64) 37 (29–45)
PASI90 at week 12 2 (2%) 273 (85%) 71 (44%) 272·2 (58·3–1269·9)† 8·0 (5·1–12·7)* 83 (78–88) 41 (33–49)
IGA response at week 12 4 (5%) 263 (82%) 85 (52%) 79·7 (28·4–223·9)† 4·4 (2·9–6·7)* 77 (71–83) 30 (22–38)
PASI75 at week 4 2 (2%) 247 (77%) 25 (15%) 123·0 (29·4–514·9)* 18·2 (11·0–30·1)* 74 (69–80) 62 (55–69)
P-SIM pain response at week 16‡ 9/54 (17%) 177/229 (77%) 73/107 (68%) 16·3 (7·4–35·9)* 1·6 (1·0–2·7) 61 (50–72) 10 (0–19)
P-SIM itch response at week 16‡ 8/61 (13%) 187/244 (77%) 77/117 (66%) 22·3 (9·8–50·7)* 1·7 (1·0–2·7)§ 64 (54–74) 11 (1–20)
P-SIM scaling response at week 16‡ 8/63 (13%) 193/246 (79%) 69/116 (60%) 23·0 (10·2–52·1)* 2·4 (1·5–3·9)† 66 (57–76) 19 (10–29)
Scalp IGA response at week 16¶ 11/72 (15%) 240/285 (84%) 103/146 (71%) 37·7 (16·9–84·0)* 2·4 (1·5–3·9)|| 70 (61–79) 14 (6–22)
PASI90 at week 52 NA 263 (82%) 91 (56%) NA 3·8 (2·4–5·9)* NA 26 (17–34)
IGA response at week 52 NA 251 (78%) 99 (61%) NA 2·4 (1·6–3·7)* NA 17 (9–26)
bimekizumab reported higher P-SIM responses based on pain, itch, and scaling item score improvement thresholds than those receiving placebo at week 16 (p<0·0001 for all comparisons; table 2). At week 16,
216 (67%) of 321 patients receiving bimekizumab reported a DLQI score of 0 or 1 compared with 69 (42%) of 163 receiving ustekinumab and ten (12%) of 83 receiving placebo (nominal p<0·0001 for both comparisons; figure 2E). The proportion of patients in the bimekizumab group reporting a DLQI score of 0 or 1 continued to increase and was maintained up to and including week 52 (figure 3F). The proportion of patients reporting a DLQI score of 0 or 1 showed a rapid increase up to and including week 52 after switching from placebo to bimekizumab and these patients had similar improve- ments to those who were randomly allocated to receive bimekizumab (figure 3F).
The frequency of treatment-emergent adverse events was similar across all treatment groups during the initial 16-week treatment period; discontinuations due to treatment-emergent adverse events in patients treated with bimekizumab and patients treated with uste- kinumab were lower than in patients treated with placebo (table 3). In weeks 0–16, treatment-emergent adverse events occurred in 181 (56%) patients receiving bimekizumab, 83 (51%) patients receiving ustekinumab, and 39 (47%) patients receiving placebo. Serious treatment-emergent adverse events were reported in five (2%) patients receiving bimekizumab, five (3%) patients receiving ustekinumab, and two (2%) patients receiving placebo (table 3). Throughout the duration of the study (weeks 0–52), 323 (82%) of 395 patients who
received at least one dose of bimekizumab (including patients who switched from placebo at week 16) and 130 (80%) of 163 patients who received at least one dose of ustekinumab had treatment-emergent adverse events. Serious treatment-emergent adverse events occurred in 24 (6%) patients receiving bimekizumab and 13 (8%) patients receiving ustekinumab (table 3).
Overall, four deaths occurred (three during the initial treatment period and one during the safety follow-up period; table 3). All were assessed by the investigator as unrelated to the study treatment. During the initial period, one patient receiving placebo had a fatal oesophageal adenocarcinoma; one patient receiving ustekinumab had a traumatic heart injury (penetrating cardiac trauma), followed by fatal cardiac arrest 7 days later; and one patient receiving bimekizumab had a fatal cardiac arrest. The one death during the safety follow-up was in a patient receiving bimekizumab who died from unknown causes 3 months after the last dose.
