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Efficacy and safety of ixekizumab in a phase III, randomized, double‐blind, placebo‐controlled study in paediatric patients with moderate‐to‐severe plaque psoriasis (IXORA‐PEDS)†

Summary Background Plaque psoriasis affects children and adults, but treatment options for paediatric psoriasis are limited. Objectives To evaluate the efficacy and safety of ixekizumab (IXE), a high‐affinity monoclonal antibody that selectively targets interleukin‐17A, for moderate‐to‐severe paediatric psoriasis. Methods In a randomized, double‐blind, placebo‐controlled, phase III study (IXORA‐PEDS), patients aged 6 to < 18 years with moderate‐to‐severe plaque psoriasis were randomized 2 : 1 to weight‐based dosing of IXE every 4 weeks (IXE Q4W, n = 115) or placebo (n = 56) through week 12, followed by open‐label IXE Q4W. Coprimary endpoints were the proportions of patients at week 12 achieving ≥ 75% improvement in Psoriasis Area and Severity Index (PASI 75) and those achieving a static Physician's Global Assessment score of 0 or 1 (sPGA 0,1). Results IXE was superior (P < 0·001) to placebo for both coprimary endpoints of PASI 75 (IXE Q4W, 89%; placebo, 25%) and sPGA (0,1) (IXE Q4W, 81%; placebo, 11%). IXE was also superior for all gated secondary endpoints, including PASI 75 and sPGA (0,1) at week 4, improvement in itch, and complete skin clearance. IXE Q4W provided significant (P < 0·001) improvements vs. placebo in quality of life and clearance of scalp and genital psoriasis. Responses at week 12 were sustained or further improved through week 48. Through week 12, 45% (placebo) and 56% (IXE) of patients reported treatment‐emergent adverse events. One serious adverse event was reported (IXE), one patient discontinued due to an adverse event (placebo) and no deaths were reported. Conclusions IXE was superior to placebo in the treatment of moderate‐to‐severe paediatric psoriasis, and the safety profile was generally consistent with that observed in adults. What is already known about this topic? Paediatric psoriasis affects approximately 1% of children and can negatively impact health‐related quality of life. Treatment options for paediatric psoriasis are typically limited to off‐label treatments and approved systemic biologics. Ixekizumab, a high‐affinity monoclonal antibody that selectively targets interleukin‐17A, is approved for moderate‐to‐severe plaque psoriasis in adults and was recently approved by the US Food and Drug Administration for moderate‐to‐severe paediatric psoriasis. What does this study add? Ixekizumab resulted in rapid and statistically significant improvements over placebo in skin involvement, itch and health‐related quality of life, which persisted through 48 weeks of treatment in paediatric patients with moderate‐to‐severe plaque psoriasis. The safety profile of ixekizumab was generally consistent with that seen in adults. Ixekizumab may be an additional potential therapeutic option and an additional class of biologic therapy (interleukin‐17A antagonist) for the treatment of moderate‐to‐severe paediatric psoriasis. Plain language summary available online

What is already known about this topic?
• Paediatric psoriasis affects approximately 1% of children and can negatively impact health-related quality of life.
• Treatment options for paediatric psoriasis are typically limited to off-label treatments and approved systemic biologics.
• Ixekizumab, a high-affinity monoclonal antibody that selectively targets interleukin-17A, is approved for moderate-to-severe plaque psoriasis in adults and was recently approved by the US Food and Drug Administration for moderate-to-severe paediatric psoriasis.
What does this study add?
• Ixekizumab resulted in rapid and statistically significant improvements over placebo in skin involvement, itch and health-related quality of life, which persisted through 48 weeks of treatment in paediatric patients with moderate-to-severe plaque psoriasis.
• The safety profile of ixekizumab was generally consistent with that seen in adults.
• Ixekizumab may be an additional potential therapeutic option and an additional class of biologic therapy (interleukin-17A antagonist) for the treatment of moderate-to-severe paediatric psoriasis.
