13652133, 2021, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/bjd.20595 by Readcube (Labtiva Inc.), Wiley Online Library on [30/01/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License BJD C L I NI C A L T R IA L British Journal of Dermatology Long-term efficacy and safety of risankizumab for the treatment of moderate-to-severe plaque psoriasis: interim analysis of the LIMMitless open-label extension trial beyond 3 years of follow-up K.A. Papp iD 1, M.G. Lebwohl,2 L. Puig iD ,3 M. Ohtsuki,4 S. Beissert,5 J. Zeng,6 S. Rubant,6 R. Sinvhal,6 Y. Zhao,6 A.M. Soliman,6 G. Alperovich7 and C. Leonardi8 1 K Papp Clinical Research and Probity Medical Research, Waterloo, ON, Canada 2 Icahn School of Medicine at Mount Sinai, New York, NY, USA 3 Hospital de la Santa Creu i Sant Pau, Barcelona, Spain 4 Jichi Medical University, Tochigi, Japan 5 Department of Dermatology, University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany 6 AbbVie Inc., North Chicago, IL, USA 7 AbbVie Inc., Madrid, Spain 8 Central Dermatology, Richmond Heights, MO, USA Linked Comment: S. Gerdes and J. Albrecht. Br J Dermatol 2021; 185: 1086–1087. Summary Correspondence Background Psoriasis is a chronic inflammatory skin disease requiring prolonged Kim A Papp. treatment. New biologic therapies require long-term evaluation to assess the Email: kapapp@probitymedical.com durability of their efficacy and safety profiles over time. Objectives To evaluate the long-term efficacy and safety of risankizumab (RZB) for Accepted for publication 17 June 2021 the treatment of psoriasis. Methods LIMMitless is an ongoing, phase III, open-label extension study evaluating Funding sources the long-term efficacy and safety of RZB in adults with moderate-to-severe pla- AbbVie Inc. funded this study, and participated in que psoriasis following multiple phase II/III studies. This analysis assessed effi- the study design, research, analysis, data collection, cacy through 172 weeks of continuous RZB treatment by examining the interpretation of data and review and approval of proportion of patients achieving ≥ 90% or 100% improvement in Psoriasis Area the publication. All authors had access to the data and participated in the development, review, cri- and Severity Index (PASI 90 and PASI 100), static Physician’s Global Assessment tique and approval of the manuscript throughout of clear or almost clear (sPGA 0/1) and Dermatology Life Quality Index of no the editorial process and approved the final manu- effect on quality of life (DLQI 0/1). Safety was assessed by recording adverse script draft submitted for publication. All authors events (AEs) through the data cutoff date. The study is registered at ClinicalTri- agree to be accountable for all aspects of the work, als.gov (identifier: NCT03047395). ensuring the accuracy and integrity of the publica- Results Of 955 patients randomized to RZB 150 mg in the base studies, 897 tion. Medical writing support was paid for by AbbVie. patients continued into LIMMitless; 799 patients were still receiving treatment in LIMMitless at the time of data cutoff for this analysis. After 172 weeks of contin- Conflicts of interest statements can be uous RZB treatment, 855% of patients achieved PASI 90, 544% achieved PASI found in Appendix 1. 100, 852% achieved sPGA 0/1, and 784% achieved DLQI 0/1 using modified nonresponder imputation. Rates of AEs leading to discontinuation and AEs of A statement of data availability can be found in Appendix 2. safety interest were low with long-term treatment and comparable with those identified in the base studies. DOI 10.1111/bjd.20595 Conclusions Overall, long-term continuous RZB was well tolerated and showed high and durable efficacy over 172 weeks. © 2021 AbbVie Inc. British Journal of Dermatology British Journal of Dermatology (2021) 185, pp1135–1145 1135 published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. 13652133, 2021, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/bjd.20595 by Readcube (Labtiva Inc.), Wiley Online Library on [30/01/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 1136 Long-term efficacy and safety of risankizumab, K.A. Papp et al. What is already known about this topic? • Risankizumab is a humanized immunoglobulin G1 monoclonal antibody that specifically inhibits interleukin-23 by binding to its p19 subunit. • In multiple phase II/III clinical trials in adults with moderate-to-severe psoriasis, risankizumab has displayed superior efficacy vs. placebo or other psoriasis treat- ments for up to 52 weeks. What does this study add? • LIMMitless is an ongoing phase III open-label extension study designed to evaluate the long-term safety and efficacy of risankizumab treatment for up to 5 years