BJD C L I NI C A L T R IA L British Journal of Dermatology Long-term efficacy and safety of tildrakizumab for moderate-to-severe psoriasis: pooled analyses of two randomized phase III clinical trials (reSURFACE 1 and reSURFACE 2) through 148 weeks* K. Reich,1,2 R.B. Warren,3 L. Iversen iD ,4 L. Puig,5 I. Pau-Charles,6 A. Igarashi,7 M. Ohtsuki,8 M. Falques,6 M. Harmut,6 S. Rozzo,9 M.G. Lebwohl,10 W. Cantrell,11 A. Blauvelt iD 12 and D. Thacßi13 1 Centre for Translational Research in Inflammatory Skin Diseases, Institute for Health Services Research in Dermatology and Nursing, University Medical Center Hamburg-Eppendorf, Skinflammationâ Center, Hamburg, Germany 2 Dermatologikum Berlin, Berlin, Germany 3 Dermatology Centre, Salford Royal NHS Foundation Trust, Manchester NIHR Biomedical Research Centre, The University of Manchester, Manchester, U.K. 4 Department of Dermatology, Aarhus University Hospital, Aarhus, Denmark 5 Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain 6 Almirall R&D, Barcelona, Spain 7 NTT Medical Center Tokyo, Tokyo, Japan 8 Department of Dermatology, Jichi Medical University, Tochigi, Japan 9 Sun Pharmaceuticals, Princeton, NJ, U.S.A. 10 Icahn School of Medicine at Mount Sinai, New York, NY, U.S.A. 11 Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL, U.S.A. 12 Oregon Medical Research Center, Portland, OR, U.S.A. 13 Institute and Comprehensive Centre for Inflammation Medicine, University of L€ubeck, L€ubeck, Germany Summary Correspondence Background Tildrakizumab is a specific anti-interleukin-23p19 monoclonal antibody Kristian Reich. approved for the treatment of plaque psoriasis. E-mail: k.reich@uke.de Objectives To evaluate the long-term efficacy and safety of tildrakizumab treatment for patients with moderate-to-severe psoriasis for up to 148 weeks. Accepted for publication 17 June 2019 Methods Pooled analysis from two double-blind, randomized controlled trials: reSURFACE 1 and reSURFACE 2. Efficacy was assessed for responders (≥ 75% Funding sources improvement in Psoriasis Area and Severity Index; PASI 75) and partial respon- This publication was funded by Almirall R&D, ders (PASI 50–75) to tildrakizumab 100 mg and 200 mg at week 28 who were Barcelona, Spain. maintained on the same dose (administered every 12 weeks), and for partial responders or nonresponders (PASI < 50) to etanercept 50 mg at week 28 who, Conflicts of interest Conflicts of interest statements can be found in the after a 4-week washout, were switched to tildrakizumab 200 mg (administered Appendix. at weeks 32 and 36, and every 12 weeks thereafter). Safety was assessed in the all-patients-as-treated population. Three different methods of imputing missing *Plain language summary available online data were used: nonresponder imputation (NRI), multiple imputation and observed cases. The Clinicaltrials.gov numbers are NCT01722331 (reSURFACE 1) DOI 10.1111/bjd.18232 and NCT01729754 (reSURFACE 2). Results At week 148 (NRI), 726%, 538% and 289% of tildrakizumab 100-mg responders and 802%, 599% and 326% of tildrakizumab 200-mg responders had PASI 75, 90 and 100 responses, respectively. For partial responders to til- drakizumab 100 mg and 200 mg, the proportions of patients achieving PASI 75, 90 and 100 responses were 325%, 250% and 100%; and 471%, 275% and 128%, respectively. For patients who were partial responders or nonresponders to etanercept, the proportions of patients achieving PASI 75, 90 and 100 responses were 669%, 438% and 149% at week 148. Rates of discontinuations due to adverse events [tildrakizumab 100 mg: 17 per 100 patient-years (PYs); © 2019 The Authors. British Journal of Dermatology British Journal of Dermatology (2020) 182, pp605–617 605 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. 606 Long-term efficacy and safety of tildrakizumab, K. Reich et al. tildrakizumab 200 mg: 12 per 100 PYs] and exposure-adjusted rates of serious adverse events (59 per 100 PYs; 55 per 100 PYs), severe infections (11 per 100 PYs; 11 per 100 PYs), malignancies (06 per 100 PYs; 04 per 100 PYs) and major adverse cardiovascular events (04 per 100 PYs; 05 per 100 PYs) were low. Conclusions Tildrakizumab was well tolerated and efficacy was well maintained in week 28 responders who continued tildrakizumab treatment through 3 years, or improved among etanercept partial responders or nonresponders who switched to tildrakizumab. What’s already known about this topic? • Tildrakizumab 100 mg and 200 mg are efficacious and well tolerated with short- term use in the treatment of patients with moderate-to-severe plaque psoriasis. What does this study add? • High levels of efficacy are maintained for up to 3 years of psoriasis treatment with tildrakizumab. • There is a favourable long-term safety profile with both tildrakizumab 100 mg and 200 mg, with a low incidence of adverse events of special interest through 3 years. Interleukin (IL)-23 is a key regulatory cytokine that is essential In part 1 (week 0 to week 12), patients were randomized in differentiation and survival of T helper 17 cells, which are 2 : 2 : 1 to tildrakizumab 200 mg, tildrakizumab 100 mg or cells fundamental in the pathogenesis of psoriasis. Thus, speci- placebo (reSURFACE 1), or 2 : 2 : 1 : 2 to tildrakizumab 200 fic and selective targeting of IL-23 has become an effective mg, tildrakizumab 100 mg, placebo or etanercept 50 mg (reS- therapeutic strategy,1–3 without targeting IL-12. Tildrakizumab URFACE 2) (Fig. 1). In part 2 (week 12 to week 28), placebo is a monoclonal antibody that specifically targets the p19 sub- patients were rerandomized 1 : 1 to tildrakizumab 200 mg or unit of IL-23, and that is approved for the treatment of plaque tildrakizumab 100 mg. In part 3 (week 28 to week 52 or psoriasis in the U.S.A. and European Union.4,5 64), PASI 75 responders in reSURFACE 1 were rerandomized The objective of this manuscript is to report the 148-week to continue the same tildrakizumab dose or to receive placebo pooled efficacy and safety results in patients from two phase (with retreatment with the same tildrakizumab