The most common treatment-emergent adverse events in bimekizumab-treated patients throughout the study were nasopharyngitis, oral candidiasis, and upper respiratory tract infection (table 3). Of the 60 (15%) patients receiving bimekizumab who reported oral candidiasis in weeks 0–52, one case was severe; all others were mild or moderate. Three patients had oral candidiasis leading to discontinuation.
Up to and including week 52, serious infectious events occurred in five (1%) patients receiving bimekizumab and four (3%) patients receiving ustekinumab (table 3). No clinically relevant opportunistic infections were reported. There were no cases of active tuberculosis
Proportion of patients with an IGA score of 0 (%)
Proportion of patients with a DLQI score of 0 or 1 (%)
Figure 3: Responses up to and including week 52 for the non-responder imputation
PASI75 response to week 52. (B) PASI90 response to week 52. (C) PASI100 response to week 52. (D) IGA response to week 52. (E) IGA score of 0 to week 52.
(F) DLQI score of 0 or 1 to week 52. At week 16, 74 of 83 patients receiving placebo continued in the study and switched to bimekizumab 320 mg every 4 weeks. DLQI=Dermatology Life Quality Index. IGA=Investigator’s Global Assessment. IGA response=Investigator’s Global Assessment score of 0 or 1 with at least a two-category improvement relative to baseline. PASI75=at least a 75% improvement from baseline in Psoriasis Area and Severity Index. PASI90=at least a 90% improvement from baseline in Psoriasis Area and Severity Index. PASI100=100% improvement from baseline in Psoriasis Area and Severity Index. *Nominal p<0·0001 versus placebo.
†Nominal p<0·0001 versus ustekinumab. ‡p<0·0001 versus placebo. §p<0·0001 versus ustekinumab. ¶Nominal p=0·0018 versus placebo. ||Nominal p=0·0016 versus placebo. **Nominal p=0·0074 versus ustekinumab. Nominal p values are not controlled for multiplicity.
Proportion of patients with PASI100 (%)
Proportion of patients with PASI75 (%)
Proportion of patients with IGA response (%)
Proportion of patients with PASI90 (%)
among patients treated with bimekizumab. There was one new case of inflammatory bowel disease (ulcera- tive colitis) in a patient receiving bimekizumab that occurred during the initial treatment period, 88 days after the first bimekizumab dose (table 3). There were two cases of adjudicated suicidal ideation and behaviour throughout the study: one was in a patient receiving
bimekizumab, the other patient was in the ustekinumab group; neither was a completed suicide. Five patients receiving bimekizumab had an adjudicated major adverse cardiovascular event, all of whom had two or more pre-existing cardiovascular risk factors. One fatal cardiac arrest occurred during the initial treatment period (as described already). All other major adverse
Placebo (n=83) Bimekizumab 320 mg every
4 weeks (n=321) Ustekinumab (n=163) Bimekizumab 320 mg every
4 weeks* (n=395) Ustekinumab (n=163)
Any treatment emergent adverse event 39 (47%) 181 (56%) 83 (51%) 323 (82%) 130 (80%)
Serious treatment emergent adverse events 2 (2%) 5 (2%) 5 (3%) 24 (6%) 13 (8%)
Discontinuation due to treatment emergent adverse events 6 (7%) 6 (2%) 3 (2%) 21 (5%) 7 (4%)
Severe treatment emergent adverse events 3 (4%) 5 (2%) 3 (2%) 21 (5%) 9 (6%)
Deaths 1 (1%) 1 (<1%) 1 (1%) 2 (1%) 1 (1%)
Most common treatment emergent adverse events
Nasopharyngitis 7 (8%) 30 (9%) 14 (9%) 86 (22%) 36 (22%)
Oral candidiasis 0 28 (9%) 0 60 (15%) 1 (1%)
Upper respiratory tract infection 2 (2%) 9 (3%) 5 (3%) 36 (9%) 18 (11%)
Treatment emergent adverse events of interest
Serious infections 0 0 2 (1%) 5 (1%) 4 (3%)
Active tuberculosis 0 0 0 0 0
Latent tuberculosis 0 0 0 0 0
Inflammatory bowel disease 0 1 (<1%)† 0 1 (<1%) 0
Adjudicated suicidal ideation and behaviour 0 0 0 1 (<1%) 1 (1%)
Malignancies 1 (1%)‡ 0 0 1 (<1%)§ 1 (1%)¶
Non-melanoma skin cancer 0 0 0 0 1 (1%)¶
Serious hypersensitivity reactions 0 0 0 0 0
Adjudicated major adverse cardiovascular events 0 1 (<1%) 0 5 (1%) 0
Hepatic events|| 1 (1%) 4 (1%) 0 10 (3%) 4 (3%)
