Secukinumab in enthesitis-related arthritis and juvenile psoriatic arthritis: a randomised, double-blind, placebo-controlled, treatment withdrawal, phase 3 trial

Background Treatment options in patients with enthesitis-related arthritis (ERA) and juvenile psoriatic arthritis (JPsA) are currently limited. This trial aimed to demonstrate the efficacy and safety of secukinumab in patients with active ERA and JPsA with inadequate response to conventional therapy. Methods In this randomised, double-blind, placebo-controlled, treatment-withdrawal, phase 3 trial, biologic-naïve patients (aged 2 to <18 years) with active disease were treated with open-label subcutaneous secukinumab (75/150 mg in patients <50/≥50 kg) in treatment period (TP) 1 up to week 12, and juvenile idiopathic arthritis (JIA) American College of Rheumatology 30 responders at week 12 were randomised 1:1 to secukinumab or placebo up to 100 weeks. Patients who flared in TP2 immediately entered open-label secukinumab TP3 that lasted up to week 104. Primary endpoint was time to disease flare in TP2. Results A total of 86 patients (median age, 14 years) entered open-label secukinumab in TP1. In TP2, responders (ERA, 44/52; JPsA, 31/34) received secukinumab or placebo. The study met its primary end point and demonstrated a statistically significant longer time to disease flare in TP2 for ERA and JPsA with secukinumab versus placebo (27% vs 55%, HR, 0.28; 95% CI 0.13 to 0.63; p<0.001). Exposure-adjusted incidence rates (per 100 patient-years (PY), 95% CI) for total patients were 290.7/100 PY (230.2 to 362.3) for adverse events and 8.2/100 PY (4.1 to 14.6) for serious adverse events in the overall JIA population. Conclusions Secukinumab demonstrated significantly longer time to disease flare than placebo in children with ERA and JPsA with a consistent safety profile with the adult indications of psoriatic arthritis and axial spondyloarthritis. Trial registration number NCT03031782.


INTRODUCTION
Juvenile idiopathic arthritis (JIA) is a heterogeneous group of inflammatory disorders that includes patients with arthritis of unknown aetiology that starts before the age of 16 years and persists for 6 or more weeks. 1 Enthesitis-related arthritis (ERA) and juvenile psoriatic arthritis (JPsA) are two

WHAT IS ALREADY KNOWN ON THIS TOPIC
⇒ Treatment options for patients with the juvenile idiopathic arthritis (JIA) subtypes of enthesitisrelated arthritis (ERA) and juvenile psoriatic arthritis (JPsA) are limited. Conventional synthetic disease-modifying antirheumatic drugs (DMARDs), glucocorticoids and nonsteroidal anti-inflammatory drugs provide limited efficacy with safety issues with longterm use. Studies have shown the efficacy of biologic DMARD (bDMARD) anti-TNF agents in patients with ERA or JPsA, but many patients continue to experience uncontrolled disease or experience treatment-related side effects.

WHAT THIS STUDY ADDS
⇒ In this double-blind, randomised, placebocontrolled, event-driven treatment withdrawal phase 3 study, the time to JIA disease flare was statistically longer in patients treated with secukinumab compared with placebo-treated patients from week 12 up to week 104 (27% vs 55%, HR, 0.28; 95% CI 0.13 to 0.63; p<0.001). ⇒ Improvements in JIA American College of Rheumatology (ACR) responses, JIA ACRinactive disease, JIA ACR core set components, Juvenile Arthritis Disease Activity Score were reported in patients treated with secukinumab up to 12 weeks. ⇒ No new safety signals were reported with secukinumab for up to 2 years.
categories of JIA that represent paediatric counterparts of adult non-radiographic axial spondyloarthritis (nr-axSpA) and psoriatic arthritis (PsA), respectively. 1 2 Non-steroidal anti-inflammatory drugs (NSAIDs) and conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) are considered first-line agents in JPsA, while NSAIDs and sulphasalazine are considered for ERA. Although the current treatment strategies for ERA and JPsA help to relieve pain, these medications often provide limited efficacy on the underlying disease. 3 This necessitates initiation of more intensive therapy, including the introduction of biologic (b)DMARDs, of which very few are approved for ERA and JPsA treatments. 4 5 The interleukin (IL)−17A pathway plays an important role in the pathogenesis of ERA and JPsA. Compared with controls, increased levels of IL-17A were reported in patients with JIA, especially in the setting of active disease. 6 Progression of structural damage is mediated by the IL-17 pathway in inflammatory arthritis. 7 Secukinumab, a fully human monoclonal antibody that directly inhibits IL-17A, has demonstrated efficacy and safety in adult patients with psoriasis (PsO), PsA, ankylosing spondylitis (AS) and nr-axSpA. [8][9][10][11] This phase 3 study demonstrated the efficacy and safety of secukinumab in patients with active ERA and JPsA.

