Head‐to‐head comparison of the pharmacokinetic profiles of a high‐purity factor IX concentrate (AlphaNine®) and a recombinant factor IX (BeneFIX®) in patients with severe haemophilia B

Head‐on comparative studies of factor IX (FIX) concentrates performed under standardized conditions are rarely conducted regardless of being a valuable instrument guiding health care providers towards better informed and cost‐effective decisions. This study is an extension of a multicentre study that assessed the efficacy, safety and pharmacokinetics (PK) of AlphaNine^® in 25 previously treated patients with severe haemophilia B (FIX:C ≤ 2%). After a washout period ≥7 days following the last PK performed with AlphaNine^® after a dose of 65–75 IU kg^?1, an identical PK study was performed with BeneFIX^® on 22 of the same patients. Venous blood samples for analysis were taken at baseline and at 0.25, 0.5, 1, 3, 6, 9, 24, 48, 72 and 74 h post infusion. The outcomes of the comparison of the PK parameters were as follows: Mean (±SD) in vivo recovery (IVR) was 1.3 ± 0.4 IU dL^?1 per IU kg^?1 for AlphaNine^® and 1.0 ± 0.3 IU dL^?1 per IU kg^?1 for BeneFIX^® (P < 0.01). Mean terminal half‐life, mean residence time, area under the curve, clearance and volume of distribution of BeneFIX^® were 36.0 ± 12.8 h, 39.3 ± 13.9 h, 1631 ± 467 IU h dL^?1, 0.046 ± 0.01 dL kg^?1 min^?1 and 1.75 ± 0.52 mL kg^?1 respectively. These values were not significantly different to those observed in AlphaNine^®, although BeneFIX^® displayed higher than expected IVR values and lower than expected clearance values. In conclusion, AlphaNine^® showed a comparable half‐life, but an IVR significantly higher than that of BeneFIX^®. This dissimilarity may have implications on dosing requirements for on‐demand treatment regimes affecting optimal resource allocation.     

An open clinical study assessing the efficacy and safety of Factor IX Grifols®, a high‐purity Factor IX concentrate,in patients with severe haemophilia B

Summary. Factor IX Grifols^® is a new high‐purity plasma‐derived FIX concentrate with two specific pathogen elimination steps. Until this study was performed, there were no detailed reports with an adequate number of patients on the clinical evaluation of this product. To determine the efficacy and safety of Factor IX Grifols^® for replacement therapy in previously treated patients with severe haemophilia B, this open, multicentre and non‐randomized study included 25 male subjects over the age of 12 with severe haemophilia B. Patients underwent prophylaxis and treatment of bleeding episodes with Factor IX Grifols^® for 1 year. The clinical efficacy and safety of this product were assessed. Forty percent of the patients were children and adolescents (12–17 years old). During the 12 months follow‐up, 1 446 000 IU of Factor IX Grifols^® were administered in 961 infusions (range 12–83 infusions per patient): 31% for prophylaxis and 69% for bleeding episodes. Only five major bleeding events were reported in two patients. These haemorrhages were successfully treated with a mean of 2900 IU per bleed (range 1500–4000 IU), and 1–3 infusions per bleed. The average time elapsed from the first infusion to resolution of bleeding was 43 h (median). Overall, haemostasis was rated as excellent or good by the investigator in 96% of the infusions. No product‐related adverse events were reported. Factor IX Grifols^® is an effective and safe Factor IX concentrate and can be considered as a first line option for replacement therapy in haemophilia B patients.     