cardiovascular events (one acute myocardial infarction, one cerebral infarction, and two myocardial infarctions) occurred during the maintenance period and resolved (table 3). None of these events led to treatment discon- tinuation, although one patient later discontinued due to gastric cancer. Malignancies were reported in one patient receiving bimekizumab (gastric cancer) and in one patient receiving ustekinumab (basal cell carcinoma), both during the maintenance period; one patient receiving placebo had a fatal oesophageal carcinoma in the initial treatment period (table 3). Across all treatment groups, there were no serious hypersensitivity reactions. In the initial treatment period, one (1%) patient in the placebo treatment group reported hepatic events. Throughout the study, a total of ten (3%) patients treated with bimekizumab and four (3%) treated with uste- kinumab reported hepatic events. The majority of these were elevated liver function tests, which were transient and resolved by the end of the study without dose adjustment.
Discussion
In this multicentre, randomised, double-blind, active comparator and placebo controlled phase 3 trial, bimekizumab was efficacious at treating patients with
moderate to severe plaque psoriasis. Bimekizumab showed greater efficacy than both ustekinumab and placebo in the coprimary endpoints (PASI90 and an IGA response at week 16). These results were further supported by bimekizumab meeting all prespecified secondary endpoints.
Faster onset of clinically meaningful responses was observed with bimekizumab compared with both ustekinumab and placebo, with responses observed at week 4 (after one dose), as expected from the rapid responses to bimekizumab reported in previous studies.16,18 Furthermore, although direct comparisons cannot be made between clinical trials due to differences in trial design, these results suggest bimekizumab might have a faster onset of treatment response than that reported with current IL-17A inhibitors, such as ixekizumab and secukinumab based on published results.6,7 This is of relevance because speed of treatment response has been found to be of high importance to patients and remains an unmet need.10
In our study, 59% of patients treated with bimekizumab had complete skin clearance (PASI100) at week 16, and this response was maintained to study completion, with 65% of patients treated with bimekizumab having complete skin clearance at week 52, both significantly
more than patients treated with ustekinumab. A conservative non-response imputation method was used for missing data. Therapies targeting IL-17A alone have reported lower proportions of patients with skin clearance at both week 16 and at study completion than we found with bimekizumab.5,7 This is relevant, because durability of initial response and complete skin clearance are crucial in the management of chronic psoriasis because patients often lose treatment response over time and switch therapies to maintain high levels of skin clearance.9
Clinical improvements in skin clearance have been found to correlate with improvements in patient-reported quality of life.26 A DLQI total score of 0 or 1 (ie, no effect of psoriasis on quality of life) was reported by a higher proportion of patients receiving bimekizumab than ustekinumab at week 16 and, importantly, at week 52. A larger proportion of bimekizumab-treated patients also had improvements on the pain, itch, and scaling items of the P-SIM at week 16 compared with placebo-treated patients.
Over 52 weeks, the occurrence of most common treatment-emergent adverse events was similar between bimekizumab and ustekinumab, except for oral candidiasis. The IL-17 pathway has a role in controlling non-systemic fungal infections, particularly Candida at the oral mucosa, so it was expected that oral candidiasis would be more common in bimekizumab-treated patients than in those treated with ustekinumab.6,8,27 The incidence of oral candidiasis infections was similar to those reported in earlier bimekizumab trials, which report higher incidence of this infection than those observed with other IL-17 inhibitors.6,7,13,16,18,19 This might be due to the mechanism of action of bimekizumab, because targeting IL-17F in addition to IL-17A might lead to greater inhibition of the IL-17 pathway, increasing the risk of oral candidiasis; additional studies are needed to confirm this.27 The vast majority of oral candidiasis cases in our study were mild or moderate. One severe case was reported, which did not lead to discontinuation and resolved with treatment. Of the 60 cases of oral candidiasis, three led to discontinuation.
