14683083, 2021, 10, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jdv.17433 by Readcube (Labtiva Inc.), Wiley Online Library on [03/02/2023]. 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.17433 JEADV ORIGINAL ARTICLE Complete clearance and Psoriasis Area and Severity Index response for brodalumab and ustekinumab by previous treatment history in AMAGINE-2 and AMAGINE-3 K. Reich,1,* J.B. Hansen,2 L. Puig,3 M.P. Konstantinou,4 R.B. Warren5 1 Translational Research in Inflammatory Skin Diseases, Institute for Health Services Research in Dermatology and Nursing, University Medical Center Hamburg-Eppendorf, Hamburg, Germany 2 LEO Pharma, Ballerup, Denmark 3 Department of Dermatology, Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, Barcelona, Spain 4 Service de Dermatologie, Larrey Hospital, Toulouse, France 5 Dermatology Centre, Salford Royal NHS Foundation Trust, Manchester NIHR Biomedical Research Centre, University of Manchester, Manchester, UK *Correspondence: K. Reich. E-mail: kreich@jerucon.com Abstract Background The pathway for treatment of psoriasis is partly dependent upon disease severity, and patients may expe- rience inadequate response at any point along the treatment pathway. Patients who repeatedly fail therapy represent a population in whom effective and well-tolerated treatment options are limited. Objectives To investigate and describe patients achieving Psoriasis Area and Severity Index (PASI) 100 and cumula- tive treatment benefit over time in patients with moderate-to-severe psoriasis receiving brodalumab or ustekinumab by prior treatment. Methods We conducted a post hoc analysis of data from two phase 3, randomized, controlled, 52-week AMAGINE tri- als of brodalumab to describe patients who achieved complete clearance as measured by PASI 100 by prior treatment subgroup (naı̈ve to systemic and biologic treatment, systemic-treated but biologic-naı̈ve, biologic-treated without failure, and biologic-treated with failure). A competing risk model was used to assess cumulative incidence over a 52-week per- iod with outcomes of PASI 100 or inadequate response. Cumulative clinical benefit of treatment was determined with an area under the curve analysis. Results The 52-week cumulative incidence of patients achieving PASI 100 was consistently higher for brodalumab vs. ustekinumab across treatment pathway subgroups (76% vs. 58% in systemic/biologic-naı̈ve patients, 78% vs. 55% in systemic-treated/biologic-naı̈ve patients, 75% vs. 41% in biologic-treated patients without failure, and 70% vs. 30% in biologic-treated patients with failure). Rates of inadequate response were lower with brodalumab compared with ustek- inumab across all subgroups. Cumulative treatment benefit was also higher for all subgroups treated with brodalumab compared with those treated with ustekinumab. Conclusion Treatment with brodalumab was associated with higher levels of complete clearance and greater cumula- tive benefit over time compared with ustekinumab, in patients with moderate-to-severe psoriasis, regardless of prior treatment experience. Received: 3 March 2021; revised: 26 April 2021; Accepted: 19 May 2021 Conflicts of interest KR 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, Frese- nius Medical Care, Galapagos, GlaxoSmithKline, Janssen, 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. JBH is an employee of LEO Pharma. MPK has been a principal and sub-investigator for AbbVie, Boehringer Ingelheim, LEO Pharma, Pfizer and Sanofi, and a speaker and consultant for AbbVie, Janssen and LEO Pharma. LP 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 Pharma. RBW has been a consultant for and has received grants from AbbVie, Almirall, Amgen, Avillion, Arena JEADV 2021, 35, 2034–2044 © 2021 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 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. 14683083, 2021, 10, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jdv.17433 by Readcube (Labtiva Inc.), Wiley Online Library on [03/02/2023]. 