dose upon III trials, reSURFACE 1 and reSURFACE 2,5 who were respon- relapse); in reSURFACE 2, PASI 75 responders to tildrak- ders [≥ 75% improvement in Psoriasis Area and Severity Index izumab 200 mg were rerandomized to tildrakizumab 200 mg (PASI 75)] or partial responders (≥ 50 to < 75% improvement or tildrakizumab 100 mg, while PASI 75 responders to tildrak- in PASI) to tildrakizumab 100 mg or 200 mg at week 28 and izumab 100 mg maintained the same dose. who continued treatment with the same dose of tildrak- In both studies, partial responders to tildrakizumab 200 mg izumab. The evolution of patients who were partial responders continued the same dose, while partial responders to tildrak- or nonresponders to etanercept 50 mg at week 28 and who izumab 100 mg were randomized 1 : 1 to tildrakizumab 200 were then treated with tildrakizumab 200 mg is also pre- mg or tildrakizumab 100 mg. Tildrakizumab 100-mg and sented. The results of these trials to week 28 have already 200-mg doses were given at week 0, week 4 and every 12 been published.5,6 weeks thereafter. In reSURFACE 2, etanercept 50 mg was given twice weekly in part 1 and once a week in part 2. At week 28, partial responders and nonresponders to etanercept Patients and methods 50 mg were crossed over to tildrakizumab 200 mg after a 4-week washout period. Tildrakizumab 200 mg was adminis- Patients and study design tered at week 32, week 36 and every 12 weeks thereafter. At Both reSURFACE 1 (64 weeks) and reSURFACE 2 (52 weeks) week 52 or 64, patients who completed part 3 with at least a were three-part, parallel-group, double-blinded, randomized, PASI 50 response entered an optional and still ongoing exten- placebo-controlled phase III trials. The detailed methodology sion period of up to extension week 256 (reSURFACE 1) or and patient characteristics have been published previously.5 up to extension week 244 (reSURFACE 2). British Journal of Dermatology (2020) 182, pp605–617 © 2019 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists Long-term efficacy and safety of tildrakizumab, K. Reich et al. 607 Fig 1. Integrated design of the reSURFACE 1 and reSURFACE 2 trials. Differences in design for reSURFACE 2 vs. reSURFACE 1 are shown in turquoise colour. Groups of interest for efficacy analyses are marked in bold. D/C, discontinued; N/A, not applicable; NR, nonresponders [< 50% improvement in Psoriasis Area and Severity Index (PASI 50)]; PR, partial responders (PASI 50–75); R, responders (PASI ≥ 75). Both studies were conducted in a double-blinded manner Safety assessments consisted of overall adverse events (AEs) for the entire duration of the base study (parts 1, 2 and 3). and AEs of special interest. Severe infections were defined as The first 28 weeks of reSURFACE 2 employed double-dummy any infection meeting the regulatory definition of a serious AE blinding, administering matching placebo doses of tildrak- (i.e. resulted in death, was life-threatening, required inpatient izumab and etanercept with identical prefilled syringes. Once hospitalization or prolongation of existing hospitalization, the base study was completed and locked at week 52 (reSUR- resulted in persistent or significant disability or incapacity, or FACE 2) or week 64 (reSURFACE 1), patients in the extension required intervention to prevent one of the other outcomes were provided open-label study medication for the rest of the listed), or any infection requiring intravenous antibiotics. study. Extended major adverse cardiovascular events (MACEs) included The main inclusion and exclusion criteria at baseline were nonfatal myocardial infarction, nonfatal stroke, unstable angina, similar for reSURFACE 1 and reSURFACE 2. Patients fulfilled coronary revascularization, resuscitated cardiac arrest, and car- the following inclusion criteria: age 18 years or older, diagno- diovascular deaths that were confirmed as ‘cardiovascular’ or sis of plaque psoriasis ≥ 6 months previously, ≥ 10% of body ‘sudden’. Deaths and serious cardiovascular events were adjudi- surface area affected, Physician’s Global Assessment score ≥ 3, cated by an external clinical adjudication committee. Safety PASI score ≥ 12, and a candidate for phototherapy or systemic measurements were done at all study visits, which coincided therapy. In reSURFACE 2, patients who had previously used between the two studies, except at weeks 44, 48 and 56 (reS- etanercept or were sensitive or allergic to latex were excluded. URFACE 1 only) and week 46 (reSURFACE 2 only). The study protocols were approved by local institutional review boards or ethics committees, and all patients provided Statistical analyses written informed consent. Responders were defined as patients with ≥ 75% improvement in PASI; partial responders were defined as patients with ≥ 50 Assessments to < 75% improvement in PASI; and nonresponders were Efficacy was assessed based on PASI 75, 90 or 100 response defined as patients with < 50% improvement in PASI. rates (proportions of patients achieving ≥ 75%, ≥ 90% or The current analyses focus on 148-week efficacy data in 100% improvement) and the proportions of patients with patients who were responders or partial responders to tildrak- absolute PASI scores < 1, < 3 or < 5. In part 3 and the exten- izumab 100 mg or 200 mg at week 28 and who continued sion period up to week 148, efficacy measurements were treatment with the same tildrakizumab dose, and in patients done at weeks 28, 32, 36, 40, 52, 60 and 64, and then every who were partial responders or nonresponders to etanercept 12 weeks until week 148. 