Trial design This 2-part, double-blinded trial assessed the ROR gamma t inhibitor BI 730357 in plaque psoriasis. Methods In part 1, patients were randomized 2:2:2:2:1 to 25, 50, 100, and 200 mg BI 730357 or placebo once daily (fasting conditions); nonresponders were switched to higher doses. In part 2, a separate patient set was randomized 4:4:1 to receive BI 730357 (400 mg once daily, 200 mg twice daily) or a placebo (fed conditions). Patients from parts 1 and 2 could enter a long-term extension trial. Coprimary endpoints included >= 75% reduction from baseline in PASI75 and static Physician's Global Assessment score of 0/1 (clear/almost clear) at week 12. Results In total, 274 patients were treated (178 [part 1] and 96 [part 2]). In part 1, 12 (30.0%) patients achieved PASI75 (P = .0062), and 11 (27.5%) achieved static Physician's Global Assessment of 0/1 (P = .0095) with BI 730357 200 mg versus none receiving placebo. Exposure-response relationship plateaued at >= 200 mg once daily BI 730357. Drug-related adverse events occurred in <= 15.8% of patients. Of 165 patients who entered the long-term extension, 93 (56.4%) achieved PASI75 during treatment, and <= 18.5% experienced a drug-related adverse event. Conclusions BI 730357 was well tolerated, with moderate efficacy versus placebo in plaque reduction (clinicaltrials.gov: NCT03635099 and NCT03835481).

Introduction:Systemic sclerosis is a rare autoimmune connective tissue disease characterised by (1) microvasculopathy; (2) immune dysregulation; and (3) progressive fibrosis of the skin and internal organs. Soluble guanylate cyclase plays an important role in maintaining vascular and immunological homeostasis and preventing organ fibrosis. Pharmacological modulation of soluble guanylate cyclase with soluble guanylate cyclase stimulators has shown anti-inflammatory and antifibrotic effects in animal models of systemic sclerosis, with a trend towards clinical efficacy in a Phase II study (RISE-SSc). However, the efficacy of soluble guanylate cyclase stimulators may be reduced under conditions of hypoxia and oxidative stress. Soluble guanylate cyclase activators have the potential to overcome this limitation. This paper describes the study design of VITALISScE™, a Phase II clinical trial assessing the efficacy, safety and tolerability of avenciguat, a novel soluble guanylate cyclase activator in patients with active systemic sclerosis at risk of progression. Methods:The VITALISScE™ study (NCT05559580) is evaluating the action of avenciguat on all three aspects of systemic sclerosis pathophysiology. The primary endpoint is the rate of decline in forced vital capacity (mL) over 48 weeks. Secondary endpoints include absolute change from baseline at Week 48 in modified Rodnan skin score, Health Assessment Questionnaire Disability Index score and the proportion of responders based on the revised Composite Response Index in Systemic Sclerosis. Additional endpoints include a composite assessment of Raynaud's phenomenon, digital ulcer burden, functional outcomes and quality of life, safety, pharmacokinetics, and biomarkers associated with systemic sclerosis and the mechanism of action of avenciguat. Results:VITALISScE™ is an ongoing, multicentre (180 sites; 38 countries), placebo-controlled, double-blind, parallel-group, Phase II clinical study. Recruitment is currently ongoing. Conclusions:The VITALISScE™ study is assessing the efficacy, safety and tolerability of avenciguat in patients with active systemic sclerosis at risk of progression. Results will inform further development of avenciguat. Trial Registration:VITALISScE™; EU CT No. 2022-500332-11-00; Clinicaltrials.gov: NCT05559580 (https://www.clinicaltrials.gov/study/NCT05559580).