There were five major adverse cardiovascular events in the bimekizumab treatment group, including one fatal cardiac arrest. All patients who had a major adverse cardiovascular event had several pre-existing cardiovas- cular risk factors and no events were assessed as treatment related. Long-term safety assessments from the bimekizumab phase 3 programme, which includes four placebo or active comparator controlled studies and one open-label extension study,22 will help to better characterise safety.
Additional head-to-head comparator studies of bimekizumab and anti-IL-17A (BE RADIANT: NCT03536884) and anti-TNFα (BE SURE: NCT03412747)
treatments will further explore bimekizumab’s novel dual mechanism of IL-17A and IL-17F inhibition and examine whether the rapid and high level of complete
response observed here can be maintained with an every 8 week bimekizumab maintenance dosing schedule.
This study is limited in both its length and the diversity of patients included; this might reduce the generalisability of these findings to both longer-term treatment with bimekizumab and to patients with psoriasis and additional comorbidities. Because psoriasis is a chronic disease, the longer-term efficacy and safety of bimekizumab will be important to allow patients and clinicians to make informed treatment decisions. An open-label extension (BE BRIGHT: NCT03598790) is ongoing and recruiting patients from this study and others in the bimekizumab for psoriasis programme. Previously, new onset inflam- matory bowel disease has been reported with the use of anti-IL-17 treatments;28,29 however, it is unclear as to what extent this is attributed to treatment or to the underlying disease. In this study, the incidence of new onset inflammatory bowel disease over 52 weeks was low, with a single case of ulcerative colitis. Final conclusions await further study and longer-term treatment with bimekizumab. Furthermore, the most common comorb- idity observed in patients with psoriasis is psoriatic arthritis; although this study did not include joint-related clinical or quality of life efficacy outcomes, clinical trials assessing bimekizumab for the treatment of psoriatic arthritis are ongoing.30
In summary, this phase 3 trial showed that inhibition of IL-17F in addition to IL-17A with bimekizumab led to higher proportions of patients with a clinical response compared with ustekinumab, a commonly prescribed IL-12/23 inhibitor. Clinically meaningful responses and improvements in patient-reported quality of life were rapid in onset and durable up to and including week 52, providing strong evidence that bimekizumab could offer an additional treatment option for patients with moderate to severe psoriasis. Incidence of oral candidiasis was increased with bimekizumab treatment; however, these cases were largely mild or moderate with low discon- tinuation rates. Bimekizumab was well tolerated and safety findings in this study were consistent with the known mechanism of action of bimekizumab and the patient population.13,16,18,19,22
Contributors
KR, KAP, AB, RGL, AA, RBW, KBG, JFM, YO, CM, MW, CC, VV, and ML
made substantial contributions to study conception and design, analysis and interpretation of the data, drafting the Article or revising it critically for important intellectual content, and final approval of the version of the Article to be published. KR, CM, MW, CC, and VV accessed and verified the data. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication.