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 Psoriasis clearance with brodalumab by prior treatment history 2035 Pharmaceuticals, Boehringer Ingelheim, Celgene, Eli Lilly, Janssen, LEO Pharma, Novartis, Pfizer, Sanofi and UCB Pharma. Funding source The brodalumab clinical study programme was sponsored by Amgen and AstraZeneca. This analysis was performed by LEO Pharma. Introduction population.12 Furthermore, in an analysis of data from these tri- Psoriasis vulgaris is a chronic inflammatory skin disease which als investigating the impact of previous biologic exposure, rates affects approximately 3% of the population and is characterized of skin clearance with brodalumab were shown to be similar in by red plaques with silvery scaling, commonly involving the biologic-naı̈ve and biologic-experienced patients.13 scalp, elbows, knees and presacral region.1-3 Psoriasis signifi- The Psoriasis Area and Severity Index (PASI) 75 (proportion cantly impacts patients’ quality of life (QoL).1 Severity of psoria- of patients with ≥75% reduction in baseline PASI) was tradi- sis is partly defined by the total body surface area (BSA) affected, tionally accepted as the primary treatment endpoint for assessing with mild, moderate and severe disease involving <3%, 3–10% efficacy in clinical trials and guidelines.5,14-16 However, more rig- and ≥10% of the BSA, respectively. orous treatment goals (PASI 90 and PASI 100) have become fea- Mild-to-moderate psoriasis can be adequately controlled in sible with the emergence of modern biologics such as the anti- most patients by topical therapies including corticosteroids and IL-17 and IL-23 therapies.17 Many patients can achieve complete vitamin D3 analogs, or phototherapy.1 In patients with skin clearance (PASI 100)11,18 resulting in further improvements moderate-to-severe disease, non-biologic systemic medications, in QoL compared with patients with almost clear skin (PASI including methotrexate, retinoids and ciclosporin, are appropri- 90).19-22 It may also change the natural history of the disease, ate. Biologic agents are used when there is an inadequate including long-term disease remission.23 Additionally, as the response to conventional systemic agents.1, 4, 5 impact of psoriasis on patients is continuous, Armstrong et al. In some patients, biologic treatment of psoriasis may result in proposed an integrated analysis of PASI over time using an area a primary failure (initial non-response), which may be influ- under the curve (AUC) analysis.24 enced by baseline characteristics such as increased body mass In this post hoc analysis, we investigated patients achieving index,6 or secondary failure (loss of efficacy after initial complete clearance and the cumulative clinical benefit of treat- response). Such loss of efficacy may reflect the development of ment with brodalumab vs. ustekinumab over a 52-week period neutralizing antidrug antibodies. Under these circumstances, in the AMAGINE-2 and AMAGINE-3 trials according to prior improved efficacy, safety and/or tolerability may be achieved by treatment with systemic medications and/or biologic agents. The switching the patient to a different biologic agent, but there are aim was to compare the rapidity and sustainability of observed currently insufficient data to support specific switching recom- treatment responses for the two treatments for patients with dif- mendations.1 Moreover, treatment efficacy is less likely to ferent prior treatment histories. improve for subsequently offered biologics.7 Consequently, there is an unmet need to establish which, if any, alternative biologic, Materials and methods will be most likely to offer benefit in patients experiencing either a primary or a secondary failure. Trial design and patients Brodalumab is a fully humanized monoclonal antibody with a Data were pooled from phase 3, 52-week, placebo- and unique mechanism of action that targets the IL-17 receptor A ustekinumab-controlled trials of brodalumab: AMAGINE-2 subunit (IL-17RA).8 Unlike biologics that target IL-17A such as (NCT01708603) and AMAGINE-3 (NCT01708629).11 The study secukinumab and ixekizumab,9,10 brodalumab inhibits the designs are provided in Figure S1 and have previously been downstream signalling of multiple members of the IL-17 family described.11 Briefly, the studies included patients ≥18 years of age, of cytokines involved in the pathogenesis of psoriasis by directly with ≥6 months’ duration of moderate-to-severe plaque psoriasis blocking the interaction of several IL-17 isoforms with the IL- (PASI score ≥12, static Physician’s Global Assessment [sPGA] 17RA subunit of their receptors.8 Results from phase 3 score ≥3 and BSA involvement ≥10%). Patients were randomized AMAGINE-2 and AMAGINE-3 clinical trials have shown that 2:2:1:1 to receive brodalumab 210 mg, brodalumab 140 mg, ustek- high levels of skin clearance in patients with moderate-to-severe inumab (45 mg for patients with bodyweight ≤100 kg and 90 mg psoriasis can be achieved with brodalumab for up to 52 weeks,11 for >100 kg) or placebo, on Day 1, and then on Weeks 1, 2, 4, 6, 8 with longer sustained response and greater cumulative clinical and 10. At Week 12, patients receiving brodalumab were re- treatment benefits vs. ustekinumab in the overall pooled study randomized 2:2:2:1 to receive a brodalumab maintenance dose of JEADV 2021, 35, 2034–2044 © 2021 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, 10, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jdv.17433 by Readcube (Labtiva Inc.), Wiley Online Library on [03/02/2023]. 