A Model-Based Framework to Inform the Dose Selection and Study Design of Emicizumab for Pediatric Patients With Hemophilia A

Abstract

Emicizumab is a bispecific antibody mimicking the cofactor function of activated coagulation factor VIII to prevent bleeds in patients with hemophilia A. The dose selection for the first-in-child phase III study of emicizumab was addressed by pediatric pharmacokinetic prediction using an adult/adolescent population pharmacokinetic model developed in phase I-I/II studies. The model was modified to incorporate functions describing the age-dependent increase in body weight (BW) with or without clearance maturation to account for the differences in emicizumab pharmacokinetics between adults/adolescents and children. A minimal dose anticipated to achieve in children the same target efficacious exposure as for adults/adolescents was identified when considering BW and clearance maturation. It was the same BW-based dose as for adults/adolescents and was selected for the starting dose for the pediatric study. Whether considering clearance maturation or not in addition to BW led to uncertainty in the pediatric pharmacokinetic prediction and dose selection, which informed implementation of a dose-adapting scheme in the study design. Exposure matching to adults/adolescents was ultimately achieved in children with the starting dose, indicating that consideration of clearance maturation in addition to BW provided adequate pediatric pharmacokinetic predictions for emicizumab. This pharmacokinetic finding in conjunction with exposure-response information served as a basis for the efficacy demonstrated in children, avoiding a time-consuming process for exploring an optimal pediatric dose of emicizumab. This experience indicates that a model-based framework helped optimize the pediatric dose selection and study design, thereby streamlining the development process with extrapolation, of emicizumab for children.

Keywords: adaptive design; dose selection; emicizumab; extrapolation; hemophilia A; monoclonal antibodies; pediatrics; pharmacokinetics and drug metabolism; pharmacometrics; rare diseases.