Clinical efficacy,safety and pharmacokinetic properties of the plasma‐derived factor IX concentrate Haemonine® in previously treated patients with severe haemophilia B

Summary. Plasma‐derived factor IX (FIX) concentrate remains an important choice for replacement therapy in haemophilia B patients. Haemonine ^® is a high purity double‐virus inactivated human plasma‐derived coagulation FIX concentrate (pdFIX). Aim was to evaluate the clinical efficacy, safety and pharmacokinetic properties of Haemonine in three prospective, open‐label uncontrolled studies and a compassionate use program in previously treated patients with severe haemophilia B. Long‐term efficacy and safety were investigated in 29 patients treated prophylactically and, in addition, treatment on‐demand (TOD) in the case of acute haemorrhage. Pharmacokinetic properties were assessed in 14 patients at baseline and after 3 months of regular treatment. Pharmacokinetic parameters were in accordance with published data and remained nearly unchanged over time, notably recovery and half‐life. Mean terminal elimination half‐life was 27.6 h and 25.0 h, mean incremental recovery (IU dL^?1/IU kg^?1) was 1.55 and 1.60, at baseline and 3 months, respectively. Haemonine was shown to be effective in preventing and controlling bleeds. 55.2% (16/29) of patients were free of bleeds under prophylaxis. 38 haemorrhages occurred, 42% (16/38) required treatment and 87.5% (14/16) resolved after a single infusion, 12.5% after 2 infusions. All responses reported on haemorrhages were rated as ‘excellent’ or ‘good’. Moreover, ‘excellent’ haemostatic efficacy was demonstrated in 12 surgeries with no complications. Few adverse events (AEs) and no thrombogenic complication, nor induction of FIX inhibitory antibodies were observed. Haemonine is effective, safe and well tolerated in long‐term prophylaxis, TOD and when applied after minor and major surgeries.     

Pharmacokinetic study of a high-purity factor IX concentrate (Factor IX Grifols®) with a 6-month follow up in previously treated patients with severe haemophilia B

Summary. Optimal replacement treatment in haemophilia B patients requires a good understanding of the pharmacokinetics of factor IX (FIX). The aim of this study was to compare the pharmacokinetic profile of Factor IX Grífols^®, a highly purified human FIX concentrate with two specific pathogen inactivation/removal steps, to that of available FIX preparations. The study was an open, non‐randomized trial including 25 male subjects older than 12 years of age with severe haemophilia B. Pharmacokinetic profile of the FIX preparation regularly used by the subjects was determined as control. Pharmacokinetic profile of Factor IX Grifols^® was determined twice, one 7–15 days after control assessment and second after a 6 months period had elapsed. Results showed that all products had peak plasma levels of FIX:C within 30 min. Mean recovery was 1.3 ± 0.3 IU dL⁻¹ per IU kg⁻¹ for Factor IX Grifols^® and 1.0 ± 0.3 IU dL⁻¹ per IU kg⁻¹ for control products (P < 0.001). The mean terminal half‐life (t_1/2) for Factor IX Grifols^® was 26.7 h and 26.8 h for control product. Pharmacokinetic parameters after 6 months of treatment with Factor IX Grifols^® did not statistically differ from the parameters obtained with the first infusion. There were no adverse events related to Factor IX Grifols^® for the duration of the study. In conclusion, Factor IX Grifols^® has adequated pharmacokinetic properties comparable to the control plasma‐derived FIX and these parameters remain stable after 6 months of treatment. Factor IX Grifols^® can be an effective and safe plasma‐derived FIX concentrate for replacement therapy in haemophilia B patients.     

Pharmacokinetics of Optivate®, a high‐purity concentrate of factor VIII with von Willebrand factor,in patients with severe haemophilia A

