Efficacy and safety of a recombinant factor IX (Bax326) in previously treated patients with severe or moderately severe haemophilia B undergoing surgical or other invasive procedures: a prospective,open‐label,uncontrolled, multicentre,phase III study

Haemostatic management of haemophilia B patients undergoing surgery is critical to patient safety. The aim of this ongoing prospective trial was to investigate the haemostatic efficacy and safety of a recombinant factor IX (rFIX) (Bax326) ¹ in previously treated subjects (12–65 years, without history of FIX inhibitors) with severe or moderately severe haemophilia B, undergoing surgical, dental or other invasive procedures. Haemostatic efficacy was assessed according to a predefined scale. Blood loss was compared to the average and maximum blood loss predicted preoperatively. Haemostatic FIX levels were achieved peri‐ and postoperatively in 100% of subjects (n = 14). Haemostasis was ‘excellent’ intraoperatively in all patients and postoperatively in those without a drain, and ‘excellent’ or ‘good’ at the time of drain removal and day of discharge in those with a drain employed. Following the initial dose, the mean FIX activity level rose from 6.55% to 107.58% for major surgeries and from 3.60% to 81.4% for minor surgeries. Actual vs. predicted blood loss matched predicted intraoperative blood loss but was equal to or higher than (but less than 150%) the maximum predicted postoperative blood loss reflecting the severity of procedure and FIX requirements. There were no related adverse events, severe allergic reactions or thrombotic events. There was no evidence that BAX326 increased the risk of inhibitor or binding antibody development to FIX. BAX326 was safe and effective for peri‐operative management of 14 subjects with severe and moderately severe haemophilia B.     

Safety and efficacy of investigator‐prescribed BeneFIX® prophylaxis in children less than 6 years of age with severe haemophilia B

Summary. Prophylaxis is increasingly prescribed in treatment of haemophilia and its benefit is believed to be most significant for the youngest patients as haemophilic arthropathy may be prevented if prophylaxis is initiated prior to recurrent haemarthroses. While clinical prophylaxis data are readily available for haemophilia A, analogous data for haemophilia B are relatively limited. A prospective clinical study of recombinant factor IX (BeneFIX^®; rFIX), designed to allow investigator prescribed prophylaxis according to customary practices, was conducted in children <6 years old with severe haemophilia B. Nearly all children were prescribed prophylaxis (22/25; 88%) for all or part of their study participation. Favourable efficacy and safety profiles were reported. Routine prophylaxis with 1 or 2 rFIX infusions per week over an average of greater than 6 months of therapy resulted in near complete prevention of spontaneous breakthrough haemorrhages (<1 per year), with most children (77%) having none, including seven patients (32%) who had no bleeding episodes at all. Haemorrhages in joints were less common than those outside joints (27% vs. 73% of haemorrhages). In a patient population that included children with multiple prior haemarthroses, 68% of children had no joint bleeding. Breakthrough haemorrhages resolved with 1 or 2 infusions in 89% of episodes. The absence of changes in prophylaxis infusion schedules suggests that 1 or 2 rFIX infusion(s) per week were well‐tolerated by these young patients, including those with (41%) and without (59%) central venous access devices. Safety was established by the low incidence of treatment‐related adverse events.     

The availability of new drugs for hemophilia treatment

ABSTRACT

Introduction

A number of new FVIII/IX concentrates enriched the portfolio of products available for the treatment of hemophilia A/B patients. Due to the large inter-patient variability, accurate tailoring of the therapy became essential to improve patients’ adherence, clinical outcomes, and cost/effectiveness ratio. Recently, non-replacement therapies have taken the limelight and succeeded in decreasing the bleedings of patients.     

Biodistribution of the recombinant fusion protein linking coagulation factor IX with albumin (rIX-FP) in rats

Introduction

The recombinant fusion protein linking coagulation factor IX with albumin (rIX-FP) is undergoing clinical trials for prophylaxis and on-demand treatment of haemophilia B patients. The aim of this study was to investigate the pharmacokinetics, whole-body and knee joint distribution of rIX-FP following intravenous administration to rats, compared with a marketed, non-fused rFIX and recombinant human albumin.

Material and Methods

[³H]-rIX-FP, [³H]-rFIX or [³H]-albumin were administered to rats followed by quantitative whole-body autoradiography over 24 or 240 hours, and the tissue distribution as well as elimination of radioactivity were measured.

Results

Elimination of all radioactivity derived from the three proteins was shown to occur primarily via the urine. The tissue distribution of [³H]-rIX-FP and [³H]-rFIX (but not of [³H]-albumin) was comparable, both penetrating predominantly into bone, and well-perfused tissues, suggesting that the rIX moiety determines the distribution pattern of rIX-FP, while the albumin moity is responsible for the prolonged plasma and tissue retention. Detailed knee-joint analysis indicated rapid presence of [³H]-rIX-FP and [³H]-rFIX in synovial and mineralised bone tissue, mostly localised to the zone of calcified cartilage. Longest retention times were observed in the bone marrow and the endosteum of long bones. Intriguingly, [³H]-rIX-FP- and [³H]-albumin-derived radioactive signals were detectable up to 240 hours, while [³H]-rFIX-derived radioactivity rapidly declined after 1 hour post-dosing correlating to the extended plasma half-life of [³H]-rIX-FP.

Conclusion

The prolonged plasma and tissue retention of rIX-FP achieved by albumin fusion may allow a reduction in dosing frequency leading to increased therapeutic compliance and convenience.     

A retrospective study to describe the incidence of moderate to severe allergic reactions to factor IX in subjects with haemophilia B

Summary. Using a patient chart review process, we conducted a retrospective study to describe the frequency of allergic reactions in individuals with haemophilia B receiving factor IX (FIX) replacement therapy. The number of allergic reactions in individuals receiving a recombinant FIX (rFIX) product (Bene Fix ^®) was then compared with the number of reactions in patients receiving plasma‐derived FIX (pdFIX) products. Of the 180 subjects in the study, 163 received rFIX, 88 received pdFIX; 71 received both product types. A total of seven (3.89%) subjects had a moderate or severe allergic reaction to a FIX product (95% confidence interval [CI], 1.06–6.71%). Among those receiving rFIX, four subjects (2.45%) had an allergic reaction (95% CI, 0.08–4.83%). Of individuals taking pdFIX products, three (3.41%) developed an allergic reaction (95% CI, 0–7.20%). It was noted that three (1.84%) of those taking rFIX developed an inhibitor to FIX (95% CI, 0–3.90%), while four (4.55%) of those receiving a pdFIX product developed an inhibitor (95% CI, 0.19–8.90%). Inhibitor development was frequently associated with allergic reaction. These results provide evidence that there is no difference in the frequency of allergic reactions or inhibitor development in individuals receiving rFIX compared with those receiving pdFIX concentrates. The current study and a previous study of similar design have now compared the rate of allergic reactions associated with rFIX and pdFIX concentrates has now been compared in a total of 414 subjects; this represents the largest collection of data to date on this rare complication of haemophilia B therapy.     

Safe switching from a pdFIX (Immunine®) to a rFIX (Bax326)

The ability to switch between coagulation factors safely is of common interest to haemophilia patients and treating physicians. This is the first formal prospective comparative evaluation of safety, efficacy and incremental recovery of a plasma‐derived FIX (pdFIX) and a recombinant FIX (rFIX) in the same haemophilia B patients following a switch from pdFIX Immunine^® to a recently developed rFIX Bax326 product. Patients (aged <65 years) who completed a pretreatment study which prospectively documented the exposure to Immunine^® and monitored FIX inhibitors while receiving prophylactic treatment were transitioned into pivotal (patients aged 12–65 years) and paediatric (patients aged <12 years) clinical studies investigating prophylaxis and treatment of bleeding episodes with Bax326. None of the 44 patients developed inhibitory or specific binding anti‐FIX antibodies during the course of the studies. A total of 38 unrelated adverse events (AEs) were occurred in 20/44 (45.5%) subjects during the Immunine^® study. Following a switch to Bax326, 51 AEs were reported in 25/44 (56.8%) subjects. The incidence of AEs related to Bax326 treatment (two episodes of dysgeusia in one patient) was low (2.3%); there were no serious adverse reactions. The comparison between Immunine^® and Bax326 demonstrated analogous haemostatic characteristics and annualized bleeding rates. Overall, there is direct evidence indicating a safe and clinically effective transition from a pdFIX (Immunine^®) to a newly developed rFIX (Bax326¹) for prophylaxis and treatment of bleeding in previously treated patients of all age cohorts with severe or moderately severe haemophilia B.