Declaration of interests
KR has been an adviser for AbbVie, Affivody, Almirall, Amgen, Biogen- Idec, Boehringer Ingelheim, Celgene, Covagen, Eli Lilly, Forward Pharma, Galderma, GSK, Janssen-Cilag, Kyowa Kirin, LEO Pharma, Medac, MSD, Novartis, Ocean Pharma, Pfizer, Samsung Bioepis, Sanofi, Sun Pharma, Takeda, UCB Pharma, and Xenoport; has been a paid speaker for AbbVie, Almirall, Biogen-Idec, Celgene, Eli Lilly, Janssen- Cilag, LEO Pharma, Medac, MSD, Novartis, Sanofi, and Valeant; and has participated in clinical trials sponsored by AbbVie, Affibody, Almirall,
Biogen-Idec, Boehringer Ingelheim, Celgene, Covagen, Eli Lilly, Forward Pharma, Fresenius Medical Care, Galapagos, Galderma, Janssen-Cilag, Kyowa Kirin, LEO Pharma, Medac, MSD, Miltenyl, Novartis, Ocean Pharma, Pfizer, Sanofi, Sun Pharma, Takeda, UCB Pharma, and XBiotech, all outside of the submitted work. KAP has been a consultant for AbbVie, Akros, Amgen, Arcutis, Astellas, Bausch Health/Valeant, Baxalta, Boehringer Ingelheim, Bristol Myers Squibb (BMS), Can-Fite Biopharma, Celgene, Coherus, Dermira, Dice Pharmaceuticals,
Dow Pharma, Eli Lilly, Evelo, Galapagos, Galderma, Genentech, Janssen, Kyowa Hakko Kirin, LEO Pharma, Meiji Seika Pharma, MSD,
Merck-Serono, Mitsubishi Pharma, Novartis, Pfizer, PRCL Research, Regeneron, Roche, Sanofi-Aventis/Genzyme, Takeda, and UCB Pharma; has been on speakers’ bureau for AbbVie, Amgen, Bausch Health/ Valeant, Celgene, Eli Lilly, Galderma, Janssen, Kyowa Hakko Kirin,
LEO Pharma, MSD, Novartis, Pfizer, and Sanofi-Aventis/Genzyme; has received clinical research grants from AbbVie, Akros, Amgen, Anacor, Arcutis, Astellas, Bausch Health/Valeant, Baxalta, Boehringer Ingelheim, BMS, Can-Fite Biopharma, Celgene, Coherus, Dermira,
Dow Pharma, Eli Lilly, Evelo, Galapagos, Galderma, Genentech, Gilead, GSK, Janssen, Kyowa Hakko Kirin, LEO Pharma, Medimmune, MSD, Merck-Serono, Moberg Pharma, Novartis, Pfizer, PRCL Research, Regeneron, Roche, Sanofi-Aventis/Genzyme, Sun Pharma, Takeda,
and UCB Pharma; has received honoraria from AbbVie, Akros, Amgen, Bausch Health/Valeant, Boehringer Ingelheim, Celgene, Coherus,
Eli Lilly, Galderma, Janssen, Kyowa Hakko Kirin, MSD, Merck-Serono, Mitsubishi Pharma, Novartis, Pfizer, PRCL Research, Sanofi-Aventis/ Genzyme, Takeda, and UCB Pharma; has been a scientific officer for Akros, Anacor, Arcutis, Dice Pharmaceuticals, and Kyowa Hakko Kirin; has been on steering committees for AbbVie, Amgen, Bausch Health/ Valeant, Boehringer Ingelheim, Celgene, Eli Lilly, Janssen, Kyowa Hakko Kirin, MSD, Merck-Serono, Novartis, Pfizer, Regeneron, and Sanofi- Aventis/Genzyme; and has been on advisory boards for AbbVie, Amgen, Astellas, Bausch Health/Valeant, Boehringer Ingelheim, BMS, Celgene, Dow Pharma, Eli Lilly, Galderma, Janssen, MSD, Novartis, Pfizer, Regeneron, Sanofi-Aventis/Genzyme, Sun Pharma, and UCB Pharma, all outside of the submitted work. AB has served as a scientific adviser for AbbVie, Almirall, Arena, Athenex, Boehringer Ingelheim, BMS, Dermavant, Eli Lilly, Evommune, Forte, Galderma, Incyte, Janssen,
LEO Pharma, Novartis, Pfizer, Rapt, Regeneron, Sanofi Genzyme, Sun Pharma, and UCB Pharma; and has been a clinical study investigator for AbbVie, Athenex, Boehringer Ingelheim, BMS,