Study design and participants
This was a 2-year, randomised, double-blind, placebocontrolled, event-driven, treatment-withdrawal, phase 3 study that consisted of three treatment periods (TPs): open-label (OL) secukinumab TP1 (up to 8 weeks); a randomised, double-blind, placebo-controlled, withdrawal period (up to week 104) TP2; OL secukinumab TP3 and a post-treatment follow-up period (online supplemental figure S1). The study was planned to be continued until 33 flare events had occurred or randomised patients had completed 104 weeks in the study. In this eventdriven, treatment-withdrawal study, the patients were treated first in an OL manner with the study drug for 12 weeks, and responders (JIA American College of Rheumatology (ACR)30 responders) were randomised to the study drug or placebo in a double-blind manner. In this phase of treatment, occurrence of a protocol-defined disease flare led to withdrawal from the double-blind treatment phase and patients were retreated with the study drug in an OL fashion. 12 Key inclusion criteria included patients aged ≥2 to <18 years at screening, classified according to the International League of Associations for Rheumatology JIA classification criteria as either ERA or JPsA, disease duration of ≥6 months with inadequate response to ≥1 csDMARDs or NSAIDs. Eligible patients were naïve to bDMARDs and had active disease. Key exclusion criteria included active uncontrolled inflammatory bowel disease (IBD) or uncontrolled uveitis. Detailed inclusion and exclusion criteria are provided in online supplemental appendix (Section S2).
Eligible patients entered TP1 and received OL subcutaneous secukinumab in prefilled syringes (75/150 mg in patients <50/≥50 kg). During TP1, secukinumab was administered weekly up to week 4, followed by every 4 weeks (Q4W). At week 12 (end of TP1), JIA ACR30 responders entered TP2 and were randomised 1:1 to continue secukinumab or receive placebo Q4W until a disease flare, or up to week 100. JIA ACR30 nonresponders at week 12 were discontinued from the study. All patients who experienced a disease flare in TP2 or completed TP2 without a disease flare entered TP3 to again receive OL secukinumab Q4W up to week 100.
The study protocol was reviewed and approved by the respective ethics committee or institutional review board of each centre. The study was conducted according to the International Council for Harmonization Good Clinical Practice guidelines.

Randomisation
Eligible patients were randomised (1:1) to continue secukinumab or newly start placebo in TP2. Randomisation was performed centrally using an Interactive Response Technology system and was stratified by JIA category (ERA, JPsA) (Section S3, online supplemental appendix).

Procedures
Secukinumab was administered subcutaneously in prefilled syringes (75/150 mg in patients <50/≥50 kg). Study visits and study drug administration were scheduled at baseline and weeks 1, 2, 3 and 4, followed by 4 weekly visits through week 104 with study drug administration until week 100. Patients could continue stable background therapies with NSAIDs, methotrexate, 13 sulfasalazine and oral glucocorticoids (Section S4, online supplemental appendix). Efficacy outcomes and adverse events (AEs) were assessed at each study visit.