Paediatric plaque psoriasis affects approximately 1% of children and adolescents, and is estimated to occur first before 20 years of age in 35-50% of adults with plaque psoriasis. [1][2][3] Paediatric psoriasis can be associated with reduced quality of life and a higher incidence of multiple comorbidities, including psoriatic arthritis, obesity, diabetes, Crohn's disease, ulcerative colitis and psychiatric comorbidities. 4 Thus, early recognition and treatment of paediatric psoriasis are important for overall health and quality of life.
As there have been few clinical studies of paediatric psoriasis, treatment options are limited and often used off-label. Topical therapies comprise first-line treatment, followed by phototherapy for moderate-to-severe paediatric psoriasis. 5 Systemic treatments are recommended for moderate-to-severe paediatric psoriasis recalcitrant to topical therapies. 5,6 Nonbiologic systemic treatments such as methotrexate or ciclosporin are used, but they may not be well tolerated or provide adequate efficacy. 5,6 Ixekizumab (IXE) is a high-affinity monoclonal antibody that selectively targets interleukin-(IL)-17A. The objective of this study was to evaluate the efficacy and safety of IXE for moderate-to-severe plaque psoriasis in paediatric patients aged 6 to < 18 years. Prior to the current study, two tumour necrosis factor inhibitors (etanercept and adalimumab) and one IL-12/23 antagonist (ustekinumab) were approved for paediatric psoriasis. 7 Based on the findings from this study, IXE was recently approved by the US Food and Drug Administration (FDA) for moderate-to-severe paediatric psoriasis in addition to previously approved indications for adult patients with moderate-to-severe plaque psoriasis, active psoriatic arthritis and ankylosing spondylitis.

Patients and methods
Patients Study participants were 6 to < 18 years of age and had moderate-to-severe plaque psoriasis, defined as Psoriasis Area and Severity Index (PASI) ≥ 12, static Physician's Global Assessment (sPGA) ≥ 3 and psoriasis-affected body surface area ≥ 10% at screening and baseline. They were also candidates for phototherapy or systemic therapy or their psoriasis was not adequately controlled by topical therapies as determined by the investigator. Patients with pustular, erythrodermic and/or guttate forms of plaque psoriasis or drug-induced psoriasis, or with clinical and/or laboratory evidence of untreated latent or active tuberculosis were excluded. Appendix S2 (see Supporting Information) provides complete eligibility criteria.

Study design
IXORA-PEDS is a 108-week multicentre, double-blind, randomized, placebo-controlled, phase III study examining the efficacy and safety of IXE vs. placebo in paediatric patients with moderate-to-severe plaque psoriasis. During a 12-week double-blind treatment period, patients were randomized 2 : 1 to subcutaneous IXE every 4 weeks (Q4W) or placebo, administered according to baseline weight categories of > 50 kg, 25-50 kg and < 25 kg (Table S1; see Supporting Information Enrolment for IXORA-PEDS occurred between 17 April 2017 and 13 November 2018. At the time of publication of this report, the study is currently ongoing. IXORA-PEDS (Clin-icalTrials.gov: NCT03073200) was conducted in accordance with the ethical principles of the Declaration of Helsinki. The study was approved by the ethical review board at each participating site. A parent or legal guardian provided written informed consent and the patient provided written assent prior to conduct of study assessments, examinations or procedures. Appendix S3 (see Supporting Information) provides additional details on the study design.

Outcomes
The prespecified coprimary objectives of the study were to assess whether IXE Q4W was superior to placebo at week 12 as measured by the proportions of patients achieving ≥ 75% improvement from baseline in PASI (PASI 75) and an sPGA score of 0 or 1 [sPGA (0,1)]. The prespecified gated secondary objectives were to assess whether IXE Q4W was superior to placebo at week 12, as measured by the proportion of patients achieving PASI 90, an sPGA score of 0 [sPGA (0)], PASI 100 and ≥ 4-point improvement from baseline in the Itch Numerical Rating Scale (Itch NRS ≥ 4, in patients with baseline score ≥ 4); as well as PASI 75 and sPGA (0,1) at week 4. Other prespecified secondary outcomes included a 0 or 1 score on the Children's Dermatology Life Quality Index (CDLQI, patients aged 6-16 years) or Dermatology Life Quality Index (DLQI, patients aged ≥ 17 years), a score of 0 or 1 on the Patient's Global Assessment of Disease Severity [PatGA (0,1)], a Nail Psoriasis Severity Index score of 0 (NAPSI = 0, in patients with baseline NAPSI > 0), a Psoriasis Scalp Severity Index score of 0 (PSSI = 0, in patients with baseline PSSI > 0), 100% improvement from baseline in the Palmoplantar Psoriasis Area and Severity Index (PPASI 100, in patients with baseline PPASI > 0), clearance of genital psoriasis (in patients with baseline genital psoriasis), mean change from baseline in Itch NRS, and mean change from baseline in NAPSI, PSSI and PPASI for patients with baseline NAPSI > 0, PSSI > 0 and PPASI > 0, respectively. Appendixes S4 and S5 (see Supporting Information) provide further details on the objectives and outcomes.
