Rheumatology 2021;60:4568–4580 Rheumatology doi:10.1093/rheumatology/keab047 Advance access publication 28 January 2021 Original article Subcutaneous dosing regimens of tocilizumab in children with systemic or polyarticular juvenile idiopathic arthritis Nicolino Ruperto 1,*, Hermine I. Brunner2,*, Athimalaipet V. Ramanan3, Gerd Horneff4,5, Rubén Cuttica6, Michael Henrickson2, Jordi Anton7, Alina Lucica Boteanu8, Inmaculada Calvo Penades9, Kirsten Minden10,11, Heinrike Schmeling12, Markus Hufnagel13, Jennifer E. Weiss14, Manuela Pardeo15, Kabita Nanda16, Johannes Roth17, Nadina Rubio-Pérez18, Joy C. Hsu19, Sunethra Wimalasundera20, Chris Wells20, Kamal Bharucha21, Wendy Douglass20, Min Bao21, Navita L. Mallalieu19, Alberto Martini22, Daniel Lovell2, and Fabrizio De Benedetti15, for the Paediatric Rheumatology INternational Trials Organisation (PRINTO) and the Paediatric Rheumatology Collaborative Study Group (PRCSG) Abstract Objectives. To determine s.c. tocilizumab (s.c.-TCZ) dosing regimens for systemic JIA (sJIA) and polyarticular JIA (pJIA). Methods. In two 52-week phase 1 b trials, s.c.-TCZ (162 mg/dose) was administered to sJIA patients every week or every 2 weeks (every 10 days before interim analysis) and to pJIA patients every 2 weeks or every 3 weeks with body weight 30 kg or <30 kg, respectively. Primary end points were pharmacokinetics, pharmacodynamics and safety; efficacy was exploratory. Comparisons were made to data from phase 3 trials with i.v. tocilizumab (i.v.-TCZ) in sJIA and pJIA. Results. Study participants were 51 sJIA patients and 52 pJIA patients aged 1–17 years who received s.c.-TCZ. CL IN IC A L SC I E NC E Steady-state minimum TCZ concentration (Ctrough) >5th percentile of that achieved with i.v.-TCZ was achieved by 49 (96%) sJIA and 52 (100%) pJIA patients. In both populations, pharmacodynamic markers of disease were simi- lar between body weight groups. Improvements in Juvenile Arthritis DAS-71 were comparable between s.c.-TCZ and i.v.-TCZ. By week 52, 53% of sJIA patients and 31% of pJIA patients achieved clinical remission on treatment. Safety was consistent with that of i.v.-TCZ except for injection site reactions, reported by 41.2% and 28.8% of 1 IRCCS Istituto Giannina Gaslini, Clinica Pediatrica e Reumatologia—PRINTO, Genoa, Italy, 2Pediatric Rheumatology Medical Center, Paediatric Rheumatology, Hackensack, NJ, USA, Collaborative Study Group (PRCSG), Cincinnati Children’s Hospital 15 Division of Rheumatology, IRCCS Ospedale Pediatrico Bambino Medical Center, Cincinnati, OH, USA, 3University Hospitals Bristol Gesù, Rome, Italy, 16Seattle Children’s Hospital, Seattle, WA, USA, NHS Foundation Trust & Bristol Medical School, University of 17 University of Ottawa and Division of Paediatric Dermatology & Bristol, Bristol, UK, 4Department of General Paediatrics, Asklepios Rheumatology, Children’s Hospital of Eastern Ontario, Ottawa, ON, Clinic Sankt Augustin, Sankt Augustin, Germany, 5Department of Canada, 18Universidad Autónoma de Nuevo León, Facultad de Pediatric and Adolescents Medicine, University Hospital of Cologne, Medicina, Departamento de Pediatria, Hospital Universitario ‘Dr. J. Cologne, Germany, 6Rheumatology Section, Hospital Pedro de E. González’, Monterrey, NL, Mexico, 19Roche Innovation Center, Elizalde, Buenos Aires, Argentina, 7Hospital Sant Joan de Déu, New York, NY, USA, 20Roche Products Ltd, Welwyn Garden City, Universitat de Barcelona, Unidad de Reumatologı́a Pediátrica, UK, 21Genentech, South San Francisco, CA, USA, 22Università degli Esplugues de Llobregat (Barcelona), Spain, 8Paediatric Studi di Genova, Dipartimento di Neuroscienze, Riabilitazione, Rheumatology Unit, University Hospital Ramón y Cajal, Madrid, Oftalmologia, Genetica e Scienze Materno-Infantili, Genoa, Italy Spain, 9Paediatric Rheumatology Unit, Hospital Universitario y Politécnico La Fe, Valencia, Spain, 10German Rheumatism Submitted 28 July 2020; accepted 9 December 2020 Research Centre Berlin, Berlin, Germany, 11Department of Rheumatology and Clinical Immunology, Charité University Correspondence to: Nicolino Ruperto, MD, MPH, IRCCS Istituto Medicine, Berlin, Germany 12Department of Paediatrics, Alberta Giannina Gaslini, Clinica Pediatrica e Reumatologia, EULAR Centre of Children’s Hospital and Cumming School of Medicine/University of Excellence in Rheumatology 2008–2023, Pediatric Rheumatology Calgary, Alberta, Canada, 13University Medical Center Freiburg, INternational Trial Organisation (PRINTO), Via Gaslini, 5, 16147 Department of Paediatrics and Adolescent Medicine, Division of Genoa, Italy. Email: nicolaruperto@gaslini.org Paediatric Infectious Diseases and Rheumatology, Medical Faculty, *Nicolino Ruperto and Hermine I. Brunner contributed equally to this University of Freiburg, Freiburg, Germany, 14Hackensack University study. C The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. V This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, [br]distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Subcutaneous tocilizumab for juvenile arthritis sJIA and pJIA patients, respectively. Infections were reported in 78.4% and 69.2% of patients, respectively. Two sJIA patients died; both deaths were considered to be related to TCZ. Conclusion. s.c.