Exposure/Response modeling for sarilumab dose regimens benefit/risk assessment
Zhaoling Meng (1), Bernard Sebastien (2), Sunny Sun (3), Clemence Rigaux-Lampe (2), Anne Paccaly (4), Christine Xu (1), Hui Quan (1)
(1) Sanofi, Bridgewater, NJ, USA, (2) Sanofi, Chilly-Mazarin, France, (3) Sanofi, Beijing, China, (4) Regeneron Pharmaceuticals, Inc, Tarrytown, NY, USA
Objectives: Sarilumab, a human mAb blocking the IL-6Rα, is being developed for the treatment of rheumatoid arthritis (RA). Exposure/Response (E/R) analyses of selected efficacy (ACR responses) and safety endpoints (absolute neutrophil count [ANC]) were conducted to better understand sarilumab E/R relationships and to support the benefit/risk assessment of the dose regimens used in phase 3 studies (sarilumab 150 mg every 2 weeks [q2w] and 200 mg q2w).
Methods: Treatment effects of different dose regimens were predicted and evaluated through the empirical E/R models established for efficacy endpoints, including proportions of ACR20, ACR50, and ACR70 responders at selected time points, and safety endpoints, including percent changes in ANC at selected time points and time to first grade 3/4 neutropenia event. In addition, potential impact of baseline covariates on the E/R relationships were explored with the purpose of identifying patient profiles with enhanced benefit and improved safety. For each endpoint, empirical linear, log-linear, and Emax PK/PD relationships were evaluated to select the model that best fitted the data, based on the distribution of the corresponding endpoint. For the time-to-event safety endpoint, either parametric log-normal or Weibull survival model for the event time was selected based on the event time distribution.
Results: Overall, the established log-linear E/R relationships indicated that higher exposure resulted in better efficacy and suggested a consistent trend toward a greater therapeutic benefit for the 200 mg q2w regimen compared with the 150 mg q2w regimen. The E/R relationships indicated that the 150 mg q2w regimen had a lower effect compared with the 200 mg q2w regimen for ANC percent reduction and neutropenia. The effect for ANC percent reduction reached a plateau as exposure increased. For time to first grade 3/4 neutropenia event, the risk of having an event decreased from week 12 to week 24 for both doses. Model-predicted treatment effects of 150 mg q2w and 200 mg q2w were consistent with clinical observed effects of ACR responses and ANC percent reduction and neutropenia. Of the covariates tested, body weight was not significant.
Conclusions: The established E/R relationships for ACR responses and ANC, in addition to observed clinical efficacy and safety findings, provided evidence to support a starting dose of 200 mg q2w with a decrease to 150 mg q2w in the event of laboratory abnormalities.