Safety outcomes included assessments of adverse events (AEs)including treatment-emergent AEs (TEAEs), serious AEs (SAEs) and AEs of special interestlaboratory tests and vital signs. Data on suspected inflammatory bowel disease (IBD) were adjudicated by an external clinical events committee. Appendixes S3 and S6 (see Supporting Information) provide details on antidrug antibody assays and safety outcomes.

Statistical analyses
A gated multiple testing strategy was implemented for the primary and major secondary objectives to control the familywise type I error rate at a two-sided a-level of 0Á05. To assess whether IXE Q4W was superior to placebo, the primary and gated secondary endpoints were tested sequentially. If any test was not successful, all subsequent tests were not tested.
Analyses are provided for the week 12 and week 48 database locks. Efficacy analyses during the double-blind treatment period were performed on all randomized patients according to the initially assigned treatment. Efficacy was also summarized using descriptive statistics for all patients randomized to IXE at week 0 who received IXE throughout their study participation up to week 48. Additional efficacy analyses were performed according to the initially assigned treatment on all randomized patients with severe psoriasis in countries where etanercept was approved for severe psoriasis. Efficacy was also analysed according to baseline weight category (< 25 kg, ≥ 25 kg to ≤ 50 kg and > 50 kg). Treatment group comparisons for categorical outcomes were performed using Fisher's exact test with nonresponder imputation for handling of missing data. Continuous outcomes were analysed using a mixed model for repeated-measures analysis, including treatment, region, baseline sPGA score, baseline weight category, baseline value, visit, treatment-by-visit and baseline-by-visit interactions as fixed factors. Type III tests for the least-squares means were used for statistical comparisons. Table S2 (see Supporting Information) lists the number of patients with nonmissing data at each postbaseline visit through week 48.
Safety was summarized using descriptive statistics. Safety analyses during the double-blind treatment period were performed on all randomized patients who took at least one dose of double-blind study treatment according to the initially assigned treatment. Safety was also summarized up to the week 48 interim database lock for the all-IXE safety population, defined as all patients who received at least one dose of IXE, including patients initially randomized to placebo or etanercept. Additional safety analyses were conducted in all randomized patients in etanercept-approved countries who took at least one dose of double-blind study treatment according to the initially assigned treatment.
Analyses of antidrug antibodies were conducted on all evaluable patients in the all-IXE safety population. Patients with treatment-emergent antidrug antibodies (TE-ADAs) were classified as having low, moderate or high titre if their last titre value within the baseline or postbaseline period was < 1 : 160, ≥ 1 : 160 to < 1 : 1280, or ≥ 1 : 1280, respectively. Appendix S7 (see Supporting Information) provides additional information on the statistical analyses.
Responses at week 12 were sustained or further improved through week 48 (Figures 2 and 3 and Table 2). For patients In analyses by baseline weight, IXE resulted in significantly greater responses than placebo at week 12 for PASI 75, PASI 90, PASI 100, sPGA (0,1) and sPGA (0) in the subgroups of ≥ 25 kg to ≤ 50 kg and > 50 kg, and responses with IXE Q4W were numerically similar between these two subgroups (Table S4; see Supporting Information). Statistical comparisons of responses in patients with baseline weight < 25 kg were limited due to the small number of patients in this category (placebo: n = 1, IXE Q4W: n = 2). Both patients receiving IXE Q4W achieved PASI 75 and one (50%) achieved PASI 90, PASI 100, sPGA (0,1) and sPGA (0) at week 12; the patient receiving placebo achieved none of these endpoints.