Dermavent, Eli Lilly, Galderma, Incyte, Janssen, LEO Pharma, Novartis, Pfizer, Regeneron, Sun Pharma, and UCB Pharma, all outside of the submitted work. RGL has been a principal investigator for AbbVie, Amgen, Boehringer Ingelheim, Celgene, Eli Lilly, LEO Pharma, Merck, Novartis, Pfizer, and UCB Pharma; has served on scientific advisory boards for AbbVie, Amgen, Boehringer Ingelheim, Celgene, Eli Lilly, LEO Pharma, Merck, Novartis, Pfizer, and UCB Pharma; and has provided lectures for AbbVie, Amgen, Celgene, LEO Pharma, Merck, Novartis, and Pfizer, all outside the submitted work. AA has been a data safety monitoring board member for Boehringer Ingelheim/Parexel; has received research funding from BMS, Dermavent, Dermira, Eli Lilly, Galderma, Janssen, Kyowa Hakko Kirin, LEO Pharma, Pfizer, and
UCB Pharma; has been a research investigator without compensation for Sanofi Genzyme; has been a scientific investigator for AbbVie, BMS, Dermavent, Eli Lilly, Janssen, LEO Pharma, Modernizing Medicine, Novartis, Ortho Dermatologics, Pfizer, Regeneron, Sanofi Genzyme, and Sun Pharma; and has been a speaker for AbbVie, Regeneron, and Sanofi Genzyme, all outside of the submitted work. RBW has received consulting fees from AbbVie, Almirall, Amgen, Arena, Avillion, BMS, Boehringer Ingelheim, Celgene, Eli Lilly, Janssen, LEO Pharma, Novartis, Pfizer, Sanofi, and UCB Pharma; and has received research grants to his institution from AbbVie, Almirall, Janssen, LEO Pharma, Novartis, and UCB Pharma, all outside of the submitted work. KBG has received consulting fees from AbbVie, Almirall, Amgen, Boehringer Ingelheim, BMS, Celgene, Dermira, Eli Lilly, Janssen, Novartis, Pfizer, Sun Pharma, and UCB Pharma; and has received research support from AbbVie, BMS, Celgene, Eli Lilly, Janssen, Novartis, and UCB Pharma,
all outside of the submitted work. JFM has been a consultant for AbbVie, Amgen, Bayer, Biogene, BMS, Celgene, Eli Lilly, Novartis, Janssen, Pfizer, Sanofi-Regeneron, and UCB Pharma; and a principal investigator
for Dermavent, LEO Pharma, and UCB Pharma, all outside of the submitted work. YO has received research grants from Eisai, Torii, Maruho, and Shiseido; has current consulting or advisory board agreements or speakers bureau from AbbVie, Amgen, Boehringer Ingelheim, BMS, Celgene, Eisai, Eli Lilly, Janssen Pharma, Jimro, Kyowa Kirin, LEO Pharma, Maruho, Novartis Pharma, Pfizer, Sanofi, Sun Pharma, Taiho, Tanabe-Mitsubishi, Torii, and UCB Pharma; and is involved in clinical trials sponsored by AbbVie, Amgen, Boehringer Ingelheim, BMS, Celgene, Eli Lilly, Janssen Pharma, LEO Pharma, Maruho, Pfizer, Sun Pharma, and UCB Pharma, all outside of the submitted work. MW is an employee of UCB Pharma. CM, VV,
and CC are employees and shareholders in UCB Pharma. ML is an employee of Mount Sinai Hospital (New York, NY), which receives research funds from AbbVie, Amgen, Arcutis, Boehringer Ingelheim, Dermavant, Eli Lilly, Incyte, Janssen Research & Development,
LEO Pharma, Ortho Dermatologics, Pfizer, and UCB Pharma. ML is also a consultant for Aditum Bio, Allergan, Almirall, Arcutis, Avotres Therapeutics, BirchBioMed, BMD Skincare, Boehringer Ingelheim, BMS, Cara Therapeutics, Castle Biosciences, Corrona, Dermavant Sciences, Evelo, Facilitate International Dermatologic Education, Foundation for Research and Education in Dermatology, Inozyme Pharma, LEO Pharma, Meiji Seika Pharma, Menlo, Mitsubishi, Neuroderm, Pfizer, Promius/Dr Reddy’s Laboratories, Serono, Theravance, and Verrica, all outside of the submitted work.