-TCZ provides exposure and risk/benefit profiles similar to those of i.v.-TCZ. S.c. administration provides an alternative administration route that is more convenient for patients and caregivers and that has poten- tial for in-home use. Trial registration. ClinicalTrials.gov, http://clinicaltrials.gov, NCT01904292 and NCT01904279 Key words: autoinflammatory conditions, biologic therapies, cytokines and inflammatory mediators, inflam- mation, juvenile idiopathic arthritis Rheumatology Key messages . Subcutaneous tocilizumab dosing in JIA was determined by bridging to data for intravenous tocilizumab. . Subcutaneously administered tocilizumab has a risk/benefit profile similar to that of intravenous tocilizumab dosing regimens. . Subcutaneous tocilizumab provides an alternative administration route that is more convenient for patients and caregivers. Introduction would achieve TCZ exposure [steady-state minimum TCZ concentration (Ctrough)] comparable with that of i.v.- JIA is classified into mutually exclusive categories [1–3]. TCZ dosing regimens [14, 15]. Based on PK analyses Children with polyarticular JIA (pJIA) have a more refrac- from i.v.-TCZ trials in sJIA and pJIA (Supplementary tory disease course than those who have fewer affected Data S1, available at Rheumatology online), a dose of joints, and they are at risk for severe disability [4, 5]. 162 mg s.c.-TCZ once weekly [QW; 162 mg every Systemic JIA (sJIA) is characterized by autoinflammatory 10 days (Q10D) for patients weighing <30 kg] for sJIA and autoimmune disease features [6, 7]. and 162 mg s.c.-TCZ every 2 weeks [Q2W; 162 mg every IL-6 plays a central role in the pathogenesis of JIA, 3 weeks (Q3W) for patients weighing <30 kg] for pJIA and levels correlate positively with the severity of joint was expected to provide exposures comparable with involvement, systemic disease features, and markers of those of i.v.-TCZ. CONSORT [22] reporting was followed inflammation such as CRP [8–11]. Tocilizumab (TCZ) is a as applicable. A sample size of 48 patients in each humanized monoclonal anti–IL-6 receptor (IL-6R)-alpha study was considered adequate to provide 80% power antibody that inhibits IL-6 function [12, 13]. Phase 3 to have the 95% CI fall within 60% and 140% of the randomized controlled trials demonstrated that i.v.-TCZ population mean estimates for the PK parameters in was an effective treatment for sJIA [14], pJIA [15] and paediatric age groups [23]. RA [16, 17]. In RA, s.c.-TCZ has efficacy and safety comparable with those of i.v.-TCZ [18, 19]. S.c. injec- Patients tions offer a convenient alternative to i.v. administration Children aged 1–17 years (12–17 years in Russia) with by allowing administration by the patient or caregiver, sJIA or pJIA (RF-positive or RF-negative polyarticular eliminating the inconvenience of short hospital admis- and extended oligoarticular JIA) according to the ILAR sion for infusions and reducing the stress of i.v. adminis- criteria were eligible [24]. sJIA patients were enrolled tration, which is particularly relevant for younger children from 15 August 2013 through 28 June 2016 at 26 [20, 21]. centres, and pJIA patients were enrolled from 24 July We report results of two clinical trials in children with 2013 through 27 May 2015 at 24 centres in 11 countries sJIA and pJIA conducted to identify optimal dosing regi- in the Paediatric Rheumatology INternational Trials mens of s.c.-TCZ. Organisation (PRINTO) and the Paediatric Rheumatology Collaborative Study Group (PRCSG) networks [25, 26]. Patients in the sJIA trial had inadequate responses to Patients and methods NSAIDs and glucocorticoids. Patients in the pJIA trial had inadequate responses or intolerance to MTX. Study designs Eligible patients were TCZ-naive or had achieved well- The sJIA trial (ClinicalTrials.gov, NCT01904292) and the controlled sJIA or pJIA with i.v.-TCZ (TCZ-prior). pJIA trial (ClinicalTrials.gov, NCT01904279) were 52- Patients for whom i.v.-TCZ was discontinued for lack of week, open-label, multicentre, pharmacokinetic (PK), efficacy or safety reasons were excluded. Full eligibility pharmacodynamic (PDy) and safety phase 1 b studies criteria are in Supplementary Data S2, available at designed to identify s.c.-TCZ dosing regimens that Rheumatology online. To adequately characterize the https://academic.oup.com/rheumatology 4569 Nicolino Ruperto et al. absorption of s.c.-TCZ, 50% of the total population Results was TCZ-naive at baseline. TCZ-prior patients received their first dose of s.c.-TCZ at their next scheduled date Patients of i.v.-TCZ. Concomitant treatment with oral glucocorti- Among 51 sJIA patients, 44 (86%) completed 52 weeks coids (doses at the investigator’s discretion), NSAIDs (Fig. 1A), 4 withdrew for lack of efficacy, 1 withdrew and non-biologic DMARDs, including MTX, was allowed. based on the physician’s decision (because of persist- Both studies were conducted in accordance with the ently low neutrophil counts) and 2 died. Among 52 pJIA Declaration of Helsinki and Good Clinical Practice, and patients (Fig. 1B), 46 (89%) completed 52 weeks, 5 with- informed consent was obtained from all patients and/or drew for lack of efficacy and 1 withdrew based on the parents. The protocols were approved by institutional patient’s decision. review boards or independent ethics committees at Demographic and disease characteristics at baseline each site. were balanced between body weight groups in both studies (Table 1). Four patients were younger than Assessments 2 years of age at baseline—three in the sJIA study (aged Primary PK and PDy objectives were to evaluate s.c.