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

Abstract

Introduction: Dalcinonacog alfa (DalcA), a novel subcutaneously administered recombinant human factor IX (FIX) variant is being developed for adult and paediatric patients with hemophilia B (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.

Methods: 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.

Results: Almost 90% of the adults were predicted to achieve desirable FIX levels, i.e. 10% FIX activity, following daily 100 IU/kg dosing, with 90% of the subjects reaching target within 1.6-7.1 days. No every-other-day regimen met the target. A dose of 125 IU/kg resulted in adequate FIX levels down to 6 years, whereas a 150 IU/kg dose was needed below 6 down to 2 years of age. For subjects down to 6 years that did not reach target with 125 IU/kg, a dose escalation to 150 IU/kg was appropriate. The children below 6 to 2 years were shown to need a dose escalation to 200 IU/kg if 150 IU/kg given daily was insufficient.

Conclusion: 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.

Keywords: Dalcinonacog alfa; Dose selection; Hemophilia B; MID3; Population pharmacokinetics.

Fig. 1

Prediction corrected visual predictive check (pcVPC) for all IV and SC data up to 120 h after DalcA administration. The solid and dashed lines are the median and 2.5th and 97.5th percentiles of the observed data, respectively. The shaded areas (top to bottom) are the 95% confidence intervals of the 97.5th (light grey), median (dark grey) and 2.5th (light grey) percentiles of the simulated data. Open circles are prediction-corrected observation points

Fig. 2

Percentage of population above target at different time points (pre-treatment, 4, 8, 12, 16 and 20 days on treatment) based on C_min levels following different doses and dosing frequencies (OD, once daily and EOD, every other day). The yellow dashed line marks 80% of the population being above the target

Fig. 3

Percentage of population above target at different time points (pre-treatment, 4, 8, 12, 16 and 20 days on treatment) for different age groups based on C_min levels following different doses given once daily (OD). The blue line is the corresponding result in adults following a 100 IU/kg dose given OD. The yellow dashed line marks 80% of the population being above the target

Fig. 4

Mean (triangle) and 90% prediction interval of C_min levels for different doses given once daily, at steady state for each age group. The blue horizontal line is the corresponding interval following once daily dosing of 100 IU/kg in adults. The vertical dashed line illustrates the target of 0.1 IU/mL