Evaluating Drug-Drug Interactions (DDIs) for new investigational compounds requires several trials evaluating different drugs with different transporter specificities. By using a cocktail of drugs with different transporter specificities, a single trial could evaluate the pharmacokinetics (PKs) of each cocktail drug simultaneously, reducing the number of clinical DDI trials required for clinical development. We aimed to investigate the effect of steady-state Boehringer Ingelheim (BI) 730357 (bevurogant) on the PKs of a validated and optimized 4-component transporter cocktail. This open-label, non-randomized, 2-period fixed-sequence phase I trial compared transporter cocktail (0.25 mg digoxin/1 mg furosemide/10 mg metformin hydrochloride/10 mg rosuvastatin) with and without BI 730357 in healthy subjects aged 18-55 years with body mass index 18.5-29.9 kg/m2 . During reference treatment/period 1, transporter cocktail was administered 90 minutes after breakfast. After a washout period, during test treatment/period 2, BI 730357 was dosed twice daily for 13 days, with transporter cocktail administered on day 1. The primary endpoints were the area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞ ) and the maximum measured concentration of the analyte in plasma (Cmax ), and the secondary endpoint was the area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz ). Steady-state BI 730357 increased digoxin (+48% to +94%), minimally affected metformin (-2% to -9%), furosemide (+12% to +18%), and rosuvastatin (+19% to +39%) exposure. Therefore, no clinically relevant inhibition of transporters OCT2/MATE-1/MATE-2K, OAT1/OAT3, OATP1B1/OATP1B3 was observed. Potential inhibition of breast cancer resistance protein noted as PK parameters of coproporphyrin I/III (OATP1B1/OATP1B3 biomarkers) remained within bioequivalence boundaries while rosuvastatin PK parameters (AUC0-∞ /Cmax /AUC0-tz ) exceeded the bioequivalence boundary. BI 730357 was safe and well tolerated. This trial confirms the usefulness and tolerability of the transporter cocktail consisting of digoxin, furosemide, metformin, and rosuvastatin in assessing drug-transporter interactions in vivo.

BI 730357 is investigated as an oral treatment of plaque psoriasis. We analyzed the impact of three dosage regimens on the Psoriasis Area and Severity Index (PASI) response with modeling based on phase I and II data from 109 healthy subjects and 274 patients with moderate-to-severe plaque psoriasis. The pharmacokinetics (PK) was characterized by a two-compartment model with dual absorption paths and a first-order elimination. Higher baseline C-reactive protein was associated with lower clearance and patients generally had lower clearance compared with healthy subjects. A bounded integer PK/pharmacodynamic model characterized the effect on the observed PASI. The maximum drug effect was largest for patients with no prior biologic use, smaller for patients with prior use of non-interleukin-17 inhibitors, and smallest for patients with prior interleukin-17 inhibitor use. The models allowed robust simulation of large patient populations, predicting a plateau in PASI outcomes for BI 730357 exposure above 2000 nmol/L.

Introduction Generalized pustular psoriasis (GPP) is a rare, severe, and potentially life-threatening systemic and chronic autoinflammatory disease characterized by sterile, neutrophilic pustules. The standard of care for GPP varies by region, with limited information and experience of flares and their treatment. Our aim was to establish current unmet needs in GPP by better understanding the natural history of GPP, examining how dermatologists diagnose GPP and GPP flares, and establishing the range and adequacy of GPP treatment options currently prescribed by dermatologists. Methods Eligible dermatologists (N = 29) completed a 28-question structured survey, covering ten themes, ranging from GPP diagnostic criteria to GPP symptoms and treatment. Results All dermatologists stated that pustules were necessary to diagnose a GPP flare. The most frequently reported triggering factors for GPP were steroid withdrawal (64%), infection (58%), and stress (50%). Most dermatologists indicated that available treatment options for GPP flares were adequate "most" (79%) or "all" (14%) of the time. Despite this reported adequacy, 38% of dermatologists reported that it was at least "somewhat common" for a flare to require hospitalization. Furthermore, 72% of dermatologists indicated that treatments were too slow to control flares, and 66% indicated that treatments did not adequately prevent new flares at least "sometimes". Conclusion This survey suggests that there are key features of GPP flares, and could initiate discussion around forming consensus guidelines for diagnosis and management. While the results suggest that moderately effective therapies may exist, the need for GPP-specific treatments remains.

