Model-Informed Support of Dose Selection for Prophylactic Treatment with Dalcinonacog Alfa in Adult and Paediatric HemophiliaB Patients.

Abstract

Dalcinonacog alfa (DalcA), a novel subcutaneously administered recombinant human factorIX (FIX) variant is being developed for adult and paediatric patients with hemophiliaB (HB). DalcA has been shown to raise FIX to clinically meaningful levels in adults with HB. This work aimed to support dosing regimen selection in adults and perform first-in-paediatric dose extrapolations using a model-based pharmacokinetic (PK) approach. A population PK model was built using adult data from two clinical trials (NCT03186677, NCT03995784). With allometry in the model, clinical trial simulations were performed to study alternative dosing regimens in adults and children. Steady-state trough levels and the time-to-reach target were derived to inform dose selection. Almost 90% of the adults were predicted to achieve desirable FIX levels, i.e. 10% FIX activity, following daily 100IU/kg dosing, with 90% of the subjects reaching target within 1.6-7.1days. No every-other-day regimen met the target. A dose of 125IU/kg resulted in adequate FIX levels down to 6years, whereas a 150IU/kg dose was needed below 6 down to 2years of age. For subjects down to 6years that did not reach target with 125IU/kg, a dose escalation to 150IU/kg was appropriate. The children below 6 to 2years were shown to need a dose escalation to 200IU/kg if 150IU/kg given daily was insufficient. This study supported the adult dose selection for DalcA in the presence of sparse data and enabled first-in-paediatric dose selection to achieve FIX levels that reduce risk of spontaneous bleeds.