Outcomes and assessments
All study outcomes are listed in the study protocol, which is provided in the online supplemental appendix (Section S5). At each planned visit, data for the six validated JIA ACR core set variables (CRVs) were recorded. 14 The JIA ACR30 response as per the JIA ACR response criteria is defined as ≥30% improvement in three or more of six CRVs, with no more than one of the remaining CRVs worsening by >30%. 14 The primary end point was time to JIA flare in TP2, defined as per the Pediatric Rheumatology Collaborative Study Group/Paediatric Rheumatology INternational Trials Organisation JIA flare criteria as ≥30% worsening from baseline in at least three of the six CRVs with no more than one of the remaining CRVs with >30% improvement relative to the end of TP1 (week 12). 15 Key secondary efficacy end points included JIA ACR30/50/70/90/100 responses, inactive disease (JIA ACR-ID) status 16 JIA ACR CRVs, Juvenile Arthritis Disease Activity Score (JADAS)−27-C reactive protein and total enthesitis and dactylitis counts at week 12 in TP1, and JIA ACR30/50/70/90/100 responses and JIA ACR-ID status at the end of TP2.
Safety analyses were conducted for the entire study period (TP1-TP3) in the overall JIA population. Safety assessments included all AEs coded as per the Medical Dictionary for Regulatory Activities (V.23.1), serious AEs (SAEs), treatment-emergent AEs (TEAEs), injection site reactions and antisecukinumab antibody development (immunogenicity).

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
⇒ The results from this study support that secukinumab, a fully human monoclonal antibody that inhibits IL-17A, is an effective and safe bDMARD in the treatment of patients with ERA and JPsA categories of JIA. Safety profile of secukinumab in JIA categories was consistent with reported adult indications of psoriatic arthritis and axial spondyloarthritis.

Statistical analysis
For sample size estimation, the HR of flare events for the secukinumab group relative to the placebo group was estimated to be 0.32 in TP2. 17 Thirty-three flares (12 for secukinumab, 21 for placebo) were estimated to detect a statistically significant difference between secukinumab and placebo to achieve 90% power by an one-sided significance level of 0.025. With an event-driven approach, the study was to be either stopped once 33 disease flares were detected or last patient's last visit over the study is achieved. We expected that a maximum 92 weeks of TP2 was necessary to observe 33 disease flares. Assuming approximately 85% of the patients respond at JIA ACR30 levels in TP1, we estimated that at most 94 patients needed to be enrolled into the study to allow for a sufficient number of patients to be randomised into TP2.
To show the superiority of secukinumab over placebo on the primary end point of time to disease flare in the two treatment groups, an one-sided stratified log-rank test was used with treatment, stratification variable of JIA category (ERA or JPsA) and methotrexate use as explanatory variables. HR and their associated 95% CIs were estimated based on a Cox proportional hazards model. Kaplan-Meier estimates (95% CI) of the probability of disease flare by treatment groups were calculated. Patients either experienced a disease flare or were censored in TP2. Subgroup analyses for time to disease flare were performed for the stratification variable of JIA category (ERA or JPsA). The intention-to-treat principle was applied for all primary and key secondary efficacy analyses.
The safety data analysis was conducted on the safety set that included all patients who received at least one dose of secukinumab. Exposure-adjusted incidence rates (per 100 patientyears (PY) of follow-up) were calculated for AEs and SAEs. An independent data safety monitoring board was responsible for ongoing monitoring of the safety of patients in the study.

Patient and public involvement
Patients or the public were not involved in the design or conduct of the trial. Written informed consent was obtained from parents or legal guardians of each patient at screening.
At baseline, there was a male preponderance in the ERA group (78.8%, 41/52) and a slight female majority in the JPsA group (52.9%, 18/34) (table 1). Of the 86 patients enrolled in TP1, 75 patients (87.2%) with a JIA ACR30 response at week 12 (end of TP1) were allowed to enter TP2. The baseline characteristics and clinical features of patients who entered TP2 were comparable to those of the overall study cohort (online supplemental table S1).
Overall, 75 patients (ERA/JPsA, 44/31) entered TP2 to be randomised 1:1 to continue secukinumab or newly receive placebo, with 67 patients completing TP2 and 26 completing TP3 (online supplemental figure S2). The most common reason for patients to discontinue the study early was lack of efficacy.