During the double-blind treatment period, treatment-emergent infections were reported in 37 (32%) patients receiving IXE Q4W and 14 (25%) receiving placebo; no serious infections were reported. In the all-IXE safety population, 129 (66%) patients reported treatment-emergent infections; one (1%) was severe (pharyngitis). Two (1%) patients reported serious infections (one acute otitis media and one tonsillitis) and no opportunistic infections were reported. In the etanercept arm, six (20%) infection-related TEAEs were reported and there were no serious infections.
During the double-blind treatment period, 14 (12%) patients receiving IXE Q4W and one (2%) receiving placebo reported injection-site reactions. In the all-IXE safety population, 39 (20%) patients reported injection-site reactions. There were no injection-site-related SAEs, and one severe injectionsite reaction (injection-site pain) was reported. Safety related to depression, allergic reaction or hypersensitivity, cytopenia, and hepatic events is summarized in Table 4; none of which were SAEs. There were no TEAEs of grade 3 or 4 cytopenia reported and there were no reports of anaphylaxis, malignancies, or interstitial lung disease.
One patient receiving IXE Q4W reported an AE of diarrhoea during the double-blind treatment period. This patient also reported intestinal inflammatory disease and abdominal pain at study day 1. The patient discontinued due to the AE of intestinal inflammatory disease and the case was adjudicated as probable Crohn's disease. Three patients reported TEAEs of IBD (adjudicated as probable Crohn's disease) during the maintenance period, each of whom reported SAEs and discontinued from the study. These discontinuations were due to withdrawal by patient (n = 1), AE of Crohn's disease (n = 1) and physician decision because of suspected IBD (n = 1). One of these patients reported autoimmune comorbidities of atopic dermatitis, alopecia areata and psoriatic arthritis. Appendix S8 (see Supporting Information) provides additional details regarding safety.
Of 194 evaluable patients, 53 (27%) were TE-ADA positive; 29 (15%) were low titre, 22 (11%) were moderate titre and two (1%) were high titre. Neutralizing antidrug antibodies were detected in five (3%) evaluable patients. The presence of TE-ADAs had no impact on efficacy regardless of neutralizing antibody status, and there were no consistent temporal relationships between the presence of TE-ADAs and the occurrence of injection-site reactions or allergic reaction or hypersensitivity TEAEs.

Discussion
IXE was superior to placebo for both coprimary endpoints and all gated secondary endpoints. Significant improvements in skin and itch were observed as early as week 1 and persisted through week 48. Itch affects many paediatric patients with psoriasis and has a high impact on quality of life. 8,9 In IXORA-PEDS, nearly 75% of patients reported Itch NRS ≥ 4 at baseline. IXE provided clinically meaningful improvements in itch for nearly 80% of patients by week 48. IXE also provided significant improvements over placebo at week 12 in health-related quality of life and clearance of scalp and genital psoriasis. Responses with IXE were generally consistent across weight subgroups, although analysis in patients with baseline weight < 25 kg was limited by the small sample size. Most AEs were mild to moderate in severity, SAEs occurred in < 7% of patients, < 2% of patients discontinued due to AEs, and no deaths occurred. Serious infections were reported in approximately 1% of patients, but there were no discontinuations due to infection-related TEAEs. Crohn's disease was reported in one patient during the double-blind treatment period and in three patients during the maintenance period, each adjudicated as probable Crohn's disease.