Summary. Optivate^® is a high purity factor VIII/von Willebrand factor (FVIII/VWF) concentrate, which is manufactured using two antiviral processes: solvent/detergent and terminal dry heating (80°C for 72 h). A multicentre, non‐randomized open‐label study in 15 patients was conducted to test the pharmacokinetics (PK) of Optivate^®. PK variables were analysed for the patients’ prior FVIII product (PK1), their first dose of Optivate^® (PK2) and at 3 months therapy (PK3). Mean non‐compartmental half‐lives (h) were 14.1, 12.4 and 12.1, respectively (P = 0.45), mean clearances (mL h^?1 kg^?1) were 3.6, 3.2 and 3.1, respectively (P = 0.051), MRTs (h) were 19.0, 17.3 and 17.4, respectively (P = 0.39) and mean AUC_0–48h (h IU mL^?1) were 14.3, 15.4 and 16.6, respectively (P = 0.051) and mean AUC_0–∞ (h IU mL^?1) were 15.9, 16.4 and 17.9, respectively (P = 0.18). The recovery data from this PK study was aggregated with recovery data collected from another study, with similar design but devoid of the other PK measurements. A total of 309 recoveries were conducted in 70 patients. The overall mean recovery per subject across 27 Optivate^® batches was 2.7 IU dL^?1 per IU kg^?1. There were no clinical differences between Optivate^® and other FVIII products, and except for volume of distribution (Vd), no statistically significant differences were seen with respect to any of the other PK variables, or in recovery between weeks 0 and 12. Therefore, the PK of FVIII is not affected by the processes used to manufacture Optivate^®, which can be expected to be effective in the management of patients with haemophilia A.     

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

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.     

Safety and efficacy of plasma‐derived coagulation factor IX concentrate (AlphaNine® SD) in patients with haemophilia B undergoing surgical intervention: a single institution retrospective analysis

Summary. While coagulation factor replacement is essential in surgical intervention in haemophilia B patients, few studies are available on the safety and efficacy of plasma‐derived factor IX (FIX) for haemostasis during surgery. This retrospective study examined outcomes in these patients. A total of 20 patients who underwent 29 surgical procedures at the Hemophilia Treatment Center at Orthopaedic Hospital in Los Angeles, California, were identified and their inpatient charts were reviewed and abstracted. Outcomes included pre‐ and postoperative FIX dosing, recovery of FIX, blood loss, use of blood products, safety and haemostatic response. Identified patients had mild (10%), moderate (15%) or severe (75%) haemophilia B, and average age at surgery was 48.5 years. All surgical procedures were major (orthopaedic 89.7%; abdominal 10.3%), all were completed under general anaesthesia, and average time in surgery was 3.25 h. Average hospital length of stay was 11.0 days [standard deviation (SD) = 8.5] and all patients were discharged home. All patients were treated with AlphaNine^® SD at an average dose of 254.9 IU kg^?1 (SD = 65.4) on the day of surgery and the dose was adjusted over the course of hospital stay. Mean perioperative blood loss was 255.5 mL (SD = 283.1) and blood replacement was required in only two surgeries (6.9%). FIX recovery analysis performed preoperatively related well to FIX levels obtained. Identified patients had little blood loss perioperatively and had no bleeding related complications. Plasma‐derived FIX pre‐ and postoperatively appeared to be a safe and effective treatment in haemophilia B patients undergoing surgery.     

Clinical assessment of Optivate®, a high‐purity concentrate of factor VIII with von Willebrand factor,in the management of patients with haemophilia A

Summary. Factor VIII (FVIII) concentrates have revolutionized the treatment of patients with haemophilia A. Concerns over the transmission of viral infections through these products have been addressed through stringent, donor‐screening procedures and robust antiviral manufacturing steps. Bio Products Laboratory has developed a high‐purity FVIII product with von Willebrand factor, Optivate^®. Its safety, tolerability and efficacy as prophylaxis and treatment of bleeds have been established in long‐term studies. Seventy previously treated patients with severe haemophilia A, with ≥20 exposure days, were recruited into two long‐term, multicentre, open‐label studies. The protocols were virtually identical. Patients received Optivate^® either prophylactically or on‐demand. A mean of 159.0 EDs were experienced over 11 320 infusions. Under both conditions, Optivate^® was well tolerated. Only 10% of patients experienced a treatment‐related adverse event; the most commonly reported were headache (4% of patients) and dizziness (3% of patients). The mean number of bleeds/patient over the 2 year treatment period was 23.5 during prophylactic use and 70.4 during on‐demand use. In patients treated prophylactically, clinical responses to breakthrough bleeds were rated by physicians as excellent or good and as very helpful or helpful by patients in 95% of bleeds. Clinical responses for on‐demand patients were rated as excellent or good by physicians and helpful or very helpful by the patients for 91% of bleeds. There were no viral transmissions or inhibitors. The studies confirm the clinical efficacy and safety of Optivate^® in both prophylactic and on‐demand management of patients with haemophilia A.     

Kinetics of factor IX activity differ from that of factor IX antigen in patients with haemophilia B receiving high-purity factor IX replacement

Pharmacokinetic studies in haemophilia B have found in vivo recovery of FIX (FIX) to be uniformly lower than the factor VIII recovery in haemophilia A. We hypothesized that this lower recovery could result from rapid binding to high-affinity receptors on platelets and endothelium. To test this hypothesis, we evaluated the kinetics of FIX activity and protein in haemophilia B patients. Twelve patients were enrolled in a double dosing, crossover study with two high-purity FIX concentrates, AlphaNine SD and MonoNine. Subjects were given 40 U kg-1 of FIX concentrate and blood samples were taken at 15, 30, and 60 min. A second infusion of 40 U kg-1 was given after the 60 min blood sample and further blood samples removed at 15, 60, 120, and 360 min after the second dose. Patients were infused with the alternate concentrate at least 7 days later. Plasma samples were assayed for FIX activity by coagulation assay and antigen by RIA. FIX antigen in the infused concentrates was measured and quantified as microg U-1. There was no difference between the two FIX concentrates (AlphaNine vs. MonoNine) in the initial (15 min) activity (57% +/-1 19% vs. 53% +/-1 12%) and antigen (62% +/-1 16% vs. 55% +/-1 19%) recoveries. Recoveries after the second FIX dose were not statistically different than those observed after the first FIX dose. In one patient, a doubling of the initial infusion dose did not increase FIX recovery after the second FIX dose. However, the recovery of FIX antigen was significantly greater than the recovery of FIX activity and the differences became more significant in the post-15 min samples. We calculated a ratio of plasma FIX antigen to FIX activity in microg U-1. Average antigen to activity ratio increased from 5.8 +/-1 1.9 microg U-1 at 15 min to 7.1 +/-1 2.2 microg U-1 at 60 min. At 420 min the ratio increased to 9.3 +/-1 2.4 microg U-1. Although these studies failed to demonstrate a significant FIX receptor pool, they did demonstrate a phenomenon of progressive loss of biologic activity of the FIX protein after infusion of FIX concentrates.     

Multicentre,randomized, open‐label study of on‐demand treatment with two prophylaxis regimens of recombinant coagulation factor IX in haemophilia B subjects

Few randomized studies have reported on the use of factor IX (FIX) for secondary prophylaxis in haemophilia B patients. This study aimed to evaluate the efficacy and safety of two secondary prophylaxis regimens of recombinant coagulation FIX, nonacog alfa, compared with on‐demand therapy. Male subjects aged 6–65 years with severe or moderately severe haemophilia B (FIX:C ≤ 2, n = 50) and ≥12 bleeding episodes (including ≥6 haemarthroses episodes) within 12 months of study participation were enrolled in this multicentre, randomized, open‐label, four‐period crossover trial. The primary measure was the annualized bleeding rate (ABR) of two prophylactic regimens vs. on‐demand therapy. In the intent‐to‐treat group, mean ABR values were 35.1, 2.6 and 4.6 for the first on‐demand period, the 50 IU kg^?1 twice‐weekly period, and the 100 IU kg^?1 once‐weekly period respectively. Differences in ABR between the first on‐demand period and both prophylaxis regimens were significant (P < 0.0001); no significant differences were observed between prophylaxis regimens (P = 0.22). Seven serious adverse events occurred in five subjects, none related to study drug. Results demonstrated that secondary prophylaxis therapy with nonacog alfa 50 IU kg^?1 twice weekly or 100 IU kg^?1 once weekly reduced ABR by 89.4% relative to on‐demand treatment. Both prophylaxis regimens demonstrated favourable safety profiles in subjects with haemophilia B.     

