Pharmacokinetics, Efficacy and Safety of BAX326, a Novel Recombinant Factor IX: A Prospective, Controlled, Multicenter Study in Previously Treated Patients with Severe (FIX Level < 1%) or Moderately Severe (FIX Level ≤ 2%) Hemophilia B.

Abstract 2222

Hemophilia B is a congenital X-linked bleeding disorder whose severity is associated with diminished or absent levels of circulating FIX. Treatment with regular prophylactic FIX infusions has significant medical and quality of life benefits by maintaining adequate plasma levels of FIX for hemostasis approximating a non-diseased state.

BAX326 nonacog gamma is a novel recombinant FIX (rFIX) that is manufactured without the addition of any materials of human or animal origin, and viral inactivation/reduction is achieved through solvent/detergent (S/D) treatment as well as 15nm nanofiltration. Pharmacokinetics, hemostatic efficacy and safety of BAX326 were assessed in a prospective clinical trial in patients aged 12 to 65 years with severe (FIX level < 1%) or moderately severe (FIX level ≤ 2%) hemophilia B, previously treated with plasma-derived and/or recombinant FIX concentrates. PK parameters were compared with a commercially-available rFIX used as an active control in a crossover design. Hemostatic efficacy of BAX326 administered twice weekly as prophylaxis was compared with a historical control group treated on-demand.

A total of 86 patients were enrolled and 73 were treated with BAX326. All subjects treated had previous exposure to a FIX concentrate for ≥ 150 days prior to entry into the study. Subjects included in the PK analysis (n=28) received one 75 ± 5 IU/kg infusion with BAX326 and one infusion with commercial rFIX in random order prior to receiving prophylactic treatment at a dose range from 40 to 60 IU/kg two times a week with BAX326. An additional 31 subjects also received prophylactic treatment (21–67 exposure days), and 14 subjects received BAX326 on-demand (5–25 exposure days). More than 70% of subjects had 50 or more exposure days to BAX326 during the study.

PK equivalence between BAX326 and the comparator rFIX was confirmed as the 90% confidence intervals of the ratio (BAX326/comparator rFIX) of the geometric mean of AUC _{0–72 h}/dose (1.063 [1.03; 1.09]) was fully contained in the margins for equivalence (0.8 to 1.25). The mean half-life (T_1/2) of BAX326 was 26.70h ± 9.55, and incremental recovery (IR) was 0.87 ± 0.22 IU/dL: IU/kg. Repeated PK analysis after 6 months of prophylactic treatment confirmed the results of the initial values.

Twice weekly prophylactic treatment with BAX326 was effective in preventing bleeding episodes, with a significantly lower (79%, p<0.001) annualized bleed rate (ABR) during prophylaxis (mean ABR 4.20) compared to an on-demand treatment in a historical control group (mean ABR 20.0). Among the 56 subjects on prophylaxis, 24 subjects (43%) did not bleed; the mean ABR for joint bleeds was 2.79, and 1.70 for spontaneous bleeds. Of 238 total acute bleeds, 201 (84.4%) were controlled with 1–2 infusions of BAX326. Hemostatic efficacy at resolution of bleed was rated excellent or good in 95.4% of all treated bleeding episodes. The efficacy as related to degree of severity of bleeding episodes was excellent or good in 96.8 % of minor bleeds, 95 % of moderate bleeds and 92.9 % of major bleeding episodes.

BAX326 was safe and well-tolerated, with similar adverse reaction rates to the comparator rFIX. The safety assessments demonstrate the safety and tolerability of BAX326 in patients with moderately severe or severe hemophilia B. There were no product related SAEs, no inhibitory or binding FIX antibodies, no antibodies to CHO, and no allergic reactions or thrombotic events; AEs considered related to BAX326 (dysgeusia and pain in extremity) were transient and mild, and occurred with an overall incidence of 2.7%. There were no treatment-related AEs within 24 hours after infusion. Elevated pre- and post-infusion values for thrombogenic markers (TAT, F1.2 and D-dimer) in some subjects did not reveal any pattern indicative of clinically relevant thrombogenicity with either BAX326 or the comparator rFIX, and were not associated with AEs.

These data indicate that BAX326 is safe and efficacious in treating bleeding episodes and in routine prophylaxis in patients aged 12 years and older with hemophilia B. None of the historical risk factors, such as hypersensitivity reactions, inhibitor formation or thrombotic events were observed and few related adverse events occurred.