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 2036 Reich et al. 210 mg every 2 weeks (Q2W) or 140 mg Q2W, every 4 weeks, or Cumulative benefit was calculated as a percentage of the every 8 weeks. Patients receiving ustekinumab continued to receive maximum possible nominal AUC of 5200 (based on a 100% ustekinumab every 12 weeks and patients receiving placebo response rate over 52 weeks). P-values for treatment differ- switched to brodalumab 210 mg Q2W. ences of brodalumab vs. ustekinumab were tested using a Patients were eligible for rescue treatment at Week 16, if they Wilcoxon test. Ratios of AUC (brodalumab total AUC value had an inadequate response (sPGA ≥3, or sPGA ≥2 for ≥4 weeks divided by ustekinumab total AUC value) were calculated, at, or after, Week 16) and were treated with brodalumab 210 mg with values >1.0 indicating a greater clinical benefit for bro- Q2W. From Week 16 through Week 52, patients on brodalumab dalumab vs. ustekinumab. Bootstrapping was used to calcu- were rescued with brodalumab 210 mg Q2W, while those on late 95% CIs. ustekinumab remained on ustekinumab. Rescue treatment was blinded, and after ≥12 weeks, patients were evaluated for response Competing risk model by prior treatment subgroup Cumula- and discontinued if they were non-responders. tive incidence of complete clearance over 52 weeks was analysed by prior treatment subgroup using a competing risk model25 Trial assessments with outcomes of: PASI, sPGA and Dermatology Life Quality Index (DLQI) scores • Achieving PASI 100, or were used to evaluate disease severity, treatment response and • Inadequate response defined as sPGA ≥3 or sPGA ≥2 for QoL, respectively. Measures were obtained throughout the trials more than 4 weeks at, or after Week 16. at least once every 2–4 weeks. Comparisons between treatment arms were performed using subdistribution hazard ratios and associated chi-squared Post hoc efficacy analyses tests26,27 and adjusted for baseline characteristics, as detailed for the responder analyses. Responder analyses for clearance (PASI 90, PASI 100) and DLQI 0/1 at a given time point (Week 0–52) by prior treatment Association between PASI response and QoL Association subgroup These analyses included data from patients random- between PASI and DLQI was examined by all pairs of PASI ized to receive constant dosing of the approved dose of either response category and DLQI 0/1 at the same time point (Weeks brodalumab (210 mg Q2W) or ustekinumab for the entire 52- 0–52), but if either DLQI or PASI were missing the data could week treatment period, subdivided into four subgroups accord- not be included in the analysis. Tests for trend were done using ing to prior treatment history: systemic/biologic-naı̈ve; logistic regression. systemic-treated, biologic-naı̈ve; biologic-treated without failure; biologic-treated with failure. Proportion of time spent in different response states The pro- Proportions of patients achieving PASI 100 and DLQI 0/1 portion of time spent from baseline through Week 52 in PASI responses were presented according to prior treatment history <50, 50–<75, 75–<90, 90–<100 and 100 and requirement for and visits, with comparisons between treatment groups being rescue treatment were calculated for brodalumab and ustek- reported as odds ratios (OR) and 95% confidence intervals (CI) inumab for each prior treatment group. PASI observed per visit calculated using the Cochran–Mantel–Haenszel method and was assumed to apply until the next scheduled visit. A PASI <50 adjusted for study, baseline total bodyweight group (≤100 kg, was assumed for all patients for the period from baseline until >100 kg), geographic region, and within study and subgroup the Week 1 visit. Missing visits were imputed with PASI <50 baseline score (≤median, >median). Non-responder imputation and the planned visit date (study start date + 7 × visit week). (NRI) was used to handle missing data. Pooled data from AMAGINE-2 and AMAGINE-3 were anal- ysed at all time points and by previous treatment subgroups to Cumulative treatment benefit as integrated AUC for PASI 100 assess the association between PASI response and the proportion and DLQI 0/1 by prior treatment subgroup Cumulative clinical of patients achieving a DLQI score of 0 or 1, as a measure of benefit was assessed as the integrated AUC over the 52-week trial QoL. The linear trend between DLQI 0/1 and PASI was