Although many biologic therapies are effective for clearing skin of patients with psoriasis, some lose effectiveness over time. This phase 2 open-label extension (OLE) trial was designed to investigate the long-term safety and efficacy of risankizumab. In the phase 2, double-blind, active comparator, predecessor trial (NCT02054481), patients with moderate-to-severe chronic plaque psoriasis were treated for 24 weeks with subcutaneous (SC) risankizumab or ustekinumab, followed by a 24-week follow-up without treatment administration. Patients could enroll in the OLE (NCT02203851) when they experienced loss of treatment response (< 50% improvement in the Psoriasis Area Severity Index [PASI 50]) during follow-up) or at the end of follow-up if treatment response was ongoing. In the OLE, patients were treated every 12 weeks for at least 48 weeks with SC risankizumab 90 or 180 mg, beginning at week 12 (OLE visit 2), if the patient had not achieved PASI 90. Efficacy endpoints included the proportions of patients who achieved PASI 50/75/90/100 and static Physician’s Global Assessment (sPGA) of clear or almost clear skin at week 48 (sPGA 0/1; OLE visit 5). Of the 110 enrolled patients, 99 (90.0%) completed the OLE. No patients discontinued the study because of adverse events. At week 48, 74.1% of patients achieved PASI 90, whereas 98.1, 91.7, 53.7, and 67.6% achieved PASI 50/75/100 and sPGA 0/1, respectively. All efficacy results were consistent or slightly increased at OLE week 48 compared with week 12. No new safety findings were observed. Risankizumab treatment was well tolerated with sustained clinical efficacy for at least 48 weeks. ClinicalTrials.gov identifier; NCT02203851.

Generalized pustular psoriasis (GPP) is a rare, systemic disease characterized by recurrent flares of painful neutrophilic aseptic pustules. There is limited real-word evidence characterizing patients with GPP. Establishing the distinguishing characteristics of GPP relative to plaque psoriasis may help inform future treatment and improve patient outcomes. Adults with GPP (n = 60) or plaque psoriasis (n = 4894) identified from the North American-based Corrona Psoriasis Registry were included in descriptive analyses. The Corrona Psoriasis Registry is a prospective, multicenter registry for patients with psoriasis. Registry enrollment data were assessed as variables, including sociodemographics, disease characteristics, medications, and patient-reported outcomes. Though there were similarities between the populations, when assessed using median (p25, p75) visual analog scores (range 0-100), patients with GPP suffered from greater pain (20 [3, 62] vs 5 [0, 35]), fatigue (44 [15, 73] vs 20 [4, 50]), and itch (59 [10, 85] vs 22 [5, 70]) than patients with plaque psoriasis. Patients with GPP also reported more anxiety and depression (38% vs 26%, EQ-5D-3L) and had more treatment experience (15% received ≥2 previous systemic agents vs 7%). Greater symptom severity and impact on quality of life was apparent for patients with GPP vs those with plaque psoriasis. Patients with GPP had more treatment experience, suggesting that current treatment options do not adequately resolve disease. Further, the inclusion criteria of the Corrona Psoriasis Registry may have excluded acute GPP cases. Thus, these findings may underestimate the severity of GPP and its impact on patients’ lives, highlighting the need to develop GPP-specific treatments.

Palmoplantar pustulosis (PPP) is a subtype of psoriasis, localized to the palms and soles. Relatively little is known about the natural history of PPP. Given the paucity of available information, this descriptive study outlines the characteristics, clinical outcomes, and patient-reported outcomes (PROs) of patients with PPP versus those with plaque psoriasis. Enrollment data from the Corrona Psoriasis Registry (a prospective, multicenter registry for patients with psoriasis) were analyzed, comparing patients with PPP (n = 64) and plaque psoriasis (n = 4894). Data include sociodemographics, disease characteristics, PROs, and medication use. There are notable differences between patients with PPP and plaque psoriasis. Although patients with PPP had a smaller median (p25, p75) percentage body surface area (BSA) affected (3 [1, 5.5] vs 5 [1, 12]), when assessing median (p25, p75) visual analog scores (range 0-100), they had greater itch (40 [15, 76] vs 22 [5, 70]), higher fatigue (35 [10, 60] vs 20 [4, 50]), and more pain (35 [5, 63] vs 5 [0, 35]) than patients with plaque psoriasis. Importantly, median reported percentage of impairment while working (10 [0, 53] vs 0 [0, 15]) and in daily activities (30 [5, 50] vs 3 [0, 25]) was greater for patients with PPP. Despite affecting a smaller BSA than plaque psoriasis, the presence of pustules on the palms and soles among patients with PPP has a distinct impact on patient wellbeing, with greater itch, fatigue, and pain reported. These translate into a considerable impairment in both work and daily activities.

Key Points Question Is continuous risankizumab treatment efficacious and safe in adults with moderate to severe plaque psoriasis? Findings In this 2-part, phase 3 randomized clinical trial in 507 patients, a significantly greater proportion of patients treated with risankizumab vs placebo achieved a treatment response at week 16 and with long-term continuous risankizumab compared with withdrawal to placebo at 52 and 104 weeks. Rates of treatment-emergent adverse events were similar to those with placebo and remained stable over time. Meaning These findings support the use of 12-week risankizumab dosing as an efficacious and well-tolerated regimen for maintenance of clinical efficacy in patients with moderate to severe plaque psoriasis.

