Safety, Efficacy and Pharmacokinetics of Nonacog Beta Pegol (N9-GP) in Prophylaxis and Treatment of Bleeding Episodes in Previously Treated Pediatric Hemophilia B Patients

Background: Primary prophylaxis in severe hemophilia patients has been shown to improve patient outcomes and quality of life by decreasing the number of joint bleeds, lowering the subsequent risk of developing hemophilic arthropathy (Blanchette et al.Haemophilia 2010 (Suppl. 5); Ljung R. Blood Rev 2009) and by reducing the incidence of other bleeds including intracranial hemorrhages. Currently licensed factor concentrates have a relatively short half-life, and require frequent infusions for effectiveness. The intensity of this prophylaxis is difficult for most patients (particularly young children) and contributes to reduced compliance and quality of life.

Nonacog beta pegol (N9-GP) is a glycoPEGylated recombinant factor IX (rFIX) with a prolonged half-life (up to 111 h in adolescent and adult patients) as compared to currently available standard plasma-derived and rFIX products (18-19 h). N9-GP is therefore expected to be effective in preventing bleeds when given less frequently than currently available FIX products. It is hoped that this will improve patient compliance, clinical outcomes and quality of life. Until now only adolescents and adults have received N9-GP. Given this experience a trial (paradigm™5) was undertaken to evaluate the safety and effectiveness of N9-GP in children ≤12 years of age.

Aims: The primary objective of this trial was to evaluate immunogenicity of N9-GP in previously treated pediatric (≤12 years of age) hemophilia B patients (FIX≤2%) with no history of inhibitors and at least 50 exposures days (ED) to other FIX products. Key secondary objectives were to evaluate efficacy, pharmacokinetic (PK) properties and general safety of N9-GP in this group of patients.

Methods: paradigm™5 was a multicenter, single arm, open label trial investigating the safety, efficacy and PK of N9-GP in this group of patients. A total of 20 children allocated to two age cohorts ≤6 years and 7-12 years (minimum 10 patients per age cohort) were required to be dosed with a prophylactic regimen of 40 U/kg N9-GP once weekly for at least 50 exposures (as per EMA guidelines), with treatment of breakthrough bleeds with 40 U/kg N9-GP (80 U/kg N9-GP for severe bleeding episodes).

Results: 25 patients were enrolled and treated in the trial: 12 in the younger (0-6 years) and 13 in the older (7-12 years) age group. No patients developed inhibitors during the trial, and no safety concerns were observed in standard safety parameters and clinical evaluation.

Among patients on prophylaxis prior to inclusion (N=22), the median (range) number of bleeds in the 12 months prior to inclusion was 2.0 (0–9). The median (range) annualized bleeding rate during the trial was 1.0 (0.0–6.5); 5 of the 12 younger patients (41.7%) and 10 of the 13 older patients (76.9%) reported bleeds. 72.7% of these bleeds in the younger cohort were reported as traumatic vs. 54.8% in the older age cohort. All bleeding episodes were treated with 40 U/kg N9-GP: 92.9% were successfully treated; 85.7% were treated with a single injection.

PK analysis showed 1) an incremental recovery (IR) of N9-GP of 0.016 (U/mL)/(U/kg) with no difference between the 2 age groups; 2) a geometric mean single-dose half-life of 69.6 (0-6 years) and 76.3 hours (7-12 years) and 3) a faster clearance in the younger vs. older age group (0.758 and 0.650 mL/h/kg, respectively). Geometric mean FIX trough levels after the first dose of N9-GP was 0.084 U/ml in the 0-6 year age group and 0.109 U/ml in the 7-12 year age group. Estimated mean steady state trough levels (95% CI) for the younger age group was 0.154 U/ml (0.127; 0.186), as compared to 0.190 U/ml (0.159; 0.228) in the older age group. Steady state trough levels were reached after approximately 4 weeks of treatment.

Conclusion: In this trial, N9-GP appeared to have a safe and well-tolerated profile. Prophylactic protection and treatment of bleeds with N9-GP in previously treated pediatric hemophilia B patients was confirmed. The PK profile of N9-GP confirmed an extended half-life and high trough levels with 40 U/kg once weekly injections in the pediatric population. As with other FIX products younger patients show lower IR, shorter half-lives and higher clearance than what is observed in adolescents and adults.