Time to JIA flare (primary endpoint)
The study was completed with last patient's last visit achieved. A total of 31 JIA flares had occurred, and all 67 remaining patients had reached week 104 (in TP2/TP3). In TP2, flare events occurred in 10/37 (27%) in the secukinumab group versus 21/38 (55%) in the placebo group. The median time to flare was not reached for the secukinumab group and was 453 (95% CI 114 to not calculable) days for the placebo group. The  In the overall JIA population, with OL secukinumab, a notable reduction of mean JADAS-27 was observed up to week 12 reaching moderate disease activity and reached minimal disease activity in both secukinumab and placebo groups in TP2 ( figure 3). In ERA and JPsA categories, JADAS-27 reached moderate and minimal disease activity, respectively, with OL secukinumab in TP1. In TP2, the scores reached minimal disease activity with secukinumab treatment in ERA and inactive disease in JPsA, whereas with placebo, the scores reached moderate and

Paediatric rheumatology
minimal disease activity in ERA and JPsA categories, respectively (online supplemental figure S3).
One patient with ERA had a medical history of uveitis that was non-recurring during the study. Two ERA patients, both aged 16 years, reported AE of acute anterior uveitis of mild or moderate severity that was not considered related to the study drug by the investigators and resolved with topical therapy; hence, the dose of study drug remains unchanged, and both the patients recovered and completed the study. One JPsA patient (2.7%) in the secukinumab group newly reported Crohn's disease during the study. There was no family history of IBD. The patient experienced disease flare and discontinued the study drug due to Crohn's disease on Day 127, entered post-treatment follow-up period and completed the same. The investigator suspected a causal relationship to secukinumab/placebo. There were no cases of mycobacterial infections, hepatitis B reactivation, malignancy or deaths. Only one patient reported injection-site reaction. No treatment-emergent antidrug antibodies were detected in any sample of patients treated with secukinumab during the study.