evalu- period for the percentage of patients achieving complete clear- ated using an adjusted generalized estimating equation (GEE) ance and using NRI for missing data. The AUC was calculated model. Missing data were handled using NRI. using the trapezoidal rule: Results N 1=2 Total AUC ¼ ∑ ¼0 ðPi þ Piþ1 Þ ðT iþ1  T i Þ i Patients A total of 929 patients (brodalumab 210 mg, n = 339; ustek- where N = number of assessment time points, 0 = baseline, inumab, n = 590) from AMAGINE-2 and AMAGINE-3 were Pi = percentage of responders, Ti = time point. included in the analyses of complete clearance and cumulative JEADV 2021, 35, 2034–2044 © 2021 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, 10, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jdv.17433 by Readcube (Labtiva Inc.), Wiley Online Library on [03/02/2023]. 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 Psoriasis clearance with brodalumab by prior treatment history 2037 Table 1 Demographic and baseline characteristics Baseline characteristics Systemic/biologic-naı̈ve Systemic-treated biologic-naive Brodalumab Ustekinumab Brodalumab Ustekinumab (n = 144, 42.5%) (n = 249, 42.2%) (n = 99, 29.2%) (n = 186, 31.5%) Age, mean (SD) 44.3 (12.8) 44.5 (13.7) 42.2 (13.4) 45.6 (12.8) Weight, mean (SD) 89.6 (19.1) 89.0 (20.9) 89.0 (23.8) 89.3 (21.7) Male, n (%) 103 (71.5) 171 (68.7) 74 (74.7) 132 (71.0) Race white, n (%) 125 (86.8) 224 (90.0) 92 (92.9) 175 (94.1) Duration of disease, years (mean [SD]) 14.1 (10.5) 17.0 (12.4) 17.2 (11.4) 19.7 (12.3) BSA, mean (SD) 25.6 (15.3) 26.8 (17.7) 30.3 (17.9) 29.7 (20.2) PASI, mean (SD) 20.1 (8.1) 19.5 (7.7) 21.7 (8.4) 21.1 (9.8) DLQI, mean (SD) 13.5 (7.0) 14.5 (7.4) 16.0 (7.2) 15.5 (7.3) NAPSI, mean (SD) 9.0 (3.0) 10.2 (3.6) 9.6 (4.1) 9.6 (3.6) PSI, n, mean (SD) 127, 17.7 (7.5) 237, 17.8 (6.9) 94, 19.4 (6.4) 175, 18.8 (6.7) PsA, n (%) 17 (11.8) 31 (12.4) 17 (17.2) 30 (16.1) Baseline characteristics Biologic-treated without failure Biologic-treated with failure Brodalumab Ustekinumab Brodalumab Ustekinumab (n = 50, 14.8%) (n = 95, 16.1%) (n = 46, 13.6%) (n = 60, 10.2%) Age, mean (SD) 49.4 (12.9) 45.1 (13.4) 45.0 (14.8) 46.1 (10.5) Weight, mean (SD) 92.1 (26.4) 96.9 (27.7) 93.8 (34.9) 95.6 (24.1) Male, n (%) 23 (46.0) 61 (64.2) 30 (65.2) 40 (66.7) Race white, n (%) 48 (96.0) 82 (86.3) 43 (93.5) 51 (85.0) Duration of disease, years (mean [SD]) 23.8 (12.0) 19.2 (11.7) 20.3 (12.4) 21.0 (11.4) BSA, mean (SD) 25.8 (15.4) 24.7 (16.9) 25.8 (15.4) 29.0 (19.4) PASI, mean (SD) 19.3 (6.8) 19.1 (7.4) 19.7 (6.7) 20.0 (7.8) DLQI, mean (SD) 15.1 (7.2) 14.8 (7.3) 15.9 (7.8) 14.8 (7.1) NAPSI, mean (SD) 9.2 (2.5) 10.4 (3.8) 9.8 (5.0) 9.4 (3.3) PSI, n, mean (SD) 46, 19.9 (7.2) 90, 20.2 (6.9) 44, 21.1 (6.0) 55, 19.5 (7.0) PsA, n (%) 27 (54.0) 30 (31.6) 18 (39.1) 19 (31.7) BSA, body surface area; DLQI, Dermatology Life Quality Index; NAPSI, Nail Psoriasis Severity Index; PASI, Psoriasis Area and Severity Index; PsA, psoriatic arthritis; PSI, Psoriasis Symptom Inventory; SD, standard deviation. treatment benefit (Table 1). Patients were generally well bal- Efficacy analyses anced in terms of age and weight. There tended to be fewer males in the biologic-treated with and without failure sub- Responder analysis for complete clearance (PASI 100) and groups. Disease durations ranged from 14 to 24 years. Baseline DLQI 0/1 at a given time point (Week 0–52) by prior treatment PASI scores and DLQI scores were similar across the subgroups subgroup There was a clear difference in favour of brodalumab and ranged from 19 to 22 and from 14 to 16. The proportions of in the proportion achieving PASI 100 (Fig. 1a) in each sub- patients with psoriatic arthritis ranged from 12% to 54% group. Regardless of treatment history, brodalumab was associ- (Table 1). ated with earlier achievement of complete clearance and Similar proportions of the brodalumab and ustekinumab consistently higher rates of complete clearance vs. ustekinumab. patients had received prior biologic treatment, with a slightly ORs (95% CI) for complete clearance with brodalumab vs. higher proportion of brodalumab patients having a treatment ustekinumab at Week 52 were as follows: systemic/biologic- failure. This mainly reflects higher rates of failure with inflix- naı̈ve, OR 2.29 (1.47–3.58, P = 0.0002); systemic-treated, imab treatment in this group (Table 2). Of note, eight biologic-naı̈ve, OR 2.87 (1.71–4.83, P < 0.0001); biologic- patients with prior ustekinumab use entered into the trials treated without failure, OR 6.89 (2.64–17.94, P < 0.0001); (Table 2); prior ustekinumab exposures were >40 weeks biologic-treated with failure, OR 5.03 (1.54–16.43, P = 0.0065). before the baseline visit. Analysis of all efficacy endpoints to Similarly, greatest brodalumab treatment benefit vs. ustek- exclude these eight subjects yielded no significant changes to inumab was observed for DLQI, with more patients in the the results. biologic-treated subgroup achieving DLQI 0/1 (Fig. 1b). JEADV 2021, 35, 2034–2044 © 2021 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, 10, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jdv.17433 by Readcube (Labtiva Inc.), Wiley Online Library on [03/02/2023]. 