Senior Director Sanofi, Morristown, NJ, USA, United States
Objectives: Sarilumab, an interleukin-6 receptor inhibitor, is approved for the treatment of patients with rheumatoid arthritis (RA) and polyarticular-course juvenile idiopathic arthritis (pcJIA). This study aimed to evaluate the exposure-response (E-R) relationship of sarilumab in pediatric patients aged 2 to 17 years with pcJIA and assess the E-R relationship similarity between adult patients with RA and pediatric patients with pcJIA.
Methods: This study analysed the data of pediatric patients with pcJIA from a phase 2 study (NCT02776735) and of adult RA patients from a phase 2 (NCT01061736) and phase 3 study (NCT01709578). The phase 2 pcJIA study (NCT02776735) included 101 patients with pcJIA (aged 2 to 17 years) with at least a 52-week treatment period (data cut off: 1 year); however, not all patients received the drug for one-year. The 12-week core treatment phase included three portions, of which the dose-finding portion was a sequential, ascending dose-cohort in which 3 dose regimens (dose 1 [2 mg/kg q2w vs. 2.5 mg/kg q2w], dose 2 [3 mg/kg q2w vs. 4 mg/kg q2w], and dose 3 [2 mg/kg q2w vs. 2.5 mg/kg q2w]) were investigated in two weight groups: Group A (patients ≥30 kg and ≤60 kg) and Group B (patients < 30 kg and ≥10 kg), respectively. The other two portions of the core treatment phase enrolled patients who received the selected dose of portion 1. A descriptive analysis was conducted to examine the concentration-response and dose-response. E-R analyses for efficacy in patients with pcJIA involved 30%/50%/70% improvement response of JIA American College of Rheumatology (JIA-ACR 30/50/70) at Week 12. To compare the E-R relationships on efficacy between adult RA and pcJIA, differences in components and response criteria between adult RA ACR 20%/50%/70% and pcJIA JIA-ACR 30%/50%/70% were used to define “JIA-ACR” responses in adult RA. E-R analyses for safety included percent change from baseline in absolute neutrophil counts (ANC) at Week 12, Week 24 and Week 48. E-R analyses were conducted using observed trough concentration of sarilumab (Ctrough) through linear, log-linear, or Emax modeling. In addition, potential impacts of baseline covariates on the E-R relationship were explored.
Results: Descriptive PK-PD analysis showed greater JIA ACR response at Dose 2 than Dose 1, while the differences between Dose 3 and Dose 2 were minimal. A linear or log-linear E-R relationship based on the logistic regression analysis was established between the JIA ACR30/50/70 and Ctrough. A log-linear E-R relationship was established between % change in ANC and Ctrough. A higher ANC reduction and a higher proportion of patients with ANC < 1.0 Giga/L with increased Ctrough were found. The risk of ANC < 1.0 Giga/L did not increase over time. Dose 2 is associated with a favourable risk-benefit profile and is effective and safe in pediatric patients with pcJIA.
Conclusions: The E-R analyses revealed that an increase in sarilumab Ctrough is associated with better responses on efficacy endpoints and a higher ANC reduction at Week 12. These findings showed a consistent E-R relationships for both efficacy and safety endpoints in pediatric patients with pcJIA and in adult patients with RA.