AIMS:To evaluate the safety, pharmacokinetics and pharmacodynamics of single- and multiple-rising doses (MRDs) of BI 705564 and establish proof of mechanism. METHODS:BI 705564 was studied in 2 placebo-controlled, Phase I clinical trials testing single-rising doses (1-160 mg) and MRDs (1-80 mg) of BI 705564 over 14 days in healthy male volunteers. Blood samples were analysed for BI 705564 plasma concentration, Bruton's tyrosine kinase (BTK) target occupancy (TO) and CD69 expression in B cells stimulated ex vivo. A substudy was conducted in allergic, otherwise healthy, MRD participants. Safety was assessed in both studies. RESULTS:All doses of BI 705564 were well tolerated. Geometric mean BI 705564 plasma terminal half-life ranged from 10.1 to 16.9 hours across tested doses, with no relevant accumulation after multiple dosing. Doses ≥20 mg resulted in ≥85% average TO that was maintained for ≥48 hours after single-dose administration. Functional effects of BTK signalling were demonstrated by dose-dependent inhibition of CD69 expression. In allergic participants, BI 705564 treatment showed a trend in wheal size reduction in a skin prick test and complete inhibition of basophil activation. Mild bleeding-related adverse events were observed with BI 705564; bleeding time increased in 1/12 participants (8.3%) who received placebo vs 26/48 (54.2%) treated with BI 705564. CONCLUSION:BI 705564 showed efficient target engagement through durable TO and inhibition of ex vivo B-cell activation, and proof of mechanism through effects on allergic skin responses. Mild bleeding-related adverse events were probably related to inhibition of platelet aggregation by BTK inhibition.

Risankizumab, a humanized immunoglobulin G1 monoclonal antibody, selectively inhibits interleukin-23, a key cytokine in the pathogenesis of psoriasis, by binding to its p19 subunit. In SustaIMM (ClinicalTrials.gov/NCT03000075), a phase 2/3, double-blinded, placebo-controlled study, Japanese patients with moderate to severe plaque psoriasis (n = 171) were stratified by bodyweight and concomitant psoriatic arthritis and randomized 2:2:1:1 to 75 mg risankizumab, 150 mg risankizumab, placebo with cross-over to 75 mg risankizumab and placebo with cross-over to 150 mg risankizumab. Dosing was at weeks 0, 4, 16, 28 and 40, with placebo cross-over to risankizumab at week 16. The primary end-point was 90% or more improvement from baseline in Psoriasis Area and Severity Index (PASI-90) at week 16 for risankizumab versus placebo. Missing data were imputed as non-response. All primary and psoriasis-related secondary end-points were met for both risankizumab doses (P < 0.001). At week 16, PASI-90 responses were significantly higher in patients receiving 75 mg (76%) or 150 mg (75%) risankizumab versus placebo (2%). Corresponding response rates were 86%, 93% and 10% for static Physician Global Assessment (sPGA) score of clear/almost clear; 90%, 95% and 9% for PASI-75; and 22%, 33% and 0% for PASI-100, with significantly higher responses for both risankizumab doses versus placebo. Through week 52, PASI and sPGA responses increased or were maintained and treatment-emergent adverse events were comparable across treatment groups. Both doses of risankizumab were superior to placebo in treating patients with moderate to severe plaque psoriasis. The safety profile was consistent with previous risankizumab trials, with no new or unexpected safety findings.