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 2038 Reich et al. Table 2 Summary of prior biologic treatment history for all patients and with respect to specific biologics Baseline characteristics Systemic/biologic-naı̈ve Systemic-treated biologic-naive Brodalumab Ustekinumab Brodalumab Ustekinumab (n = 144, 42.5%) (n = 249, 42.2%) (n = 99, 29.2%) (n = 186, 31.5%) Prior biologic experience 0 (0) 0 (0) 0 (0) 0 (0) Prior biologic-failure 0 (0) 0 (0) 0 (0) 0 (0) Prior biologic use Adalimumab 0 (0) 0 (0) 0 (0) 0 (0) Infliximab 0 (0) 0 (0) 0 (0) 0 (0) Ustekinumab 0 (0) 0 (0) 0 (0) 0 (0) Golimumab 0 (0) 0 (0) 0 (0) 0 (0) Etanercept 0 (0) 0 (0) 0 (0) 0 (0) Onercept 0 (0) 0 (0) 0 (0) 0 (0) Abatacept 0 (0) 0 (0) 0 (0) 0 (0) Alefacept 0 (0) 0 (0) 0 (0) 0 (0) Briakinumab 0 (0) 0 (0) 0 (0) 0 (0) Efalizumab 0 (0) 0 (0) 0 (0) 0 (0) Baseline characteristics Biologic-treated without failure Biologic-treated with failure Brodalumab Ustekinumab Brodalumab Ustekinumab (n = 50, 14.8%) (n = 95, 16.1%) (n = 46, 13.6%) (n = 60, 10.2%) Prior biologic experience 50 (100.0) 95 (100.0) 46 (100.0) 60 (100.0) Prior biologic-failure 0 (0) 0 (0) 46 (100.0) 60 (100.0) Prior biologic use Adalimumab 12 (24.0) 16 (16.8) 30 (65.2) 33 (55.0) Infliximab 6 (12.0) 3 (3.2) 10 (21.7) 11 (18.3) Ustekinumab 0 (0) 2 (2.1) 2 (4.3) 4 (6.7) Golimumab 0 (0) 2 (2.1) 0 (0) 0 (0) Etanercept 25 (50.0) 64 (67.4) 28 (60.9) 47 (78.3) Onercept 2 (4.0) 0 (0) 0 (0) 0 (0) Abatacept 0 (0) 0 (0) 1 (2.2) 0 (0) Alefacept 2 (4.0) 2 (2.1) 2 (4.3) 0 (0) Briakinumab 5 (10.0) 6 (6.3) 2 (4.3) 4 (6.7) Efalizumab 1 (2.0) 2 (2.1) 5 (10.9) 4 (6.7) Cumulative treatment benefit as integrated AUC for PASI 100 for the brodalumab, systemic-treated, biologic-naı̈ve sub- and DLQI 0/1 by prior treatment subgroup Brodalumab group (2941 units). AUC ratios ranged from 1.3 (systemic/ demonstrated similar cumulative treatment benefit (PASI 100) for biologic-naı̈ve) to 1.7 (biologic-treated with failure), all all treatment subgroups, except those who previously experienced P < 0.01 with the highest ratio being observed in the bro- a treatment failure with a biologic (Fig. 1a; Table 3). The decrease dalumab vs. ustekinumab biologic-treated with failure sub- in efficacy in biologic-treated patients was higher with ustek- group (Table 3). inumab, with greater than two-fold reduction in complete clear- ance. Treatment escalation with brodalumab was more likely to Competing risk model by prior treatment subgroup The 52- result in achievement of PASI 100 compared with ustekinumab week cumulative incidence of patients achieving PASI 100 was (AUC ratios ranging from 1.5 [systemic/biologic-naı̈ve] to 2.4 consistently higher for brodalumab vs. ustekinumab across [biologic-treated without failure], all P < 0.001) (Table 3). Differ- prior treatment subgroups (all P < 0.0001). In systemic/ ences in cumulative treatment benefit favouring brodalumab were biologic-naı̈ve patients, 76% [95% CI: 69–84%] of bro- also observed for PASI 90. AUC ratios ranged from 1.3 (systemic/ dalumab patients achieved PASI 100 vs. 58% [52–65%] of biologic-naı̈ve) to 1.9 (biologic-treated with failure) across prior ustekinumab patients (Fig. 2a). In the systemic-treated/ treatment groups with all P < 0.001 (Table 3). biologic-naı̈ve subgroup, 78% [70–87%] of brodalumab Similar findings were observed with respect to achieve- patients vs. 55% [48–62%] of ustekinumab patients achieved ment of DLQI 0/1. The highest mean AUC was observed PASI 100 (Fig. 2b). In the biologic-treated without failure JEADV 2021, 35, 2034–2044 © 2021 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, 10, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jdv.17433 by Readcube (Labtiva Inc.), Wiley Online Library on [03/02/2023]. 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 Psoriasis clearance with brodalumab by prior treatment history 2039 (a) (b) Brodalumab n = 339 Ustekinumab n = 590 PASI 100 Brodalumab Ustekinumab Maximum AUC value: 52 weeks × PASI maximum response (100%) = 5200 Normalized AUC Brodalumab Ustekinumab Systemic/biologic-naïve OR OR OR OR Week 12 Week 52 Week 12 Week 52 1.97 2.29 1.79 1.62 (95% CI 1.23, 3.14) (95% CI 1.47, 3.58) (95% CI 1.14, 2.81) (95% CI 1.04, 2.52) 100 100 80 80 Patients (%) Patients (%) 60 60 AUC ratio AUC ratio 1.27 1.50 (1.12, 1.46) 40 (1.26, 1.78) 40 20 20 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 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 Week Systemic-treated, biologic-naïve OR OR OR OR Week 12 Week 52 Week 12 Week 52 3.08 2.87 1.71 1.82 (95% CI 1.77, 5.34) (95% CI 1.71, 4.83) (95% CI 1.02, 2.85) (95% CI 1.08, 3.07) 100 100 80 80 Patients (%) Patients (%) AUC ratio 60 AUC ratio 60 1.29 1.66 (1.11, 1.48) 40 (1.36, 2.03) 40 20 20 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 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 Week Biologic-treated without failure OR OR OR OR Week 12 Week 52 Week 12 Week 52 4.03 6.89 1.84 3.01 (95% CI 1.67, 9.70) (95% CI 2.64, 17.94) (95% CI 0.91, 3.75) (95% CI 1.45, 6.26) 100 100 80 80 Patients (%) Patients (%) 60 60 AUC ratio 40 AUC ratio 40 1.56 2.44 (1.25, 1.95) (1.86, 3.36) 20 20 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 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 Week Biologic-treated with failure OR OR OR OR Week 12 Week 52 Week 12 Week 52 4.96 5.03 1.49 1.62 (95% CI 1.58, 15.57) (95% CI 1.54, 16.43) (95% CI 0.64, 3.44) (95% CI 0.63, 4.16) 100 100 80 80 Patients (%) Patients (%) 60 60 AUC ratio 40 40 1.68 AUC ratio (1.27, 2.32) 2.30 20 (1.50, 3.87) 20 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 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 Week Figure 1 Percentage of patients achieving PASI 100 (a) and DLQI 0/1 (b) and normalized AUC through Week 52 by prior treatment sub- group. Pooled data from the AMAGINE-2 and AMAGINE-3 trials. AUC, area under the curve; CI, confidence interval; DLQI, Dermatology Life Quality Index; OR, odds ratio; PASI, Psoriasis Area and Severity Index. JEADV 2021, 35, 2034–2044 © 2021 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, 10, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jdv.17433 by Readcube (Labtiva Inc.), Wiley Online Library on [03/02/2023]. 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 2040 Reich et al. Table 3 Cumulative treatment benefit of brodalumab and ustekinumab at Week 52 by prior treatment subgroup Brodalumab 210 mg Ustekinumab Difference (BRO vs. UST) N AUC Normalized N AUC Normalized Mean % Normalized AUC P-value mean AUC (%) mean AUC (%) AUC difference ratio PASI 100 Systemic/biologic-naı̈ve 144 2198 42.3 249 1469 28.3 729 14.0 1.50 (1.26, 1.78) <0.0001 Systemic-treated, biologic-naı̈ve 99 2518 48.4 186 1521 29.3 998 19.2 1.66 (1.36, 2.03) <0.0001 Biologic-treated without failure 50 2391 46.0 95 980 18.9 1411 27.1 2.44 (1.86, 3.36) <0.0001 Biologic-treated with failure 46 1691 32.5 60 735 14.1 956 18.4 2.30 (1.50, 3.87) 0.0002 PASI 90 Systemic/biologic-naı̈ve 144 3254 64.6 249 2546 49.0 709 13.6 1.28 (1.14, 1.43) <0.0001 Systemic-treated, biologic-naı̈ve 99 3362 71.7 186 2403 46.2 959 18.4 1.40 (1.23, 1.60) <0.0001 Biologic-treated without failure 50 3129 56.0 95 1703 32.8 1426 27.4 1.84 (1.50, 2.28) <0.0001 Biologic-treated with failure 46 2700 47.8 60 1434 27.6 1266 24.3 1.88 (1.38, 2.64) 0.0003 DLQI 0/1 Systemic/biologic-naı̈ve 144 2779 53.4 249 2184 42.0 594 11.4 1.27 (1.12, 1.46) 0.0013 Systemic-treated, biologic-naı̈ve 99 2941 56.6 186 2284 43.0 657 12.6 1.29 (1.11, 1.48) 0.0036 Biologic-treated without failure 50 2686 51.7 95 1718 33.0 967 18.6 1.56 (1.25, 1.95) 0.0045 Biologic-treated with failure 46 2380 45.8 60 1420 27.3 960 18.5 1.68 (1.27, 2.32) 0.0077 P = Wilcoxon test. AUC, area under the curve; BRO, brodalumab; DLQI, Dermatology Life Quality Index; PASI, Psoriasis Area and Severity Index; UST, ustekinumab. subgroup, 75% [63–89%] of brodalumab patients achieved Discussion PASI 100 compared with 41% [32–53%] of ustekinumab With the emergence of modern biologic therapies such as bro- patients (Fig. 2c). In the biologic-failure subgroup, 70% [57– dalumab and ustekinumab, achievement of PASI 100 (com- 86%] of brodalumab patients achieved PASI 100 compared plete skin clearance) becomes a viable treatment endpoint. with 30% [20–45%] of ustekinumab patients (Fig. 2d). More- Here, we assessed the cumulative attainment of different levels over, there were fewer inadequate responders to brodalumab of PASI or requirement for rescue treatment to better under- compared with ustekinumab (Fig. 2). stand the rapidity and sustainability of any observed treatment The incidence of treatment response and inadequate response responses, with patients being subdivided into four subgroups was not affected by prior treatment history for brodalumab according to prior treatment history. We found that, regard- (P = 0.709), unlike for ustekinumab (P = 0.001). The median less of prior treatment history, proportionately more patients time to achieve complete clearance could not be estimated for treated with brodalumab compared with ustekinumab ustekinumab patients in the biologic-treated with and without achieved PASI 100 and proportionately fewer of them required failure subgroups, as <50% of patients achieved complete clear- rescue treatment. We also demonstrated that complete clear- ance by Week 52. ance was achieved more rapidly in more patients treated with brodalumab compared with ustekinumab, consistent with Proportion of time spent in PASI response states The propor- findings of a previous analysis of AMAGINE-2 and tion of time spent in PASI 100 was consistently higher following AMAGINE-3 trial data; rates of complete clearance at Week treatment with brodalumab (32–47%) compared with ustek- 12 were equivalent in patients treated with brodalumab with inumab (14–29%) across all treatment subgroups (Fig. 3). Fur- (40.9%) or without (39.5%) prior exposure to biologics, ther, proportionately less time was spent on rescue treatment for including whether (41.7%) or not (32.0%) they were respon- patients treated with brodalumab (13–22%) compared with sive to prior biologics.13 Furthermore, our analyses showed ustekinumab (21–40%) across treatment groups, with the high- that response rates with brodalumab were consistent across est proportion of time spent in rescue treatment in the prior four subgroups in the treatment pathway (systemic/biologic- biologic-failure group for both treatments (Fig. 3). naı̈ve, systemic-treated/biologic-naı̈ve, biologic-treated without failure, biologic-treated with failure). These findings are partic- Association between skin clearance and QoL A significant ularly promising with respect to the latter group. In addition association was observed between the PASI response level and to intolerance/side-effects, or even commercial withdrawal, a QoL, as measured by achievement of DLQI 0/1, across all treat- substantial number of patients discontinue biologic treatment ment subgroups (P < 0.0001; Fig. 4). because of primary or secondary treatment failure. JEADV 2021, 35, 2034–2044 © 2021 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, 10, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jdv.17433 by Readcube (Labtiva Inc.), Wiley Online Library on [03/02/2023]. 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 Psoriasis clearance with brodalumab by prior treatment history 2041 (a) Systemic/biologic-naïve Brodalumab Ustekinumab HRa (95%CI) Cumulative incidence (%) 100 100 Cumulative incidence (%) 19.6% 32.5% 80 4.5% 80 60 16 weeks 60 26 weeks 9.2% 1.67 (1.30–2.14)b 40 75.9% 40 58.2% 20 20 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) (b) Systemic-treated, biologic-naïve Brodalumab Ustekinumab 100 100 Cumulative incidence (%) Cumulative incidence (%) 20.2% 36.6% 80 2.0% 80 60 12 weeks 60 36 weeks 8.5% 2.05 (1.52–2.76)b 40 77.8% 40 55.0% 20 20 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) (c) Biologic-treated without failure Brodalumab Ustekinumab 100 100 Cumulative incidence (%) Cumulative incidence (%) 20.8% 80 4.5% 80 51.2% 60 12 weeks 60 40 74.8% 40 7.5% 2.74 (1.76–4.28)b 20 20 41.3% 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) (d) Biologic-treated with failure Brodalumab Ustekinumab 100 100 Cumulative incidence (%) Cumulative incidence (%) 23.9% 80 80 5.8% 61.3% 60 12 weeks 60 40 70.3% 40 8.5% 3.55 (2.04–6.20) 20 20 10 30.2% 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) Complete clearance Inadequate response Never achieved complete clearance or had inadquate responsea a Time to achievement of complete clearance by 50% of patients Figure 2 Cumulative incidence of patients in AMAGINE-2 and AMAGINE-3 trials achieving PASI 100 at least once at any given time point (competing risk analysis). aDefined 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. bHR of complete clearance cumulative incidence. CI, confidence interval; HR, hazard ratio; PASI, Psoriasis Area and Severity Index. JEADV 2021, 35, 2034–2044 © 2021 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, 10, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jdv.17433 by Readcube (Labtiva Inc.), Wiley Online Library on [03/02/2023]. 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 2042 Reich et al. Figure 3 Proportion of time spent in different response states. PASI, Psoriasis Area and Severity Index. Furthermore, in subsequent biologic treatment, the second may offer a viable treatment strategy for some of these patients agent typically offers reduced benefit compared with the first since consistent rates of complete clearance were observed even treatment.7 in the patients who had previously failed to respond to biologics. AUC analyses which capture the sustainability of treatment There are a number of limitations to this study. Firstly, the response over time24 suggested the cumulative benefit of bro- data analysed were from a clinical trial population with strict dalumab was greater than with ustekinumab over 52 weeks for entry criteria and as such findings may not be generalizable to each of the treatment pathway subgroups. Our analyses further broader populations. Secondly, four patients previously treated suggest that unlike ustekinumab, response to brodalumab was with ustekinumab with failure were retreated with ustekinumab. not dependent on prior treatment history. This may have contributed to the lack of efficacy in this sub- Improvement in QoL as measured by DLQI has been shown to group. Thirdly, these were post hoc efficacy analyses of data associate with achievement of PASI in patients treated with bro- from trials not specifically statistically powered to assess the end- dalumab,12 with patients achieving PASI 100 being more likely to points of interest here. The analyses were also restricted to also achieve DLQI 0/1 than those with PASI 90. These findings patients in constant treatment arms, thus reducing the number are analogous to earlier observations of Revicki et al. who showed of patients available for inclusion. This particularly affected the that the PASI 90 or 100 responders among 1469 patients in two subgroup analyses. Finally, the determination of PASI assess- adalimumab clinical trials had greater improvements in their ment response is subjective, as minor psoriatic lesions may be DLQI total score than the PASI 75 responders.28 To achieve clini- missed during examination. cally meaningful benefit for patients affected by plaque psoriasis, In conclusion, the results of these analyses suggest higher rates it is clearly important to target the rigorous treatment goals of of complete clearance are achieved and maintained with bro- PASI 90 or ideally, PASI 100. Recent data suggest that PASI 100 is dalumab compared with ustekinumab regardless of prior treat- associated with substantially reduced physical burden of psoria- ment history. Furthermore, these excellent response rates remain sis, increased treatment satisfaction, and improved QoL in both high over time. Brodalumab, with its unique mechanism of the clinical trial and real-world settings.19-21,28-30 action, may offer a good treatment option for patients who have The achievement of complete clearance may be of particular failed previous therapies. importance for patients who have failed multiple prior therapies. These patients have had a longer disease duration, negatively Acknowledgements impacting on QoL with a consequent higher disease burden. The RBW is supported by the Manchester NIHR Biomedical patients are also the ones least likely to respond to any new treat- Research Centre. Medical writing support provided by Susan ment. The data from this study suggest switching to brodalumab Dyas, MSc, from Adelphi Communications Ltd, Bollington, UK, JEADV 2021, 35, 2034–2044 © 2021 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, 10, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jdv.17433 by Readcube (Labtiva Inc.), Wiley Online Library on [03/02/2023]. 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 Psoriasis clearance with brodalumab by prior treatment history 2043 Achieved DLQI 0 DLQI 0 DLQI 1 (a) Systemic/biologic-naïve (b) Systemic-treated, biologic-naïve 100 100 84.3 82.3 80 80 Patients achieving Patients achieving 16.9 DLQI 0 or 1 (%) DLQI 0 or 1 (%) 16.2 64.6 65.0 60 60 24.4 24.2 42.8 42.4 40 40 67.4 21.5 66.1 21.7 22.9 19.7 20 40.2 20 40.8 15.1 12.4 21.3 20.7 4.8 3.9 7.8 7.3 0 0 PASI 50≤PASI 75≤PASI 90≤PASI PASI PASI 50≤PASI 75≤PASI 90≤PASI PASI <50 <75 <90 <100 100 <50 <75 <90 <100 100 PASI response PASI response n= 4698 2435 3572 5176 8053 n= 3489 1717 2486 3500 6067 (c) Biologic-treated without failure (d) Biologic-treated with failure 100 100 83.6 85.8 80 80 Patients achieving Patients achieving 13.4 16.0 DLQI 0 or 1 (%) DLQI 0 or 1 (%) 65.7 60.9 60 60 24.9 42.4 24.1 43.9 40 65.6 40 72.4 22.4 21.9 18.7 20.1 20 36.8 20 40.8 12.0 14.2 20.0 22.0 4.2 3.1 6.7 5.9 0 0 PASI 50≤PASI 75≤PASI 90≤PASI PASI PASI 50≤PASI 75≤PASI 90≤PASI PASI <50 <75 <90 <100 100 <50 <75 <90 <100 100 PASI response PASI response n= 2346 1100 1695 1879 3179 n= 1803 840 1119 1332 1747 Figure 4 Association between PASI response and QoL. 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