of continuous use. • The results from this interim analysis demonstrate that risankizumab offers sus- tained efficacy after more than 3 years of continuous use, with no new safety sig- nals identified. Psoriasis is a chronic, immune-mediated inflammatory skin integrated data from the LIMMitless study and the preceding disease that can negatively impact a patient’s quality of life base studies. and requires long-term control.1,2 Although multiple treat- ment options are currently available to manage psoriasis, clini- Patients and methods cians need further guidance on the safety concerns that may arise when using long-term therapies. Additionally, the effi- Study design and treatment cacy of psoriasis treatments may also decline after prolonged periods of use. While a number of inflammatory cytokines LIMMitless is an ongoing, phase III, single-arm, global, multi- have been implicated in the development and maintenance of centre, OLE trial to evaluate the long-term efficacy and safety of psoriatic lesions, interleukin (IL)-23 has emerged as a key dis- RZB in adults with moderate-to-severe psoriasis who have par- ease regulator.2,3 However, data demonstrating the effect of ticipated in multiple phase II/III studies. The LIMMitless study long-term IL-23 inhibition on the durability of response and is designed for all patients to receive RZB 150 mg subcuta- the safety profile in patients with psoriasis are limited. neously every 12 weeks for 252 weeks. To date, efficacy and Risankizumab (RZB) is a humanized immunoglobulin G1 safety assessments have been performed at study visits occur- monoclonal anti–IL-23 antibody developed to treat inflamma- ring every 12 weeks until week 156 and then every 24 weeks tory diseases4 and is an approved therapy for moderate-to- thereafter. At weeks 168, 192, 216 and 240, patients self- severe plaque psoriasis in adults.5 RZB specifically inhibits IL- administer RZB at home after proper training. The study is reg- 23 by binding to its p19 subunit.4,6 In multiple phase II/III istered at ClinicalTrials.gov (identifier: NCT03047395). clinical trials, RZB demonstrated superior efficacy compared Patients who were initially randomized to receive RZB (week with placebo or other psoriasis treatments: vs. placebo at week 0, week 4, and every 12 weeks thereafter) in one of the five 16 (UltIMMa-1, UltIMMa-2, IMMhance and SustaIMM),6–8 vs. phase II/III studies that included a continuous RZB treatment adalimumab at weeks 16 and 44 (IMMvent study),9 vs. fuma- arm (UltIMMa-1, UltIMMa-2, SustaIMM, NCT03255382 or ric acid esters at week 24 (NCT03255382),10 vs. ustekinumab IMMvent) were included in this analysis.6,8–10 Three of the base at weeks 16 and 52 (UltIMMa-1 and UltIMMa-2)6 and vs. studies were 52 weeks long (UltIMMa-1, UltIMMa-2 and IMM- secukinumab at week 52 (IMMerge).11 vent), while SustaIMM was 44 weeks long and NCT03255382 LIMMitless (open-Label extension study to assess the safety was 24 weeks long. Our interim analysis assessed the efficacy and efficacy of rIsankizuMab for Maintenance in moderate-to- of continuous RZB use through 172 weeks (week 120 of the severe plaque type psoriasis) is an ongoing, phase III, single- LIMMitless study), while safety was assessed through the cutoff arm, multicentre, open-label extension (OLE) study that builds date (26 March 2020; up to 208 weeks of treatment). on the findings derived from the shorter-term base studies The study is being conducted in accordance with the Good described in the methods section and evaluates long-term RZB Clinical Practice Guideline as defined by the International Con- treatment. The LIMMitless study will eventually provide treat- ference on Harmonisation, the Declaration of Helsinki and/or ment data on up to 5 years of continuous RZB therapy. Our all applicable federal and local regulations, and all patients current analysis evaluates the long-term efficacy of RZB ther- provided written informed consent. All protocols were apy through 172 weeks of continuous treatment and safety approved by an institutional review board (Quorom Review through the cutoff date for this interim analysis, using IRB, Seattle, WA, USA). British Journal of Dermatology (2021) 185, pp1135–1145 © 2021 AbbVie Inc. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists 13652133, 2021, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/bjd.20595 by Readcube (Labtiva Inc.), Wiley Online Library on [30/01/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Long-term efficacy and safety of risankizumab, K.A. Papp et al. 1137 then characterized as responders or nonresponders based on the Patients imputed values. Regardless of imputed values, patients who dis- Eligible patients were adults with a history of moderate-to- continued because of worsening of psoriasis were counted as severe chronic plaque psoriasis. To enrol in the study, patients nonresponders thereafter. Sensitivity analyses were performed must have completed one of the preceding studies and met all using two additional imputation methods. Using the last obser- inclusion criteria for long-term, open-label RZB treatment. vation carried forward (LOCF) method, missing data were Patients were ineligible to enrol if they had developed guttate, imputed from the completed evaluation from the most recent erythrodermic, pustular or drug-induced psoriasis during the visit. Using the observed cases (OC) method, patients with base study; used prohibited medication; had a known diagno- missing data at a visit were excluded from the analysis for that sis or evidence of tuberculosis; developed a malignancy during visit and there was no data imputation. the base study; were diagnosed with HIV or hepatitis B or C infection; had > 8 weeks’ time elapse since completion of the Results base study; or had any evidence of other medical conditions that might compromise the quality of the study data (e.g. Patients pregnancy, chronic alcohol or drug abuse, organ transplant, abnormal clinical laboratory values, or history of hypersensi- In total, 955 patients with moderate-to-severe plaque psoriasis tivity to a systemically administered biologic therapy). were randomized to receive RZB 150 mg and completed one of the preceding base studies; of these, 897 patients were enrolled in the LIMMitless study (Figure 1). The demographics Assessments and baseline disease characteristics at the time of base study Efficacy was evaluated using the Psoriasis Area and Severity enrolment were representative of the psoriasis population Index (PASI) and the Static Physician’s Global Assessment (Table 1). In total, 706% of the patients were male and the (sPGA), both of which are established clinical measures for average age was 469 years. Before enrolling in the base study, psoriasis severity. For all efficacy analyses, baseline refers to the 309% of patients had no prior systemic therapy use, while last nonmissing value before the first dose of study drug in the 378% had received a biologic treatment (195% had received a preceding base studies. Efficacy assessments included the pro- tumour necrosis factor antagonist). At baseline, the mean PASI portion of patients achieving ≥ 90% improvement in PASI was 205 and the proportions of patients with sPGA of moder- (PASI 90) or 100% improvement in PASI (PASI 100), and the ate or severe were 806% and 186%, respectively. The mean proportion of patients achieving sPGA of clear or almost clear baseline DLQI total score was 139, indicating that psoriasis (sPGA 0/1). Other efficacy assessments included the percentage had a very large effect on the patients’ quality of life.12 improvement in PASI from baseline of the base study and qual- ity of life as determined by the proportion of patients who Efficacy achieved a score of 0 or 1 on the Dermatology Life Quality Index (DLQI; measured every 24 weeks). Safety assessments Analyses of efficacy demonstrated substantial improvements in were performed continuously throughout the trial by monitor- psoriasis severity during the base studies that were maintained ing of adverse events (AEs) and tabulated using MedDRA sys- during the LIMMitless study. All three statistical methods used tem organ class and preferred terms (version 221). AEs were for efficacy analyses (mNRI, LOCF and OC) demonstrated con- calculated as the number of events per 100 patient-years (PY) sistent results. After 16 weeks of RZB treatment, > 75% of to account for differences in base study lengths. patients achieved PASI 90 and > 40% achieved PASI 100; after 52 weeks of RZB treatment, > 86% of patients achieved PASI 90 and > 58% of patients achieved PASI 100, and these levels Statistical analysis remained largely constant through 172 weeks of treatment The expected sample size was 2200, which included patients (Figure 2). sPGA of 0 or 1 was achieved by > 87% of patients from all treatment groups in the base studies, based on esti- after 16 weeks of treatment and was generally maintained mated rates of base study completion and consent for the throughout the OLE study (Figure 3). extension study and an anticipated dropout rate of 10–15%. Following 16 weeks of RZB treatment, the mean percentage Safety and efficacy were assessed in all patients who received change from baseline in PASI was > 92%, increasing to > 95% at least one dose of study drug during the LIMMitless study. throughout the OLE study (Figure S1; see Supporting Informa- Data were described using summary statistics and