Background Psoriasis is an autoimmune disease that affects approximately 100 million people worldwide, and is a disease that can be ameliorated by anti-cytokine treatment. We aimed to compare the efficacy and safety of risankizumab with adalimumab in patients with moderate-to-severe plaque psoriasis. Methods IMMvent was a phase 3, randomised, double-blind, active-comparator-controlled trial completed at 66 clinics in 11 countries. Eligible patients were aged 18 years or older with moderate-to-severe chronic plaque psoriasis. Patients were randomly assigned 1: 1 using interactive response technology to receive 150 mg risankizumab subcutaneously at weeks 0 and 4 or 80 mg adalimumab subcutaneously at randomisation, then 40 mg at weeks 1, 3, 5, and every other week thereafter during a 16-week double-blind treatment period (part A). For weeks 16-44 (part B), adalimumab intermediate responders were re-randomised 1: 1 to continue 40 mg adalimumab or switch to 150 mg risankizumab. In part A, participants and investigators were masked to study treatment. Randomisation was stratified by weight and previous tumour necrosis factor inhibitor exposure. Co-primary endpoints in part A were a 90% improvement from baseline (PASI 90) and a static Physician's Global Assessment (sPGA) score of 0 or 1 at week 16, and for part B was PASI 90 at week 44 (non-responder imputation). Efficacy analyses were done in the intention-to-treat population and safety analyses were done in the safety population (all patients who received at least one dose of study drug or placebo). This study is registered with ClinicalTrials.gov, number NCT02694523. Findings Between March 31, 2016, and Aug 24, 2017, 605 patients were randomly assigned to receive either risankizumab (n=301, 50%) or adalimumab (n=304, 50%). 294 (98%) of patients in the risankizumab group and 291 (96%) in the adalimumab group completed part A, and 51 (96%) of 53 patients re-randomised to risankizumab and 51 (91%) of 56 patients re-randomised to continue adalimumab completed part B. At week 16, PASI 90 was achieved in 218 (72%) of 301 patients given risankizumab and 144 (47%) of 304 patients given adalimumab (adjusted absolute difference 24.9% [95% CI 17.5-32.4]; p<0.0001), and sPGA scores of 0 or 1 were achieved in 252 (84%) patients given risankizumab and 252 (60%) patients given adalimumab (adjusted absolute difference 23.3% [16.6-30.1]; p<0.0001). In part B, among adalimumab intermediate responders, PASI 90 was achieved by 35 (66%) of 53 patients switched to risankizumab and 12 (21%) of 56 patients continuing adalimumab (adjusted absolute difference 45.0% [28.9-61.1]; p<0.0001) at week 44. Adverse events were reported in 168 (56%) of 301 patients given risankizumab and 179 (57%) of 304 patients given adalimumab in part A, and among adalimumab intermediate responders, adverse events were reported in 40 (75%) of 53 patients who switched to risankizumab and 37 (66%) of 56 patients who continued adalimumab in part B. Interpretation Risankizumab showed significantly greater efficacy than adalimumab in providing skin clearance in patients with moderate-to-severe plaque psoriasis. No additional safety concerns were identified for patients who switched from adalimumab to risankizumab. Treatment with risankizumab provides flexibility in the long-term treatment of psoriasis. Funding AbbVie and Boehringer Ingelheim. Copyright (c) 2019 Elsevier Ltd. All rights reserved.

Background The small molecule BI 705564 is a highly selective, covalent and potent inhibitor (B cell CD69 activation IC50=2.2 nM) of the Brutons tyrosine kinase (BTK). BTK plays a critical role in the differentiation and function of B cells and myeloid cell lineages and may play a major role in autoimmune diseases. Blocking the BTK pathways may be a promising new treatment of autoimmune diseases like SLE. Methods BI 705564 has been studied in 43 male healthy volunteers (HV) in a single-blinded, partially randomized, placebo-controlled trial testing single rising doses from 10 to 160 mg. In a double-blinded, randomized, placebo-controlled study BI 705564 was administered to 50 male HV at doses from 10 to 80 mg once daily for 14 days. Blood samples were analyzed for BI 705564 plasma concentrations, BTK target occupancy (TO) and CD69 expression in B cells stimulated ex-vivo with anti-IgD. Results All doses of BI 705564 were well-tolerated in both studies. There were no serious adverse events (AEs) and reported AEs were mainly of mild intensity and not dose-limiting. There was no difference in the total number of subjects with AEs (combined data from both trials) between BI 705564 [28/75 (37.3%)] and placebo [8/18 (44.4%)] and no dose-relationship of AEs. The most frequently reported AE was headache (BI 705564: 8.0% vs placebo: 5.6%, combined data). There was no difference in the occurrence of infections (BI 705564: 6.5% vs placebo: 11.1%) or gastrointestinal disorders (BI 705564: 13.3% vs. placebo 11.1%) in both studies (combined data). There were no relevant drug-related changes in vital signs, ECGs and standard safety laboratory tests. Analysis of BI 705564 plasma exposures showed a terminal half-life between 5.7 and 14.2 hour with no relevant accumulation after multiple dosing. Doses of 20 mg and above resulted in an average TO 85% which is expected to result in clinical efficacy based on preclinical studies. After a single dose administration, TO was maintained for at least 48 hour consistent with the mechanism of a covalent irreversible inhibitor. Functional effects on BTK signalling were demonstrated by dose-dependent inhibition up to 100% of CD69 expression on anti-IgD stimulated B cells. Conclusions BI 705564 was well-tolerated in healthy subjects after single and multiple doses. The favorable clinical safety profile and the high potential based on pre-clinical studies and effects on CD69 support further investigation of BI 705564 in patients with autoimmune diseases like SLE. Funding Source(s): This study was funded by Boehringer Ingelheim.

