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 who failed treatment with corticosteroids and NSAIDs and had no history of allergy to TCZ or other biologics received open-label TCZ 12 mg/kg intravenously (IV) every 2 weeks (dose calculated at 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) at week 12, PD and efficacy (exploratory), and safety. Comparison was made with exposures 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; median (range) age was 16 (10-22) months and weight was 10.40 (6.8-11.5) kg. Serum TCZ concentrations, estimated using population PK analysis, peaked immediately after infusion; median (range) maximum concentration was 282 (195-347) μg/mL (steady state reached by week 12) and median (range) trough concentration was 34.3 (19.2-59.7) μg/mL. Peak and trough exposures were within the exposure range in older children (244 [109-382] to 54.3 [10.9-117] μg/mL; Figure). Observed mean±SD soluble IL-6 receptor levels were 47.65±16.40 ng/mL at baseline and 927.83±148.07 ng/mL at day 71. CRP levels were 250.81±425.11 mg/L and 2.80±3.56 mg/L and ESR levels were 59.40±27.47 mm/h and 2.00±1.00 mm/h, respectively. Mean±SD Juvenile Arthritis Disease Activity Score-71 improved from 22.27±10.09 at baseline to 3.66±4.66 at day 71. 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; 3 patients had SAEs of hypersensitivity that led to treatment withdrawal; 1 of these patients then experienced SAEs of foot and mouth disease and sJIA flare after study withdrawal. No actual cases of MAS were reported, but 2 patients had laboratory abnormalities indicative of MAS according to 2016 criteria (Ravelli A et al. Ann Rheum Dis. 2016;75:481-9). 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, but there was a higher incidence of serious hypersensitivity events and suspected MAS.