Intravenous dosing of tocilizumab in patients younger than two years of age with systemic juvenile idiopathic arthritis: results from an open-label phase 1 clinical trial

Abstract

Background: The anti-interleukin-6 receptor-alpha antibody tocilizumab was approved for intravenous (IV) injection in the treatment of patients with systemic juvenile idiopathic arthritis (sJIA) aged 2 to 17 years based on results of a randomized controlled phase 3 trial. Tocilizumab treatment in systemic juvenile idiopathic arthritis (sJIA) patients younger than 2 was investigated in this open-label phase 1 trial and compared with data from the previous trial in patients aged 2 to 17 years.

Methods: Patients younger than 2 received open-label tocilizumab 12 mg/kg IV every 2 weeks (Q2W) during a 12-week main evaluation period and an optional extension period. The primary end point was comparability of pharmacokinetics during the main evaluation period to that of the previous trial (in patients aged 2-17 years), and the secondary end point was safety; pharmacodynamics and efficacy end points were exploratory. Descriptive comparisons for pharmacokinetics, pharmacodynamics, safety, and efficacy were made with sJIA patients aged 2 to 17 years weighing < 30 kg (n = 38) who received tocilizumab 12 mg/kg IV Q2W in the previous trial (control group).

Results: Eleven patients (mean age, 1.3 years) received tocilizumab during the main evaluation period. The primary end point was met: tocilizumab exposures for patients younger than 2 were within the range of the control group (mean [±SD] μg/mL concentration at the end-of-dosing interval [Cmin]: 39.8 [±14.3] vs 57.5 [±23.3]; maximum concentration [Cmax] postdose: 288 [±40.4] vs 245 [±57.2]). At week 12, pharmacodynamic measures were similar between patients younger than 2 and the control group; mean change from baseline in Juvenile Arthritis Disease Activity Score-71 was - 17.4 in patients younger than 2 and - 28.8 in the control group; rash was reported by 14.3 and 13.5% of patients, respectively. Safety was comparable except for the incidence of serious hypersensitivity reactions (27.3% in patients younger than 2 vs 2.6% in the control group).

Conclusions: Tocilizumab 12 mg/kg IV Q2W provided pharmacokinetics, pharmacodynamics, and efficacy in sJIA patients younger than 2 comparable to those in patients aged 2 to 17 years. Safety was comparable except for a higher incidence of serious hypersensitivity events in patients younger than 2 years.

Classification: Juvenile idiopathic arthritis.

Trial registration: ClinicalTrials.gov, NCT01455701 . Registered, October 20, 2011, Date of enrollment of first participant: October 26, 2012.

Keywords: Biological therapy; Inflammation; Juvenile idiopathic arthritis; Pharmacokinetics.

Conflict of interest statement

NLM – Employee of Roche, owns shares in Roche.

SW – Employee of Roche.

JCH – Employee of Roche, owns share in Roche.

WD – Employee of Roche, owns shares in Roche.

CWells – Employee of Roche, owns shares in Roche.

ICP – Research grants to institution from Roche.

RC – Consultant and speaker for Roche, Novartis, Lilly, GlaxoSmithKline, Bristol Myers Squibb, Janssen.

H-IH – None.

RJ – None.

YK – Salary support from CARRA; research grant from Genentech.

DM – None.

MR – None.

KS – Research grant support from SOBI and CARRA.

TC – None.

CWouters – Research grants to institution from GlaxoSmithKline, Pfizer, Roche

Figures

Fig. 1

Patients younger than 2 years of age: patient disposition. aTwo patients completed the OEP upon reaching age 2, 1 at week 20 and 1 at week 56; 3 patients completed the OEP (last dose), 2 at week 50 and 1 at week 48. AE: adverse event; MEP: main evaluation period; OEP: optional extension period; Q2W: every 2 weeks; TCZ: tocilizumab

Fig. 2

a Mean observed serum TCZ concentration–time profile in patients younger than 2 years of age and in patients 2 to 17 years of age and model-predicted steady state pharmacokinetic parameters in patients younger than 2 years and in patients 2 to 17 years of age for (b) Cmin, (c) Cmax, and (d) AUC2weeks. a Data are mean ± SD. b-d Data are medians and interquartile ranges (boxes) and minimum, maximum values (whiskers). Patients weighing < 30 kg and receiving TCZ 12 mg/kg IV Q2W were included from the study in patients 2 to 17 years of age (n = 38). AUC2weeks: area under the concentration–time curve to 2 weeks; Cmax: maximum observed postinfusion serum concentration; Cmin: concentration at the end of a dosing interval; IV: intravenous; Q2W: every 2 weeks; SD: standard deviation; TCZ: tocilizumab; y: year

Fig. 3

Mean observed serum concentrations at baseline and week 12 in patients younger than 2 years of age and in patients 2 to 17 years of age for a sIL-6R, b CRP, and c ESR. Data are mean ± SD. Patients younger than 2 years (n = 11); patients weighing < 30 kg and receiving TCZ 12 mg/kg IV Q2W were included from the study in patients 2 to 17 years of age (n = 38). ESR: upper limit of normal, 20 mm/h; CRP: upper limit of normal, generally considered to be 0–4.9 mg/L in adults. CRP: C-reactive protein; ESR: erythrocyte sedimentation rate; IV, intravenous; Q2W: every 2 weeks; sIL-6R: soluble interleukin-6 receptor; SD: standard deviation; TCZ: tocilizumab; Tx: treatment; y: year