Nonacog Beta Pegol for Prophylactic Treatment of Children with Hemophilia B: Up to 3.5-Year Data from the Paradigm™5 Clinical Trial

Introduction: Nonacog beta pegol is a recombinant glycoPEGylated factor IX (FIX) with an extended half-life compared with conventional FIX products developed for the treatment of hemophilia B. Here, we review new interim findings from the ongoing extension of paradigm™5, a noncontrolled, phase 3 trial investigating the safety, efficacy, and pharmacokinetics of nonacog beta pegol for the prophylaxis and treatment of bleeds in previously treated pediatric patients.

Methods: The main trial enrolled and treated 25 children (aged ≤12 years) with hemophilia B (FIX ≤2%). Patients were stratified into 2 age groups, younger (0-6 years) and older (7-12 years) children, and received nonacog beta pegol 40 IU/kg once weekly for 52 weeks. A total of 22 patients entered the subsequent extension phase: 11 younger and 11 older children. Here we present findings from a planned interim analysis, including all relevant exposures in the main and extension phases (cut-off date: April 1, 2016).

Results: No patients developed inhibitors over a total in-trial exposure time of 71.03 years (mean [range] exposure: 2.84 years/patient [0.21-3.76 years]; total in-trial exposure days: 3811 [152.4/patient]). The mean nonacog beta pegol prophylaxis dose was 43.2 IU/kg and the mean annualized consumption was 2305.8 IU/kg/patient. Overall, 80 bleeds were reported in 20 patients, of which 37 occurred in 15 patients during the main phase (mean treatment period: 0.97 years/patient) and 43 bleeds occurred in 12 patients during the extension phase (2.13 years/patient). The overall estimated mean annualized bleeding rate (ABR; bleeds per patient per year) was 1.52 during the main phase and 0.92 during the extension phase. Overall, there were 25 spontaneous bleeds in 8 patients (estimated ABR_spontaneous: 0.35), 51 traumatic bleeds in 18 patients (estimated ABR_traumatic: 0.72), and 35 joint bleeds in 15 patients (estimated ABR_joint: 0.49). The overall proportion of bleeds that showed a successful hemostatic response to treatment was 88.8% (91.7% and 87.5% in younger and older children, respectively) and 80.0% of bleeds resolved after 1 dose. In total, 459 treatment-emergent adverse events (AEs) were reported in 24 (96%) patients; the most common were cough (14 [56%] patients), contusion (10 [40%]), and pyrexia (10 [40%]). Only 8 AEs, occurring in 1 younger and 3 older children, were considered to be possibly/probably related to study medication; these were 2 occurrences of infusion/injection site pain and 1 each of abdominal pain, diarrhea, nausea, eosinophilia, headache, and wheezing. Four serious AEs (device-related infection, upper respiratory tract infection, food poisoning, and hemoptysis) occurred in 3 (12%) patients; none were considered to be related to study medication. No AEs led to study withdrawal. No systematic changes over time were seen for any hematologic, hepatic, or renal parameters. There were no indications of neurological adverse reactions and no developmental concerns in these young children who had been on-study for up to 3.5 years.

Discussion/Conclusion: Up to 3.5-year data from the ongoing paradigm™5 extension trial confirm the longer-term safety and efficacy of nonacog beta pegol for the prevention and treatment of bleeds in children with hemophilia B. ABR generally decreased over time, with fewer bleeds throughout the extension phase of the trial compared with the main phase. Overall, N9-GP was well tolerated and no unexpected safety concerns were identified.