- 17, 19 and 22 months) and one in the pJIA study (aged TCZ in patients with sJIA or pJIA to identify fixed-dosing 23 months). Demographics of TCZ-naive patients with regimens of TCZ 162 mg that provide TCZ exposures sJIA and pJIA were similar to those in the TCZ-prior groups, except for higher JADAS-71 and CHAQ-DI similar to those achieved with i.v.-TCZ. Blood samples scores at baseline (Table 1). for PK/PDy analysis were obtained per protocol (Supplementary Data S3, available at Rheumatology on- line). Safety assessments included adverse events (AEs), Pharmacokinetics serious AEs (SAEs) and laboratory parameters. AEs Ctrough values reached stable levels around week 12 or were classified using the Medical Dictionary for 14 in TCZ-naive sJIA and pJIA patients newly initiating Regulatory Activities 20.0 (sJIA) or 19.0 (pJIA). Efficacy s.c.-TCZ. Ctrough levels were maintained in TCZ-prior was an exploratory objective. Anti-TCZ antibodies were patients on switching to s.c.-TCZ. assayed at prespecified intervals with a tiered testing Median steady-state Ctrough levels were similar across strategy [27]. body weight groups in sJIA patients after dose adjust- Exploratory efficacy measures included disease activ- ment to Q2W in the <30-kg group (<30 kg, 64.2 mg/ml; ity measured by Juvenile Arthritis DAS including 71 30 kg, 72.4 mg/ml) and in pJIA patients (<30 kg, joints (JADAS-71) (cut-off scores for pJIA: high disease 13.4 mg/ml; 30 kg, 12.7 mg/ml) (Fig. 2, Supplementary activity, >10.5; moderate disease activity, 3.9–10.5; low Table S1, available at Rheumatology online). Among disease activity, 3.8; inactive disease, 1) [28–31], TCZ-naive patients with sJIA, median steady-state proportions of patients with inactive disease (JIA ACR Ctrough (range) was higher in the <30-kg group treated inactive disease criteria) [32] and clinical remission on with s.c.-TCZ Q10D [116 (91.8–256.0) mg/ml] than with treatment (inactive disease for 6 months continuously), s.c.-TCZ Q2W [41.4 (12.8–114.0) mg/ml], which led to functional ability using the Childhood HAQ–Disability dose reduction to Q2W in this group after the interim Index (CHAQ-DI; range, 0–3) [33] and growth measured analysis. For pJIA patients, and to a lesser extent sJIA using height velocity (cm/year). patients, median steady-state Cmax and overall exposure (AUC) were slightly higher in patients weighing <30 kg Statistical analysis than in those weighing 30 kg (Fig. 2, Supplementary Fig. S1, Supplementary Table S1, available at Descriptive statistical analyses were planned. Population Rheumatology online). Comparison of exposure after PK models previously developed for i.v.-TCZ in sJIA and s.c. vs i.v. administration indicated that, consistent with pJIA were used to delineate the weight-based s.c.-TCZ initial model predictions, a high percentage (96%; 49/51) dose regimens. Subsequently, individual model–com- of sJIA patients and all (100%) pJIA patients treated puted PK parameters were estimated after data were with s.c.-TCZ had a steady-state Ctrough at or above the incorporated from the s.c.-TCZ trials [Ctrough, area under 5th percentile of that achieved in the i.v.-TCZ trial the concentration-time curve (AUC), and maximum con- across the body weight range (Fig. 2). Similarly, 80.4% centration (Cmax) at steady-state]. Dense sampling after (41/51) of sJIA patients and 78.8% (41/52) of pJIA the first s.c.-TCZ dose allowed for characterization of patients had steady-state Ctrough values between the 5th absorption parameters. and 95th percentiles of values achieved with i.v.-TCZ. At the week 14 interim analysis, a dosing change from As expected, the Cmax attained with s.c.-TCZ was lower Q10D to Q2W was introduced for sJIA patients weighing than that attained with i.v.-TCZ (Fig. 2). <30 kg, because the Q10D regimen resulted in expo- Ctrough values in the three sJIA patients aged <2 years sures higher than those observed with i.v.-TCZ for some were at the higher end of the exposure spectrum (above patients. the 53rd percentile of exposure in the <30-kg group) fol- All enrolled patients who received 1 dose of lowing treatment with s.c.-TCZ, but were within the s.c.-TCZ were included in the PK/PDy, safety and range of model-predicted exposures in sJIA patients intention-to-treat analysis populations. aged 2 years (19.5–158 mg/ml). 4570 https://academic.oup.com/rheumatology Subcutaneous tocilizumab for juvenile arthritis FIG. 1 Patient disposition in the trial of (A) patients with sJIA and (B) patients with pJIA Withdrawal by patient: TCZ-naive, n ¼ 1. Withdrawal because of lack of efficacy: TCZ-naive, n ¼ 4; TCZ-prior, n ¼ 1. BW: body weight; Q10D: every 10 days; QW: every week; Q2W: every 2 weeks; TCZ: tocilizumab; pJIA: polyarticular JIA; sJIA: systemic JIA. Pharmacodynamics of moderate disease activity (JADAS-71 3.9–10.5), and Changes in PDy parameters over time were comparable 40 of 43 (93.0%) children with sJIA and 35 of 47 for TCZ-naive patients initiating treatment with s.c.