Dermatol Ther (Heidelb) (2022) 12:2325–2341 https://doi.org/10.1007/s13555-022-00793-z ORIGINAL RESEARCH Efficacy of Tildrakizumab Across Different Body Weights in Moderate-to-Severe Psoriasis Over 5 Years: Pooled Analyses from the reSURFACE Pivotal Studies Diamant Thaçi . Sascha Gerdes . Kristian Gaarn Du Jardin . Jean-Luc Perrot . Lluı́s Puig Received: July 20, 2022 / Accepted: August 5, 2022 / Published online: September 13, 2022 Ó The Author(s) 2022 ABSTRACT patients with high BW. This post-hoc study describes the long-term efficacy of TIL across Introduction: Tildrakizumab (TIL), a mono- different BWs in pivotal clinical trials. clonal antibody that selectively targets inter- Methods: A 5-year pooled analysis of two dou- leukin-23p19, has been approved for the ble-blind, randomised, controlled phase III tri- treatment of moderate-to-severe plaque psoria- als—reSURFACE 1 and 2—was performed. sis. According to the European Medicines Efficacy measures were the proportions of the Agency Summary of Product Characteristics, patients with an absolute Psoriasis Area and the recommended dose is 100 mg, but a 200 mg Severity Index (PASI) of \ 3 and \ 1 and a dose can be used in patients with certain char- Dermatology Life Quality Index (DLQI) of 0/1. acteristics, such as a high disease burden or The study population included patients ran- body weight (BW) C 90 kg. Fixed one-dose bio- domised to TIL 100 mg or TIL 200 mg who logical therapies tend to become less effective in received C 1 TIL dose up to week 12 (part 1 of the trial) or up to week 28 (part 2) and patients who were responders (C 75% improvement in D. Thaçi (&) PASI) to TIL 100 or TIL 200 mg at week 28 and Institute and Comprehensive Center for who were maintained on the same dose up to Inflammation Medicine, University of Lübeck, week 244. Efficacy was evaluated by analysing Ratzeburger Allee 160, 23562 Lübeck, Germany e-mail: Diamant.Thaci@uksh.de BW subgroups at weeks 28, 52 and 244. Missing data were analysed using multiple imputation. S. Gerdes Safety was assessed in the all-patients-as-treated Department of Dermatology, Venereology and Allergology, Center for Inflammatory Skin Diseases, population. University Medical Center Schleswig-Holstein, Results: The proportions of TIL-treated patients Campus Kiel, Kiel, Germany with PASI \ 3 and \ 1 (up to week 244) and DLQI 0/1 (up to week 52) were similar for K. G. Du Jardin Almirall R&D, Barcelona, Spain patients with BW \ 90 or C 90 kg, regardless of dose. Patients C 120 kg had greater efficacy J.-L. Perrot outcomes at the 200 mg dose. Safety outcomes Department of Dermatology, University Hospital of St-Etienne, St-Etienne, France were similar regardless of treatment dose and weight (\ 120/C 120 kg). L. Puig Conclusion: In patients with BW C 120 kg, TIL Department of Dermatology, Hospital de La Santa 200 mg is more efficacious than TIL 100 mg, Creu I Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain 2326 Dermatol Ther (Heidelb) (2022) 12:2325–2341 with similar favourable safety profiles obtained mass on therapeutic response could be regardless of dose and BW group. explained in part by the pharmacokinetics (PK) Trial registration: ClinicalTrials.gov NCT0 and pharmacodynamics (PD) of biologics. The 1722331 (reSURFACE 1) and NCT01729754 pharmacokinetics of biologics are influenced by (reSURFACE 2). BW [6], and increasing BW decreases serum concentrations and increases total serum clear- Keywords: Body weight; DLQI; PASI; Psoriasis; ance and volume of distribution [7, 8]. In Tildrakizumab addition, the negative effects of obesity on therapeutic response may also include the up- regulation of pro-inflammatory cytokines pro- Key Summary Points duced by adipose tissue [9, 10]. Tildrakizumab (TIL, SCH-900222, MK-3222) Why carry out this analysis? is a humanised anti-interleukin (IL)-23p19 Biologic treatments for psoriasis often monoclonal antibody approved for the treat- show differences in efficacy depending on ment of moderate-to-severe chronic plaque the patient’s weight. psoriasis in adults [11–16]. Tildrakizumab inhi- bits the IL-23/IL-17 axis, the signalling pathway For some biologics, a diminished clinical primarily involved in the immunopathogenesis response has been described in patients of psoriasis [17]. Tildrakizumab prevents the with higher weight. release of proinflammatory cytokines and There is limited evidence on the impact of chemokines and has a limited impact on the body weight on the effects of rest of the immune system [18]. tildrakizumab (TIL) at different doses. Pooled data from the reSURFACE 1 and reS- URFACE 2 phase III trials showed equal sus- The effects of weight on drug efficacy and tained efficacy, maintenance of response, and safety for two different doses of TIL safety over 5 years with TIL 100 and 200 mg in (100 mg and 200 mg) have not been moderate-to-severe chronic plaque psoriasis reported in sufficient detail. patients [19]. Moreover, TIL 100 mg has been What was learned from this analysis? shown to be highly effective and well tolerated in real-world practice [20–23]. As per the label, Both doses of TIL were similarly efficacious the recommended dose of TIL is 100 mg in patients C 90 kg and \ 90 kg. administered at 0 and 4 weeks and then every Patients with body weight C 120 kg 12 weeks thereafter. The European Medicines achieve better responses with TIL 200 mg Agency TIL Summary of Product Characteristics compared to TIL 100 mg. (SmPC) provides prescribers with the opportu- nity to use the 200 mg dose in patients with certain characteristics (e.g. a high disease bur- den, BW C 90 kg). However, limited evidence is available on the effect of patient BW on the response to TIL 100 mg and 200 mg. INTRODUCTION The objective of the present study was to examine the impact of BW on the efficacy Psoriasis is a chronic immune-mediated response to TIL 100 mg and 200 mg over 5 years inflammatory disease that affects patients in the pivotal reSURFACE trials [24], including globally [1]. The disease is associated with being long-term extensions [19, 25]. Efficacy analyses overweight, obesity, and increased abdominal included pooled patients randomised to TIL and visceral fat [2]. Psoriasis in obese patients 100 mg and 200 mg in the pivotal studies [24], responds less effectively to treatments, includ- with efficacy defined as achieving a Psoriasis ing various biological therapies [3–5]. The Area and Severity Index (PASI) of \ 3, a PASI of detrimental effect of body weight (BW) or body Dermatol Ther (Heidelb) (2022) 12:2325–2341 2327 \ 1 and/or a Dermatology Life Quality Index chronic plaque psoriasis diagnosed C 6 months (DLQI) of 0 or 1. prior to enrolment with a body surface area of C 10%, a Physician’s Global Assessment of C 3 and a PASI of C 12 were included in these piv- METHODS otal clinical trials (772 in reSURFACE 1 and 1090 in reSURFACE 2) [24]. Patients were ran- Study Design and Participants domised to TIL 100 mg, TIL 200 mg or placebo in reSURFACE 1 (2:2:1), or to TIL 100 mg, TIL The reSURFACE 1 (ClinicalTrials.gov 200 mg, placebo or etanercept 50 mg in reSUR- NCT01722331) and reSURFACE 2 (ClinicalTri- FACE 2 (2:2:1:2). reSURFACE 1 and reSURFACE als.gov NCT01729754) phase III trials evaluated 2 included three parts: part 1, weeks 0–12; part the efficacy and safety of TIL in patients with 2, weeks 12–28; and part 3, weeks 28–64 (reS- moderate-to-severe chronic plaque psoriasis for URFACE 1)/52 (reSURFACE 2). Tildrakizumab up to 5 years [19, 25]. reSURFACE 1 and reS- 100 mg and 200 mg were administered subcu- URFACE 2 were three-part, randomised, double- taneously at weeks 0 and 4 and every 12 weeks blind, placebo-controlled, parallel-group trials; thereafter. At week 28, patients with a C 75% reSURFACE 2 included an active comparator improvement in baseline PASI (PASI 75 arm (etanercept) [24]. responders) in reSURFACE 1 were re-ran- The detailed baseline study inclusion and domised to continue the same TIL dose or to exclusion criteria, patient characteristics, treat- receive placebo; in reSURFACE 2, PASI 75 ment, and methodology have been previously responders to TIL 200 mg were re-randomised to published [24, 25]. Briefly, a total of 1,862 TIL 100 or 200 mg, while PASI 75 responders to patients C 18 years old with moderate-to-severe TIL 100 mg maintained the same dose. At week Fig. 1 Study design. White letters represent differences improvement in PASI), PASI Psoriasis Area and Severity between the reSURFACE 1 and reSURFACE 2 trials. The Index, PR partial responder (50–75% improvement in sample assessed for efficacy in this study is shown in red. PASI), R responder (C 75% improvement in PASI), TIL D/C discontinued, NR non-responder (\ 50% tildrakizumab Table 1 PASI \ 3 and DLQI 0/1 at weeks 28, 52 and 244, obtained using a multiple imputation methodology and stratified by BW 2328 group (\ 90 kg, C 90 kg, \ 120 kg and C 120 kg) BW < 90 kg BW ‡ 90 kg BW < 120 kg BW ‡ 120 kg TIL 100 mg TIL 200 mg TIL 100 mg TIL 200 mg TIL 100 mg TIL 200 mg TIL 100 mg TIL 200 mg PASI \ 3 Week 28 69.0 70.0 59.2 66.3 66.4 68.7 48.8 65.2 (63.7–73.9) (64.8–74.8) (53.0–65.2) (60.1–72.1) (62.2–70.4) (64.6–72.6) (35.3–62.4) (50.4–78.1) Week 52 86.5 84.0 73.1 84.5 82.8 83.4 60.0 94.4 (80.8–91.0) (76.8–89.8) (65.0–80.3) (75.4–91.2) (78.0–86.9) (77.6–88.1) (39.9–77.9) (72.7–99.9) Week 244 77.7 80.8 72.3 76.0 76.6 78.3 62.1 85.6 (71.1–83.4) (73.2–87.1) (64.1–79.5) (66.0–84.3) (71.5–81.3) (72.1–83.7) (42.0–79.6) (61.5–96.9) DLQI 0/1 Week 28 56.0 62.1 49.0 55.4 54.3 59.6 40.0 55.4 (50.5–61.4) (56.7–67.2) (42.8–55.2) (49.1–61.6) (50.0–58.6) (55.3–63.7) (27.3–53.8) (40.7–69.5) Week 52 74.2 68.1 53.8 74.4 67.4 70.0 44.6 77.8 (67.3–80.3) (59.6–75.8) (45.2–62.2) (64.2–83.0) (61.8–72.7) (63.3–76.1) (26.0–64.5) (52.4–93.6) Sample sizes at each time point: TIL 100 mg, week 28: n = 593; TIL 100 mg, weeks 52 & 244: n = 329; TIL 200 mg, week 28: n = 597; TIL 200 mg, weeks 52 & 244: n = 227 Data shown as % of responders (95% confidence interval) BW body weight, DLQI Dermatology Life Quality Index, PASI Psoriasis Area and Severity Index, TIL tildrakizumab Dermatol Ther (Heidelb) (2022) 12:2325–2341 Dermatol Ther (Heidelb) (2022) 12:2325–2341 2329 Fig. 2 PASI \ 3 responders over time by BW and TIL a multiple imputation approach. BW body weight, PASI dose. The vertical lines on the bars represent 95% Psoriasis Area and Severity Index, TIL tildrakizumab confidence intervals. These analyses were performed using 64 (reSURFACE 1) or week 52 (reSURFACE 2), the Helsinki Declaration of 1964 and its later patients with an improvement of C 50% from amendments. The study protocols received baseline PASI entered an optional extension local institutional review board or ethics com- period of up to week 256 (reSURFACE 1) or week mittee approvals. All subjects provided written 244 (reSURFACE 2) [19, 25]. The investigators, informed consent to participate in the trials. participants, study staff and analysis team did The study sites of these trials have been previ- not know the treatment assignment until all ously described [24]. patients had completed the third part (Fig. 1). Both the reSURFACE 1 and reSURFACE 2 trials were conducted in accordance with Good Clinical Practice guidelines and the principles of Table 2 PASI \ 3 and PASI \ 1 at weeks 28, 52 and 244, obtained using a multiple imputation methodology and stratified by 20 kg BW group 2330 BW < 60 kg 60 £ BW < 80 kg 80 £ BW < 100 kg 100 £ BW < 120 kg BW ‡ 120 kg TIL 100 mg TIL 200 mg TIL 100 mg TIL 200 mg TIL 100 mg TIL 200 mg TIL 100 mg TIL 200 mg TIL 100 mg TIL 200 mg PASI \ 3 Week 28 62.1 59.5 65.6 70.3 69.0 72.0 63.3 62.1 48.8 65.2 (45.9–76.6) (42.4–75.1) (57.9–72.8) (63.2–76.8) (62.6–74.9) (65.6–77.9) (52.7–73.0) (52.1–71.5) (35.3–62.4) (50.4–78.1) Week 52 95.2 86.7 87.3 85.5 81.5 83.7 72.5 75.3 60.0 94.4 (76.2–99.9) (59.5–98.3) (78.9–93.2) (75.4–92.6) (73.8–87.7) (74.4–90.6) (58.4–84.0) (56.3–89.1) (39.9–77.9) (72.7–99.9) Week 78.6 85.3 78.0 81.8 76.1 78.9 74.8 64.7 62.1 85.6 244 (55.6–93.1) (58.3–97.4) (68.4–85.8) (71.1–89.7) (67.9–83.0) (69.0–86.8) (60.9–85.8) (45.3–81.0) (42.0–79.6) (61.5–96.9) PASI \ 1 Week 28 50.0 45.8 42.5 48.8 41.2 45.2 33.0 31.4 29.0 36.0 (34.2–65.8) (29.6–62.7) (35.0–50.4) (41.4–56.2) (34.8–47.8) (38.5–52.1) (23.6–43.4) (22.6–41.2) (17.7–42.5) (22.9–50.8) Week 52 85.7 73.3 56.8 60.5 59.2 57.3 40.6 58.3 37.1 72.2 (63.7–97.0) (44.9–92.2) (46.3–66.9) (48.5–71.7) (50.4–67.7) (46.5–67.7) (27.2–55.1) (39.0–75.9) (19.8–57.3) (46.5–90.3) Week 51.9 39.3 49.8 59.3 46.1 56.1 40.4 49.7 34.3 51.7 244 (29.5–73.8) (16.0–67.0) (39.4–60.2) (47.3–70.6) (37.4–55.0) (45.3–66.6) (27.0–54.9) (31.1–68.3) (17.6–54.5) (27.5–75.3) Sample sizes at each time point: TIL 100 mg, week 28: n = 593; TIL 100 mg, weeks 52 & 244: n = 329; TIL 200 mg, week 28: n = 597; TIL 200 mg, weeks 52 & 244: n = 227 Data shown as % of responders (95% confidence interval) BW body weight, PASI Psoriasis Area and Severity Index, TIL tildrakizumab Dermatol Ther (Heidelb) (2022) 12:2325–2341 Dermatol Ther (Heidelb) (2022) 12:2325–2341 2331 Fig. 3 PASI \ 3 by 20 kg BW group. The vertical lines on the bars represent the 95% confidence intervals. These analyses were performed using a multiple imputation approach. BW body weight, PASI Psoriasis Area and Severity Index 2332 Dermatol Ther (Heidelb) (2022) 12:2325–2341 Fig. 4 PASI \ 1 by 20 kg BW group. The vertical lines on the bars represent the 95% confidence intervals. These analyses were performed using a multiple imputation approach. BW body weight, PASI Psoriasis Area and Severity Index Dermatol Ther (Heidelb) (2022) 12:2325–2341 2333 Fig. 5 DLQI 0/1 responders over time by BW group and a multiple imputation approach. BW body weight, DLQI TIL dose. The vertical lines on the bars represent the 95% Dermatology Life Quality Index, TIL tildrakizumab confidence intervals. These analyses were performed using Assessments responses at week 28 and week 52 (1 year). All analyses were stratified into BW \ 60 kg, 60 Efficacy outcomes were defined as the propor- B BW \ 80 kg, 80 B BW \ 100 kg, 100 B BW tions of patients who achieved absolute \ 120 kg, and BW C 120 kg groups (henceforth PASI \ 3 and PASI \ 1 throughout 5 years of ‘‘20 kg BW groups’’), and comparisons treatment—that is, at week 28, week 52 (1 year) of \ 90 kg versus C 90 kg BW patients and and week 244 (5 years)—and DLQI 0/1 2334 Dermatol Ther (Heidelb) (2022) 12:2325–2341 Fig. 6 Sensitivity analysis: correlation between BW and the absolute PASI change from baseline at week 28. BW body weight, PASI Psoriasis Area and Severity Index Fig. 7 Sensitivity analysis: correlation between BW and the absolute DLQI change from baseline at week 28. BW body weight, DLQI Dermatology Life Quality Index \ 120 kg versus C 120 kg BW patients were \ 120 kg versus C 120 kg. Medical Dictionary performed. for Regulatory Activities preferred terms for Safety assessments focused on adverse events each AE were assigned to the treatment dose (AEs). Pre-specified treatment-emergent AEs that the patient was actively receiving when the (TEAEs) comprised severe infections, malig- AE occurred. nancies, non-melanoma skin cancer (NMSC), melanoma, confirmed extended major adverse Statistical Analyses cardiovascular events, injection site reactions and drug-related hypersensitivity reactions No formal hypothesis testing was performed for [24, 25]. Adverse events were assessed at all these post hoc analyses. Based on the authors’ study visits during the base period pool (three expert opinion, a difference of * 15% in parts) plus the extension period up to weeks response rates was considered clinically mean- 256/244 over 5 years for TIL 100 mg versus ingful. All subjects randomised to TIL 100 mg 200 mg, separately, and were stratified into BW and TIL 200 mg who received at least one dose Dermatol Ther (Heidelb) (2022) 12:2325–2341 2335 Table 3 Pooled exposure-adjusted rates of AEs in the reSURFACE 1 and 2 trials for patients with BW \ 120 kg and C 120 kg (base period safety pool plus 4 years of extension up to weeks 256 and 244) TIL 100 mg TIL 200 mg BW < 120 kg BW ‡ 120 kg BW < 120 kg BW ‡ 120 kg (n = 790) (n = 82) (n = 854) (n = 74) Total follow-up, patient-years 2468.2 220.2 2536.3 217.3 Severe infection 31 (1.3) [0.8–1.7] 7 (3.2) [0.8–5.6] 42 (1.7) [1.1–2.2] 6 (2.8) [0.5–5.0] Malignancy excluding NMSC 18 (0.7 [0.4–1.1] 3 (1.4) [0.0–2.9] 16 (0.6) [0.3–1.0] 1 (0.5) [0.0–1.4] NMSC 13 (0.5) [0.2–0.8] 1 (0.5) [0.0–1.4] 13 (0.5) [0.2–0.8] 3 (1.4) [0.0–3.0] Melanoma* 3 (0.1) [0.0–0.3] – 3 (0.1) [0.0–0.3] – Confirmed extended MACE 14 (0.6) [0.3–0.9] 1 (0.5) [0.0–1.4] 22 (0.9) [0.5–1.2] 2 (0.9) [0.0–2.2] Injection-site reaction 62 (2.5) [1.9–3.2] 5 (2.3) [0.2–4.3] 82 (3.2) [2.5–4.0] 4 (1.8) [0.0–3.7] Drug-related hypersensitivity 11 (0.5) [0.2–0.7] 3 (1.4) [0.0–2.9] 5 (0.2) [0.0–0.4] 0 reaction Any TEAE 4690 (190.0) 542 (246.1) 5061 (199.5) 516 (237.5) [184.5–195.6] [225.0–267.2] [193.9–205.2] [216.6–258.4] Drug-related TEAEs 721 (29.2) 72 (32.7) 935 (36.9) 105 (48.3) [27.0–31.4] [25.0–40.4] [34.5–39.3] [38.9–57.8] Any SAE 220 (8.9) [7.7–10.1] 29 (13.2) 219 (8.6) [7.5–9.8] 26 (12.0) [8.3–18.1] [7.3–16.7] Drug-related SAEs 22 (0.9) [0.5–1.3] 2 (0.9) [0.0–2.2] 15 (0.6) [0.3–0.9] 1 (0.5) [0.0–1.4] Deaths 9 (0.4) [0.1–0.6] 2 (0.9) [0.0–2.2] 5 (0.2) [0.0–0.4] 0 TEAEs leading to discontinuation 47 (1.9) [1.4–2.5] 5 (2.3) [0.2–4.3] 36 (1.4) [1.0–1.9] 4 (1.8) [0.0–3.7] Drug-related AEs leading to 18 (0.7) [0.4–1.1] 1 (0.5) [0.0–1.4] 10 (0.4) [0.1–0.6] 0 discontinuation SAEs leading to discontinuation 29 (1.2) [0.7–1.6] 2 (0.9) [0.0–2.2] 22 (0.9) [0.5–1.2] 1 (0.5) [0.0–1.4] Drug-related SAEs leading to 9 (0.4) [0.1–0.6] – 5 (0.2) [0.0–0.4] – discontinuation* Data shown as n (number of events per 100 patient-years of exposure) [95% confidence interval] * For the C 120 kg group, there were no melanomas or drug-related SAEs leading to discontinuation AE(s) adverse event(s), MACE major adverse cardiovascular event, NMSC nonmelanoma skin cancer, SAE(s) serious AE(s), TEAE(s) treatment-emergent AE(s) of the part 1 or part 2 study medication were and 244) (TIL 100 mg: n = 329; TIL 200 mg: included in the week 28 analyses (TIL 100 mg: n = 227). n = 593; TIL 200 mg: n = 597), while all patients Efficacy analyses used a multiple imputation who were responders at week 28 and who con- approach (10 imputations) for missing data, as tinued treatment with the same TIL dose were previously described [25]. Assessments at weeks included in the long-term analyses (weeks 52 28, 52 and 244 are reported. Observed cases were used as sensitivity analyses at week 28: 2336 Dermatol Ther (Heidelb) (2022) 12:2325–2341 Pearson’s correlation (r) was calculated for the The proportions (95% CIs) of the patients relationship between BW and efficacy who were treated with TIL 100 mg and TIL endpoints. 200 mg and had BW \ 90 kg, C 90 kg, \ 120 kg Safety analyses were performed in the all- and C 120 kg who achieved DLQI 0/1 scores at patients-as-treated population, including all weeks 28 and 52 are shown in Table 1 and in patients who received at least one dose of the Fig. 5. The most notable differences between the study drug according to the treatment received TIL 100 mg and 200 mg doses are again seen for (n = 1800). Safety data from week 0 through the heaviest patients, with the C 120 kg group 5 years were pooled between reSURFACE 1 (up treated with the TIL 200 mg dose showing the to week 256) and reSURFACE 2 (up to week 244) highest proportion of patients who achieved and were presented for