Subcutaneous dosing regimens of tocilizumab in children with systemic or polyarticular juvenile idiopathic arthritis

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. 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 similar 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 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 potential for in-home use.

Trial registration: ClinicalTrials.gov, http://clinicaltrials.gov, NCT01904292 and NCT01904279.

Keywords: autoinflammatory conditions; biologic therapies; cytokines and inflammatory mediators; inflammation; juvenile idiopathic arthritis.

Fig. 1

Patient disposition in the trial of (A) patients with sJIA and (B) patients with pJIA Withdrawal by patient: TCZ-naive, n = 1. Withdrawal because of lack of efficacy: TCZ-naive, n = 4; TCZ-prior, n = 1. BW: body weight; Q10D: every 10 days; QW: every week; Q2W: every 2 weeks; TCZ: tocilizumab; pJIA: polyarticular JIA; sJIA: systemic JIA.

Fig. 2

Model-computed median steady-state C_min and C_max 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; C_max: maximum concentration; C_min: minimum concentration; IQR: interquartile range; PK: pharmacokinetic; QW: every week; Q2W: every 2 weeks; Q3W: every 3 weeks; TCZ: tocilizumab; sJIA: systemic JIA.

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 = 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.

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) include 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.