-TCZ (74.5%) children with pJIA were able to reach a status and i.v.-TCZ and remained stable for patients switching of a low disease activity (3.8). By week 52, 68.6% (35/ from i.v.-TCZ to s.c.-TCZ. Median soluble IL-6R (sIL-6R) 51) of sJIA patients and 63.5% (33/52) of pJIA patients serum concentrations increased rapidly in TCZ-naive had inactive disease; 52.9% (27/51) of sJIA and 30.8% patients after the first TCZ dose through week 12 and (16/52) of pJIA patients achieved clinical remission on then stabilized between 500 and 800 ng/ml. Among treatment. TCZ-prior patients, median sIL-6R concentrations The proportion of patients with sJIA receiving gluco- remained stable over time compared with baseline lev- corticoid therapy decreased from 27 of 51 (52.9%) at els. Consistent with TCZ exposures, sIL-6R levels were baseline to 7 of 51 (13.7%) at week 52 and from a mean slightly higher in patients weighing <30 kg than 30 kg dose of 2.7 mg/kg/day to 0.6 mg/kg/day, respectively, over the dosing period in both disease populations for patients <30 kg and from 0.3 mg/kg/day to 0.1 mg/ (Fig. 3). Median IL-6 concentrations stabilized by week kg/day, respectively, for patients 30 kg. The proportion 12 (Supplementary Fig. S2, available at Rheumatology of pJIA patients receiving glucocorticoid therapy online). Median CRP levels and ESR decreased rapidly decreased from 17 of 52 (32.7%) at baseline to 5 of 52 among TCZ-naive patients with s.c.-TCZ and remained (9.6%) at week 52 and from a mean dose of 0.2 mg/kg/ within the normal range reported in the i.v.-TCZ studies day to 0 mg/kg/day, respectively, for patients <30 kg [14, 15] among TCZ-prior patients (Supplementary Fig. and from 0.2 mg/kg/day to 0.1 mg/kg/day, respectively, S3, available at Rheumatology online). for patients 30 kg (Supplementary Table S2, available at Rheumatology online). Exploratory analysis of growth Exploratory efficacy analysis showed that the distribution of height velocities was consistent with World Health Organization normative val- JADAS-71 improved in TCZ-naive sJIA and pJIA ues (Supplementary Fig. S5, available at Rheumatology patients treated with s.c.-TCZ, similar to improvements online) and in line with observations for pJIA and sJIA observed with i.v.-TCZ, indicating that comparable effi- with i.v.-TCZ [34, 35]. cacy was achieved with the s.c. and i.v. formulations (Supplementary Fig. S4, available at Rheumatology on- Safety line). In addition, JADAS-71 was maintained in TCZ-prior patients (Fig. 4; Supplementary Fig. S4, available at A total of 46.7 patient-years (PY) of follow-up for sJIA Rheumatology online), indicating that patients could patients was available for safety assessment: 23.0 PY in switch from i.v. to s.c. and maintain the same level of the <30-kg group and 23.8 PY in the 30-kg group. efficacy. Among all patients who had efficacy data at Total follow-up in the pJIA study was 50.4 PY overall: week 52, 3 of 43 (7.0%) children with sJIA and 8 of 47 26.6 PY for the <30-kg group and 23.8 PY for the 30- (17.0%) children with pJIA were able to reach a status kg group. https://academic.oup.com/rheumatology 4571 4572 TABLE 1 Baseline demographics and disease characteristics of patients with sJIA and patients with pJIA Nicolino Ruperto et al. Characteristic sJIA pJIA TCZ-naive n ¼ 26 TCZ-prior n ¼ 25 All TCZ n ¼ 51 TCZ-naive n ¼ 37 TCZ-prior n ¼ 15 All TCZ n ¼ 52 <30 kg 30 kg <30 kg 30 kg <30 kg 30 kg <30 kg 30 kg <30 kg 30 kg <30 kg 30 kg Q10D/Q2W QW Q10D/Q2W QW Q10D/Q2W QW Q3W Q2W Q3W Q2W Q3W Q2W n ¼ 15 n ¼ 11 n ¼ 10 n ¼ 15 n ¼ 25 n ¼ 26 n ¼ 23 n ¼ 14 n¼4 n ¼ 11 n ¼ 27 n ¼ 25 Age, years, mean (S.D.) 5.2 (3.0) 13.1 (3.2) 4.9 (3.6) 13.5 (3.2) 5.1 (3.2) 13.3 (3.2) 5.3 (2.1) 14.9 (2.2) 6.8 (1.0) 12.7 (2.9) 5.5 (2.1) 13.9 (2.7) Females, n (%) 7 (46.7) 6 (54.5) 6 (60.0) 10 (66.7) 13 (52.0) 16 (61.5) 14 (60.9) 10 (71.4) 4 (100.0) 8 (72.7) 18 (66.7) 18 (72.0) Weight, kg, mean (S.D.) 19.1 (5.4) 52.2 (14.3) 18.1 (6.4) 51.3 (12.8) 18.7 (5.7) 51.7 (13.2) 19.2 (4.9) 60.4 (15.1) 22.2 (1.3) 51.9 (15.3) 19.7 (4.7) 56.7 (15.5) No. of active joints, 11.6 (11.6) 6.6 (8.1) 1.3 (1.8) 1.2 (2.2) 7.5 (10.3) 3.5 (6.0) 9.4 (7.5) 11.4 (8.5) 1.3 (1.9) 7.0 (11.2) 8.2 (7.5) 9.5 (9.8) mean (S.D.) CHAQ-DI score, mean (S.D.) 1.28 (0.93) 0.78 (1.00) 0.28 (0.42) 0.45 (0.77) 0.88 (0.90) 0.59 (0.88) 0.95 (0.66) 0.88 (0.70) 0.50 (0.51) 0.59 (0.73) 0.88 (0.65) 0.76 (0.72) JADAS-71 score, mean 23.6 (15.6) 15.9 (12.4) 3.2 (3.3) 3.5 (5.2) 15.5 (15.8) 8.7 (10.8) 19.7 (9.8) 21.0 (9.9) 5.9 (7.1) 11.4 (14.6) 17.6 (10.6) 16.8 (12.9) (S.D.) Concurrent MTX use, n (%) 8 (53.3) 5 (45.5) 5 (50.0) 9 (60.0) 13 (52.0) 14 (53.8) 18 (78.3) 7 (50.0) 3 (75.0) 8 (72.7) 21 (77.8) 15 (60.0) Concurrent glucocorticoid 14 (93.3) 8 (72.7) 6 (60.0) 4 (26.7) 20 (80.0) 12 (46.2) 11 (47.8) 6 (42.9) 0 6 (54.5) 11 (40.7) 12 (48.0) use, n (%)a Previous biologic use, n (%) 4 (26.7) 8 (72.7) 10 (100.0) 15 (100.0) 14 (56.0) 23 (88.5) 6 (26.1) 10 (71.4) 4 (100) 11 (100) 10 (37.0) 21 (84.0) CHAQ-DI: Childhood HAQ–Disability Index; JADAS-71: Juvenile Arthritis DAS including 71 joints; pJIA: polyarticular JIA; Q10D: every 10 days; QW: every week; Q2W: every 2 weeks; Q3W: every 3 weeks; sJIA systemic JIA; TCZ: tocilizumab. aIncluded all prior and concomitant use. https://academic.oup.com/rheumatology Subcutaneous tocilizumab for juvenile arthritis FIG. 2 Model-computed median steady-state Cmin and Cmax from s.c. dosing vs i.v. dosing Median values are designated by black lines in the centres of the boxes. Boxes indicate the IQR. Whiskers represent 1.5  IQR. Horizontal red line denotes the model-computed 5th percentile from the i.v.