14683083, 2021, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jdv.16816 by Readcube (Labtiva Inc.), Wiley Online Library on [25/01/2023]. 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 DOI: 10.1111/jdv.16816 JEADV ORIGINAL ARTICLE Complete clearance and psoriasis area and severity index response for brodalumab and ustekinumab in AMAGINE-2 and -3 R.B. Warren,1,* J.B. Hansen,2 K. Reich,3 C. Paul,4 L. Puig5 1 Dermatology Centre, The University of Manchester, Salford Royal NHS Foundation Trust, NIHR Manchester BRC Centre, Manchester, UK 2 LEO Pharma, Ballerup, Denmark 3 Institute for Health Services Research in Dermatology and Nursing, University Medical Center Hamburg-Eppendorf , Skinflammation® Center, Hamburg, Germany 4 Toulouse University and Larrey Hospital, Toulouse, France 5 Department of Dermatology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona School of Medicine, Barcelona, Spain *Correspondence: R.B. Warren. E-mail: richard.warren@manchester.ac.uk Abstract Background Modern biologics achieve complete skin clearance [100% improvement in psoriasis area and severity index (PASI 100)] in 30–45% of psoriasis patients. Cumulative benefit considering rapidity, frequency and sustainability of response has not been thoroughly investigated. Objectives Compare the frequency, rapidity and sustainability of PASI 90 and 100 response in patients with moderate- to-severe psoriasis treated with brodalumab or ustekinumab. Methods Integrated analyses of the brodalumab Phase III AMAGINE-2 (NCT01708603) and -3 (NCT01708629) trials were performed to determine proportion of patients achieving PASI response per visit; corresponding odds ratios (OR) were calculated. Cumulative clinical benefit of treatment was determined with area-under-the-curve (AUC) analysis. Cumulative incidence of response was analysed using a competing risk model of PASI response or rescue. Sustained response was evaluated by time to inadequate response using Kaplan–Meier methods. Proportion of time spent in differ- ent response states was descriptively analysed. Association between PASI response and health-related quality of life [Dermatology Life Quality Index (DLQI)] was assessed using data from all treatment groups from AMAGINE-1, -2 and -3. Results A significantly higher proportion of patients treated with brodalumab achieved PASI 100 vs. ustekinumab (Week 52: 51% vs. 28%; OR [95% CI] 2.8 [2.1, 3.7]; P < 0.0001), with significant differences observed from Week 4. Cumulative benefit through 52 weeks was 69% higher with brodalumab (AUC ratio: 1.69; P < 0.001). Brodalumab patients were also significantly more likely to achieve a PASI 100 at least once over 52 weeks vs. ustekinumab (76% vs. 52%; P < 0.0001). Once response was achieved, brodalumab patients had a low likelihood of failure or need for rescue. There was significant positive association between PASI response level and DLQI0/1 achievement (P < 0.0001). Conclusion Brodalumab treatment resulted in significantly higher levels of skin clearance, longer sustained response and greater cumulative treatment benefit vs. ustekinumab. Received: 8 April 2020; Accepted: 2 July 2020 Conflicts of interest JB Hansen is an employee of LEO Pharma. No other conflicts of interest have been declared. Dr Warren has been a con- sultant for and has received grants from AbbVie, Almirall, Amgen, Avillion, Arena Pharmaceuticals. Boehringer Ingelheim, Celgene, Eli Lilly, Janssen, LEO Pharma, Novartis, Pfizer, Sanofi and UCB Pharma. Dr Puig has received grants/research funding, honoraria or consultation fees from, or has served as a speaker or clinical trial investigator for Abbvie, Almirall, Amgen, Baxalta, Biogen, Boehringer Ingelheim, Celgene, Gebro, Janssen, LEO Pharma, Lilly, Merck-Serono, MSD, Mylan, Novartis, Pfizer, Regeneron, Roche, Samsung-Bioepis, Sandoz, Sanofi and UCB. Dr Paul has been a consultant for and has received grants from AbbVie, Almirall, Amgen, Boehringer Ingelheim, Celgene, Eli Lilly, Janssen, LEO Pharma, Novartis, Pfizer, Sandoz and UCB Pharma. Dr. Reich has been a consultant for and/or has received honoraria and/or investigator fees from AbbVie, Affibody, Almirall, Amgen, Biogen-Idec, Boehringer Ingelheim; Bristol-Myers Squibb, Celgene, Covagen, Eli Lilly, Forward Pharma, Fresenius Medical Care, Galapagos, GlaxoSmithKline, Janssen, JEADV 2021, 35, 450–457 © 2020 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. 