50 mg at week 28 and who were crossed over to © 2019 The Authors. British Journal of Dermatology British Journal of Dermatology (2020) 182, pp605–617 published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists 608 Long-term efficacy and safety of tildrakizumab, K. Reich et al. tildrakizumab 200 mg (Fig. 1). Safety data for the 148-week The number of patients used (sample size) for NRI and MI period, pooled across reSURFACE 1 and reSURFACE 2, were (NNRI and NMI) were 329, 227, 40, 102 and 121 for responders also included. to tildrakizumab 100 mg, responders to tildrakizumab 200 mg, The patient populations were different for the safety and partial responders to tildrakizumab 100 mg, partial responders efficacy analyses. Efficacy analyses were performed on the full to tildrakizumab 200 mg and partial responders or nonrespon- analysis set of part 3, which consisted of all patients who ders to etanercept 50 mg, respectively. entered part 3 (at week 28) and received at least one dose of Safety analyses were conducted on all of the tildrak- study treatment in part 3, based on the treatment assigned. izumab-treated patients and were based on the all-patients- Responders to tildrakizumab 100 mg, responders to tildrak- as-treated population, defined as all randomized patients who izumab 200 mg, partial responders to tildrakizumab 100 mg, received at least one dose of study treatment based on the partial responders to tildrakizumab 200 mg, and partial treatment received. Data were pooled from patients treated responders or nonresponders to etanercept 50 mg were anal- with either tildrakizumab 100 mg (patients who received til- ysed as separate subgroups. drakizumab 100 mg in at least one part of the study), til- The presented data are based on nonresponder imputation drakizumab 200 mg (patients who received tildrakizumab (NRI), where patients with missing data were treated as non- 200 mg in at least one part of the study) or placebo (pa- responders. Observed cases (OC) and multiple imputation tients who received placebo in at least one part of the (MI) data are presented as sensitivity analyses. A monotone study). Medical Dictionary for Regulatory Activities preferred missing data pattern and regression were used to generate terms were assigned to tildrakizumab 100 mg, tildrakizumab multiple imputed datasets according to the different treatment 200 mg or placebo if the AE occurred when the patient was schemes. The imputation model used for analysis of dichoto- actively being treated with tildrakizumab 100 mg, tildrak- mized PASI response based on the multiple imputed PASI izumab 200 mg or placebo, respectively. The etanercept 50- score included demographic variables and baseline disease mg group is presented alongside the pooled data groups. characteristics such as age, sex, body mass index, presence of Preferred terms were assigned to etanercept 50 mg if the AE psoriatic arthritis, prior exposure to biologics, baseline PASI, occurred when the patient was actively being treated with baseline Physician’s Global Assessment or baseline body sur- etanercept 50 mg. Patients were counted in each assigned face area, as covariates. After imputation, dichotomized treatment group after starting a different treatment. responses (PASI 75, 90 or 100, PASI < 1, < 3 or < 5) were Exposure-adjusted incidence rates (EAIRs) [i.e. events per 100 computed for each dataset and then reported as n (%) com- patient-years (PYs) of exposure] for overall AEs and AEs of spe- puting the average from the 10 imputed datasets. cial interest, are reported. EAIRs were computed using the num- The 95% confidence interval (CI) for the proportion with ber of events for a particular event, adjusting by the total PYs of NRI was computed as follow-up for each treatment, where total PYs of follow-up was sffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi the sum of the individual exposures in years for all patients by ^pNRI ð1  ^pNRI Þ treatment. Different crossovers due to the study design were CINRI ¼ ^pNRI  za=2  ; NNRI taken into account (e.g. patients who were taking tildrakizumab 100 mg or 200 mg during part 1 and then crossed to placebo in where ^pNRI = proportion with NRI; NNRI = sample size per part 3). Computation of EAIRs by treatment was as follows: treatment; CINRI = 95% CI for ^pNRI and za/2 is the 1  a/2 quantile of the standard normal distribution (i.e. z005/2 = Number of events d ¼ EAIR 196). Total patient-years of follow-up The 95% CI for the proportion with OC was computed as Number of events sffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi ¼ SUM(individual exposure in years) ^pOC ð1  ^pOC Þ CIOC ¼ ^pOC  za=2  ; NOC d ð100 patient-yearsÞ ¼ EAIR:100 EAIR where ^pOC = proportion with OC; NOC = sample size per week Using the previous formula for the computation of EAIRs, and treatment; CIOC = 95% CI for ^pOC and za/2 = 196. the 95% CI for an EAIR was computed from the standard error For MI data, the proportion used for the computation of (SE) for an incidence rate, estimated as the 95% CI was obtained using the average of the 10 propor- tions (i.e. 10 imputed datasets) from MI analysis. The 95% CI pffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi b EAIRÞ Number of events was then computed as SEð d ¼ Total patient-years of follow-up sffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi pffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi ^pMI ð1  ^pMI Þ Number of events CIMI ¼ ^pMI  za=2  ; ¼ NMI SUM(individual exposure in years) where ^pMI = proportion with MI; NMI = sample size per treat- The 95% CI for the (estimated) incidence rate (IR) was ment; CIMI = 95% CI for ^pMI and za/2 = 196. then computed as: British Journal of Dermatology (2020) 182, pp605–617 © 2019 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists Long-term efficacy and safety of tildrakizumab, K. Reich et al. 609 CIIR ¼ EAIR b EAIRÞ; d  za=2  SEð d 90 and PASI 100 responses with tildrakizumab 200 mg at weeks 52 and 148. The responses were maintained during where za/2 = 196. the 2-year extension period at week 148. The proportions with absolute PASI < 5, < 3 and < 1 are shown in Fig- ure 4(c) and Table S6 (see Supporting Information). Results Efficacy population Safety results At week 28, 329 patients who were responders to tildrak- In the 148-week period (base study plus 2-year extension izumab 100 mg, 227 patients who were responders to tildrak- period; total exposure to tildrakizumab 100 mg and 200 mg izumab 200 mg, 40 patients who were partial responders to of 40612 PYs), EAIRs