were anal- tion). The proportions of patients with PASI 90 and PASI 100 ysed using SASâ software (SAS Institute Inc., Cary, NC, USA). responses after 172 weeks of continuous treatment were simi- Efficacy was calculated using three different statistical meth- lar, regardless of patient baseline characteristics (Tables S1 and ods to impute missing data. In the modified nonresponder S2; see Supporting Information). Among patients who entered imputation (mNRI) method, which was the primary method of the LIMMitless OLE study with PASI 90 and PASI 100 analysis, a mixed-effect model was used to impute the missing responses, > 90% and > 67%, respectively, maintained that values with efficacy outcome as the response variable and visit response through 120 weeks of treatment in the LIMMitless and baseline measurement as the fixed effects; patients were study (i.e. 172 weeks of continuous RZB treatment; Figure 4). © 2021 AbbVie Inc. British Journal of Dermatology British Journal of Dermatology (2021) 185, pp1135–1145 published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists 13652133, 2021, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/bjd.20595 by Readcube (Labtiva Inc.), Wiley Online Library on [30/01/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 1138 Long-term efficacy and safety of risankizumab, K.A. Papp et al. Figure 1 Patient disposition. RZB, risankizumab. Table 1 Demographics and baseline disease characteristics (n = 897)a Quality of life Continuous risankizumab Quality of life was evaluated using DLQI, results from which Characteristic 150 mg showed substantial improvements during the base studies that Male, n (%) 633 (706) were maintained during the LIMMitless study. After 16 weeks Age (years) of RZB treatment, > 66% of patients achieved a DLQI score of Mean (SD) 469 (135) 0 or 1 (DLQI 0/1); this percentage increased to > 77% after Median (IQR) 470 (370–570) Weight (kg) 52 weeks of treatment and > 78% after 172 weeks of treat- Mean (SD) 885 (224) ment (Figure 5). More than half of patients (569%) achieved Median (IQR) 852 (727–1020) both PASI 90 and DLQI 0/1 after 16 weeks of treatment; this Psoriatic arthritis,b,c n (%) 195 (233) percentage increased to ≥ 70% in the LIMMitless study and Prior treatment, n (%) remained stable through 172 weeks of treatment (Figure 6). Naive to systemic therapyc 259 (309) Prior biologic therapyc 317 (378) Prior TNF antagonist therapy 163 (195) Safety BSA involvement (%) Mean (SD) 267 (165) Compared with data from the initial 16 weeks of trials in the Median (IQR) 210 (150–330) psoriasis clinical development programme (4022 PY), rates of PASI treatment-emergent AEs remained stable with long-term treat- Mean (SD) 205 (80) ment through the OLE study (up to 208 weeks of exposure Median (IQR) 180 (147–237) by the cutoff date, 31062 PY; Table 2). Incidence rates of sPGA, n (%) AEs leading to discontinuation of RZB were low (14 events Moderate (3) 723 (806) Severe (4) 167 (186) per 100 PY), as were the rates of serious AEs (67 events per DLQI, mean (SD) 139 (72) 100 PY). There were five deaths during the OLE study (one from natural causes, one car accident, one cardiopulmonary BSA, body surface area; DLQI, Dermatology Life Quality Index; arrest, one sudden cardiac death and one unknown cause); IQR, interquartile range; sPGA, static Physician’s Global Assess- none of these deaths were considered by the investigator to ment; TNF, tumour necrosis factor. aBaseline at the start of the be related to the study drug. The standardized mortality ratio base study. bDiagnosed or suspected. cBased on n = 838 as this information was not collected in NCT03255382; 59 patients for treatment-emergent deaths at the time of data cutoff was from NCT03255382 continued into LIMMitless. 032 (95% confidence interval 018–053). The most fre- quently reported treatment-emergent AEs through the cutoff British Journal of Dermatology (2021) 185, pp1135–1145 © 2021 AbbVie Inc. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists 13652133, 2021, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/bjd.20595 by Readcube (Labtiva Inc.), Wiley Online Library on [30/01/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Long-term efficacy and safety of risankizumab, K.A. Papp et al. 1139 (a) (b) Figure 2 Patients achieving improvement in Psoriasis Area and Severity Index (PASI). Proportions of patients achieving (a) ≥ 90% improvement in PASI and (b) 100% improvement in PASI. aBecause of differences in base study lengths, some patients enrolled in LIMMitless earlier than 52 weeks. b675 of the 722 ongoing patients completed the assessment visit at week 172; 47 ongoing patients have reached the assessment window but have not yet completed the assessment visit at week 172. CI, confidence interval; LOCF, last observation carried forward; mNRI, modified nonresponder imputation; OC, observed cases. © 2021 AbbVie Inc. British Journal of Dermatology British Journal of Dermatology (2021) 185, pp1135–1145 published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists 13652133, 2021, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/bjd.20595 by Readcube (Labtiva Inc.), Wiley Online Library on [30/01/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 1140 Long-term efficacy and safety of risankizumab, K.A. Papp et al. Figure 3 Patients achieving static Physician’s Global assessment of clear or almost clear (0 or 1). aBecause of differences in base study lengths, some patients enrolled in the LIMMitless study earlier than 52 weeks. b675 of the 722 ongoing patients completed the assessment visit at week 172; 47 ongoing patients have reached the assessment window but have not yet completed the assessment visit at week 172. CI, confidence interval; LOCF, last observation carried forward; mNRI, modified nonresponder imputation; OC, observed cases. date were nasopharyngitis (310%; 17.3 events per 100 PY), continuous RZB treatment. This degree of response remained upper respiratory tract infections (200%; 10.7 events per 100 stable through 120 further weeks of continuous RZB treatment. PY) and arthralgia (107%; 3.8 events per 100 PY; Table 3). The improvements observed in patient quality of life during the There were 37 cases of serious infections (Table S3; see base studies were maintained at consistently high levels Supporting Information) and 25 cases of malignant tumours throughout the OLE study. At each timepoint through (10 excluding nonmelanoma skin cancer). The incidence of 172 weeks of treatment, > 75% of patients reported no effect malignancies did not increase with longer durations of RZB on their quality of life (per responses on the DLQI). treatment, and the most frequently reported malignancies These results demonstrate sustained improvements in psori- were similar to those observed in the general population asis severity with long-term RZB therapy. Other studies have (breast cancer and colorectal cancer); there were no haemato- reported prolonged efficacy with different biologic psoriasis logical malignancies, including leukaemias or lymphomas. The treatments; however, comparisons between studies must be ratio of squamous cell carcinoma to basal cell carcinoma was made with caution because of differences in study designs and 1 : 2. There were no reported cases of systemic Candida infec- patient populations. Results from a 5-year evaluation from the tion, inflammatory bowel disease or active tuberculosis. There BioCAPTURE registry evaluating the efficacy of adalimumab (a were 20 cases of Candida infection reported (06 events per tumour necrosis factor inhibitor), etanercept (a tumour necro- 100 PY): seven cases of oral candidiasis, seven cases of genital sis factor inhibitor) and ustekinumab (an IL-12/23 inhibitor) candidiasis, four cases of oesophageal candidiasis, one case of showed that treatment with any of these biologic agents intestinal candidiasis and one case of skin candidiasis. In sum- resulted in sustained reductions in mean PASI.13 mary, no new safety concerns were identified. The level of sustained response observed in this study is greater than that observed for adalimumab over 3 to > 4 years of treatment in clinical studies.14,15 Similar trends were Discussion observed for the IL-23 inhibitor guselkumab, which was anal- In this study, we demonstrate that long-term treatment with ysed in the phase III VOYAGE 1 and 2 studies, where 821% RZB provides durable efficacy beyond 3 years of follow-up in and 772% of patients, respectively, achieved PASI 90 response patients with moderate-to-severe plaque psoriasis. Most patients at 3 years.16 Among IL-17 inhibitors, the proportions of had clinically relevant improvements in disease severity, and patients who achieved long-term PASI 90 response in clinical nearly 90% of patients achieved PASI 90 after 52 weeks of trials were numerically lower. In the phase III SCULPTURE British Journal of Dermatology (2021) 185, pp1135–1145 © 2021 AbbVie Inc. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists 13652133, 2021, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/bjd.20595 by Readcube (Labtiva Inc.), Wiley Online Library on [30/01/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Long-term efficacy and safety of risankizumab, K.A. Papp et al. 1141 (a) (b) Figure 4 Patients maintaining Psoriasis Area and Severity Index (PASI) response from 52 to 172 weeks of continuous risankizumab treatment. Proportions of patients maintaining (a) ≥ 90% improvement in PASI and (b) 100% improvement in PASI. CI, confidence interval; LOCF, last observation carried forward; mNRI, modified nonresponder imputation; OC, observed cases. study, in which secukinumab was analysed, 664% of patients discontinuation rates after more than 3 years of continuous achieved PASI 90 response at 5 years.17 In the phase III RZB treatment. UNCOVER-3 study, in which ixekizumab (every 4 weeks) The main strengths of this study include long-term follow- was analysed, 664% of patients achieved PASI 90 response at up for over 172 weeks of continuous RZB therapy, from a 4 years.18 In a phase II study in which brodalumab was anal- consistent population of patients who require long-term treat- ysed, around 65% of patients achieved PASI 90 at 5 years.19 ment and were treated with RZB since the base studies. This RZB was generally well tolerated throughout the LIMMitless study also includes a large patient population with a low dis- study; safety findings were similar to those observed during continuation rate, which provides reliable and consistent data. the base studies, with no new safety signals identified and low Additionally, while the methods used to analyse missing data © 2021 AbbVie Inc. British Journal of Dermatology British Journal of Dermatology (2021) 185, pp1135–1145 published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists 13652133, 2021, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/bjd.20595 by Readcube (Labtiva Inc.), Wiley Online Library on [30/01/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 1142 Long-term efficacy and safety of risankizumab, K.A. Papp et al. Figure 5 Patients achieving a Dermatology Life Quality Index score of 0 or 1 (no effect on quality of life). aBecause of differences in base study lengths, some patients enrolled in the LIMMitless study earlier than 52 weeks. b697 of the 722 ongoing patients completed the assessment visit at week 172; 25 ongoing patients have reached the assessment window but have not yet completed the assessment visit at week 172. CI, confidence interval; LOCF, last observation carried forward; mNRI, modified nonresponder imputation; OC, observed cases. Figure 6 Patients achieving both ≥ 90% improvement in Psoriasis Area and Severity Index and Dermatology Life Quality Index score of 0 or 1 (no effect on quality of life). aBecause of differences in base study lengths, some patients enrolled in the LIMMitless study earlier than 52 weeks. b 674 of the 722 ongoing patients completed the assessment visit at week 172; 48 ongoing patients have reached the assessment window but have not yet completed the assessment visit at week 172. CI, confidence interval; LOCF, last observation carried forward; mNRI, modified nonresponder imputation; OC, observed case. in OLE studies are not standardized, our study used three dif- Overall, the results from the ongoing LIMMitless trial ferent statistical methods to handle missing data, all of which demonstrate substantial and durable maintenance of response yielded consistent results. Limitations of this study include the with RZB over time in patients with moderate-to-severe pla- open-label and single-arm study design. que psoriasis, with a safety profile similar to that observed in British Journal of Dermatology (2021) 185, pp1135–1145 © 2021 AbbVie Inc. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists 13652133, 2021, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/bjd.20595 by Readcube (Labtiva Inc.), Wiley Online Library on [30/01/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Long-term efficacy and safety of risankizumab, K.A. Papp et al. 1143 Table 2 Summary of treatment-emergent adverse events Primary psoriasis safety pool LIMMitless study (up to 208 weeks (16 weeksa) at time of data cutoff) RZB 150 mg Placebo Continuous RZB 150 mg Number of patients 1306 300 897 Number of PY 4022 920 31062 Events (events per 100 PY) Any TEAE 1279 (3180) 261 (2837) 5295 (1705) Serious AE 40 (99) 16 (174) 209 (67) AE leading to discontinuation of study medication 11 (27) 9 (98) 44 (14) Deaths 2 (05) 0 5 (02)b TEAEs of safety interest Adjudicated MACE 1 (02) 1 (11) 5 (02) Serious infections 7 (17) 1 (11) 37 (12) Malignant tumours (including NMSC) 6 (15) 1 (11) 25 (08)c NMSC 3 (07) 1 (11) 15 (05) Excluding NMSC 3 (07) 0 10 (03) Serious hypersensitivity reactions 0 0 3 (<01)d Candida infection 2 (05) 0 20 (06)e Systemic candidiasis 0 0 0 AE, adverse event; MACE, major adverse cardiac event; NMSC, nonmelanoma skin cancer; PY, patient-years; RZB, risankizumab; TEAE, treatment- emergent adverse event. aPrimary psoriasis safety pool includes NCT02054481,20 UltIMMa-1,6 UltMMa-2,6 IMMhance (NCT02672852)7 and IMM- vent.9 