Background Tocilizumab (TCZ) is approved for the treatment of systemic juvenile idiopathic arthritis (sJIA) based on clinical trials in patients (pts) ≥2 years of age. This study (NP25737) is the first for a biologic in sJIA pts <2 years of age.
Objectives To evaluate the pharmacokinetics (PK), pharmacodynamics (PD), efficacy, and safety of TCZ in sJIA pts <2 years of age in a phase 1 trial.
Methods Pts 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). Pts were treated up to week 12 and could continue until the age of 2 years 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 to exposures from a previous trial in sJIA pts ≥2 years of age (WA18221) that was the basis for approval of TCZ in sJIA.
Results Eleven pts 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, respectively. 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 pts had 32 adverse events (AEs) and 4 withdrew due to AEs. Infections or infestations were the most frequently reported AEs (10 events, 9 pts). Five serious AEs (SAEs) occurred; 3 pts had SAEs of hypersensitivity that led to withdrawal; 1 of these pts then experienced SAEs of foot and mouth disease and sJIA flare after study withdrawal. No actual cases of MAS were reported, but 2 pts had laboratory abnormalities indicative of MAS according to 2016 criteria.1 No deaths occurred during the study.
Conclusions TCZ exposures achieved in this study fell within the range of the previous trial in sJIA pts ≥2 years of age. This study provides evidence that TCZ is effective in sJIA pts <2 years of age, achieves PK and efficacy similar to those demonstrated previously in older pts, and has a similar AE safety profile, but there was a higher incidence of serious hypersensitivity events and suspected MAS.
Ravelli A et al. Ann Rheum Dis. 2016;75:481–9.
Disclosure of Interest N. Mallalieu Shareholder of: Roche, Employee of: Roche, J. Hsu Employee of: Roche, K. Wang Employee of: Roche, S. Wimalasundera Employee of: Roche Products Ltd., C. Wells Employee of: Roche Products Ltd., I. Calvo Penades: None declared, R. Cuttica Consultant for: Roche, Novartis, Lilly, GlaxoSmithKline, Bristol-Myers Squibb, Janssen, Speakers bureau: Roche, Novartis, Lilly, GlaxoSmithKline, Bristol-Myers Squibb, Janssen, H. Huppertz: None declared, R. Joos: None declared, Y. Kimura Consultant for: Novartis, SOBI, D. Milojevic: None declared, M. Rosenkranz: None declared, K. Schikler: None declared, T. Constantin: None declared, C. Wouters: None declared