patients who received DLQI 0/1. TIL 100 mg or TIL 200 mg during any part of the Sensitivity analyses (Figs. 6 and 7) showed no study, with a BW of 120 kg used as the com- significant relationship between BW in kg and parison threshold. Safety data are reported as changes in efficacy endpoints from baseline. the number of events per 100 patient-years of The correlation between the absolute change in exposure; exposure-adjusted incidence rates PASI score from baseline at week 28 and BW was and 95% confidence intervals (CIs) were com- r = 0.046 (p = 0.276) in the TIL 100 mg cohort puted as previously described [24, 25]. and r = 0.012 (p = 0.773) in the TIL 200 mg cohort. The correlation between the absolute change in DLQI score from baseline at week 28 RESULTS and BW was r = 0.043 (p = 0.302) in the TIL 100 mg cohort and r = 0.029 (p = 0.484) in the The demographic and baseline characteristics of TIL 200 mg cohort. the patients are reported elsewhere [24, 25] and were similar across treatment groups. Safety Outcomes Efficacy Outcomes Exposure-adjusted incidence rates of TEAEs are shown in Table 2. There were no significant A total of 593 and 597 patients randomised to differences between the treatment and BW TIL 100 mg and TIL 200 mg, respectively, were groups in rate of TEAEs. The cumulative inci- included in week 28 analyses, while a total of dence for TIL 100 mg/TIL 200 mg treatment in 329 responders to TIL 100 mg and 227 respon- patients \ 120 kg versus patients C 120 kg was ders to TIL 200 mg at week 28 were included in 18/16 versus 3/1 per 100 patient-years of expo- week 52 and week 244 analyses. sure for malignancy excluding NMSC, 13 in The proportions (95% CIs) of patients treated both cases versus 1/3 per 100 patient-years of with TIL 100 mg and TIL 200 mg and stratified exposure for NMSC, 3 in both cases versus 0 per by BW \ 90 kg, C 90 kg, \ 120 kg and C 120 kg 100 patient-years of exposure for melanoma, who achieved absolute PASI scores \ 3 at each and 9/5 versus 0 per 100 patient-years of expo- timepoint (weeks 28, 52 and 244) are shown in sure for drug-related serious AEs leading to dis- Table 1 and Fig. 2. The most notable differences continuation (Table 3). between the two doses are observed for the C 120 kg group, which shows that more patients achieved PASI \ 3 when they were DISCUSSION treated with TIL 200 mg. Similar results were found for PASI \ 3 and PASI \ 1 scores stratified The current work presents post-hoc efficacy and by 20 kg BW group (see Table 2 and Figs. 3 and safety analyses by BW of randomised subjects 4), especially at weeks 52 and 244 (although the who received at least one dose of TIL (week 28 proportion of responders was higher for PASI 3 results) and of responders at week 28 who at those weeks). entered TIL extension treatments (100 mg and 200 mg) and received continuous TIL treatment Dermatol Ther (Heidelb) (2022) 12:2325–2341 2337 through week 244 (week 52 and week 244 responses to biologics and a higher risk of results). For the overall dataset at week 28, no treatment discontinuation [31–34]. correlation was found between PASI or DLQI Diminished responses in obese patients with change from baseline and BW, indicating a psoriasis have been reported for every class of limited impact of BW on the TIL response in the biological agents [35]. For tumour necrosis fac- general psoriasis study population. Moreover, tor (TNF)-alpha inhibitors, several studies PASI \ 3, PASI \ 1 and DLQI 0/1 response rates demonstrate that obesity and BW appear to be were similar for TIL 100 mg and 200 mg in predictors of inferior clinical response to anti- patients with BW [ 90 kg, with no clinically TNF agents (i.e. etanercept, adalimumab) in meaningful difference consistently observed at different immune-mediated inflammatory dis- weeks 28, 52 and 244. On the other hand, eases, including psoriasis [36–40]. For IL-12/23 patients with C 