Long-acting recombinant coagulation factor IX albumin fusion protein (rIX-FP) in hemophilia B: results of a phase 3 trial

Abstract

A global phase 3 study evaluated the pharmacokinetics, efficacy, and safety of recombinant fusion protein linking coagulation factor IX with albumin (rIX-FP) in 63 previously treated male patients (12-61 years) with severe hemophilia B (factor IX [FIX] activity ≤2%). The study included 2 groups: group 1 patients received routine prophylaxis once every 7 days for 26 weeks, followed by either 7-, 10-, or 14-day prophylaxis regimen for a mean of 50, 38, or 51 weeks, respectively; group 2 patients received on-demand treatment of bleeding episodes for 26 weeks and then switched to a 7-day prophylaxis regimen for a mean of 45 weeks. The mean terminal half-life of rIX-FP was 102 hours, 4.3-fold longer than previous FIX treatment. Patients maintained a mean trough of 20 and 12 IU/dL FIX activity on prophylaxis with rIX-FP 40 IU/kg weekly and 75 IU/kg every 2 weeks, respectively. There was 100% reduction in median annualized spontaneous bleeding rate (AsBR) and 100% resolution of target joints when subjects switched from on-demand to prophylaxis treatment with rIX-FP (P< .0001). The median AsBR was 0.00 for all prophylaxis regimens. Overall, 98.6% of bleeding episodes were treated successfully, including 93.6% that were treated with a single injection. No patient developed an inhibitor, and no safety concerns were identified. These results indicate rIX-FP is safe and effective for preventing and treating bleeding episodes in patients with hemophilia B at dosing regimens of 40 IU/kg weekly and 75 IU/kg every 2 weeks. This trial was registered at www.clinicaltrials.gov as #NCT0101496274.

Trial registration: ClinicalTrials.gov NCT01496274.

Figure 1

Study design. The study consisted of a 1-month screening period, 14-day PK assessment, followed by active treatment of at least 12 months. Patients were assigned to either prophylaxis treatment (group 1) or on-demand treatment (group 2) based on previous treatment regimen. Group 1 patients received weekly prophylaxis for 26 weeks and then were evaluated for eligibility to switch to a longer treatment interval (star). Group 2 received on-demand treatment of the first 26 weeks followed by weekly rIX-FP prophylaxis for an additional 26 weeks or longer. Subjects were required to have no spontaneous bleeds for at least 1 month and be on a stable dose of ≤40 IU/kg or ≤50 IU/kg rIX-FP to switch to a 14-day or 10-day treatment interval, respectively. Subjects continued on 7-, 10-, or 14-day prophylaxis for the remaining treatment period. A subset of subjects in group 1 (the first 15 patients naïve to rIX-FP to enroll) repeated the PK assessment of 50 IU/kg rIX-FP at approximately week 26, prior to switching to a longer treatment interval. EOS, end of study.

Figure 2

Patient enrollment and study flow diagram. The diagram shows the flow and disposition of patients in the trial. Following screening, 63 subjects were enrolled in the study. All subjects who had not previously undergone PK analysis of rIX-FP in a previous study participated in PK evaluation of 25 IU/kg (n = 6) or 50 IU/kg rIX-FP (n = 46). A subset of subjects (n = 13) also participated in a PK evaluation of their previous FIX product (pdFIX or rFIX). A subset of subjects (n = 15) repeated PK analysis of 50 IU/kg rIX-FP at approximately week 26. Subjects were assigned either weekly prophylaxis (group 1) or on-demand treatment (group 2) with rIX-FP, based on their prior treatment regimen. Eight subjects discontinued from the study for the following reasons: AEs (n = 2), subject decision (n = 2), lost to follow-up (n = 3), and protocol violation (n = 1, unwillingness to switch to prophylaxis after on-demand treatment).

Figure 3

FIX activity after injection of a single dose of rIX-FP or previous FIX product (PK population). Mean baseline-uncorrected plasma FIX activity after administration of a single infusion of 25 or 50 IU/kg of rIX-FP or 50 IU/kg previous FIX product (pdFIX or rFIX). Linear (A) and semilog (B) plots of rIX-FP over time. (C) Matched-pair plot patients who participated in both 50 IU/kg rIX-FP and 50 IU/kg previous FIX product. FIX activity was measured in international units per deciliter. Vertical bars represent SD. A horizontal dotted line represents the 5 IU/dL FIX activity level. (D) Box plot of FIX activity of rIX-FP at day 7 and day 14; the bar within the box represents the median, diamond represents the mean, the ends of the box are the IQR, and whiskers represent minimum and maximum values. FIX activity levels are not available for a dose of 25 IU/kg rIX-FP at day 14.