Data sharing
Underlying data from this manuscript can be requested by qualified researchers 6 months after product approval in the USA or Europe,
or when global development is discontinued, and 18 months after trial completion, at www.Vivli.org. Investigators can request access to anonymised individual patient-level data and redacted trial documents, which might include analysis-ready datasets, study protocol, annotated case report form, statistical analysis plan, dataset specifications, and clinical study report. Before use of the data, proposals need to be approved by an independent review panel at www.Vivli.org and a signed data sharing agreement will need to be executed. All documents are available in English only, for a prespecified time, typically 12 months, on a password protected portal.
Acknowledgments
We thank the patients, the investigators, and their teams who took part in this study. We also acknowledge Susanne Wiegratz (UCB Pharma,
Monheim, Germany) for publication coordination, Eva Cullen (UCB Pharma, Brussels, Belgium) for critical review, and
Louise Whiteley and Emma Phillips (Costello Medical, UK) for medical writing and editorial assistance based on the authors’ input and direction, and the UCB Pharma BE VIVID clinical team. This study was funded by UCB Pharma. RBW is supported by the Manchester National Institute for Health Research Biomedical Research Centre.
Support for third-party writing assistance for this article was funded by UCB Pharma in accordance with Good Publication Practice 3 guidelines.
References
Boehncke WH, Schön MP. Psoriasis. Lancet 2015; 386: 983–94.
Kimball AB, Jacobson C, Weiss S, Vreeland MG, Wu Y.
The psychosocial burden of psoriasis. Am J Clin Dermatol 2005;
6: 383–92.
Oliveira MF, Rocha BO, Duarte GV. Psoriasis: classical and emerging comorbidities. An Bras Dermatol 2015; 90: 9–20.
Sbidian E, Chaimani A, Afach S, et al. Systemic pharmacological treatments for chronic plaque psoriasis: a network meta-analysis. Cochrane Database Syst Rev 2020; 1: CD011535.
Gordon KB, Blauvelt A, Papp KA, et al. Phase 3 trials of ixekizumab in moderate-to-severe plaque psoriasis. N Engl J Med 2016;
375: 345–56.
Griffiths CE, Reich K, Lebwohl M, et al. Comparison of ixekizumab with etanercept or placebo in moderate-to-severe psoriasis (UNCOVER-2 and UNCOVER-3): results from two phase 3 randomised trials. Lancet 2015; 386: 541–51.
Langley RG, Elewski BE, Lebwohl M, et al. Secukinumab in plaque psoriasis—results of two phase 3 trials. N Engl J Med 2014;
371: 326–38.
For the Good Publication Practice 3 guidelines see http://www.ismpp.org/gpp3
Lebwohl M, Strober B, Menter A, et al. Phase 3 studies comparing brodalumab with ustekinumab in psoriasis. N Engl J Med 2015; 373: 1318–28.
Warren RB, Smith CH, Yiu ZZN, et al. Differential drug survival of biologic therapies for the treatment of psoriasis: a prospective observational cohort study from the British Association of Dermatologists Biologic Interventions Register (BADBIR).
J Invest Dermatol 2015; 135: 2632–40.
Kornmehl H, Callis Duffin K, Salame N, et al. Examination of treatment satisfaction instruments in psoriasis: 2017 results from the Psoriasis Working Group of the International Dermatology Outcome Measures (IDEOM). Dermatology 2020; 28: 1–7.
Blauvelt A, Chiricozzi A. The immunologic role of IL-17 in psoriasis and psoriatic arthritis pathogenesis. Clin Rev Allergy Immunol 2018; 55: 379–90.
Johnston A, Fritz Y, Dawes SM, et al. Keratinocyte overexpression of IL-17C promotes psoriasiform skin inflammation. J Immunol 2013; 190: 2252–62.
Glatt S, Baeten D, Baker T, et al. Dual IL-17A and IL-17F neutralisation by bimekizumab in psoriatic arthritis: evidence from preclinical experiments and a randomised placebo-controlled clinical trial that IL-17F contributes to human chronic tissue inflammation. Ann Rheum Dis 2018; 77: 523–32.
Wright JF, Bennett F, Li B, et al. The human IL-17F/IL-17A heterodimeric cytokine signals through the IL-17RA/IL-17RC receptor complex. J Immunol 2008; 181: 2799–805.