120 kg demonstrated a consis- antagonists (i.e. ustekinumab), reduced efficacy tent trend toward greater clinical benefit from (PASI) outcomes have been found with TIL 200 mg compared to TIL 100 mg across increasing body mass [41–44]. The clinical effi- endpoints and time points. Likewise, when cacies of IL-17 inhibitors (i.e. secukinumab, considering the PASI \ 3 and PASI \ 1 response bimekizumab, ixekizumab) in overweight [45] rates for the two doses in subgroups of 20 kg BW and/or obese [46] psoriatic patients appear to be intervals, a consistent numerical difference in lower than those in non-obese patients, with favour of TIL 200 mg across time points only dose optimisation appearing to be highly ben- appeared for the heaviest patients ([ 120 kg). eficial clinically for patients with higher body The SmPC of TIL [18], in which early PK and PD weight [47, 48]. Recent real-world evidence models from 2017 are outlined, indicates that suggests that an obese or overweight status exposure to TIL decreases with increasing BW. might lead to decreased efficacy, even in IL- In this regard, the mean exposure in adult 23p19 inhibitors (i.e. guselkumab, risankizu- patients weighing [ 90 kg after a dose of TIL mab) [49–52]. In clinical trials, however, this 100 mg or 200 mg was predicted to be approxi- was not the case [53, 54]. Considering these mately 30% lower than that in an adult patient previously reported findings, along with the weighing B 90 kg. Consequently, while TIL data presented here for TIL, a lower clinical 100 mg is the recommended dose, the European response to all approved biological therapies is TIL label provides prescribers with the oppor- more likely in psoriasis patients with high BW, tunity to use the 200 mg dose in patients with who may benefit from intensified dosing, which ‘‘certain characteristics’’, and mentions may be more difficult to accommodate with BW C 90 kg as one possible example [18]. Our fixed-dose biological therapies. pooled analyses of the complete phase III trial The main limitation of this analysis is the dataset including extensions suggest that 120 kg relatively small number of patients with a BW of may be a more appropriate weight cut-off point over 120 kg, corresponding to * 8–9% of the to guide clinical decision-making. study population, but this distribution is largely The safety analyses showed equal rates of AEs representative of the general psoriasis popula- for different doses and for BW \ 120 kg tion [55, 56]. or C 120 kg, thus suggesting that the potential additional benefit of 200 mg in patients [ 120 kg does not come with a safety CONCLUSION trade-off. An increasing number of reports are estab- Tildrakizumab 100 mg has been demonstrated lishing a negative impact of obesity on response to provide long-term control with a favourable to biological therapies [9, 26–28]. Prevalences of safety profile both in clinical trials and in real- overweight and obese patients in clinical reg- world practice [19–22, 57]. The data presented istries range between 40% [5, 29] and 57% [30], here suggest that TIL 200 mg may be more and 29% [29] and 30% [5], respectively, with efficacious than the standard 100 mg dose in overweight/obese patients showing lower patients weighing C 120 kg. 2338 Dermatol Ther (Heidelb) (2022) 12:2325–2341 ACKNOWLEDGEMENTS Amgen, Anaptys Bio, Argenx BV, AstraZeneca AB, Biogen Idec, Bioskin, BoehringerIngelheim, We thank the participants of the study. Celgene, Dermira, Eli Lilly, Forward Pharma, Galderma, Hexal AG, Incyte Inc., Janssen-Cilag, Johnson & Johnson, Kymab, Leo Pharma, Funding. The post hoc analyses and Rapid Medac, MSD, Neubourg Skin Care GmbH, Service Fee for this manuscript were sponsored Novartis, Pfizer, Principia Biopharma, Regen- by Almirall R&D, Barcelona, Spain. eron Pharmaceutical, Sandoz Biopharmaceuti- Medical Writing, Editorial, and Other cals, Sanofi-Aventis, Trevi