Background: IL-23 contributes to the activation, maintenance, and proliferation of TH17 cells and plays a major role in psoriasis pathophysiology. IL-23p19 inhibition with risankizumab resulted in superior clinical responses in patients with psoriasis compared with ustekinumab (dual IL-12/IL-23 inhibitor), but comparative molecular effects have not been established. Objective: We investigated the similarities and differences in molecular and histopathologic profiles in skin lesions from patients with psoriasis receiving risankizumab versus ustekinumab at an early time point. Methods: Lesional skin biopsy samples from 81 patients with moderate-to-severe plaque psoriasis participating in 2 different studies (a phase I risankizumab study and a phase II study of risankizumab vs ustekinumab) were analyzed by using histopathology, immunohistochemistry, and RNA sequencing. Results: Risankizumab induced a rapid decrease in levels of proteins and transcriptomic biomarkers associated with the IL-23 pathway, which were maintained through 8 weeks. At week 4, risankizumab decreased histopathologic expression of biomarkers, including K16, Ki67, CD3, lipocalin-2, CD11c, dendritic cell lysosome-associated membrane glycoprotein, beta-defensin 2, and S100A7; global histopathologic scoring revealed that 54% and 69% of patients treated with 90 or 180 mg of risankizumab, respectively, were graded as experiencing "excellent improvement'' versus 29% of patients treated with ustekinumab. At week 4, there was a common decrease in expression of 2645 genes expressed in lesional skin between patients receiving risankizumab and ustekinumab and a significant decrease in 2682 genes unique to risankizumab treatment. Risankizumab more strongly downregulated expression of genes associated with keratinocytes, epidermal cells, and monocytes, versus ustekinumab. Conclusion: Risankizumab demonstrated more pronounced changes in the molecular and histopathologic profile of psoriatic skin lesions compared with ustekinumab at week 4.

