Favorable pharmacokinetics in hemophilia B for nonacog beta pegol versus recombinant factor IX-Fc fusion protein: A randomized trial

Abstract

Background and objective: Nonacog beta pegol (N9-GP) and recombinant factor IX-Fc fusion protein (rFIXFc) are extended half-life rFIX compounds. We report the first single-dose pharmacokinetic trial of N9-GP and rFIXFc.

Patients/methods: Paradigm 7 was a multicenter, open-label, randomized, crossover trial in previously treated (>150 exposure days) adults with congenital hemophilia B (FIX activity ≤2%). Patients received single intravenous injections (50 IU/kg) of N9-GP and rFIXFc with at least 21 days between doses. Plasma FIX activity, predose, and at serial time points up to 240 hours postdose, was measured using validated one-stage clotting assays (SynthAFax for N9-GP; Actin FSL for rFIXFc) and a chromogenic assay (ROX factor IX) with normal human plasma as calibrator. The primary endpoint was area under the FIX activity-time curve from 0 to infinity, dose-normalized to 50 IU/kg (AUC0-inf,norm).

Results: Fifteen patients received study treatment. Based on FIX activity results from the one-stage clotting assays, estimated AUC0-inf,norm was significantly greater for N9-GP than rFIXFc (ratio: 4.39; P <0.0001, based on a two-sided test on 5% significance level). In addition, N9-GP had a longer terminal half-life, two times higher incremental recovery at 30 minutes and maximum FIX activity (dose-normalized to 50 IU/kg) and six times higher FIX activity at 168 hours than rFIXFc. These findings were largely comparable with the chromogenic assay data and are consistent with published data for each compound.

Conclusions: In this comparison, N9-GP demonstrated favorable pharmacokinetic characteristics versus rFIXFc, helping clinicians to understand differences between N9-GP and rFIXFc.

Registration: This trial is registered with clinicaltrials.gov (NCT03075670) and the European Clinical Trials Database (EudraCT: 2016-001149-25).

Keywords: crossover trial; factor IX; hemophilia B; pharmacokinetics; phase I; randomized clinical trial.

Figures

Figure 1

Trial design and pharmacokinetic sampling. Doses of each trial product were separated by at least 21 d; each dose administration was preceded by a 96‐h washout from non‐modified FIX products. FIX, factor IX; PK, pharmacokinetic; rFIXFc, recombinant factor IX‐Fc fusion protein; V, visit

Figure 2

Mean FIX activity profiles following single 50‐IU/kg doses of N9‐GP and rFIXFc, measured using one‐stage clotting and chromogenic assays. Mean (±SD) FIX activity profiles following single 50‐IU/kg doses of N9‐GP and rFIXFc are shown, measured using one‐stage clotting assays (A) and the chromogenic assay (B). Panel (C) collates the mean plots with an insert magnifying FIX activity over the first 24 h. The aPTT reagents used for the one‐stage clotting assay were SynthAFax and Actin FSL for N9‐GP and rFIXFc, respectively. The ROX factor IX kit was used for the chromogenic assay with both treatments. All assays were calibrated using NHP. aPTT, activated partial thromboplastin time; FIX, factor IX; NHP, normal human plasma; PK, pharmacokinetic, rFIXFc, recombinant factor IX‐Fc fusion protein; SD, standard deviation

Figure 3

Analysis of PK endpoints for N9‐GP versus rFIXFc, derived from FIX activity measured using one‐stage clotting and chromogenic assays. All PK endpoints were log‐transformed before being analyzed using a mixed‐effects model that included product and period as fixed effects and patients as a random effect. Estimates with two‐sided 95% CIs were provided for each treatment, back‐transformed to the original scale; the two‐sided 95% CIs for the comparisons between treatments were expressed as ratios and provided together with the P‐values. The aPTT reagents used for the one‐stage clotting assay were SynthAFax and Actin FSL for N9‐GP and rFIXFc, respectively. The ROX factor IX kit was used for the chromogenic assay with both treatments. All assays were calibrated using NHP. *P < 0.0001 for all comparisons, except for t½, for which P < 0.001 for both assays. aPTT, activated partial thromboplastin time; AUC0‐inf,norm, area under the FIX activity–time curve from 0 to infinity, dose‐normalized to 50 IU/kg; C168h, FIX activity at 168 h; C240h, FIX activity at 240 h; CI, confidence interval; CL, clearance; Cmax,norm, maximum FIX activity dose‐normalized to 50 IU/kg; FIX, factor IX; IR30min, incremental recovery at 30 min; NHP, normal human plasma; PK, pharmacokinetic; rFIXFc, recombinant factor IX‐Fc fusion protein; t½, terminal half‐life; Vss, apparent volume of distribution at steady state

Figure 4

Log‐scale mean FIX activity profiles following single 50‐IU/kg doses of N9‐GP and rFIXFc, measured using one‐stage clotting and chromogenic assays. Log‐scale mean FIX activity profiles following single 50‐IU/kg doses of N9‐GP and rFIXFc are shown, measured using one‐stage clotting assays and the chromogenic assay. The aPTT reagents used for the one‐stage clotting assay were SynthAFax and Actin FSL for N9‐GP and rFIXFc, respectively. The ROX factor IX kit was used for the chromogenic assay with both treatments. All assays were calibrated using NHP. aPTT, activated partial thromboplastin time; FIX, factor IX; NHP, normal human plasma; rFIXFc, recombinant factor IX‐Fc fusion protein