Enhanced pharmacokinetic properties of a glycoPEGylated recombinant factor IX: a first human dose trial in patients with hemophilia B

Négrier, Claude; Knobe, Karin; Tiede, Andreas; Giangrande, Paul; Møss, Judi

doi:10.1182/blood-2011-02-335596

Cited by 172 publications

(199 citation statements)

References 36 publications

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“…The requirement for frequent dosing can be a deterrent for adhering to a prophylactic regimen because of concerns about venous access and associated complications, such as thrombosis and infection. 6,7 Thus, extending rFIX t 1/2 and prolonging its protective hemostatic effect [8][9][10] may reduce the number of injections needed to achieve effective hemostasis with the use of a prophylaxis regimen or to control breakthrough bleeds in on-demand therapy.…”

Section: Introductionmentioning

confidence: 99%

Recombinant factor IX-Fc fusion protein (rFIXFc) demonstrates safety and prolonged activity in a phase 1/2a study in hemophilia B patients

Shapiro

Ragni

Valentino

et al. 2012

Blood

164

149

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Section: Introductionmentioning

confidence: 99%

Recombinant factor IX-Fc fusion protein (rFIXFc) demonstrates safety and prolonged activity in a phase 1/2a study in hemophilia B patients

Shapiro

Ragni

Valentino

et al. 2012

Blood

164

149

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“…However, concerns remain over potential contamination by prions, unencapsulated viruses and other unknown pathogens [Ludlam and Turner, 2006;Key and Negrier, 2007;Dietrich et al 2013]. More recently, recombinant FIX (rFIX) products, which have a lower risk of pathogenic contamination, have been developed [Østergaard et al 2011;Negrier et al 2011;Shapiro et al 2012;Santagostino et al 2012]. FIX replacement therapy in the USA primarily consists mostly of rFIX [WFH, 2013].…”

Section: Introductionmentioning

confidence: 99%

BAX326 (RIXUBIS): a novel recombinant factor IX for the control and prevention of bleeding episodes in adults and children with hemophilia B

Windyga

Trujillo

Hafeman

2014

Therapeutic Advances in Hematology

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Hemophilia B management has improved considerably since the introduction of high-purity plasma-derived factor IX (pdFIX) products in the early 1990s. Recombinant FIX (rFIX) was introduced more recently and has potential safety advantages over the older bloodbased products. Until recently, only one such product, nonacog alfa (BeneFIX ® , Pfizer, Inc.), has been available. However, a new rFIX product, BAX326 (RIXUBIS, Baxter Healthcare Corp.), has now been approved by the US Food and Drug Administration. BAX326 undergoes rigorous virus elimination and purification steps during manufacture, and has low activated FIX activity, which confers low thrombogenic potential in humans. Preclinical studies showed promising pharmacokinetic and safety profiles, and these early findings have since been expanded in a series of prospective, multicenter, clinical studies. Foremost among these is a pivotal phase I/ III study of BAX326 and its use in routine prophylaxis or on-demand treatment in patients aged 12-65 years with severe (FIX level <1%) or moderately severe (FIX level ⩽2%) hemophilia B. This study confirmed the pharmacokinetic equivalence of BAX326 and nonacog alfa, and showed a significant reduction in annualized bleeding rate with BAX326 prophylaxis compared with on-demand treatment (79% versus historic controls; p < 0.001). The hemostatic efficacy of BAX326 was rated as 'excellent' or 'good' in 96% of bleeds. BAX326 was also associated with statistically significant and clinically meaningful improvements in physical health-related quality of life. Results are similarly encouraging in a pediatric study in children aged up to 12 years and in a study in hemophilia B patients undergoing surgery. A further study showed safe transition, with no inhibitor formation in any patient, from treatment with a pdFIX product to BAX326. Overall, the safety profile of BAX326 in clinical trials has been strong, with no inhibitor or specific antibody formation, thrombosis, or treatment-related serious adverse events or anaphylaxis.

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“…Novel therapeutic approaches involving proteases employ glycan modifications and may be applicable to KLKs and their inhibitors, in particular to those present in skin. For example, an engineered factor IX with an N-glycan that was extended by PEG units showed an improved pharmacokinetic behavior (Negrier et al, 2011). Artificial glycosylation of proteases and their inhibitors appears to be a useful approach for the extension of their biostability and lifetime.…”

Section: Discussionmentioning

confidence: 99%

Sweetened kallikrein-related peptidases (KLKs): glycan trees as potential regulators of activation and activity

Guo

Skala

Magdolen

et al. 2014

Biological Chemistry

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Most kallikrein-related peptidases (KLKs) are N-glycosylated with N-acetylglucosamine 2 -mannose 9 units at Asn-Xaa-Ser/Thr sequons during protein synthesis and translocation into the endoplasmic reticulum. These N-glycans are modified in the Golgi machinery, where additional O-glycosylation at Ser and Thr takes place, before exocytotic release of the KLKs into the extracellular space. Sequons are present in all 15 members of the KLKs and comparative studies for KLKs from natural and recombinant sources elucidated some aspects of glycosylation. Although glycosylation of mammalian KLKs 1, 3, 4, 6, and 8 has been analyzed in great detail, e.g., by crystal structures, the respective function remains largely unclear. In some cases, altered enzymatic activity was observed for KLKs upon glycosylation. Remarkably, for KLK3/PSA, changes in the glycosylation pattern were observed in samples of benign prostatic hyperplasia and prostate cancer with respect to healthy individuals. Potential functions of KLK glycosylation in structural stabilization, protection against degradation, and activity modulation of substrate specificity can be deduced from a comparison with other glycosylated proteins and their regulation. According to the new concept of protein sectors, glycosylation distant from the active site might significantly influence the activity of proteases. Novel pharmacological approaches can exploit engineered glycans in the therapeutical context.

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Enhanced pharmacokinetic properties of a glycoPEGylated recombinant factor IX: a first human dose trial in patients with hemophilia B

Cited by 172 publications

References 36 publications

Recombinant factor IX-Fc fusion protein (rFIXFc) demonstrates safety and prolonged activity in a phase 1/2a study in hemophilia B patients

Recombinant factor IX-Fc fusion protein (rFIXFc) demonstrates safety and prolonged activity in a phase 1/2a study in hemophilia B patients

BAX326 (RIXUBIS): a novel recombinant factor IX for the control and prevention of bleeding episodes in adults and children with hemophilia B

Sweetened kallikrein-related peptidases (KLKs): glycan trees as potential regulators of activation and activity

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