-TCZ trials. The number of i.v.- TCZ sJIA patients includes all patients randomly assigned to TCZ in part 1 of the i.v.-TCZ trial and any patient who escaped from placebo to TCZ in part 1 for whom a PK sample was available. BW: body weight; Cmax: maximum con- centration; Cmin: minimum concentration; IQR: interquartile range; PK: pharmacokinetic; QW: every week; Q2W: every 2 weeks; Q3W: every 3 weeks; TCZ: tocilizumab; sJIA: systemic JIA. Most AEs in both studies were mild or moderate in in- 1015.3/100 PY (889.1–1154.3) in sJIA patients and tensity and were considered unrelated to TCZ treatment. 944.2/100 PY (824.8–1076.0) vs 680.5/100 PY (584.9– A higher AE rate was observed in patients in the 30-kg 787.1) in pJIA patients. Similar AE rates were observed body weight group than the <30-kg group in both in TCZ-naive patients and TCZ-prior patients with sJIA studies: 1378.7/100 PY (95% CI, 1233.5–1536.3) vs (1196.2/100 PY and 1205.0/100 PY), whereas in pJIA https://academic.oup.com/rheumatology 4573 Nicolino Ruperto et al. FIG. 3 sIL-6R concentration-time profiles with s.c.-TCZ treatment of TCZ-prior (A, B) and TCZ-naive (C, D) patients Data are shown as median (IQR) values. Error bars ¼ IQR. BW: body weight; IQR: interquartile range; Q10D: every 10 days; QW: every week; Q2W: every 2 weeks; Q3W: every 3 weeks; sIL-6R: serum IL-6 receptor; TCZ: tocilizumab. patients, the AE rate was higher in TCZ-naive patients Two patients with sJIA died, both in the <30-kg than in TCZ-prior patients (876.1/100 PY vs 631.0/100 group. Both deaths were considered related to TCZ. A PY). The most common AEs were from the infections TCZ-naive patient had oral candidiasis and pneumonia and infestations system organ class (Table 2), reported and died of pulmonary hemorrhage on day 15 after by a higher proportion of patients in the <30-kg group receiving a single TCZ dose on day 1, and another pa- than in the 30-kg group (88% vs 69.2%, respectively, tient died of suspected sepsis on day 262. Both patients for sJIA; 74.1% vs 64%, respectively, for pJIA). Overall, were receiving concomitant steroids and other medica- nine SAEs occurred in seven sJIA patients (five serious tions (Supplementary Data S4, available at infections, two sJIA flares, vertigo and pulmonary hem- Rheumatology online). No deaths occurred during the orrhage), and four SAEs occurred in three pJIA patients pJIA study. (croup, varicella, worsening of anorexia and arthralgia) The AE profile for s.c.-TCZ was comparable with that (Supplementary Data S4, available at Rheumatology on- observed with the i.v.-TCZ regimens in sJIA and pJIA line). AEs and SAEs among the three sJIA patients who (Supplementary Table S3, available at Rheumatology on- were aged <2 years at the time of enrolment were con- line) except for injection site reactions (ISRs), which are sistent with those observed in the older sJIA patients. applicable only for patients receiving s.c.-TCZ. Overall, No serious or clinically significant hypersensitivity reac- 41.2% of sJIA patients treated with s.c.-TCZ reported tions and no cases of anaphylaxis or macrophage acti- 1 ISR (20% of patients weighing <30 kg, 61.5% of vation syndrome, gastrointestinal perforations, serious patients weighing 30 kg), as did 28.8% of pJIA patients hepatic AEs, malignancies, serious myocardial infarc- (14.8% of patients weighing <30 kg, 44.0% of patients tions, opportunistic infections or serious strokes were weighing 30 kg). All ISRs were considered non-serious, reported during this study. and none required withdrawal from treatment. There 4574 https://academic.oup.com/rheumatology Subcutaneous tocilizumab for juvenile arthritis FIG. 4 JADAS-71 over time for sJIA and pJIA patients treated with s.c.-TCZ Data are shown as median (IQR) valuesData points at weeks 4 and 8 for the <30kg group (left-hand sJIA panel) in- clude only those for patients receiving Q10D dosing. Horizontal dashed lines represent inactive disease (JADAS- 71 < 1.0), low disease activity (3.8), moderate disease activity (3.9–10.5) and high disease activity (>10.5). BW: body weight; IQR: interquartile range; JADAS-71: Juvenile Arthritis DAS including 71 joints; pJIA: polyarticular JIA; Q10D: every 10 days; QW: every week; Q2W: every 2 weeks; Q3W: every 3 weeks; s.c.