for treatment-emergent AEs for til- tildrakizumab 100 mg and 102 patients who were partial drakizumab 100 mg, tildrakizumab 200 mg, placebo and responders to tildrakizumab 200 mg were maintained on the etanercept were 352, 372, 1486 and 1486 events per 100 same dose. In addition, 121 patients who were partial respon- PYs, respectively (Table 2). The most common treatment- ders (70%) or nonresponders (30%) to etanercept 50 mg emergent AE in all treatment groups was nasopharyngitis were switched to tildrakizumab 200 mg (Fig. 2). Few patients (102, 98, 224 and 411 events per 100 PYs for tildrak- discontinued due to lack of efficacy or AEs during part 3 or izumab 100 mg, tildrakizumab 200 mg, placebo and etaner- the extension period (Fig. 2). For example, in the tildrak- cept, respectively). Other frequent AEs (occurring at a izumab 100-mg (n = 302) and 200-mg (n = 213) analysis frequency ≥ 5% in one or more treatment groups) were groups, there were three (10%) and one (05%), respectively, infections such as upper respiratory tract infection, influenza, who discontinued due to lack of efficacy, and five (17%) and bronchitis and sinusitis (Table 3). Candida infections were five (23%), respectively, due to an AE during the extension infrequent (010 events per 100 PYs in the tildrakizumab period. The demographics and disease characteristics at base- 100-mg group and 039 events per 100 PYs in the tildrak- line were similar across treatment groups (Table 1), and were izumab 200-mg group). also similar to those of the general trial population. Few patients discontinued due to AEs (169 and 122 events per 100 PYs of exposure to tildrakizumab 100 mg or 200 mg), and the rates of drug-related serious AEs per 100 PYs of Efficacy results exposure to either tildrakizumab 100 mg or 200 mg were 079 and 054 events per 100 PYs, respectively (Table 2). Responders to tildrakizumab 100 mg or 200 mg Nine deaths (six patients in the tildrakizumab 100-mg group The proportions of responders to tildrakizumab 100 mg (Fig. 3a) and three patients in the tildrakizumab 200-mg group) or 200 mg (Fig. 3b) achieving PASI 75, PASI 90 and PASI 100 occurred during the trials. Six deaths (already reported by responses at weeks 28, 52 and 148 are shown in Table S1 (see Blauvelt et al.)7 occurred during the base study, and were due Supporting Information). Responses were maintained at week to steatohepatitis and alcoholic cardiomyopathy, acute myeloid 148 (2-year extension period). The proportions of responders to leukaemia, respiratory arrest, myocardial infarction, aneurysm tildrakizumab 100 mg (Fig. 4a) or 200 mg (Fig. 4b) achieving and sepsis. During the extension period of reSURFACE 2, three absolute PASI < 5, < 3 and < 1 at weeks 28, 52 and 148 are additional deaths were reported: (i) an intoxication by the shown in Table S2 (see Supporting Information). combined effects of fluoxetine and cyclobenzaprine; (ii) an unknown reason of death; and (iii) a case of asphyxiation due to a tractor accident. All deaths were assessed by the investiga- Partial responders to tildrakizumab 100 mg or 200 mg tors to be not related to the study medication. One case of The proportions of partial responders to tildrakizumab 100 suicide attempt was reported in the tildrakizumab 200-mg mg or 200 mg achieving PASI 75, PASI 90 and PASI 100 at group, which resulted in a suicide attempt rate of 005 events weeks 52 and 148 are shown in Table S3 (see Supporting per 100 PYs. Information). Again, responses were maintained during the Incidences of severe infections, malignancies, confirmed 2-year extension period at week 148. The proportions of par- extended MACEs and hypersensitivity reactions were low and tial responders to tildrakizumab 100 mg or 200 mg achieving comparable across treatment groups, although rates of severe absolute PASI < 5, < 3 and < 1 are shown in Table S4 (see infections tended to be higher for etanercept 50 mg (Table 4). Supporting Information). The most common severe infections were cellulitis – three patients in the tildrakizumab 100-mg group (015 events per 100 PYs), four patients in the tildrakizumab 200-mg group Partial responders or nonresponders to etanercept 50 mg (020 events per 100 PYs), two patients in the placebo group who were treated with tildrakizumab 200 mg (097 events per 100 PYs) and one patient in the etanercept Table S5 (see Supporting Information) and Figure 3(c) show 50-mg group (065 events per 100 PYs); herpes zoster – one the proportions of patients who were partial responders or patient in the tildrakizumab 200-mg group (005 events per nonresponders to etanercept 50 mg who had PASI 75, PASI 100 PYs) and one patient in the etanercept 50-mg group © 2019 The Authors. British Journal of Dermatology British Journal of Dermatology (2020) 182, pp605–617 published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists 610 Long-term efficacy and safety of tildrakizumab, K. Reich et al. Fig 2. Patient disposition. *One patient did not receive study medication (placebo) and was excluded from the all-patients-as-treated population. † Seven patients with observed Psoriasis Area and Severity Index score at week 148 discontinued thereafter. ‡Four patients with observed Psoriasis Area and Severity Index score at week 148 discontinued thereafter. British Journal of Dermatology (2020) 182, pp605–617 © 2019 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists Long-term efficacy and safety of tildrakizumab, K. Reich et al. 611 Table 1 Baseline demographics and disease characteristics of the efficacy population Tildrakizumab 100 mg Tildrakizumab 200 mg Placebo Etanercept 50 mg (n = 616) (n = 622) (n = 310) (n = 313) Male, n (%) 427 (693) 451 (725) 212 (684) 222 (709) Age (years), mean  SD 455  134 458  134 471  129 458  140 Weight (kg), mean  SD 889  230 886  227 881  244 880  215 BMI (kg m2), mean  SD 300  71 298  74 301  77 289  64 BSA (%), mean  SD 320  181 314  175 304  161 316  166 PASI, mean  SD 202  77 202  80 196  73 202  74 DLQI, mean  SD 144  70 133  70 136  71 145  72 PGA category, n (%) ≤3 414 (672) 