OP0197 Evaluation of a dosing regimen for tocilizumab in patients younger than two years of age with systemic juvenile idiopathic arthritis
Authors: NL Mallalieu, J Hsu, K Wang, S Wimalasundera, C Wells, I Calvo Penades, R Cuttica, HI Huppertz, R Joos, Y Kimura, D Milojevic, M Rosenkranz, K Schikler, T Constantin, C Wouters
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> 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 &lt;2 years of age. <h3>Objectives</h3> To evaluate the pharmacokinetics (PK), pharmacodynamics (PD), efficacy, and safety of TCZ in sJIA pts &lt;2 years of age in a phase 1 trial. <h3>Methods</h3> 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. <h3>Results</h3> 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.<sup>1</sup> No deaths occurred during the study. <h3>Conclusions</h3> 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 &lt;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. <h3>References</h3> Ravelli A et al. Ann Rheum Dis. 2016;75:481–9. <h3>Disclosure of Interest</h3> 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