14683083, 2021, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jdv.16816 by Readcube (Labtiva Inc.), Wiley Online Library on [25/01/2023]. 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 Skin clearance: brodalumab vs. ustekinumab 451 Kyowa Kirin, LEO Pharma, Medac, Merck Sharp & Dohme, Miltenyi, Novartis, Ocean Pharma, Pfizer, Samsung Bioepis, Sandoz, Sanofi, Sun Pharma, Takeda, UCB Pharma, Valeant, XBiotech and Xenoport. Funding sources The AMAGINE-1, AMAGINE-2 and AMAGINE- 3 trials were sponsored by Amgen and AstraZeneca; this analysis was performed by LEO Pharma. Medical writing support was provided by Ian Eustace from Adelphi Communications Ltd, Bollington, UK, funded by LEO Pharma. Introduction We report an integrated analysis of the AMAGINE Phase III Psoriasis is a chronic, systemic inflammatory skin disease that randomized controlled trials evaluating proportions of patients affects 2–3% of the worldwide population.1–3 Management of achieving PASI 100 and PASI 90 with brodalumab vs. ustek- moderate-to-severe psoriasis may require phototherapy, non-bi- inumab [a human immunoglobulin G1κ (IgG1κ) monoclonal ologic systemic agents and biologics.4 These agents target cytoki- antibody targeting the p40 subunit that is common to IL-12 and nes responsible for psoriasis manifestations, including IL-23] over 52 weeks. We determined the cumulative benefit of interleukin 17 (IL-17), interleukin 23 (IL-23) and tumour necro- brodalumab treatment in patients with moderate-to-severe pso- sis factor-alpha (TNF-alpha).4,5 riasis using an AUC analysis and investigated the association Brodalumab is a fully human monoclonal antibody that tar- between PASI response and QoL. gets the IL-17 receptor A (IL-17 RA), a common subunit of mul- tiple heterodimeric IL-17 receptor complexes.6 It directly blocks Methods IL-17 by binding to its receptor, thereby inhibiting downstream signalling of multiple IL-17 family cytokines that are involved in Trial design and patients the pathogenesis of psoriasis,6 as opposed to specifically target- Data were pooled from a Phase III randomized, double-blind, ing IL-17A like secukinumab and ixekizumab.7,8 Results from placebo-controlled, 52-week trial of brodalumab (AMAGINE-1, Phase III clinical trials show that brodalumab provides high NCT01708590)9 and two Phase III randomized, double-blind, levels of skin clearance for up to 52 weeks, in patients with mod- placebo- and ustekinumab-controlled 52-week trials of bro- erate-to-severe psoriasis.9,10 dalumab (AMAGINE-2, NCT01708603 and AMAGINE-3, Despite the availability of numerous therapies, many patients NCT01708629).10 Detailed descriptions of these trial designs do not achieve complete clearance.11–14 The Psoriasis Area and were previously published9,10 and are illustrated in Figure S1. In Severity Index (PASI) is the most widely used tool for measuring brief, all three trials enrolled patients ≥18 years of age with mod- treatment effect of psoriasis medications. PASI 75 response erate-to-severe plaque psoriasis of ≥6 months’ duration, defined (≥75% reduction from baseline in PASI score) has long been a as a PASI score ≥12, static Physician’s Global Assessment treatment goal for plaque psoriasis,15–18 but studies of newer (sPGA) score of ≥3, and ≥10% body surface area (BSA) involve- biologics (particularly anti-IL-17 and IL-23 therapies) also ment. A description of AMAGINE-1 is provided in the include PASI 90 and 100.9,10,19–23 Complete skin clearance may Appendix S1, and the study design is summarized in Figure S1a. be the next clinically meaningful treatment goal, as it is associ- Results of AMAGINE-1 were analysed for associations between ated with substantially reduced psoriasis symptom severity and PASI and