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
Navita L Mallalieu, Sunethra Wimalasundera, Joy C Hsu, Wendy Douglass, Chris Wells, Inmaculada Calvo Penades, Ruben Cuttica, Hans-Iko Huppertz, Rik Joos, Yukiko Kimura, Diana Milojevic, Margalit Rosenkranz, Kenneth Schikler, Tamas Constantin, Carine Wouters, Navita L Mallalieu, Sunethra Wimalasundera, Joy C Hsu, Wendy Douglass, Chris Wells, Inmaculada Calvo Penades, Ruben Cuttica, Hans-Iko Huppertz, Rik Joos, Yukiko Kimura, Diana Milojevic, Margalit Rosenkranz, Kenneth Schikler, Tamas Constantin, Carine Wouters
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
References
- De Benedetti F, Brunner HI, Ruperto N, Kenwright A, Wright S, Calvo I, et al. Randomized trial of tocilizumab in systemic juvenile idiopathic arthritis. N Engl J Med. 2012;367:2385–2395. doi: 10.1056/NEJMoa1112802.
- Giancane G, Minoia F, Davi S, Bracciolini G, Consolaro A, Ravelli A. IL-1 inhibition in systemic juvenile idiopathic arthritis. Front Pharmacol. 2016;7:467. doi: 10.3389/fphar.2016.00467.
- Petty RE, Southwood TR, Manners P, Baum J, Glass DN, Goldenberg J, et al. International league of associations for rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol. 2004;31:390–392.
- Grevich S, Shenoi S. Update on the management of systemic juvenile idiopathic arthritis and role of IL-1 and IL-6 inhibition. Adolesc Health Med Ther. 2017;8:125–135. doi: 10.2147/AHMT.S109495.
- Yokota S, Tanaka T, Kishimoto T. Efficacy, safety and tolerability of tocilizumab in patients with systemic juvenile idiopathic arthritis. Ther Adv Musculoskelet Dis. 2012;4:387–397. doi: 10.1177/1759720X12455960.
- Yokota S, Kishimoto T. Tocilizumab: molecular intervention therapy in children with systemic juvenile idiopathic arthritis. Expert Rev Clin Immunol. 2010;6:735–743. doi: 10.1586/eci.10.41.
- de Benedetti F, Massa M, Robbioni P, Ravelli A, Burgio GR, Martini A. Correlation of serum interleukin-6 levels with joint involvement and thrombocytosis in systemic juvenile rheumatoid arthritis. Arthritis Rheum. 1991;34:1158–1163. doi: 10.1002/art.1780340912.
- Murakami M, Tomiita M, Nishimoto N. Tocilizumab in the treatment of systemic juvenile idiopathic arthritis. Open Access Rheumatol. 2012;4:71–79.
- Actemra® (tocilizumab) injection, for intravenous or subcutaneous use. South San Francisco: Genentech, Inc.; 2019. .
- RoActemra 162 mg solution for injection in pre-filled syringe. Welwyn Garden City. In: UK: Roche products limited; 2019. .
- Russo RA, Katsicas MM. Patients with very early-onset systemic juvenile idiopathic arthritis exhibit more inflammatory features and a worse outcome. J Rheumatol. 2013;40:329–334. doi: 10.3899/jrheum.120386.
- Frey N, Grange S, Woodworth T. Population pharmacokinetic analysis of tocilizumab in patients with rheumatoid arthritis. J Clin Pharmacol. 2010;50:754–766. doi: 10.1177/0091270009350623.
- Malik P, Edginton A. Pediatric physiology in relation to the pharmacokinetics of monoclonal antibodies. Expert Opin Drug Metab Toxicol. 2018;14:585–599. doi: 10.1080/17425255.2018.1482278.
- Uchiyama Y, Yoshida H, Koike N, Hayakawa N, Sugita A, Nishimura T, et al. Anti-IL-6 receptor antibody increases blood IL-6 level via the blockade of IL-6 clearance, but not via the induction of IL-6 production. Int Immunopharmacol. 2008;8:1595–1601. doi: 10.1016/j.intimp.2008.07.002.
- Ravelli A, Minoia F, Davi S, Horne A, Bovis F, Pistorio A, et al. 2016 classification criteria for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis: a European league against rheumatism/American College of Rheumatology/Paediatric rheumatology international trials organisation collaborative initiative. Arthritis Rheum. 2016;68:566–576. doi: 10.1002/art.39332.
Source: PubMed