Recombinant factor IX-Fc fusion protein (rFIXFc) demonstrates safety and prolonged activity in a phase 1/2a study in hemophilia B patients

Abstract

Current factor IX (FIX) products display a half-life (t(1/2)) of ∼ 18 hours, requiring frequent intravenous infusions for prophylaxis and treatment in patients with hemophilia B. This open-label, dose-escalation trial in previously treated adult subjects with hemophilia B examined the safety and pharmacokinetics of rFIXFc. rFIXFc is a recombinant fusion protein composed of FIX and the Fc domain of human IgG(1), to extend circulating time. Fourteen subjects received a single dose of rFIXFc; 1 subject each received 1, 5, 12.5, or 25 IU/kg, and 5 subjects each received 50 or 100 IU/kg. rFIXFc was well tolerated, and most adverse events were mild or moderate in intensity. No inhibitors were detected in any subject. Dose-proportional increases in rFIXFc activity and Ag exposure were observed. With baseline subtraction, mean activity terminal t(1/2) and mean residence time for rFIXFc were 56.7 and 71.8 hours, respectively. This is ∼ 3-fold longer than that reported for current rFIX products. The incremental recovery of rFIXFc was 0.93 IU/dL per IU/kg, similar to plasma-derived FIX. These results show that rFIXFc may offer a viable therapeutic approach to achieve prolonged hemostatic protection and less frequent dosing in patients with hemophilia B. The trial was registered at www.clinicaltrials.gov as NCT00716716.

Figures

Figure 1

Dose-dependent PK profiles and correlation of rFIXFc activity and Ag in plasma. (A) Plasma FIX activity and (B) plasma rFIXFc Ag levels over time after a single intravenous infusion of 12.5 (n = 1), 25 (n = 1), 50 (n = 5), or 100 (n = 5) IU/kg rFIXFc. Results presented are group mean ± SEM. (C) Correlation between plasma rFIXFc activity and Ag levels in 12 subjects who received a single dose of 12.5-100 IU/kg rFIXFc. Samples were collected up to 336 hours after dosing.

Figure 2

Monte Carlo simulation for rFIXFc doses to achieve a trough of 1 IU/dL (1%) or 3 IU/dL (3%) above baseline. The rFIXFc dosing intervals considered were (A) weekly, (B) every 10 days, or (C) every 2 weeks. The mean population PK parameters and relevant intersubject and intrasubject variability were adopted from this phase1/2a study. On the basis of the simulated activity-time profiles, the mean and 95% CI of the activity-time profiles of the 1000 subjects was constructed graphically for different dosing regimens for a total of 5 dosing cycles when the steady state was achieved.