bDue to natural causes (n = 1), accident (n = 1), cardiac arrest (n = 1), sudden cardiac death (n = 1) and cause unknown (n = 1); none related to risankizumab. cMalignancies were colorectal adenocarcinoma (n = 2), metastatic colon cancer (n = 1), basal cell carcinoma (n = 9), Bowen disease (n = 1), breast cancer (n = 3), endometrial cancer (n = 1), oral metastatic squamous cell carcinoma with lymph node metastasis (n = 1), metastatic squamous cell carcinoma (n = 1), prostate cancer (n = 2) and squamous cell carcinoma of the skin (n = 4). dSerious hypersensitivity reactions (all of which were unrelated to study drug) were para-phenylenediamine allergy (n = 1; mild, attributed to hair dye application), generalized microbial eczema (n = 1; moderate, attributed to prolonged duration of generalized eczema and lack of response to treatment with hydrocortisone) and Stevens–Johnson syndrome (n = 1; severe, attributed to addition of chlorpromazine). eTwenty Candida-related events were reported in 16 patients. More than half occurred in patients with known risk factors such as diabetes, steroid use and prior Candida episodes. None were serious or led to study drug discontinuation. Table 3 Most frequently reported treatment-emergent adverse events the pivotal studies. The response will be further investigated with incidence > 1 event per 100 patient-years in the remaining time of this OLE study. Continuous risankizumab 150 mg Acknowledgments Preferred term n = 897; PYs = 31062 AbbVie and the authors thank all of the study investigators for Nasopharyngitis 537 (173) their contributions, and the patients who participated in this Upper respiratory tract infection 332 (107) study. AbbVie funded the research for this study and provided Arthralgia 119 (38) writing support for this manuscript. Medical writing assis- Headache 96 (31) Hypertension 87 (28) tance, funded by AbbVie, was provided by Callie A.S. Corsa, Back pain 86 (28) PhD, and Jennifer C. Jaworski, MS, of JB Ashtin. 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Pharma, Takeda and UCB; is a speaker for AbbVie, Amgen, 11 Warren RB, Blauvelt A, Poulin Y et al. Efficacy and safety of risan- Arcutis, Astellas, Bausch Health, Boehringer Ingelheim, Bristol kizumab vs. secukinumab in patients with moderate-to-severe pla- que psoriasis (IMMerge): results from a phase III, randomized, Myers Squibb, Celgene, Dermavant, Dermira, Incyte, Janssen, open-label, efficacy-assessor-blinded clinical trial. Br J Dermatol LEO Pharma, Lilly, Novartis, Pfizer, Sandoz, Sanofi Genzyme 2021; 184:50–9. and UCB; and is a committee member for the PSOLAR and 12 Hongbo Y, Thomas CL, Harrison MA et al. Translating the science PURE registries. M.G.L. is an employee of Mount Sinai and of quality of life into practice: what do Dermatology Life Quality receives research funds from AbbVie, Amgen, Arcutis, Boeh- Index scores mean? J Invest Dermatol 2005; 125:659–64. ringer Ingelheim, Dermavant, Evommune, Incyte, Janssen, 13 Zweegers J, Groenewoud JMM, van den Reek J et al. Comparison LEO Pharma, Lilly, Ortho Dermatologics, Pfizer and UCB; and of the 1- and 5-year effectiveness of adalimumab, etanercept and ustekinumab in patients with psoriasis in daily clinical practice: is a consultant for Aditum Bio, Allergan, Almirall, Arcutis, results from the prospective BioCAPTURE registry. Br J Dermatol Avotres, BirchBioMed, BMD Skincare, Boehringer Ingelheim, 2017; 176:1001–9. Bristol Myers Squibb, Cara Therapeutics, Castle Biosciences, 14 Asahina A, Ohtsuki M, Etoh T et al. Adalimumab treatment opti- Corrona, Dermavant, Dr. Reddy’s Laboratory (Promius), EMD mization for psoriasis: results of a long-term phase 2/3 Japanese Serono, Evelo Biosciences, Evommune, Facilitate International study. J Dermatol 2015; 42:1042–52. Dermatologic Education, Foundation for Research and Educa- 15 Gordon K, Papp K, Poulin Y et al. Long-term efficacy and safety of tion in Dermatology, Inozyme Pharma, Kyowa Kirin, LEO adalimumab in patients with moderate to severe psoriasis treated continuously over 3 years: results from an open-label extension Pharma, Meiji Seika Pharma, Menlo Therapeutics, Mitsubishi study for patients from REVEAL. J Am Acad Dermatol 2012; 66:241– Tanabe Pharma, NeuroDerm, Pfizer, Theravance and Verrica. 