Reformulated BeneFix^®: efficacy and safety in previously treated patients with moderately severe to severe haemophilia B

Abstract

BeneFix, the only recombinant factor IX (FIX), has been reformulated. The reformulation involves a change in diluent and allows for more concentrated infusions of recombinant FIX. A double-blind, randomized, pharmacokinetic (PK) crossover study demonstrated that reformulated BeneFix was bioequivalent to original BeneFix and follow-up PK evaluation after 6 months of treatment demonstrated the PK stability of reformulated BeneFix after multiple exposures. Favourable efficacy and safety profiles, consistent with those already well-established for original BeneFix, were observed: 81.1% of haemorrhages resolved with only a single infusion; 85.3% of initial treatment response ratings were Excellent or Good; more than half of the subjects using reformulated BeneFix for routine prophylaxis (11 of 17, 64.7%) had no spontaneous haemorrhages during their 6-12 month course of prophylactic treatment, with an overall spontaneous bleeding rate of 0.72 year(-1); and for the single surgical procedure (knee washing), treatment was rated Useful. In addition, there was no FIX inhibitor development, allergic-type manifestations, or thrombogenic complications with more than 1100 infusions (nearly 5.2 million IUs) administered in this trial. All efficacy and safety outcomes from this study were achieved with more concentrated recombinant protein infusions than that possible with original BeneFix, and utilization of the 2000 IU per vial dosage strength, newly introduced with the reformulated product, was high (>62%). The reformulation of BeneFix allows smaller delivery volumes and an increased choice of dosage strengths without altering the PK properties (including incremental recovery and half-life) or the established efficacy and safety profile of recombinant FIX.

Factor IX ectopically expressed in platelets can be stored in α-granules and corrects the phenotype of hemophilia B mice

“…Furthermore, the life span of platelets is 12 days, 33 but the half-life of circulating free FIX is only 18 hours. 34 In our studies, the protective effect of platelet FIX can last for 48 hours after platelet infusion, demonstrating that the efficacy of platelet FIX may be maintained longer than plasma FIX. In addition, the existence of a small amount of plasma FIX in 2bF9 gene-transferred animals might be of extra benefit for hemostasis at the site of injury.…”

Implications of coagulation factor VIII and IX pharmacokinetics in the prophylactic treatment of haemophilia

“…Data for rFIX are available, however, for the entire age range of patients with haemophilia B [9,[37][38][39][40][41]43]. There was no relationship between age and terminal half-life.…”

Prolonged half-life and preserved enzymatic properties of factor IX selectively PEGylated on native N-glycans in the activation peptide

“…The therapeutic goal is to prevent bleeding episodes and to provide safe and efficacious treatment of bleedings when they occur. Because of the relatively short half-life of FIX (18-24 hours [6][7][8] ), the recommended prophylaxis regimen consists of 2 to 3 weekly infusions of 40-100 IU/kg 9 FIX to maintain trough levels above 1% and thus shifting patients from a severe to a milder phenotype. When adhered to, prophylaxis in patients without severe joint disorder is efficacious with a frequency of only 0-2 breakthrough bleeds per year in the majority of patients.…”

“…When adhered to, prophylaxis in patients without severe joint disorder is efficacious with a frequency of only 0-2 breakthrough bleeds per year in the majority of patients. 8,10 However, the need for multiple weekly infusions present challenges in terms of repeated venous access which may affect adherence to treatment and necessitate placement of indwelling catheters with the inherent risk of infection. 11 Various approaches have been pursued to extend the half-life of coagulation factors including genetic fusions to albumin and the Fc fragment of IgG as well as chemical modification by hydrophilic polymers such as polyethylene glycol (PEG).…”