Background/Purpose: Tocilizumab (TCZ) is approved for the treatment of systemic juvenile idiopathic arthritis (sJIA) based on clinical trials in patients ≥2 years of age. This phase 1 study (NP25737), the first of a biologic in patients with sJIA <2 years of age, evaluated the pharmacokinetics (PK), pharmacodynamics (PD), efficacy, and safety of TCZ.

Methods: Patients with uncontrolled sJIA and symptoms for ≥1 month prescreening whose treatment with corticosteroids and NSAIDs failed and who had no history of allergy to TCZ or other biologics received open-label TCZ 12 mg/kg intravenously every 2 weeks (dose calculated each visit based on body weight). Patients were treated up to Week 12 and could continue until they reached 2 years of age or were treated for 1 year from baseline. End points included PK (primary), safety (secondary), PD, and efficacy (exploratory) at Week 12. Comparison was made with data from a previous trial in sJIA patients ≥2 years of age (WA18221) that formed the basis for approval of TCZ in sJIA.

Results: Eleven patients were enrolled; mean (SD) age was 1.3 (0.33) years, and weight was 9.97 (1.38) kg. Serum TCZ concentrations, estimated using population PK analysis, peaked immediately after infusion; median (range) maximum concentration was 282 (195-347) mcg/mL (steady state reached by Week 12), and median (range) trough concentration was 34.3 (19.2-59.7) mcg/mL. Peak and trough exposures were within the exposure range in older children (244 [109-382] to 54.3 [10.9-117] mcg/mL) (Figure). Observed mean±SD soluble IL-6 receptor levels increased from 47.65±16.40 ng/mL at baseline to 1461.14±852.71 ng/mL at Day 85. CRP and ESR levels, which were elevated at baseline, decreased to 3.35±3.77 mg/L and 3.50±0.84 mm/h, respectively. Mean±SD Juvenile Arthritis Disease Activity Score-71 improved from 22.27±10.09 at baseline to 4.90±6.11 at Day 85. By Week 12, 10 patients had 32 adverse events (AEs); 4 withdrew due to AEs. Infections or infestations were the most frequently reported AEs (10 events, 9 patients). Five serious AEs (SAEs) occurred in 3 patients; all had SAEs of hypersensitivity that led to treatment withdrawal, and 1 of these 3 patients then experienced SAEs of foot and mouth disease and sJIA flare after study withdrawal. No deaths occurred during the study.

Conclusion: TCZ exposures achieved in this study fell within the exposure range of the previous trial in sJIA patients ≥2 years of age. This study provides evidence that TCZ is effective in sJIA patients <2 years of age and achieves PK and efficacy similar to those demonstrated previously in older patients. The safety profile was similar to that observed in patients ≥2 years of age in types of AEs observed, with the exception of a higher incidence of serious hypersensitivity events.