51. L.P. has received consultancy or speaker’s honoraria from 16 Reich K, Griffiths CEM, Gordon KB et al. Maintenance of clinical and/or participated in clinical trials sponsored by AbbVie, response and consistent safety profile with up to 3 years of con- Almirall, Amgen, Baxalta, Biogen, Boehringer Ingelheim, Cel- tinuous treatment with guselkumab: results from the VOYAGE 1 gene, EMD Serono, Gebro, Janssen, LEO Pharma, Lilly, Merck, and VOYAGE 2 trials. J Am Acad Dermatol 2020; 82:936–45. Mylan, Novartis, Pfizer, Regeneron, Roche, Samsung Bioepis, 17 Bissonnette R, Luger T, Thacßi D et al. Secukinumab demonstrates high sustained efficacy and a favourable safety profile in patients Sandoz, Sanofi and UCB. M.O. has received honoraria or fees with moderate-to-severe psoriasis through 5 years of treatment for serving on advisory boards or speakers’ bureaus, or for (SCULPTURE Extension Study). J Eur Acad Dermatol Venereol 2018; consulting, and grants for investigator activities from AbbVie, 32:1507–14. Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eisai, 18 Lebwohl MG, Gordon KB, Gallo G et al. Ixekizumab sustains high Janssen, Kyowa Kirin, LEO Pharma, Lilly, Maruho, Mitsubishi level of efficacy and favourable safety profile over 4 years in Tanabe Pharma, Novartis, Pfizer, Sanofi, Sun Pharma, Torii patients with moderate psoriasis: results from UNCOVER-3 study. Pharmaceutical and UCB. S.B. has received honoraria as an J Eur Acad Dermatol Venereol 2020; 34:301–9. 19 Lebwohl MG, Blauvelt A, Menter A et al. Efficacy, safety, and advisory board member for AbbVie, Actelion, Almirall, patient-reported outcomes in patients with moderate-to-severe Amgen, Celgene, Galderma, Janssen, LEO Pharma, Lilly, Menlo plaque psoriasis treated with brodalumab for 5 years in a long- Therapeutics, Merck, Novartis, Pfizer, Sanofi and UCB; and as term, open-label, phase II study. Am J Clin Dermatol 2019; a speaker for AbbVie, Actelion, Almirall, Bristol Myers Squibb, 20:863–71. Celgene, GlaxoSmithKline, Janssen, Merck, Novartis, Pfizer, 20 Papp KA, Blauvelt A, Bukhalo M et al. Risankizumab versus ustek- Roche and Sandoz. J.Z., S.R., R.S., Y.Z. and A.M.S. are full- inumab for moderate-to-severe plaque psoriasis. N Engl J Med 2017; time employees of AbbVie, and may hold AbbVie stock and/ 376:1551–60. British Journal of Dermatology (2021) 185, pp1135–1145 © 2021 AbbVie Inc. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists 13652133, 2021, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/bjd.20595 by Readcube (Labtiva Inc.), Wiley Online Library on [30/01/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Long-term efficacy and safety of risankizumab, K.A. Papp et al. 1145 or stock options. G.A. is a former employee of AbbVie, and for unlicensed products and indications. This clinical trial data- may hold AbbVie stock and/or stock options. C.L. has received set can be requested by any qualified researchers who engage honoraria as a consultant or advisory board member for Abb- in rigorous, independent scientific research and will be pro- Vie, Amgen, Boehringer Ingelheim, Celgene, Dermira, Janssen, vided following review and approval of a research proposal LEO Pharma, Lilly, Ortho Dermatologics, Pfizer, Sandoz, UCB and statistical analysis plan and execution of a data sharing and Vitae Pharmaceuticals; and as a speaker for AbbVie, agreement. Data requests can be submitted at any time and Amgen, Celgene, Lilly, Novartis, Sun Pharma and UCB; and the data will be accessible for 12 months, with possible exten- has received fees for services as a principal investigator for sions considered. For more information on the process, or to Actavis, Amgen, Boehringer Ingelheim, Celgene, Cellceutix, submit a request, visit the following link: https://www.Abb Coherus, Corrona, Dermira, Galderma, Glenmark, Janssen, Vie.com/our-science/clinical-trials/clinical-trials-data-and-inf LEO Pharma, Lilly, Merck, Novartis, Novella Clinical, Pfizer, ormation-sharing/data-and-information-sharing-with-qualif Sandoz, Sienna Biopharmaceuticals, Stiefel, UCB and Warner ied-researchers.html. Chillcott. Supporting Information Appendix 2 Additional Supporting Information may be found in the online version of this article at the publisher’s website: Data availability Figure S1 Mean percentage change from baseline in Psoria- AbbVie is committed to responsible data sharing regarding the sis Area and Severity Index. clinical trials we sponsor. This includes access to anonymized, Table S1 Patients achieving ≥ 90% improvement in Psoria- individual and trial-level data (analysis datasets), as well as sis Area and Severity Index by patient subgroup. other information (e.g. protocols and clinical study reports), Table S2 Patients achieving 100% improvement in Psoriasis as long as the trials are not part of an ongoing or planned reg- Area and Severity Index by patient subgroup. ulatory submission. This includes requests for clinical trial data Table S3 Treatment-emergent serious infections. © 2021 AbbVie Inc. British Journal of Dermatology British Journal of Dermatology (2021) 185, pp1135–1145 published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists