Safety and Efficacy of Nonacog Beta Pegol (N9-GP) for Prophylaxis and Treatment of Bleeding Episodes in Previously-Treated Patients with Hemophilia B: Results from an Extension Trial

Background: Prolongation technology has recently been employed to advance the treatment in hemophilia. Nonacog beta pegol (N9-GP) is a glycoPEGylated recombinant factor IX (rFIX) with a significantly extended half-life in hemophilia B adults (Negrier et al. Blood 2011), up to 111 h, as compared to currently available treatment options. The pivotal phase 3 trial, paradigm™2, demonstrated that the prophylactic protection of 40 U/kg N9-GP once weekly significantly reduced the risk of bleeding as well as successfully controlled the bleeding episodes (Collins et al. JTH (Suppl.2) 2013). It also demonstrated a potential to improve clinical outcomes, reduce joint damage and improve quality of life with fewer injections. The phase 3 extension trial, paradigm™4, was designed to investigate the safety and efficacy of long-term treatment with N9-GP in severe and moderately severe hemophilia B patients.

Aims: The primary objective of this trial was to evaluate immunogenicity of N9-GP. Key secondary objectives were to assess therapeutic and prophylactic efficacy and safety of N9-GP.

Methods: 71 hemophilia B patients above 12 years of age with ≤2% FIX activity, with no history of inhibitors, at least 150 exposures days (ED) to other FIX products, and who completed the pivotal phase 3 trial, paradigm™2, or the pivotal surgery trial, paradigm™3, were included. The trial was approved by local IRB/REC and all participants signed an informed consent before any trial related activity. Patients were allowed to change the treatment regimen at trial start or during the trial based on their clinical manifestation and investigator recommendation; options included on-demand treatment, or once weekly prophylaxis with 10 or 40 U/kg N9-GP. Immunogenicity was evaluated as the primary endpoint; incidence of inhibitory antibodies against FIX defined as titer ≥0.6 Bethesda Units (BU). Efficacy endpoints included frequency of bleeds among prophylaxis patients, hemostatic response to N9-GP infusion based on a 4-point categorical scale, as well as FIX activity as a surrogate marker.

Results: A total of 71 patients were treated for at least 12 months, 67 of whom received a prophylactic regimen of N9-GP either 10 U/kg or 40 U/kg once weekly; there were considerable movements between treatment arms, with approximately one third of the patients moving from on-demand or 10 U/kg at the start of this extension trial, up to 40 U/kg, with a smaller proportion moving from 40 U/kg to 10 U/kg, or from 10 U/kg to on-demand. None of the patients in the trial developed inhibitors. There were no differences relating to adverse events or standard safety parameters between the treatment groups. In paradigm™4 a total of 94.6% of all bleeding episodes were successfully treated, with 87.9% of all bleeding episodes treated with a single infusion. Among patients on prophylaxis, a median (IQR) annualized bleeding rate of 1.1 (0.0 – 2.2) episodes per year was observed. There was a higher proportion of traumatic bleeding episodes in the patients on 40 U/kg N9-GP compared with patients on 10 U/kg N9-GP (57.1% vs. 28.6%, respectively), though the annualized bleeding rates were similar in both prophylactic groups, with median (IQR) ABR of 0.0 (0.0 – 1.0) and 0.0 (0.0 – 1.1) in 10 U/kg and 40 U/kg N9-GP, respectively. For spontaneous bleeds only, the median (IQR) annualized bleeding rate was 1.1 (0.0 – 2.2) and 0.0 (0.0 – 1.0) among patients treated with 10 U/kg and 40 U/kg N9-GP, respectively.

Conclusion: The outcome of the trial confirmed the results from paradigm™2 that N9-GP appeared to have a safe and well-tolerated profile with good prophylactic protection and control of bleeding.