PASI 75 was achieved by 89% of patients receiving IXE Q4W at week 12, a result consistent with the phase III UNCOVER-1 (89%), UNCOVER-2 (90%) and UNCOVER-3 studies (87%) in adult patients with moderate-to-severe psoriasis. 10,11 PASI 75 responses persisted through week 48 (90%), which was greater than week 60 responses in UNCOVER-3 (83%). 10 More patients achieved complete skin clearance (PASI 100) with IXE at week 12 in IXORA-PEDS (50%) than in UNCOVER-3 (38%), but responses were similar between IXORA-PEDS (55%) at week 48 and UNCOVER-3 (55%) at week 60. Placebo responses in IXORA-PEDS were greater than those observed in adults in the UNCOVER studies. At week 12, PASI 75 was achieved by 25% of paediatric patients receiving placebo in IXORA-PEDS, compared with 3Á9% (UNCOVER-1), 2Á4% (UNCOVER-2) and 7Á3% (UNCOVER-3) in adult patients. 10,11 These findings are consistent with conclusions from reviews and meta-analyses of clinical trials, in which placebo response rates in paediatric populations are generally higher than in adult populations. 12 The placebo effect observed in IXORA-PEDS was considerably lower for more stringent endpoints such as PASI 90 (5%) and PASI 100 (2%) at week 12, which was similar to placebo responses observed in adults (PASI 90: UNCOVER-1, 0Á5%; UNCOVER-2, 0Á6%; UNCOVER-3, 3Á1%; PASI 100: UNCOVER-1, 0%; UNCOVER-2, 0Á6%; UNCOVER-3, 0%). 10,11 IXE was recently approved by the FDA for moderate-tosevere psoriasis in patients aged ≥ 6 years and is the first biologic therapy approved for paediatric psoriasis that targets IL-17A. Other biologic therapies approved for paediatric psoriasis include two tumour necrosis factor inhibitors (etanercept and adalimumab) and the IL-12/23 antagonist,  ustekinumab. PASI 75 was achieved by 57% (week 12) and 58% of patients (week 16) in phase III studies of etanercept (0Á8 mg kg À1 ) and adalimumab (0Á8 mg kg À1 ) for paediatric psoriasis, respectively. 13,14 In adolescent patients (aged 12-17 years) with moderate-to-severe psoriasis, PASI 75 response at week 12 was achieved by 81% of patients receiving ustekinumab. 15 Approved use of these treatments differs across geographies, ages and severities. The FDA approved etanercept and ustekinumab in patients ≥ 4 and ≥ 12 years old, respectively, for moderate-to-severe plaque psoriasis but has not approved adalimumab for paediatric psoriasis. The European Medicines Agency approved etanercept and adalimumab in patients with severe psoriasis who are ≥ 6 and ≥ 4 years old, respectively, and ustekinumab for moderate-to-severe psoriasis in patients ≥ 6 years old. This study suggests that IXE may be an additional and efficacious treatment option for paediatric patients with moderate-to-severe plaque psoriasis.
A strength of IXORA-PEDS is enrolment of a geographically diverse population. IXE was administered on site during study visits to ensure consistent dosing and administration in paediatric patients. IXE provided consistent efficacy across weight subgroups; however, analysis of patients with baseline weight < 25 kg was limited to a small sample size of three patients. IXE Q4W showed significantly greater skin improvements [PASI 90, PASI 100 and sPGA (0)] compared with etanercept, although this comparison was for patients with severe psoriasis in etanercept-approved countries outside the USA. Limitations of this comparison include a small patient number and the comparison of double-blind IXE Q4W vs. open-label etanercept. However, the outcomes assessors were blinded to treatment assignments to minimize potential bias.
In conclusion, IXE provided rapid, statistically significant and clinically meaningful improvements over placebo in skin, itch and health-related quality of life that persisted for up to 48 weeks in paediatric patients with moderate-to-severe plaque psoriasis. The safety profile of IXE was generally consistent with that in adults with moderate-to-severe plaque psoriasis. Thus, IXE may be an additional therapeutic option for moderate-to-severe paediatric psoriasis. and critical revision of the manuscript. All authors provided approval of the final manuscript for submission and publication.

Supporting Information
Additional Supporting Information may be found in the online version of this article at the publisher's website: Appendix S1 List of IXORA-PEDS investigators. Appendix S2 Inclusion and exclusion criteria. Appendix S3 Study design. Appendix S4 List of all study endpoints in IXORA-PEDS. Appendix S5 Description of efficacy outcomes. Appendix S6 Additional details regarding safety outcomes. Appendix S7 Statistical analyses. Appendix S8 Safety results. Figure S1 Trial profile for patients with severe paediatric psoriasis in etanercept-approved countries. Figure S2 Efficacy outcomes in patients with severe paediatric psoriasis in etanercept-approved countries.