Objective:
Nonacog beta pegol (N9-GP) and recombinant factor IX-Fc fusion protein (rFIXFc) are two modified rFIX compounds with extended half-lives compared with standard FIX products. We report results from two head-to-head, single-dose pharmacokinetic (PK) trials comparing N9-GP with standard FIX and rFIXFc in previously-treated patients (PTPs) with congenital hemophilia B (≤2% FIX).
Methods:
paradigm™1 (NCT00956345) was a first human-dose trial in PTPs investigating the safety and PK of a single N9-GP dose. Sixteen PTPs (21-55 years) received one dose of their previous FIX product, followed by one dose of N9-GP at the same dose level (25, 50, or 100 IU/kg) with ≥7 days between doses. FIX activity was assessed up to 48 hours (standard FIX) or 168 hours (N9-GP) with additional samples at 2 and 4 weeks analyzed by one-stage clotting assay (TriniCLOT™) with product-specific standard as calibrator. paradigm™7 (NCT00956345) was a multicenter, randomized, head-to-head trial where 15 patients (21-65 years) received single injections (50 IU/kg) of N9-GP and rFIXFc with ≥21 days between doses. FIX activity was assessed for up to 240 hours using a one-stage clotting assay (SynthAFax or Actin FSL) 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).
Summary:
In paradigm™1, the estimated terminal half-life of N9-GP was 93 hours, 4.8 times longer than for patients’ previous product. For N9-GP, estimated incremental recovery at 30 minutes (IR30min) (1.33 IU/dL per IU/kg) was 94% and 20% higher compared with rFIX and plasma-derived FIX (pdFIX), respectively. AUC0-inf,norm with N9-GP was 10.1 times and 7.7 times higher compared with rFIX and pdFIX, respectively. Time to 3% and 1% FIX activities was 16.2 and 22.5 days, respectively. In paradigm™7, the estimated AUC0-inf,norm measured with one-stage clotting assay was 4.4 times higher for N9-GP compared with rFIXFc (9656 versus 2199 IU*h/dL). IR30min was 2.2 times higher (1.7 versus 0.8 IU/dL per IU/kg), maximum activity, dose normalized to 50 IU/kg, was 2 times higher (91% versus 45%), and FIX activity at 168 hours was 5.8 times higher (19% versus 3%). N9-GP had a longer terminal half-life (103.2 versus 84.9 hours; ratio: 1.22). Results were similar when measuring FIX activity with chromogenic assay. One patient in paradigm™1 developed transient hypersensitivity symptoms during administration of N9-GP and was excluded from PK analyses. No patient developed inhibitors in either trial, and no unexpected safety concerns were identified.
Conclusion:
These two single-dose PK trials show that N9-GP achieves higher FIX activity levels and greater AUC than pdFIX, rFIX, and rFIXFc through higher recovery and longer terminal half-life. These findings will support clinicians’ understanding of differences in PK between specific FIX products.