Dermatology Life Quality Index (DLQI). improved quality of life (QoL).24–26 Even limited residual skin The studies were conducted in accordance with applicable disease can impact patients’ QoL, since incremental improve- country and International Conference on Harmonisation (ICH) ments in QoL have been observed between PASI 100 and PASI Good Clinical Practice (GCP) regulations/guidelines. The insti- 90.24–26 tutional review board at each participating centre approved the Traditional efficacy end points at fixed time points in clinical study protocols. All patients provided written informed consent. trials may not be sufficient for fully understanding treatment Sites maintained compliance with the Health Insurance Portabil- benefit over time. The physical, psychological, social and eco- ity and Accountability Act or relevant regional regulations. nomic burden of psoriasis may cumulatively result in failure to In AMAGINE-2 and AMAGINE-3 (Figure S1b), patients were achieve ‘full life potential’ in some patients, a concept known as randomized 2 : 2 : 1 : 1 to receive brodalumab 210 mg, bro- ‘cumulative life course impairment’ (CLCI).27–29 As the impact dalumab 140 mg, ustekinumab (45 mg for patients with a body of psoriasis is continuous, cumulative treatment benefit using an weight ≤100 kg and 90 mg for patients >100 kg on Day 1, Week area-under-the-curve (AUC) analysis should be considered.30 4, and Q12W thereafter) or placebo on Day 1, as well as Weeks This estimates total time spent at a particular PASI response 1, 2, 4, 6, 8 and 10. At Week 12, brodalumab patients were re- level, capturing the rapidity and sustainability of response. randomized 2 : 2 : 2 : 1 to receive a brodalumab maintenance JEADV 2021, 35, 450–457 © 2020 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology 14683083, 2021, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jdv.16816 by Readcube (Labtiva Inc.), Wiley Online Library on [25/01/2023]. 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 452 Warren et al. dose of 210 mg Q2W or 140 mg Q2W, Q4W or Q8W, while rate over 52 weeks). P-values for treatment differences of bro- ustekinumab patients continued to receive ustekinumab Q12W, dalumab vs. ustekinumab were tested using a t-test. Ratios of and placebo patients received 210 mg of brodalumab Q2W. AUC (brodalumab total AUC value divided by ustekinumab total Patients were eligible for rescue treatment if they had inade- AUC value) were calculated, with values >1.0 indicating a greater quate response (defined as sPGA ≥3 or persistent values of 2 clinical benefit for brodalumab vs. ustekinumab, and 95% confi- over a ≥4-week period at, or after, Week 16). At Week 16, all dence intervals (CIs) were calculated via bootstrapping. patients received rescue treatment with brodalumab 210 mg. 3 Cumulative incidence of skin clearance over 52 weeks, After Week 16 and through Week 52, patients on brodalumab together with adjusted hazard ratios (HR) and 95% confi- were rescued with brodalumab 210 mg Q2W, while those on dence intervals, was calculated using a competing risk model ustekinumab remained on ustekinumab. Rescue treatment was with outcomes of the following: blinded. After receiving rescue treatment for ≥12 weeks, patients a Achieving PASI 90/100 were assessed for non-response and discontinued if they were b Inadequate response defined as sPGA ≥3 or persistent val- non-responders. ues of 2 over at least a 4-week period at or after Week 16. The primary objectives of AMAGINE-2 and -3 were to evalu- Different outcomes were used because PASI 90/100 is the ate the efficacy of brodalumab vs. placebo at Week 12 with most sensitive measure of skin clearance and sPGA is more respect to the proportion of patients achieving PASI 75, and appropriate for capturing response. sPGA score of 0 or 1, as well as the efficacy of brodalumab vs. Once PASI 90/100 was achieved, sustained response was eval- ustekinumab at Week 12, with respect to the proportion of uated as the time to an inadequate response, using Kaplan–- patients achieving PASI 100. Meier methods. Results were analysed descriptively, as the subpopulations of PASI responders with brodalumab and ustek- Trial assessments inumab might be different. We used PASI, sPGA and DLQI scores, measured throughout 4 Proportions of patients achieving different levels of treatment the trials at least once every 2–4 weeks, to evaluate disease sever- response (rescue treatment, PASI <50, 50 to <75, 75 to <90, ity, treatment response and patient-reported outcomes, respec- 90 to <100 and 100) and number of days spent in the differ- tively. ent levels of response were determined. 5 Association between skin clearance and QoL Integrated efficacy analyses Pooled data from all treatment arms in AMAGINE-1, -2 and -3 were analysed at all time points and for all treatment arms to Treatment benefit: skin clearance These analyses included assess the association between PASI response and the proportion pooled data from AMAGINE-2 and -3 patients randomized to of patients achieving a DLQI score of 0 or 1 (no effect at all on receive the approved dose of brodalumab (210 mg Q2W) or patient’s life31,32), as a measure of QoL. The linear trend between ustekinumab at constant dosing for the entire 52-week treatment DLQI 0/1 and PASI was evaluated using an adjusted generalized period. estimating equation (GEE) model. Missing data were handled The analyses compared the efficacy of brodalumab vs. ustek- using non-responder imputation. inumab in terms of the following: 1 Proportion of patients with PASI 90 and PASI 100 at a given time point over Weeks 0–52 and corresponding adjusted Results odds ratio (OR) using Cochran–Mantel–Haenszel method Patients were determined. A total of 929 patients (brodalumab 210 mg, n = 339; ustek- 2 Cumulative clinical benefit was assessed as the integrated inumab, n = 590) from AMAGINE-2 and -3 were included in AUC over 52 weeks for the percentage of patients achieving the analyses of skin clearance and cumulative treatment benefit. PASI 90 and 100. The AUC was calculated using the trape- Overall, treatment groups were well balanced in terms of patient zoidal rule: demographics and baseline characteristics (Table 1). Pooled data from 4373 patients from all treatment arms of 1 AMAGINE-1, -2 and -3 were included in the analysis of correla- Total AUC ¼ ∑N i¼0 ðP i þ P iþ1 ÞðT iþ1  T i Þ tion between skin clearance and QoL. 2 where N = number of assessment time points, 0 = baseline, Efficacy analyses Pi = percentage of responders, Ti = time point. Cumulative benefit was calculated as a percentage of the maxi- Proportion of patients achieving skin clearance through mum possible nominal AUC of 5200 (based on a 100% response 52 weeks A consistently higher proportion of brodalumab- JEADV 2021, 35, 450–457 © 2020 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology 14683083, 2021, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jdv.16816 by Readcube (Labtiva Inc.), Wiley Online Library on [25/01/2023]. 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 Skin clearance: brodalumab vs. ustekinumab 453 Table 1 Patient demographic and baseline characteristics (pooled significantly greater cumulative benefit for PASI 100 than ustek- data by treatment arm from the AMAGINE-2 and -3 trials) inumab (Fig. 1). Cumulative benefit (nominal AUC value) for Baseline characteristic Brodalumab Ustekinumab PASI 100 was 2251 (43.3%) for brodalumab vs. 1332 (25.6%) (n = 339) (n = 590) for ustekinumab, with a treatment difference of 919 (17.7%; Age, years 44.5 (13.4) 45.1 (13.0) P < 0.0001). Incremental clinical benefit for PASI 100 with bro- Male, n (%) 230 (67.8) 404 (68.5) dalumab was 69% higher than ustekinumab (AUC ratio: 1.69 Weight, kg 90.4 (24.2) 91.0 (22.9) [95% CI, 1.5, 1.9]; P < 0.0001). Cumulative benefit for PASI 90 Race white, n (%) 308 (90.9) 532 (90.2) was 3192 (61.4%) for brodalumab vs. 2252 (43.3%) for ustek- Disease duration, years 17.3 (11.7) 18.6 (12.2) inumab, with a treatment difference of 940 (18.1%; P < 0.0001) % BSA involvement 27.0 (16.2) 27.6 (18.6) (Fig. 1). Incremental clinical benefit for PASI 90 was 42% higher PASI