Background Risankizumab is a humanised IgG1 monoclonal antibody that binds to the p19 subunit of interleukin-23, inhibiting this key cytokine and its role in psoriatic inflammation. We aimed to assess the efficacy and safety of risankizumab compared with placebo or ustekinumab in patients with moderate-to-severe chronic plaque psoriasis. Methods UltIMMa-1 and UltIMMa-2 were replicate phase 3, randomised, double-blind, placebo-controlled and active comparator-controlled trials done at 139 sites in Australia, Austria, Belgium, Canada, Czech Republic, France, Germany, Japan, Mexico, Poland, Portugal, South Korea, Spain, and the USA. Eligible patients were 18 years or older, with moderate-to-severe chronic plaque psoriasis. In each study, patients were stratified by weight and previous exposure to tumour necrosis factor inhibitor and randomly assigned (3:1:1) by use of interactive response technology to receive 150 mg risankizumab, 45 mg or 90 mg ustekinumab (weight-based per label), or placebo. Following the 16-week double-blind treatment period (part A), patients initially assigned to placebo switched to 150 mg risankizumab at week 16; other patients continued their originally randomised treatment (part B, double-blind, weeks 16-52). Study drug was administered subcutaneously at weeks 0 and 4 during part A and at weeks 16, 28, and 40 during part B. Co-primary endpoints were proportions of patients achieving a 90% improvement in the Psoriasis Area Severity Index (PASI 90) and a static Physician's Global Assessment (sPGA) score of 0 or 1 at week 16 (non-responder imputation). All efficacy analyses were done in the intention-to-treat population. These trials are registered with ClinicalTrials.gov, numbers NCT02684370 (UltIMMa-1) and NCT02684357 (UltIMMa-2), and have been completed. Findings Between Feb 24, 2016, and Aug 31, 2016, 506 patients in UltIMMa-1 were randomly assigned to receive 150 mg risankizumab (n= 304), 45 mg or 90 mg ustekinumab (n= 100), or placebo (n= 102). Between March 1, 2016, and 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). Co-primary endpoints were met for both studies. At week 16 of UltIMMa-1, PASI 90 was achieved by 229 (75.3%) patients receiving risankizumab versus five (4.9%) receiving placebo (placebo-adjusted difference 70.3% [95% CI 64.0-76.7]) and 42 (42.0%) receiving ustekinumab (ustekinumab-adjusted difference 33.5% [22.7-44.3]; p<0.0001 vs placebo and ustekinumab). At week 16 of UltIMMa-2, PASI 90 was achieved by 220 (74.8%) patients receiving risankizumab versus two (2.0%) receiving placebo (placebo-adjusted difference 72.5% [95% CI 66.8-78.2]) and 47 (47.5%) receiving ustekinumab (ustekinumab-adjusted difference 27.6% [16.7-38.5]; p<0.0001 vs placebo and ustekinumab). In UltIMMa-1, sPGA 0 or 1 at week 16 was achieved by 267 (87.8%) patients receiving risankizumab versus eight (7.8%) receiving placebo (placebo-adjusted difference 79.9% [95% CI 73.5-86.3]) and 63 (63.0%) receiving ustekinumab (ustekinumab-adjusted difference 25.1% [15.2-35.0]; p<0.0001 vs placebo and ustekinumab). In UltIMMa-2, 246 (83.7%) patients receiving risankizumab versus five (5.1%) receiving placebo (placebo-adjusted difference 78.5% [95% CI 72.4-84.5]) and 61 (61.6%) receiving ustekinumab achieved sPGA 0 or 1 at week 16 (ustekinumab adjusted difference 22.3% [12.0-32.5]; p<0.0001 vs placebo and ustekinumab). The frequency of treatment-emergent adverse events in UltIMMa-1 and UltIMMa-2 was similar across risankizumab (part A:151 [49.7%] of 304 and 134 [45.6%] 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), 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 to risankizumab (part B:65 [67.0%] of 97 and 61 [64.9%] of 94) treatment groups throughout the study duration. Interpretation Risankizumab showed superior efficacy to both placebo and ustekinumab in the treatment of moderate-to-severe plaque psoriasis. Treatment-emergent adverse event profiles were similar across treatment groups and there were no unexpected safety findings. Copyright (c) 2018 Elsevier Ltd. All rights reserved.

Abstract Not Available Disclosures: Study supported by AbbVie.

BACKGROUNDInterleukin-23 is thought to be critical to the pathogenesis of psoriasis. We compared risankizumab (BI 655066), a humanized IgG1 monoclonal antibody that inhibits interleukin-23 by specifically targeting the p19 subunit and thus prevents interleukin-23 signaling, and ustekinumab, an interleukin-12 and interleukin-23 inhibitor, in patients with moderate-to-severe plaque psoriasis.METHODSWe randomly assigned a total of 166 patients to receive subcutaneous injections of risankizumab (a single 18-mg dose at week 0 or 90-mg or 180-mg doses at weeks 0, 4, and 16) or ustekinumab (45 or 90 mg, according to body weight, at weeks 0, 4, and 16). The primary end point was a 90% or greater reduction from baseline in the Psoriasis Area and Severity Index (PASI) score at week 12.RESULTSAt week 12, the percentage of patients with a 90% or greater reduction in the PASI score was 77% (64 of 83 patients) for risankizumab (90-mg and 180-mg groups, pooled), as compared with 40% (16 of 40 patients) for ustekinumab (P<0.001); the percentage of patients with a 100% reduction in the PASI score was 45% in the pooled 90-mg and 180-mg risankizumab groups, as compared with 18% in the ustekinumab group. Efficacy was generally maintained up to 20 weeks after the final dose of 90 or 180 mg of risankizumab. In the 18-mg and 90-mg risankizumab groups and the ustekinumab group, 5 patients (12%), 6 patients (15%), and 3 patients (8%), respectively, had serious adverse events, including two basal-cell carcinomas and one major cardiovascular adverse event; there were no serious adverse events in the 180-mg risankizumab group.CONCLUSIONSIn this phase 2 trial, selective blockade of interleukin-23 with risankizumab was associated with clinical responses superior to those associated with ustekinumab. This trial was not large enough or of long enough duration to draw conclusions about safety.