DISCUSSION
Secukinumab is a monoclonal antibody targeting IL-17A that was found to result in rapid improvement of arthritis, dactylitis and enthesitis in children with ERA and JPsA. This study met its primary end point and demonstrated that time to disease flare in TP2 was significantly longer with secukinumab treatment than placebo in the overall JIA population. At the tested weight-stratified dosages, secukinumab markedly decreased the flare risk by 72% compared with placebo, and there was no new safety signal.
There remains a high unmet medical need for therapies indicated for ERA and JPsA as there is a dearth of tested therapies. 18 In order to limit or even avoid the negative impact of ERA and JPsA on patient development, QoL or disease-associated joint damage, rapid and sustained control of disease signs and symptoms is recommended, 19 20 which can be achieved with early initiation of anti-inflammatory treatment in JIA. 21 Current treatment guidelines recommend initial bDMARD treatment for patients with risk factors, high disease activity and those who are intolerant to csDMARDs. 21 22 We consider secukinumab an important new treatment option for children with ERA and JPsA as secukinumab resulted in a rapid and profound improvement of signs and symptoms of both ERA and JPsA in this study, including the resolution of dactylitis and enthesitis. The achievement of inactive disease, a preferred treatment target for JIA, was achieved in over 30% of patients by week 12, and in over 40% of patients who  received secukinumab throughout the entire study. Resolution of enthesitis is highly impactful given the known profound detrimental effects of enthesitis, including pain, in both adults and children. 23 The responses in children with JPsA receiving secukinumab in this study are consistent with the findings from studies in patients with PsA where secukinumab has demonstrated sustained improvements in ACR responses, in resolution of enthesitis and dactylitis, in skin clearance with sustained improvement across the six key manifestations of PsA through 5 years. [24][25][26] ERA is considered the paediatric counterpart of nr-axSpA 2 and children with ERA also experienced a profound improvement of signs and symptoms of their disease. The role of IL-17A in spondyloarthritide manifestations of skin, joints and entheses is well known, and profound improvement with secukinumab was reported in patients with PsO, PsA and AS. 11 27 Prior bDMARD exposure was an exclusion criterion for study participation. Earlier studies in JIA support that exposure to prior bDMARDs decreases the response rate to subsequent treatments in medication trials. 28 29 Although this trial does not provide information about secukinumab efficacy in the setting of prior bDMARD exposure, we note that a retrospective study in patients with ERA who failed anti-TNF treatment reported significant improvement in JIA disease activity as measured by JADAS with secukinumab treatment. 30 Consistent with this finding, patients in this study experienced a rapid, profound, and sustained decrease in disease activity as measured by JADAS-27 for up to 2 years.
There was only one reported injection-site reaction during the study, and no antisecukinumab antibodies were detected. Indeed, secukinumab was generally well tolerated, and its safety profile in this study population of patients with ERA or JPsA was consistent with that observed in adult patients with axial spondyloarthritis and PsA. 8 9 25 There was one reported case of Crohn's disease that was categorised as an important potential risk, consistent with prior reports in the medical literature based on a postmarketing study in Vigibase. 31 Anterior chronic non-infectious uveitis is quite common, especially with early onset of JPsA, 32 but was not observed in this study. On the contrary, two cases of new acute anterior uveitis were reported, both regarded unrelated to the study treatment by the treating physicians, and a patient with a history of acute anterior uveitis prior to baseline did not experience reactivation of uveitis during the study.
Limitations of the trial must be considered. Secukinumab efficacy was assessed indirectly by the occurrence of JIA flares. Owing to the large number of placebo-treated patients who met flare criteria in TP2 and who stopped placebo when entering TP3, observed differences in efficacy between secukinumab versus placebo may be blunted. The trial population was relatively small and predominantly white but was in line with other JIA trials. Thus, it was not possible to detect rare AEs. Another limitation of this study is the lack of data on skin manifestations, especially in JPsA patients, although it has been acknowledged that secukinumab demonstrated sustained efficacy across various skin outcomes in previously reported randomised trials in paediatric patients with PsO. 33 In conclusion, secukinumab demonstrated efficacy and safety in the JIA categories of ERA and JPsA. The significantly longer time to disease flare in TP2 and improvement in disease activity observed establish secukinumab as a candidate in the treatment of patients with ERA and JPsA.

Paediatric rheumatology
Healthcare Research (CHR), Celegene, Domain therapeutic, Eli Lilly, EMD Serono, GlaxoSmith and Kline, Idorsia, Janssen, Novartis, Pfizer, SOBI and UCB; payment/ honoria for lectures, presentations, speakers bureaus from Eli Lilly, GlaxoSmith and Kline, Pfizer, SOBI and UCB; has received payment for participation on data safety monitoring board or advisory board from Eli Lilly and Pfizer; has received funding from Bristol Myers and Squibb, Eli Lilly, F Hoffmann-La Roche, Novartis, Pfizer and SOBI.

Patient and public involvement
Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

Patient consent for publication Not applicable.
Ethics approval The study protocol was reviewed and approved by the respective ethics committee or institutional review board of each centre. The trial was designed jointly by PRINTO/PRCSG officers (NR, HIB, AM and DJL) and the sponsor (Novartis Pharmaceuticals). Data were collected by the PRINTO/PRCSG investigators. The study was conducted according to the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) E6 Guideline for Good Clinical Practice that has its origin in the Declaration of Helsinki clinical practice guidelines. Written informed consent was obtained from parents or legal guardians of each patient at screening. Participants gave informed consent to participate in the study before taking part.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available upon reasonable request. The datasets generated and analysed for this study are not publicly available. Novartis will review requests for data from qualified external researchers for scientific merit. All patient-level data must obscure patient identity, to respect patient privacy and conform to applicable laws and regulations. Any requests should be made to Luminita Pricop, Novartis Pharmaceutical Corporation, at luminita. pricop@ novartis. com.
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