Pharmacokinetic Results of Two Phase III Clinical Studies of Coagulation Factor IX (Recombinant) Albumin Fusion Protein (rIX-FP) in Previously Treated Patients with Hemophilia B (PROLONG-9FP)

A recombinant fusion protein linking recombinant coagulation factor IX (FIX) with recombinant human albumin (rIX-FP) has been developed to extend the plasma half-life of FIX, thus improving hemophilia B treatment by allowing less frequent dosing than required with standard plasma-derived (pd) and recombinant (r) FIX products. The PROLONG-9FP clinical program aims to evaluate the use of rIX-FP for prophylaxis and on-demand treatment of bleeding in patients with severe hemophilia B. In a completed Phase I pharmacokinetic (PK) study in subjects aged 15 to 58 years (y), the mean half-life of rIX-FP was 92 hours, 5 times longer than the half-life of the FIX products previously used by the subjects. The mean trough FIX activity after injection of rIX-FP was 7.4% (day 7) at a dose of 25 IU/kg, and 13.4% (day 7) and 5.5% (day 14) at a dose of 50 IU/kg (Santagostino E, et al. Blood 2012; 120:2405-11). A Phase II study demonstrated the efficacy of weekly prophylaxis with rIX-FP, with excellent safety and an improved PK profile.

Following completion of these studies, 2 Phase III, open-label, multicenter studies have been conducted in previously treated patients (PTPs) with severe hemophilia B, aged 12 to 65 years (NCT01496274) and < 12 years (NCT01662531). Both studies, which were designed to evaluate the long term safety and efficacy of rIX-FP for both prophylaxis and on-demand treatment of bleeding episodes, consisted of an initial PK evaluation period followed by a treatment period during which subjects were administered rIX-FP as prophylaxis and on-demand treatment. Subjects from 42 hemophilia treatment centers in 12 countries participated; to date, the PROLONG-9FP clinical program encompasses over 100 hemophilia B subjects for the PK evaluation. Here, we report on the PK results from these 2 studies.

During the 14-day PK evaluation periods, blood samples for PK analysis were taken before dosing, and then at 30 minutes, 3, 24, 48, 72, 120, 168, 240 and 336 hours after injection of 50 IU/kg rIX-FP. A subgroup of subjects also completed a PK evaluation of their previously used Factor IX products (pdFIX and rFIX), with sampling before dosing, and then at 30 minutes, 3, 6, 12, 24 and 48 hours after 50 IU/kg FIX injection. Plasma FIX activity (FIX:C) was measured by a one-stage clotting assay (CSL Behring central laboratory).

The mean plasma FIX half-life after injection of 50 IU/kg rIX-FP was 105, 92 and 84 hours in the respective age groups of 12 to 61 years (n = 46), 6 to 11 years (n = 15) and 1 to 5 years (n = 12); the baseline corrected mean incremental recovery (IR) was 1.3, 1.1 and 1.0 IU/dL per IU/kg, the mean area under the curve (AUC) was 7,360, 4,949 and 4,358 IU*hr/dL, and the clearance was 0.7, 1.1 and 1.3 mL/h/kg in the respective age groups. The time to 5% FIX:C after injection of 50 IU/kg rIX-FP administration was Day 10 for children and Day 14 for adults; at Day 14, the mean trough FIX activity in children was 3%. Compared with the FIX products previously used by the subjects, rIX-FP had a 30 to 40% higher incremental recovery, > 5-times longer half-life, larger AUC and lower clearance.

In conclusion, compared with standard FIX products, rIX-FP demonstrated an improved PK profile with a prolonged half-life in all age groups (1 to 61 years). At 14 days after injection of rIX-FP, the mean trough FIX activity is 3% in children and above 5% in adults, supporting a treatment interval of 14 days for routine prophylaxis. Treatment intervals of 7-, 10- and 14 days for routine prophylaxis were tested in the pivotal Phase III studies; every 21 day regimen will be tested in selected age groups during the Phase IIIb extension study. Detailed PK results will be presented during the meeting.