409 (661) 209 (676) 200 (639) ≥4 202 (328) 210 (339) 100 (324) 110 (351) Psoriatic 102 (166) 102 (164) 42 (136) 41 (131) arthritis (yes), n (%) Previously treated 110 (179) 109 (175) 54 (174) 37 (118) with biologics, n (%) Previously treated 196 (318) 213 (342) 99 (319) 117 (374) with nonbiologic systemic therapy (excluding phototherapy), n (%) BMI, body mass index; BSA, body surface area; DLQI, Dermatology Life Quality Index; PASI, Psoriasis Area and Severity Index; PGA, Physi- cian’s Global Assessment. (065 events per 100 PYs) and urosepsis – one patient in the many effective therapies. Numerous factors, including fre- etanercept 50-mg group (065 events per 100 PYs). quency of injection and presence of comorbidities, affect The most common malignancies (excluding nonmelanoma selection of therapies.8,9 For many patients, IL-23p19 inhibi- skin cancer) were breast cancer – one patient in the tildrak- tors have demonstrated high levels of efficacy and safety, izumab 100-mg group (005 events per 100 PYs), one patient effectively confirming a key regulatory role of IL-23 in disease in the tildrakizumab 200-mg group (005 events per 100 pathogenesis.10,11 As a chronic disease, psoriasis requires PYs) and one patient in the etanercept 50-mg group (065 long-term treatment. Thus, data on long-term maintenance of events per 100 PYs) and lung adenocarcinoma – one patient clinical responses and long-term safety are needed for all treat- in the etanercept 50-mg group (065 events per 100 PYs). ment options, especially new biologic agents. The pooled The most common nonmelanoma skin cancer was basal cell analyses from the reSURFACE 1 and reSURFACE 2 trials carcinoma – six patients in the tildrakizumab 100-mg group presented here demonstrate long-term efficacy and safety data (030 events per 100 PYs), seven patients in the tildrakizumab for tildrakizumab 100 mg and 200 mg from over 1500 200-mg group (034 events per 100 PYs), one patient in the patients with moderate-to-severe psoriasis treated for up to 3 placebo group (049 events per 100 PYs) and two patients in years, with approximately 4000 PYs of follow-up. While the etanercept 50-mg group (130 events per 100 PYs). tildrakizumab 100 mg is the recommended dose in major Malignant melanoma occurred in one patient in the tildrak- regions of the world, the European label accepts the use izumab 100-mg group (005 events per 100 PYs). of 200 mg in certain conditions (e.g. high disease burden, The most common MACEs were coronary artery disease – four bodyweight ≥ 90 kg). patients in the tildrakizumab 200-mg group (020 events per 100 Overall, these analyses indicate that most patients who ini- PYs); acute myocardial infarction – three patients in the tildrak- tially respond to tildrakizumab (achieving PASI 75 after 28 izumab 200-mg group (015 events per 100 PYs) and one patient weeks) and who continue treatment with tildrakizumab main- in the tildrakizumab 100-mg group (005 events per 100 PYs) tain this efficacy over time. PASI 75 responses were well and cerebellar infarction – one patient in the placebo group (049 maintained with continued tildrakizumab 100 mg or 200 mg events per 100 PYs). One case of suspected new-onset Crohn dis- in 8 out of every 10 patients through 148 weeks of treatment ease occurred in the tildrakizumab 100-mg group, which resulted (NRI). PASI 90 and PASI 100 responses were also stable in a rate of Crohn disease of 005 events per 100 PYs. throughout the analysis period, and approximately 60% of patients had PASI 90 responses at week 148. Looking at abso- lute PASI scores, about 70% and 50% of patients, respectively, Discussion maintained PASI scores of < 3 and < 1 at week 148. In this The treatment of moderate-to-severe plaque psoriasis has regard, looking at absolute PASI may provide additional clini- rapidly progressed in the last 20 years, and there are now cal value to PASI response in clinical practice. © 2019 The Authors. British Journal of Dermatology British Journal of Dermatology (2020) 182, pp605–617 published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists 612 Long-term efficacy and safety of tildrakizumab, K. Reich et al. (a) (b) (c) Fig 3. Proportions of patients achieving ≥ 75% improvement in Psoriasis Area and Severity Index (PASI 75), PASI 90 and PASI 100 responses through week 148. (a) Responders to tildrakizumab 100 mg. (b) Responders to tildrakizumab 200 mg. (c) Partial responders or nonresponders to etanercept 50 mg who switched to tildrakizumab 200 mg. OC, observed cases; MI, multiple imputation; NRI, nonresponder imputation. n = number of cases in the OC analyses. Error bars represent 95% confidence intervals. British Journal of Dermatology (2020) 182, pp605–617 © 2019 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists Long-term efficacy and safety of tildrakizumab, K. Reich et al. 613 (a) (b) (c) Fig 4. Proportions of patients achieving absolute Psoriasis Area and Severity Index (PASI) of < 5, < 3 and < 1 through week 148. (a) Responders to tildrakizumab 100 mg. (b) Responders to tildrakizumab 200 mg. (c) Partial responders or nonresponders to etanercept 50 mg who switched to tildrakizumab 200 mg. OC, observed cases; MI, multiple imputation; NRI, nonresponder imputation. n = number of cases in the OC analyses. Error bars represent 95% confidence intervals. In addition, these data show that tildrakizumab has increasing tildrakizumab should be considered in patients who have efficacy over time in certain subgroups of patients. For example, shown partial responses after the first 28 weeks of therapy. a substantial proportion of patients with initial partial responses In partial responders or nonresponders to etanercept 50 mg achieved good levels of response if treatment was maintained. at week 28, switching to tildrakizumab 200 mg resulted in Continuing treatment with tildrakizumab in partial responders PASI 75 responses in approximately 8 out of every 10 patients beyond week 28 led to PASI 75 responses in approximately and PASI 90 responses in 4 out of every 10 patients after only 60% of