score 20.4 (7.9) 20.0 (8.4) with brodalumab than ustekinumab (AUC ratio: 1.42 [95% CI, DLQI score 14.8 (7.3) 14.9 (7.3) 1.3, 1.5]; P < 0.0001). NAPSI score 9.3 (3.6) 9.9 (3.6) PSI score 19.1 (7.0) 18.7 (6.9) Competing risk model for achieving skin clearance Cumula- PsA, n (%) 79 (23.3) 110 (18.6) Systemic/biologic naive, n (%) 144 (42.5) 246 (41.7) tive incidence of PASI 100 over 52 weeks showed that bro- Systemic experienced without 99 (29.2) 188 (31.9) dalumab patients were significantly more likely to achieve PASI biologics, n (%) 100 at least once over 52 weeks, than ustekinumab patients, with Biologic experienced without 50 (14.8) 95 (16.1) 76% (95% CI, 71–80%) responders on brodalumab vs. 52% failure, n (%) (95% CI, 48–56%) on ustekinumab (HR 2.06; 95% CI, 1.74, Biologic failure, n (%) 46 (13.6) 61 (10.3) 2.44; P < 0.0001) (Fig. 2). Median time to PASI 100 was Data are mean (SD) unless otherwise stated. 14 weeks with brodalumab vs. 44 weeks with ustekinumab. BSA, body surface area; DLQI, Dermatology Life Quality Index; NAPSI, Nail Cumulative incidence of achieving PASI 90 at least once over Psoriasis Severity Index; PASI, Psoriasis Area and Severity Index; PsA, 52 weeks was also higher 87.3% (95% CI, 83.3, 90.5) with bro- psoriatic arthritis; PSI, Psoriasis Symptom Inventory. dalumab vs. 71.4% (95% CI, 67.6, 74.8) for ustekinumab (HR treated patients achieved PASI 100 and PASI 90 at any given 2.08; 95% CI, 1.78, 2.43; P < 0.0001). time point over the 52-week treatment period, compared with At the end of the maintenance phase, 90.1% (95% CI, 86.2, ustekinumab-treated patients (Fig. 1). Brodalumab was associ- 94.2%) of patients who achieved PASI 100 with brodalumab had ated with more rapid achievement of PASI 100 and PASI 90 vs. sustained response vs. 76.7% (95% CI, 66.8–88.2%) on ustek- ustekinumab, with significant differences observed by Week 4: inumab. 83.2% (95% CI, 78.9, 87.7) of brodalumab patients and PASI 100 was achieved in 9.4% (95% CI, 6.5, 13.1) of bro- 62.2% (95% CI, 50.9, 75.9) of ustekinumab patients sustained dalumab patients vs. 0.7% (95% CI, 0.2, 1.7) of ustekinumab PASI 90. patients (P < 0.0001), and PASI 90 was achieved in 26.8% of brodalumab patients vs. 3.4% of ustekinumab patients Proportion of time spent in treatment response Overall, a (P < 0.0001). Skin clearance rates remained higher with bro- higher proportion of time was spent in PASI 100 response on dalumab throughout the study period, with 51.0% (95% CI, brodalumab (42.5%) than ustekinumab (25.2%) (Fig. 3). The 45.6, 56.5) and 63.1% (95% CI, 57.7, 68.3) of brodalumab mean (SD) number of days spent in PASI 100 response was patients achieving PASI 100 and PASI 90, respectively, at Week 154.7 (124.4) days with brodalumab vs. 91.7 (112.4) days with 52 vs. 28.1% (95% CI, 24.5, 32.0) and 42.7% (95% CI, 38.7, ustekinumab. Additionally, rescue treatment accounted for a 46.8) of ustekinumab patients, respectively (all P < 0.0001). greater proportion of time in ustekinumab patients (25.7%) vs. The likelihood of achieving complete clearance was numeri- brodalumab patients (15.2%). cally greater for brodalumab than ustekinumab at all time points assessed, from Week 2, and was significant from Week 4 (OR Association between skin clearance and QoL A significant 15.5; 95% CI, 5.4, 44.4), with ORs at Weeks 12 and 52 of 2.8 association was observed between the PASI response level and (95% CI, 2.1, 3.8) and 2.8 (95% CI, 2.1, 3.7), respectively(all QoL measured by achievement of DLQI 0/1, regardless of treat- P < 0.0001). The likelihood of achieving PASI 90 consistently ment arm (P < 0.0001; Fig. 4). A higher proportion of patients and significantly favoured brodalumab over ustekinumab from who achieved PASI 100 also achieved DLQI 0/1 (83.5%) vs. PASI Week 2 (OR 4.8; 95% CI, 1.7, 13.5: P = 0.001), with ORs at 90 to <100 (64.3%). Weeks 12 and 52 of 2.3 (95% CI 1.8, 3.1) and 2.5 (95% CI 1.9, 3.4), respectively (both P < 0.0001). Discussion In this integrated analysis of data from the AMAGINE trials, Cumulative treatment benefit Based on an analysis of the AUC brodalumab rapidly achieved high levels of complete and sus- through 52 weeks, brodalumab was associated with a tained skin clearance and a greater overall cumulative treatment JEADV 2021, 35, 450–457 © 2020 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology 14683083, 2021, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jdv.16816 by Readcube (Labtiva Inc.), Wiley Online Library on [25/01/2023]. 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 454 Warren et al. (a) PASI 100 rates and normalized AUC 100 OR* OR* Cumulative (week 52) OR* 100 Week 4 Week 12 clinical benefit ratio Week 52 15.5 2.8 2.8 90 (95% CI 5.4, 44.4) (95% CI 2.1, 3.8) 1.69 (95% CI 2.1, 3.87) 90 (1.50, 1.92) Normalized AUC of PASI 100 PASI 100 responders (%) 80 80 (% of maximum value) 70 70 60 60 50 50 40 40 30 30 20 20 Brodalumab 10 Absolute incremental 10 Brodalumab benefit = 17.7% Ustekinumab 0 0 Ustekinumab 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 Week (b) PASI 90 rates and normalized AUC Cumulative (week 52) clinical benefit ratio 1.42 100 OR* OR* (1.30, 1.54) OR* Week 4 Week 12 Week 52 100 90 11.1 2.3 2.4 (95% CI 6.6, 18.5) (95% CI 1.7, 3.0) (95% CI 1.8, 3.3) 90 80 Normalized AUC of PASI 90 80 PASI 90 responders (%) (% of maximum value) 70 70 60 60 50 50 40 40 30 30 Absolute incremental 20 benefit = 18.1% 20 Brodalumab 10 10 Brodalumab Ustekinumab Ustekinumab 0 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 Week Figure 1 Percentage of patients achieving (a) PASI 100 and cumulative benefit (AUC as % of maximum AUC value) and (b) PASI 90 and cumulative benefit (AUC as % of maximum AUC value) at each time point. Pooled data from the AMAGINE-2 and -3 trials. Brodalumab n = 339; Ustekinumab n = 590; Maximum AUC value: 52 weeks × PASI maximum response (100%) = 5200. *OR values apply to per- centage of patients achieving PASI response. AUC, area under the curve; CI, confidence interval; NRI, non-responder imputation; OR, odds ratio; Q2W, every 2 weeks. benefit in patients with moderate-to-severe psoriasis through treatment satisfaction and QoL in both clinical trial and real- 52 weeks vs. ustekinumab. world settings.24–26,33,34 In our analysis, level of PASI response Complete skin clearance (PASI 100) is associated with sub- was closely associated with degree of QoL improvement, as mea- stantially reduced physical burden of psoriasis, improved sured by DLQI 0/1. PASI 100 responders appeared more likely to JEADV 2021, 35, 450–457 © 2020 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology 14683083, 2021, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jdv.16816 by Readcube (Labtiva Inc.), Wiley Online Library on [25/01/2023]. 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 Skin clearance: brodalumab vs. ustekinumab 455 Complete clearance Inadequate response* Never achieved complete clearance or had inadequate response* Time to achievement of complete clearance by 50% of patients Brodalumab 210 mg Q2W (n = 339) Ustekinumab (n = 590) 100 100 20% 90 90 80 80 40% 4% Cumulative incidence (%) Cumulative incidence (%) 70 70 60 60 8% 14 weeks 44 weeks 50 50 76% 40 40 30 30 52% 20 20 10 10 0 0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Time to event (weeks) Time to event (weeks) Induction Maintenance Induction Maintenance Figure 2 Cumulative incidence of patients achieving PASI 100 at least once at any given time point (competing risk analysis). *Defined as a static Physician’s Global Assessment ≥3 or persistent values of 2 over at least a 4-week period at or after week 16. Q2W, every 2 weeks. achieve DLQI 0/1 than those with PASI 90. These findings reflect added benefit in patients achieving PASI 90. A greater cumula- those reported by Armstrong et al.,35 showing that the PASI 90 tive benefit over 52 weeks was also recently observed with the or 100 responders among 1829 patients in two guselkumab clini- anti-IL-17A monoclonal antibody, secukinumab, when com- cal trials had greater improvements in their DLQI total score pared with the TNF-alpha inhibitor, etanercept, in patients with than PASI 75 to