Therapeutics, and Assistance. Medical writing assistance in the UCB Pharma; Kristian Gaarn Du Jardin is an preparation of this manuscript was provided by employee of Almirall; Jean-Luc Perrot has been Mónica Giménez, PhD, and Eva Mateu, PhD, of an advisor for and/or received speakers’ hono- TFS HealthScience. Support for this assistance raria from and/or received grants from and/or was funded by Almirall R&D, Barcelona, Spain. participated in clinical trials by the following companies: Abbott/AbbVie Inc, Amgen, Cel- Authorship. All named authors meet the gene, Eli Lilly and Company, Galderma, Incyte International Committee of Medical Journal Corporation, Janssen-Cilag Ltd, Johnson & Editors (ICMJE) criteria for authorship for this Johnson, LEO Pharma, Merck Serono, Merck article, take responsibility for the integrity of Sharp & Dohme, Novartis, Pierre Fabre, Pfizer, the work as a whole, and have given their Sanofi-Aventis, Schering-Plough, and UCB approval for this version to be published. Pharma; Lluı́s Puig has received grants/research support from or participated in clinical trials Author Contributions. DT made a signifi- (paid to the institution) by AbbVie, Almirall, cant contribution to the conception and design Amgen, Boehringer Ingelheim, Celgene, Jans- of the study, the analysis and interpretation, sen, LEO Pharma, Lilly, Novartis, Pfizer, Regen- the drafting of the manuscript and the criti- eron, Roche, Sanof, and UCB; received cal review of it for important intellectual con- honoraria or consultation fees from AbbVie, tent. SG and KGdJ contributed to the Almirall, Amgen, Baxalta, Biogen, Boehringer conception and study design and critically Ingelheim, Bristol Myers Squibb, Celgene, Fre- reviewed the article. JLP and LLP critically senius-Kabi, Janssen, JS BIOCAD, LEO Pharma, reviewed the manuscript. Lilly, Mylan, Novartis, Pfizer, Regeneron, Roche, Sandoz, Samsung-Bioepis, Sanof, and UCB; and Prior Presentation. Part of this manuscript participated in company-sponsored speaker’s is based on work that was previously presented bureaus for Celgene, Janssen, Lilly, Novartis, at the 31st Congress of the European Academy and Pfizer. of Dermatology and Venereology (EADV), Milan, 7–10 September 2022. Compliance with Ethics Guidelines. The reSURFACE 1 and reSURFACE 2 trials received Disclosures. Diamant Thaçi has received approval from local institutional review boards honoraria as an advisor, speaker and/or inves- or ethics committees. The studies were per- tigator from AbbVie, Almirall, Amgen, Biogen- formed in accordance with Good Clinical Prac- Idec, Boehringer Ingelheim, Bristol Myers tice guidelines and the Helsinki Declaration of Squibb, Eli Lilly, Galapagos, Janssen-Cilag, LEO 1964 and its later amendments. All subjects Pharma, Novartis, Pfizer, Regeneron, Roche- provided written informed consent to partici- Possay, Samsung, Sanofi and UCB; Sascha pate in the studies. Gerdes has been an advisor for and/or received speakers’ honoraria from and/or received grants Data Availability. The datasets generated from and/or participated in clinical trials by the during and/or analysed during the current following companies: AbbVie, Affibody AB, study are available from the corresponding Akari Therapeutics Plc, Almirall-Hermal, author on reasonable request. Dermatol Ther (Heidelb) (2022) 12:2325–2341 2339 Open Access. This article is licensed under a 7. Zhu Y, Hu C, Lu M, Liao S, Marini JC, Yohrling J, Creative Commons Attribution-Non- et al. Population pharmacokinetic modeling of ustekinumab, a human monoclonal antibody tar- Commercial 4.0 International License, which geting IL-12/23p40, in patients with moderate to permits any non-commercial use, sharing, severe plaque psoriasis. J Clin Pharmacol. 2009;49: adaptation, distribution and reproduction in 162–75. any medium or format, as long as you give 8. 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