patients at week 52. Also, PASI 90 responses were two doses. Additionally, absolute PASI scores < 3 and < 1 achieved in approximately one-third of patients who were par- were achieved by approximately 60% and 25% of these tial responders at week 28. Notably, clinical responses were patients at week 52. These responses were maintained at week maintained through 148 weeks. Therefore, continuing 148. Thus, tildrakizumab may be a good alternative for those © 2019 The Authors. British Journal of Dermatology British Journal of Dermatology (2020) 182, pp605–617 published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists 614 Long-term efficacy and safety of tildrakizumab, K. Reich et al. Table 2 148-Week cumulative exposure-adjusted incidence rates of adverse events (AEs) (events per 100 patient-years of exposure) Tildrakizumab Tildrakizumab 100 mg 200 mg Placebo Etanercept 50 mg Total patient-years 201449 204671 20530 15342 of follow-up TEAE 709; 3520 (3255–3784) 761; 3718 (3449–3988) 305; 1486 228; 1486 (1316–1656) (1289–1683) SAE 118; 586 (478–694) 112; 547 (444–651) 13; 633 (282–984) 20; 1304 (721–1887) Deaths 6; 030 (005–054) 3; 015 (000–032) 0; 000 0; 000 Drug-related AE 229; 1137 (987–1287) 263; 1285 (1127–1443) 73; 3556 112; 7300 (2723–4388) (5921–8680) Drug-related SAE 16; 079 (040–119) 11; 054 (021–086) 2; 097 (000–235) 5; 326 (034–617) Discontinued 34; 169 (111–227) 25; 122 (073–171) 4; 195 (000–390) 9; 587 (196–978) due to AE Discontinued 19; 094 (051–138) 16; 078 (039–117) 1; 049 (000–146) 5; 326 (034–617) due to SAE Discontinued 15; 074 (036–113) 7; 034 (008–060) 1; 049 (000–146) 4; 261 (000–521) due to drug-related AE Discontinued due 7; 035 (008–061) 4; 020 (000–039) 0; 000 1; 065 (000–196) to drug-related SAE The data are represented as n; events per 100 patient-years of exposure (95% confidence interval). TEAE, treatment-emergent AE; SAE, serious AE. Table 3 148-Week cumulative exposure-adjusted incidence rates of the most common adverse events (AEs)a Tildrakizumab 100 mg Tildrakizumab 200 mg Placebo Etanercept 50 mg Nasopharyngitis 205; 1018 (875–1160) 201; 982 (844–1121) 46; 2241 63; 4106 (3072–5141) (1580–2901) Injection-site erythema 9; 045 (015–074) 10; 049 (018–080) 2; 097 (000–235) 28; 1825 (1135–2515) Upper respiratory 76; 377 (291–464) 114; 557 (453–661) 32; 1559 11; 717 (285–1149) tract infection (1008–2110) Headache 54; 268 (195–341) 63; 308 (230–385) 12; 585 (247–922) 19; 1238 (670–1807) Injection-site reaction 6; 030 (005–054) 10; 049 (018–080) 2; 097 (000–235) 17; 1108 (571–1646) Influenza 49; 243 (174–313) 65; 318 (239–396) 18; 877 (463–1290) 5; 326 (034–617) Urinary tract infection 40; 199 (136–261) 29; 142 (089–194) 9; 438 (146–731) 12; 782 (331–1234) Cough 48; 238 (169–307) 60; 293 (217–369) 15; 731 (353–1108) 8; 521 (153–890) Pruritus 31; 154 (099–209) 29; 142 (089–194) 11; 536 (213–859) 11; 717 (285–1149) Viral upper respiratory 139; 690 (573–807) 138; 674 (559–789) 3; 146 (000–315) 2; 130 (000–315) tract infection Arthralgia 68; 338 (256–419) 57; 278 (205–352) 9; 438 (146–731) 10; 652 (240–1064) Back pain 55; 273 (199–347) 58; 283 (209–358) 8; 390 (114–665) 9; 587 (196–978) Hypertension 53; 263 (191–335) 53; 259 (188–330) 8; 390 (114–665) 9; 587 (196–978) Gastroenteritis 37; 184 (123–244) 42; 205 (142–269) 6; 292 (054–531) 8; 521 (153–890) Diarrhoea 51; 253 (182–324) 43; 210 (146–274) 4; 195 (000–390) 8; 521 (153–890) Oropharyngeal pain 27; 134 (082–186) 35; 171 (113–229) 5; 244 (026–461) 8; 521 (153–890) Sinusitis 48; 238 (169–307) 37; 181 (121–240) 10; 487 (179–795) 4; 261 (000–521) Bronchitis 40; 199 (136–261) 53; 259 (188–330) 5; 244 (026–461) 5; 326 (034–617) Nausea 26; 129 (078–180) 28; 137 (085–189) 3; 146 (000–315) 3; 196 (000–421) The data are represented as n; events per 100 patient-years of exposure (95% confidence interval). aDefined as adverse events occurring at a frequency of ≥ 5% in one or more treatment groups. Ordered by the highest exposure-adjusted incidence rate in any of the treatment groups. patients with moderate-to-severe plaque psoriasis who have approved for the treatment of moderate-to-severe plaque pso- not responded well to etanercept. riasis. Results from the phase III VOYAGE 1 trial showed that These results are in line with published data on other IL- clinical responses in guselkumab-treated patients were main- 23p19 inhibitors such as guselkumab, which is also tained through 2 years.12 Other IL-23p19 subunit-specific British Journal of Dermatology (2020) 182, pp605–617 © 2019 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists Long-term efficacy and safety of tildrakizumab, K. Reich et al. 615 Table 4 148-Week cumulative exposure-adjusted incidence rates of adverse events (AEs) of special interest Tildrakizumab 100 mg Tildrakizumab 200 mg Placebo Etanercept 50 mg a Severe infection 23; 114 (067–162) 23; 112 (066–159) 2; 097 (000–235) 3; 196 (000–421) Malignancy 11; 055 (022–088) 8; 039 (011–067) 0; 000 2; 130 (000–315) (excluding NMSC) NMSC 10; 050 (018–081) 10; 049 (018–080) 2; 097 (000–235) 2; 130 (000–315) Melanoma 1; 005 (000–015) 0; 000 0; 000 0; 000 Confirmed 8; 040 (012–068) 11; 054 (021–086) 1; 049 (000–146) 1; 065 (000–196) extended MACEb Injection-site 39; 194 (132–256) 47; 230 (163–297) 11; 536 (213–859) 62; 4041 (3015–5068) reactionc Drug-related 6; 030 (005–054) 3; 015 (000–032) 1; 049 (000–146) 0; 000 hypersensitivity reactiond The data are represented as n; events per 100 patient-years of exposure (95% confidence interval). MACE, major adverse cardiovascular event; NMSC, nonmelanoma skin cancer; SAE, serious AE. aDefined as any infection meeting the regulatory definition of an SAE, or any infection requiring intravenous antibiotics whether reported as an SAE or not. bDefined as nonfatal myocardial infarction, nonfatal stroke, unstable ang- ina, coronary revascularization, resuscitated cardiac arrest, and cardiovascular deaths that were confirmed as ‘cardiovascular’ or ‘sudden’. cThe following preferred terms were included: injection-site bruising, injection-site discomfort, injection-site dryness, injection-site erythema, injection-site haematoma, injection-site haemorrhage, injection-site hypoaesthesia, injection-site induration, injection-site inflammation, injection-site oedema, injection-site pain, injection-site papule, injection-site paraesthesia, injection-site pruritus, injection-site reaction, injec- tion-site swelling and injection-site urticaria. This information was only collected for AEs in the base study. dThe following preferred terms were included: angio-oedema, hypersensitivity, injection-site urticaria, lip swelling, swelling face, swollen tongue and urticaria. antibodies approved or under development are risankizumab were not included in this report. However, more conservative and mirikizumab; however, no data beyond week 52 or NRI data from week 28 onwards are presented as a primary week 16, respectively, have been published for these drugs analysis. Etanercept was the standard of care when the trials to date.13,14 were designed and was chosen as a comparator in the reSUR- The combination of durable efficacy and favourable safety, FACE 2 clinical trial. Patients responding to etanercept were together with infrequent dosing (once every 8–12 weeks), char- withdrawn from the study at week 28 as per the study design; acterize IL-23p19 inhibitors. Regarding safety, no new or unex- therefore, no active comparator is available beyond that time pected AEs have been described with these drugs over time.7,13– point. Finally, patients in the extension period were provided 15 Here, we have specifically demonstrated low rates of severe open-label study medication. infections, malignancies and MACEs for treatment with tildrak- In conclusion, in patients who initially responded to either izumab 100 mg and 200 mg over a 148-week period. EAIRs of tildrakizumab 100 mg or 200 mg, efficacy with continued severe infections, malignancies, nonmelanoma skin cancer, mel- treatment was maintained over time up to 148 weeks. Among anoma skin cancer and extended MACEs with tildrakizumab partial responders or nonresponders to etanercept, tildrak- were low and comparable with placebo, indicating no increased izumab demonstrated high levels of efficacy after a few doses, risk of these events with tildrakizumab treatment. Also, the fre- and efficacy was also maintained over time. Lastly, the safety quency of Candida infections was very low. Only one event of profile of tildrakizumab was favourable over 3 years, with low inflammatory bowel disease was reported (005 events of Crohn rates of severe infections, malignancies and MACEs. disease per 100 PYs), even though an increased risk of incident Crohn disease among patients with psoriasis has been reported Acknowledgments (relative risk of 4).16 Aside from these prespecified AEs, no new or unexpected AEs were reported with tildrakizumab, and rates The authors would like to acknowledge Eva Mateu, PhD of of discontinuations due to AEs were very low. Although these TFS S.L. for editorial assistance and writing support, and data are very promising, patients with moderate-to-severe psori- Andreu Schoenenberger of Almirall S.A. for statistical support. asis may need treatment for years or even decades. Thus, longer-term safety data are needed for tildrakizumab and the References other IL-23p19 inhibitors. Of note, the reSURFACE 1 and reS- URFACE 2 trials are both 5-year trials, with long-term results to 1 Reich K, Armstrong AW, Foley P et al. Efficacy and safety of be published upon their completion. guselkumab, an anti-interleukin-23 monoclonal antibody, com- pared with adalimumab for the treatment of patients with moder- Our analyses had several limitations. Nonresponders to til- ate to severe psoriasis with randomized withdrawal and drakizumab 100 mg or 200 mg discontinued at week 28 and retreatment: results from the phase III, double-blind, placebo- and © 2019 The Authors. British Journal of Dermatology British Journal of Dermatology (2020) 182, pp605–617 published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists 616 Long-term efficacy and safety of tildrakizumab, K. Reich et al. active comparator-controlled VOYAGE 2 trial. J Am Acad Dermatol AbbVie, Affibody, Almirall, Amgen, Biogen, Boehringer Ingel- 2017; 76:418–31. heim, Celgene, Centocor, Covagen, Forward Pharma, Fresenius 2 Blauvelt A, Papp KA, Griffiths CEM et al. Efficacy and safety of Medical Care, GlaxoSmithKline, Janssen-Cilag, Kyowa Hakko guselkumab, an anti-interleukin-23 monoclonal antibody, com- Kirin, LEO Pharma, Lilly, Medac, Merck Sharp & Dohme, Mil- pared with adalimumab for the continuous treatment of patients with moderate to severe psoriasis: results from the phase III, dou- tenyi Biotec, Novartis, Ocean Pharma, Pfizer, Regeneron, Sam- ble-blinded, placebo- and active comparator-controlled VOYAGE 1 sung Bioepis, Sanofi, Takeda, UCB, Valeant and Xenoport. trial. J Am Acad Dermatol 2017; 76:405–17. R.B.W. has received grants and/or honoraria from AbbVie, 3 Papp KA, Blauvelt A, Bukhalo M et al. Risankizumab versus ustek- Almirall, Amgen, Boehringer Ingelheim, Celgene, Janssen, inumab for moderate-to-severe plaque psoriasis. N Engl J Med 2017; Lilly, LEO Pharma, Novartis, Pfizer, Sanofi, UCB Pharma and 376:1551–60. Xenoport. L.I. has served as a consultant and/or paid speaker 4 Papp K, Thacßi D, Reich K et al. Tildrakizumab (MK-3222), an anti-inter- for and/or participated in clinical trials sponsored by AbbVie, leukin-23p19 monoclonal antibody, improves psoriasis in a phase IIb randomized placebo-controlled trial. Br J Dermatol 2015; 173:930–9. Almirall, Amgen, AstraZeneca, BMS, Boehringer Ingelheim, 5 Reich K, Papp KA, Blauvelt A et al. Tildrakizumab versus placebo Celgene, Centocor, Eli Lilly, Janssen-Cilag, Kyowa, LEO or etanercept for chronic plaque psoriasis (reSURFACE 1 and reS- Pharma, MSD, Novartis, Pfizer and UCB. L.P. has received URFACE 2): results from two randomised controlled, phase 3 tri- grants or research support from or participated in clinical trials als. Lancet 2017; 390:276–88. (paid to the institution) for AbbVie, Almirall, Amgen, Boeh- 6 Papp KA, Reich K, Blauvelt A et al. Efficacy of tildrakizumab for ringer Ingelheim, Janssen, LEO Pharma, Lilly, Novartis, Pfizer, moderate-to-severe plaque psoriasis: pooled analysis of three ran- Regeneron, Roche, Sanofi and UCB; has received honoraria or domized controlled trials at weeks 12 and 28. J Eur Acad Dermatol Venereol 2019; 33:1098–106. consultation fees from AbbVie, Almirall, Amgen, Baxalta, Bio- 7 Blauvelt A, Reich K, Papp KA et al. Safety of tildrakizumab for gen, Boehringer Ingelheim, Celgene, Gebro, Janssen, LEO moderate-to-severe plaque psoriasis: pooled analysis of three ran- Pharma, Lilly, Merck-Serono, Merck Sharp & Dohme, Mylan, domized controlled trials. Br J Dermatol 2018; 179:615–22. Novartis, Pfizer, Regeneron, Roche, Samsung Bioepis, Sandoz, 8 Kaushik SB, Lebwohl MG. Psoriasis: which therapy for which Sanofi and UCB; and has participated in company-sponsored patient. Focus on special populations and chronic infections. J Am speakers’ bureaus for Celgene, Janssen, Lilly, Merck Sharp & Acad Dermatol 2019; 80:43–53. Dohme, Novartis and Pfizer. A.I. has received honoraria for 9 Kaushik SB, Lebwohl MG. Psoriasis: which therapy for which patient. Psoriasis comorbidities and preferred systemic agents. J Am serving on advisory boards from Maruho, Janssen, AbbVie, Acad Dermatol 2019; 80:27–40. Novartis, Eli Lilly Japan, Celgene and Sun Pharma Japan. M.O. 10 Ibler E, Gordon KB. IL-23 inhibitors for moderate-to-severe psoria- has received honoraria for serving on advisory boards from sis. Semin Cutan Med Surg 2018; 37:158–62. Maruho, Janssen, AbbVie, Novartis, Eli Lilly Japan, Celgene, 11 Ogawa E, Sato Y, Minagawa A, Okuyama R. Pathogenesis of psori- Eisai, Kyowa Hakko Kirin, LEO Pharma, Pfizer Japan, Mit- asis and development of treatment. J Dermatol 2018; 45:264–72. subishi Tanabe Pharma, Boehringer Ingelheim, Bristol-Myers 12 Griffiths CEM, Papp KA, Kimball AB et al. Long-term efficacy of Squibb Company and Sun Pharma Japan. I.P.-C. and M.F. are guselkumab for the treatment of moderate-to-severe psoriasis: results from the phase 3 VOYAGE 1 trial through two years. J Drugs employees of Almirall. M.H. has served as a statistical consul- Dermatol 2018; 17:826–32. tant for Almirall. S.R. is an employee of Sun Pharmaceuticals. 13 Gordon KB, Strober B, Lebwohl M et al. Efficacy and safety of M.G.L. has received research funds (paid to the institution) risankizumab in moderate-to-severe plaque psoriasis (UltIMMa-1 from AbbVie, Amgen, Boehringer Ingelheim, Celgene, Eli and UltIMMa-2): results from two double-blind, randomised, pla- Lilly, Incyte, Janssen/Johnson & Johnson, Kadmon, LEO cebo-controlled and ustekinumab-controlled phase 3 trials. Lancet Pharma, Medimmune/AstraZeneca, Novartis, Ortho-dermato- 2018; 392:650–61. logics, Pfizer, Sciderm, UCB5 and Vidac; and is a consultant 14 Reich K, Rich P, Maari C et al. Efficacy and safety of mirikizumab (LY3074828) in the treatment of moderate-to-severe plaque psoriasis: for Allergan, Aqua, Arcutis, Boehringer Ingelheim, Bristol- results from a randomized phase II study. Br J Dermatol 2019; Myers Squibb, LEO Pharma, Menlo, Mitsubishi Pharma/Neu- 181:88–95. roderm LTD, Promius/Dr Reddy, Regeneron, Theravance Bio- 15 Galluzzo M, D’Adamio S, Campione E et al. A safety evaluation of pharma and Verrica. W.C. has received honoraria or fees for guselkumab for the treatment of psoriasis. Expert Opin Drug Saf 2018; serving on advisory boards or as a speaker from Sun Pharma- 17:741–51. ceuticals, Lilly, Novartis and Janssen. A.B. has served as a sci- 16 Li W-Q, Han J-L, Chan AT, Qureshi AA. Psoriasis, psoriatic arthri- entific adviser and/or clinical study investigator for AbbVie, tis and increased risk of incident Crohn’s disease in US women. Ann Rheum Dis 2013; 72:1200–5. Aclaris, Akros, Allergan, Almirall, Amgen, Arena, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Dermavant, Der- mira, Inc., Eli Lilly and Company, FLX Bio, Galderma, Genen- tech/Roche, GlaxoSmithKline, Janssen, LEO, Meiji, Merck Sharp & Dohme, Novartis, Pfizer, Purdue Pharma, Regeneron, Revance, Sandoz, Sanofi Genzyme, Sienna Pharmaceuticals, Sun Pharma, UCB Pharma, Valeant and Vidac; and as a paid Appendix speaker for Janssen, Regeneron and Sanofi Genzyme. D.T. has Conflicts of interest: K.R. has served as an advisor and/or paid received honoraria or fees for serving on advisory boards, or speaker for and/or participated in clinical trials sponsored by as a speaker or consultant, from AbbVie, Almirall, Bioskin, British Journal of Dermatology (2020) 182, pp605–617 © 2019 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists Long-term efficacy and safety of tildrakizumab, K. Reich et al. 617 Boehringer Ingelheim, Celgene, Dignity, Galapagos, Table S4 Partial responders to tildrakizumab 100 mg or GlaxoSmithKline, Janssen, LEO Pharma, Lilly, Medac, Merck 200 mg: absolute Psoriasis Area and Severity Index. Sharp & Dohme, Morphosys, Novartis, Pfizer, Regeneron, Table S5 Partial responders or nonresponders to etanercept Samsung, Sandoz-Hexal, Sanofi, Sun Pharmaceuticals and UCB; 50 mg who were treated with tildrakizumab 200 mg: changes and has received grants from Celgene and Novartis. in Psoriasis Area and Severity Index. Table S6 Partial responders or nonresponders to etanercept 50 mg who were treated with tildrakizumab 200 mg: absolute Supporting Information Psoriasis Area and Severity Index. Additional Supporting Information may be found in the online Video S1 Author video. version of this article at the publisher’s website: Powerpoint S1 Journal Club Slide Set. Table S1 Responders to tildrakizumab 100 mg or 200 mg: changes in Psoriasis Area and Severity Index. Table S2 Responders to tildrakizumab 100 mg or 200 mg: absolute Psoriasis Area and Severity Index. Table S3 Partial responders to tildrakizumab 100 mg or 200 mg: changes in Psoriasis Area and Severity Index. © 2019 The Authors. British Journal of Dermatology British Journal of Dermatology (2020) 182, pp605–617 published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists