Alan Faraj (1), Natacha Le Moan (2), Eduard Gorina (2), Tom Knudsen (2), Ulrika S.H. Simonsson (1)
(1) Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden, (2) Catalyst Biosciences, South San Francisco, CA, USA
Introduction: Factor IX dalcinonacog alfa (DalcA/CB 2679d) is being developed by Catalyst Biosciences to address the unmet need for medical management of patients with Hemophilia B. DalcA has an improved catalytic efficiency allowing the potential subcutaneous prophylactic treatment of hemophilia B patients and has shown significantly higher potency in preclinical and early clinical studies compared with other Factor IX products on the market and in development.
Objectives: This work aimed to characterize the population pharmacokinetics (PK) of DalcA after administration of different intravenous (IV) and subcutaneous (SC) doses in subjects with hemophilia and to conduct clinical trial simulations of DalcA exposure after different regimens to support dose selection for prophylaxis in clinical trials for the adult and pediatric populations.
Methods: A population PK model including allometric scaling was developed based on all available IV and SC data from clinical trials DLZ-201 (NCT03995784)1 and ISU304-001 (NCT03186677)2. Clinical trial simulations were conducted for a population of one thousand adult virtual subjects with hemophilia weighing 40 to 105 kg. Different dosing regimens were simulated and minimal concentration (Cmin) at steady state was derived. The simulated population PK profiles were compared to a pre-defined minimum target (10% FIX equal to 0.1 IU/mL). Furthermore, the time to target and the proportion of the population above target at different time points for different regimens were calculated. In addition, to predict doses in pediatrics that match the predefined target (same for adults and pediatrics), concentration-time profiles in 1000 pediatric subjects with different age categories (total of four thousand subjects) were simulated using the adult population PK model including allometric scaling.
Results: The final population PK model including allometric scaling with BW described the clinical adult DalcA PK data well. In subjects with hemophilia, DalcA bioavailability after SC administration was estimated to 18.2%. Terminal elimination half-life was estimated through simulations to be 24 hours after IV administration. The absorption half-life after SC administration was estimated to be 30.5 hours with inter-individual (IIV) of 42%, indicating flip-flop kinetics. The terminal elimination half-life in a typical individual after a SC dose of 100 IU/kg was estimated to 130 hours. The typical time to reach target was 3.3 days following 100 IU/kg once daily (OD) in adult subjects with hemophilia B. The simulations indicated that following OD daily dosing of 100 IU/kg, almost 90% of the adult subjects reached through levels above the target at steady state. A DalcA dose of 125 IU/kg was found to generate adequate FIX levels in the majority of children of 12 years down to 6 years of age, whereas below 6 years and down to 2 year of age, the simulations suggested 150 IU/kg to be more appropriate.
Conclusions: An adult population PK model including allometric scaling was developed for IV as well as SC administered DalcA with good precision in parameter estimates. The model described the clinical data well and was used for clinical trial simulations to support prophylaxis dosing regimen in a planned clinical phase 3 trial that includes adults and children. We propose to revisit the simulations after pediatric data above 2 years of age is available for further extrapolation below 2 years of age.
References:
[1] Mahlangu, J., Levy, H., Lee, M. & Del Greco, F. Efficacy and safety of subcutaneous prophylaxis with dalcinonacog alfa in adults with haemophilia B. Haemophilia 27, 574–580 (2021)
[2] You, C. W. et al. Safety, pharmacokinetics, and pharmacodynamics of a next-generation subcutaneously administered coagulation factor IX variant, dalcinonacog alfa, in previously treated hemophilia B patients. J. Thromb. Haemost. 19, 967–975 (2021)
Reference: PAGE 30 (2022) Abstr 10008 [www.page-meeting.org/?abstract=10008]
Poster: Drug/Disease Modelling - Other Topics