-TCZ: subcutaneous tocilizumab; sJIA: systemic JIA; TCZ: tocilizumab. were no serious or clinically significant hypersensitivity (sJIA, 23.5%; pJIA 25.0%; all grade 3) (Supplementary reactions (defined as hypersensitivity reactions leading Data S5, available at Rheumatology online). to withdrawal) or confirmed anaphylaxis (Supplementary No patients with sJIA developed detectable anti-TCZ Data S4, available at Rheumatology online). Laboratory antibodies. Among pJIA patients, three who were TCZ- abnormalities were consistent with those expected in naive (one weighing <30 kg, two weighing 30 kg) children treated with TCZ—most commonly, decrease in developed anti-TCZ antibodies after baseline, but not of neutrophil count (sJIA, 54.9%; pJIA, 42.3%; all grade the immunoglobulin E isotype. One of these patients 3), elevated alanine aminotransferase levels (sJIA, was withdrawn because of lack of efficacy (treating 33.3%; pJIA 38.5%; all grade 3 except one grade 4 physician decision). One patient who developed anti- for sJIA) and elevated aspartate aminotransferase levels TCZ antibodies after baseline had injection site https://academic.oup.com/rheumatology 4575 TABLE 2 Safety profile of s.c.-TCZ in patients with sJIA and patients with pJIA 4576 Safety outcomes sJIA pJIA <30 kg Q10D/Q2W n ¼ 25 30 kg QW n ¼ 26 All TCZ n ¼ 51 <30 kg Q3W n ¼ 27 30 kg Q2W n ¼ 25 All TCZ n ¼ 52 Nicolino Ruperto et al. TCZ- TCZ- TCZ- TCZ- TCZ- TCZ- TCZ- TCZ- TCZ- TCZ- TCZ TCZ- naive prior naive prior naive prior naive prior naive prior naive prior n ¼ 15 n ¼ 10 n ¼ 11 n ¼ 15 n ¼ 26 n ¼ 25 n ¼ 23 n¼4 n ¼ 14 n ¼ 11 n ¼ 37 n ¼ 15 PY of follow-up 13.9 9.1 11.2 12.6 25.1 21.7 22.6 4.0 13.3 10.5 35.8 14.6 Patients with 1 AE, n (%) 15 (100) 10 (100) 11 (100) 14 (93.3) 26 (100) 24 (96) 21 (91.3) 4 (100) 13 (92.9) 10 (90.9) 34 (91.9) 14 (93.3) Total AEs, n 131 102 169 159 300 261 167 14 147 78 314 92 Patients with 1 SAE, n (%) 3 (20) 2 (20) 1 (9.1) 1 (6.7) 4 (15.4) 3 (12) 1 (4.3) 0 1 (7.1) 1 (9.1) 2 (5.4) 1 (6.7) AEs by system organ class, n (%)a Infections and infestationsb 12 (80)e 10 (100) 9 (81.8) 9 (60) 21 (80.8) 19 (76) 18 (78.3) 2 (50) 9 (64.3) 7 (63.6) 27 (73) 9 (60) Musculoskeletal and CTDs 3 (20) 4 (40) 3 (27.3) 4 (26.7) 6 (23.1) 8 (32) 11 (47.8) 0 7 (50.0) 5 (45.5) 18 (48.6) 5 (33.3) Gastrointestinal disordersc 5 (33.3) 6 (60) 3 (27.3) 9 (60) 8 (30.8) 15 (60) 8 (34.8) 2 (50.0) 7 (50.0) 4 (36.4) 15 (40.5) 6 (40.0) General disorders and 5 (33.3) 4 (40) 6 (54.5) 12 (80) 11 (42.3) 16 (64) 4 (17.4) 2 (50.0) 9 (64.3) 5 (45.5) 13 (35.1) 7 (46.7) administrative site conditions Respiratory, thoracic and 9 (60) 4 (40) 6 (54.5) 6 (40) 15 (57.7) 10 (40) 10 (43.5) 1 (25.0) 1 (7.1) 6 (54.5) 11 (29.7) 7 (46.7) mediastinal disorders Skin and s.c. tissue disorders 5 (33.3) 3 (30) 6 (54.5) 1 (6.7) 11 (42.3) 4 (16) 5 (21.7) 0 5 (35.7) 2 (18.2) 10 (27.0) 2 (13.3) Nervous system disorders 0 0 2 (18.2) 5 (33.3) 2 (7.7) 5 (20.0) 2 (8.7) 0 5 (35.7) 3 (27.3) 7 (18.9) 3 (20.0) Psychiatric disordersd 0 0 1 (9.1) 0 1 (3.8) 0 3 (13.0) 1 (25.0) 3 (21.4) 1 (9.1) 6 (16.2) 2 (13.3) Blood and lymphatic 5 (33.3) 3 (30) 4 (36.4) 6 (40) 9 (34.6) 9 (36) 3 (13.0) 0 1 (7.1) 0 4 (10.8) 0 system disorders Injury, poisoning and 3 (20) 4 (40) 5 (45.5) 3 (20) 8 (30.8) 7 (28) 3 (13.0) 1 (25.0) 2 (14.3) 1 (9.1) 5 (13.5) 2 (13.3) procedural complications Investigations 2 (13.3) 3 (30) 2 (18.2) 1 (6.7) 4 (15.4) 4 (16) 4 (17.4) 0 2 (14.3) 0 6 (16.2) 0 Multiple occurrences of the same event in a patient were counted once. AE: adverse event; BW: body weight; pJIA: polyarticular JIA; PY: patient years; Q10D: every 10 days; QW: every week; Q2W: every 2 weeks; Q3W: every 3 weeks; SAE: serious adverse event; sJIA: systemic JIA; SOC: system organ class; TCZ: tocilizumab. aSOC included if all- grade AEs within that SOC occurred in 15% of sJIA patients or pJIA patients overall. bThe most common infections (10% of all patients) were nasopharyngitis (34.6%), gastroenteritis (11.5%) and upper respiratory tract infections (9.6%) in pJIA patients and viral upper respiratory tract infection (25.5%), upper respiratory tract infection (21.6%) and rhinitis (11.8%) in sJIA patients. cNo patients experienced gastrointestinal perforations. dThe most common psychiatric disorder in pJIA patients was insomnia (four TCZ- naive patients). Others included depression (one TCZ-naive patient) and fear of injections (one patient who previously received TCZ). eOne patient was receiving QW dosing at the time of infection (serious sepsis infection that was fatal) after a body weight increase to 30 kg. https://academic.oup.com/rheumatology Subcutaneous tocilizumab for juvenile arthritis hematomas on days 2 and 16. The other two patients following serious infections compared with one death did not experience ISRs. from suspected pneumothorax observed over a similar treatment duration in the i.v.-TCZ sJIA trial [14]; none died in the i.v.-TCZ pJIA trial [15]. Serious and some- Discussion times fatal infections have been reported in patients receiving immunosuppressive therapies, including TCZ, Bridging of PK and PDy to efficacy data is recognized highlighting the vigilance required for timely detection by the US Food and Drug Administration (FDA) [36] and and treatment. the International Council for Harmonisation of Technical Given the similar PK/PDy results for s.c.-TCZ vs i.v.- Requirements for Pharmaceuticals for Human Use [37] TCZ, comparable efficacy can be expected. Patients to support new dose regimens, new dosage forms and newly initiating TCZ therapy had efficacy responses with new formulations and routes of administration based on s.c.