Kolbinger F, Loesche C, Valentin MA, et al. β-Defensin 2 is a responsive biomarker of IL-17A-driven skin pathology in patients with psoriasis. J Allergy Clin Immunol 2017; 139: 923–32.
Glatt S, Helmer E, Haier B, et al. First-in-human randomized study of bimekizumab, a humanized monoclonal antibody and selective dual inhibitor of IL-17A and IL-17F, in mild psoriasis.
Br J Clin Pharmacol 2017; 83: 991–1001.
Adams R, Maroof A, Baker T, et al. Bimekizumab, a novel humanized IgG1 antibody that neutralizes both IL-17A and IL-17F. Front Immunol 2020; 11: 1894.
Papp KA, Merola JF, Gottlieb AB, et al. Dual neutralization of both interleukin 17A and interleukin 17F with bimekizumab in patients with psoriasis: results from BE ABLE 1, a 12-week randomized, double-blinded, placebo-controlled phase 2b trial.
J Am Acad Dermatol 2018; 79: 277–86.
Blauvelt A, Papp KA, Merola JF, et al. Bimekizumab for patients with moderate to severe plaque psoriasis: 60-week results from BE ABLE 2, a randomized, double-blinded, placebo-controlled, phase 2b extension study. J Am Acad Dermatol 2020; 83: 1367–74.
US Food and Drug Administration. Ustekinumab prescribing information. 2020. https://www.accessdata.fda.gov/drugsatfda_ docs/label/2016/761044lbl.pdf (accessed Oct 16, 2020).
European Medicines Agency. Ustekinumab summary of product characteristics. 2020. https://www.ema.europa.eu/en/documents/ product-information/stelara-epar-product-information_en.pdf (accessed Oct 16, 2020).
Gordon KB, Foley P, Krueger JG, et al. Bimekizumab efficacy and safety in moderate to severe plaque psoriasis (BE READY):
a multicentre, double-blind, placebo-controlled, randomised withdrawal phase 3 trial. Lancet 2021; 397: 475–86.
Gottlieb AB, Ciaravino V, Cioffi C, Peterson L, Warren RB. Development and content validation of the Psoriasis Symptoms and Impacts Measure (P-SIM) for assessment of plaque psoriasis. Dermatol Ther (Heidelb) 2020; 10: 1255–72.
Thaçi D, Blauvelt A, Reich K, et al. Secukinumab is superior to ustekinumab in clearing skin of subjects with moderate to severe plaque psoriasis: CLEAR, a randomized controlled trial.
J Am Acad Dermatol 2015; 73: 400–09.
US Food and Drug Administration. Non-inferiority clinical trials to establish effectiveness. Guidance for industry. 2016. https://www. fda.gov/media/78504/download (accessed Nov 4, 2020).
Strober B, Papp KA, Lebwohl M, et al. Clinical meaningfulness of complete skin clearance in psoriasis. J Am Acad Dermatol 2016; 75: 77–82.
Blauvelt A, Lebwohl MG, Bissonnette R. IL-23/IL-17A dysfunction phenotypes inform possible clinical effects from anti-IL-17A therapies. J Invest Dermatol 2015; 135: 1946–53.
Schreiber S, Colombel JF, Feagan BG, et al. Incidence rates of inflammatory bowel disease in patients with psoriasis, psoriatic arthritis and ankylosing spondylitis treated with secukinumab: a retrospective analysis of pooled data from 21 clinical trials. Ann Rheum Dis 2019; 78: 473–79.
Reich K, Leonardi C, Langley RG, et al. Inflammatory bowel disease among patients with psoriasis treated with ixekizumab:
a presentation of adjudicated data from an integrated database of
7 randomized controlled and uncontrolled trials. J Am Acad Dermatol
2017; 76: 441–48.
Ritchlin CT, Kavanaugh A, Merola JF, et al. Bimekizumab in patients with active psoriatic arthritis: results from a 48-week, randomised, double-blind, placebo-controlled, dose-ranging phase 2b trial. Lancet 2020; 395: 427–40.