GlycoPEGylated recombinant factor IX for hemophilia B in context

Abstract

Decisions over hemophilia treatment selection and switching involve balancing many clinical and patient-related factors. The current standard of care for patients with hemophilia B is prophylaxis with plasma-derived or recombinant factor IX (rFIX) concentrates. However, several extended half-life (EHL) rFIX products have recently been developed to improve treatment convenience and clinical outcomes for these patients. Nonacog beta pegol, an rFIX product that combines the FIX protein with a 40 kDa polyethylene glycol moiety, has been evaluated in 115 previously treated patients with hemophilia B (including 25 children) in the paradigm clinical trial program. FIX activity levels and pharmacokinetics were monitored throughout these trials and showed that nonacog beta pegol offers significant pharmacological improvements over standard FIX products. Once-weekly prophylaxis with nonacog beta pegol 40 IU/kg resulted in fewer bleeds in all patients (median annualized bleeding rate of 1.0 across all ages), resolved 90% of target joints, and improved health-related quality of life. No patients developed FIX inhibitors, and there were no thromboembolic events or unexpected safety concerns. Nonacog beta pegol was also safe and effective in the perioperative setting. These findings show that nonacog beta pegol is highly effective, while also offering more convenient dosing than standard FIX products. Nonacog beta pegol represents a significant advance in the current context of treatment for hemophilia B, offering effective management across several treatment modalities and settings, and potentially easing the treatment burden for patients of all ages. Meanwhile, the development of novel treatment strategies, such as gene therapy, anti-tissue factor pathway inhibitor antibodies, and RNA interference therapy, may provide patients with additional therapeutic options, which would require reassessment of the role of EHL products in the future.

Keywords: PEGylated rFIX; extended half-life; long-acting FIX; prophylaxis.

Figure 1

Domain structure of nonacog beta pegol. Notes: Two N-linked glycans are uniformly present at Asn157 and Asn167 in the rFIX AP domain. These are predominantly core-fucosylated tri- and tetra-antennary complex structures composed of fucose (◁), N-acetylglucosamine (□), mannose (○), galactose (⊙), and sialic acid (◊). Arrows indicate the enzymatic transfer of 40k-PEG-sialic acid to desialylated nonacog beta pegol and sialylation of remaining exposed galactoses. PEG is unequally distributed between the two N-linked glycans, as shown in parentheses (55% and 45%, respectively). Locations of identified O-linked carbohydrates are also shown (●). Reproduced with permission of American Society of Hematology. Østergaard H, Bjelke JR, Hansen L, et al. Prolonged half-life and pre served enzymatic properties of factor IX selectively PEGylated on native N-glycans in the activation peptide. Blood. 2011;118(8):2333–2341. Permission conveyed through the Copyright Clearance Center, Inc. Copyright 2011, American Society of Hematology. Abbreviations: AP, activation peptide; PEG, polyethylene glycol; rFIX, recombinant factor IX.

Figure 2

Overview of the paradigm clinical trial program. Notes: ClinicalTrials.gov identifiers: NCT00956345, NCT01333111, NCT01386528, NCT01395810, NCT01467427, and NCT02141074. Abbreviations: PK, pharmacokinetics; PTPs, previously treated patients; PUPs, previously untreated patients.

Figure 3

Estimated mean FIX activity profiles adjusted to a dose of 50 IU/kg nonacog beta pegol. Abbreviations: FIX, factor IX; N9-GP, nonacog beta pegol; pdFIX, plasma-derived factor IX; rFIX, recombinant factor IX.

Figure 4

Mean steady-state trough FIX activity with once-weekly nonacog beta pegol during (A) paradigm 2 and (B) paradigm 5. Notes: Mean (± standard error of the mean) steady-state FIX activity (IU/mL) determined by a one-stage clotting assay in predose blood samples collected at clinical visits during each trial. Analyses were performed at a central laboratory, using a product-specific reference standard for calculation of the FIX activity. Abbreviation: FIX, factor IX.