-TCZ comparable with those observed in i.v.-TCZ known exposure–response relationships from existing sJIA and pJIA studies, and disease control was main- clinical trial data as particularly relevant for children. In tained for patients who switched from i.v.-TCZ to the s.c.-TCZ trials, 162 mg QW dosing for sJIA patients s.c.-TCZ at study entry and began s.c. injections when weighing 30 kg (162 mg Q2W for patients <30 kg) and the next i.v.-TCZ dose was due. Safety assessment is Q2W dosing for pJIA patients weighing 30 kg (162 mg ongoing in patients with sJIA or pJIA treated with s.c.- Q3W for patients <30 kg) provided TCZ exposures simi- TCZ in a long-term extension study that includes lar to those of approved i.v.-TCZ regimens and resulted 5 years of s.c.-TCZ treatment (ClinicalTrials.gov, in comparable PDy, safety and exploratory efficacy. NCT02165345). Based on these data, the FDA and the European The design of the s.c.-TCZ studies in patients with sJIA Medicines Agency approved these s.c. dosing regimens and pJIA allowed for robust confirmation of optimal s.c.- for the treatment of sJIA and pJIA [38, 39]. TCZ dosing regimens of the s.c. formulation. Eligibility cri- A relationship between TCZ predose concentration teria were similar to those of the i.v.-TCZ studies, enabling (Ctrough or Cmin, as a measure of exposure) and efficacy comparison for confirmation of the dosing strategy and of has been established for patients with sJIA (data on file) PK, PDy, safety and efficacy. This meant fewer patients and patients with pJIA [40]. Evaluation and comparison had to undergo the clinical trial procedure, which acceler- of TCZ exposure after s.c. administration formed the ated the approval and subsequent availability of the s.c.- basis of bridging to the pivotal i.v.-TCZ trials in sJIA or TCZ formulation compared with a traditional phase 3 trial pJIA. Consistent with comparable exposures, PDy approach. Limiting the number of TCZ-prior patients to responses measured by changes in sIL-6R, IL-6, CRP <50% of the total population allowed more precise esti- and ESR were comparable with those observed for i.v.- mation of PK absorption parameters and determination of TCZ regimens. The increase observed in serum sIL-6R the onset of PDy effects after s.c. administration during is consistent with the formation of sIL-6R/TCZ immune collection of clinical data for patients switching from i.v.- complexes [41]. Some measures of TCZ exposure, and TCZ to s.c.-TCZ. correspondingly sIL-6R levels, were slightly higher in the Both studies had limitations. The number of patients <30-kg group but had no effect on safety or efficacy. across the body weight spectrum (at individual ages) The s.c.-TCZ trials confirmed that starting s.c.-TCZ in might have been too small to enable detection of poten- sJIA or pJIA patients previously treated with i.v.-TCZ tially important immunogenicity and safety differences can be achieved safely and effectively with the first s.c.- between s.c.-TCZ and i.v.-TCZ. Other limitations include TCZ dose delivered when the next i.v.-TCZ dose is due. sparse data for children <2 years (n ¼ 3, sJIA; n ¼ 1, The safety profile of s.c.-TCZ was consistent with that pJIA), the open-label nature of s.c.-TCZ administration observed with the i.v.-TCZ regimen for sJIA and pJIA and the lack of statistical comparisons (all comparisons patients [14, 15]. The most common AEs were infec- were between-study and descriptive). tions, consistent with the safety profile for TCZ. No new In conclusion, appropriate s.c.-TCZ dosing regimens types of AE were observed except for ISRs (consistent were successfully identified from studies in patients with with s.c. administration). ISR rates of 291.0/100 PY in sJIA or pJIA that bridged to data from studies of sJIA patients and 93.2/100 PY in pJIA patients with s.c.- i.v.-TCZ. The overall benefit/risk profile for s.c.-TCZ was TCZ were higher than those observed in s.c.-TCZ trials favourable and comparable with that for i.v.-TCZ in in adult RA patients (11.5–26.1/100 PY) [18, 42] (data on patients with sJIA and in patients with pJIA. These find- file). Fewer patients in the <30-kg groups (sJIA 20%, ings highlight the ability of PK/PDy bridging to provide a pJIA 14.8%) than in the 30-kg groups (sJIA 61.5%, path towards regulatory approval of agents for the treat- pJIA 44.0%) reported ISRs, possibly because of a more ment of paediatric patients. limited ability of younger patients to articulate certain ISR symptoms. Consistent with previous observations, Acknowledgements there was a low incidence of anti-drug antibodies among pJIA patients and none among sJIA patients. The authors thank all additional PRINTO and PRCSG Anti-drug antibodies in pJIA patients did not negatively investigators for their participation in the study (see affect the clinical effectiveness of TCZ. Two patients Supplementary Data S6, available at Rheumatology on- died in the s.c.-TCZ sJIA trial because of complications line, for the full list of investigators). Jianmei Wang of https://academic.oup.com/rheumatology 4577 Nicolino Ruperto et al. Genentech provided input into the conception and de- Pfizer, Roche, Sobi; travel support: AbbVie, Novartis, sign of the study and analysis and interpretation of the Pfizer, Roche, Sobi; grants to institution: AbbVie, Bristol- data. Ruchi Upmanyu, Mohamed Kamal and Alysha Myers Squibb, GlaxoSmithKline, Lilly, Novartis, Kadva of Roche Products Ltd provided assistance with Novimmune, Pfizer, Roche, Sanofi, Sobi. I.C.P. – expert study design and analysis and interpretation of the data. testimony: Novartis, GlaxoSmithKline, AbbVie, Roche. The study was designed jointly by the academic authors K.M. – lectures/speaker bureaus: Sanofi, Roche; devel- (N.R., H.I.B., A.M., D.L., andF.D.B.) and Roche, with opment of educational presentations: AbbVie; board data collected by PRINTO and PRCSG investigators. membership: GlaxoSmithKline, Chugai, Sanofi. H.S. – The first and subsequent versions of the manuscript travel support: Hoffmann-La Roche; grant to institution: were written by N.R., H.I.B. and F.D.B., and it was Hoffmann-La Roche. M.H. – development of educational edited by A.M. and D.L. and revised critically by all presentations: Novartis, Roche; payment to institution: remaining coauthors. All authors attest to the complete- Roche. K.N. – consultancy: Novartis; salary support: ness and veracity of data and data analyses. Abbott. J.C.H. – employee: Roche; stock/stock options: Consistency in reporting the study data to healthcare Roche. S.W. – former employee: Roche Products Ltd. authorities and institutional review boards was ensured C.W. – employee: Roche Products Ltd; stock/stock by Roche. All authors had full access to the study data, options: Roche Products Ltd. K.B. – former employee: and all authors reviewed and revised the manuscript for Roche/Genentech. W.D. – employee: Roche Products important intellectual content and approved the final ver- Ltd. M.B. – employee: Roche; patent: subcutaneously sion to be published. All authors were involved in the administered anti IL-6 receptor antibody. N.L.M. – for- decision to submit the manuscript for publication and mer employee: Roche. A.M. – consultancy/honoraria: had the right to accept or reject comments or sugges- Eli-Lilly, EMD Serono, Janssen, Novartis, Pfizer, AbbVie; tions. Professional writing and editorial assistance was consultancy/lectures/speaker bureaus: Eli-Lilly, EMD provided by Sara Duggan, PhD, of ApotheCom, on be- Serono, Janssen, Novartis, Pfizer, AbbVie; travel half of F. Hoffmann-La Roche Ltd. Acquisition of data: support: Hoffmann-LaRoche; grants to institution: All PRINTO and PRCSG participating centres. Analysis Bristol-Myers Squibb, Eli-Lilly, GlaxoSmithKline, F. and interpretation of data: M.B., K.B., H.I.B., F.D.B., Hoffmann-La Roche, Janssen, Novartis, Pfizer, Sobi. W.D., J.C.H., N.L.M., N.R., C.W. and S.W. D.L. – consultancy: Takeda; lectures/speaker bureaus: Genentech. Data Safety and Monitoring Board member- Funding: This work was supported by the sponsor, ship: Forest Research, National Institutes of Health; con- Roche. Funding for manuscript preparation was pro- sultancy/paid to institution: Boehringer Ingelheim, vided by F. Hoffmann-La Roche Ltd. The sponsor was Celgene, GlaxoSmithKline, Hoffmann-La Roche. involved in the study design, analysis and interpretation Novartis, Pfizer, UBC; grants to institution: AbbVie, of data, critical review of the manuscript and decision to Bristol-Myers Squibb, Janssen, Novartis, Pfizer, Roche submit the manuscript for publication. NIH, NIH/NICHD. F.D.B. – grants to institution: Roche, Novimmune, Sobi, Sanofi, Novartis, Pfizer. Disclosure statement: N.R. – consultancy/honoraria/ speaker fees: Ablynx, AbbVie, AstraZeneca- Medimmune, Biogen, Boehringer, Bristol-Myers Squibb, Eli-Lilly, EMD Serono, GlaxoSmithKline, Hoffmann-La Data availability statement Roche, Janssen, Merck, Novartis, Pfizer, R-Pharma, Sanofi, Servier, Sinergie, Sobi, Takeda; travel support: Qualified researchers may request access to individual Hoffmann-La Roche; grants to institution: Bristol-Myers patient level data through the clinical study data request Squibb, Eli-Lilly, GlaxoSmithKline, F. Hoffmann-La platform (https://vivli.org/). Further details on Roche’s Roche, Janssen, Novartis, Pfizer, Sobi. H.I.B. – consult- criteria for eligible studies are available here (https://viv- ancy: Bristol-Myers Squibb, Pfizer, Lilly, R-Pharm, li.org/members/ourmembers/). For further details on Roche, Novartis, Janssen, EMD Serono, AstraZeneca; Roche’s Global Policy on the Sharing of Clinical consulting fees/honorarium/travel support/review activ- Information and how to request access to related clinical ities/speaker burePfizer; money paid to institution: Pfizer study documents, see here (https://www.roche.com/ (presentation of abstracts at various national and inter- research_and_development/who_we_are_how_we_work/ national meetings), Novartis (development of educational clinical_trials/our_commitment_to_data_sharing.htm). presentations), Roche (development of educational pre- sentations). A.V.R. – consultancy: AbbVie, Eli Lilly, References Novartis, UCB; lectures/speaker bureaus: AbbVie, Roche, Sobi, UCB. G.H. – fees to institution: travel sup- 1 Ravelli A, Martini A. Juvenile idiopathic arthritis. Lancet port from Roche and grant support for the BiKeR regis- 2007;369:767–78. try. 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