Pharmacokinetics, thrombogenicity and safety of a double viral inactivated factor IX concentrate compared with a prothrombin complex concentrate

Therapeutic options for developing countries have to assure an optimum safety and efficacy and low-cost antihaemophilic concentrates. A single blind randomized crossover study was carried out in 12 previously treated HB patients, comparing the pharmacokinetics (PK), thrombogenicity (TG) and safety of two plasma-derived double-inactivated (solvent/detergent heating at 100 degrees C, 30 min) factor IX (FIX) concentrates, UMAN COMPLEX DI (product A) [plasma-derived prothrombin concentrates (PCC)] and a high purity FIX concentrate AIMAFIX DI (product B, HPFIX). In a non-bleeding state, they received one single intravenous dose 50 IU FIX kg(-1) of PCC or HPFIX, and after a wash-out period of 14 days, the other product. We evaluated acute tolerance and determined PK parameters based on FIX levels measured over a 50 h postinfusion period. We studied fibrinogen, platelets, antithrombin, F1 + 2, TAT, D-dimer, over a 360 min postinfusion period. Ten cases remained in on-demand treatment for 6 months, five with PCC and five with HPFIX. PK and anti-FIX inhibitors were repeated at 3 and 6 months. No inhibitors were detected. PK values (PCC vs. HPFIX): clearence (CL; mL h(-1) kg(-1)) 5.2 +/- 1.4 vs. 6.5 +/- 1.4; the volume of distribution at steady state (mL kg(-1)) 154.9 +/- 54.9 vs. 197.5 +/- 72.5; mean residence time (h) 29.7 +/- 8.1 vs. 30.7 +/- 9.2; T(1/2) (h) 22.3 +/- 7 vs. 23.5 +/- 12.3; incremental recovery (IR; U dL(-1) U(-1) kg(-1)) 0.96 +/- 0.17 vs. 0.76 +/- 0.13. HPFIX showed significant lower IR and higher CL. There were no differences in PK at 3 and 6 months. In TG, significant increments in TAT and F1 + 2 at 30 min and 6 h were found with PCC. Product B PK results agrees with reported results for other HPFIX preparations. Use of PCC product A has to consider its thrombogenic activity.     

Efficacy of a high purity, chemically treated and nanofiltered factor IX concentrate for continuous infusion in haemophilia patients undergoing surgery

We have evaluated the haemostatic efficacy of plasma derived, highly purified, solvent-detergent treated factor IX concentrate (Nanotiv®), to which a nanofiltration step has recently been added to improve safety with regard to parvovirus B19, hepatitis A and other nonlipid enveloped viruses. Thirteen surgical procedures, including eight orthopaedic operations, were carried out using continuous infusion of Nanotiv in 10 haemophilia B patients (nine severe and one mild). Tranexamic acid was used for 11 of the 13 procedures. The mean factor IX levels on the day of surgery and postoperative days 1–3 were 0.77, 0.89, 0.80 and 0.73 IU mL^–1, respectively. The haemostatic effect was rated as normal or excellent and no blood transfusions were needed. One patient had thrombophlebitis twice at the infusion site. The remaining cases received heparin, 5 units per 100 IU of Nanotiv, and had neither superficial nor deep venous thromboembolic complications. The requirement for factor IX in the four joint replacement operations was 663 IU kg^–1 during the first 9 days, which compares favourably with previous materials. Thus, continuous infusion with this highly purified factor IX concentrate with improved viral safety is effective for surgery in haemophilia B.     

Efficacy and safety of monoclonal antibody purified factor IX concentrate in haemophilia B patients undergoing surgical procedures

The present study summarizes results of the efficacy and safety of monoclonal antibody (MAb) purified factor IX concentrate [Mononine® Coagulation Factor IX (Human), Centeon L.L.C., King of Prussia, PA, USA] for surgical prophylaxis in 74 patients with mild, moderate or severe haemophilia B who underwent a total of 81 different operative interventions. Surgical procedures included joint replacement/arthroplasty ( n = 12), gastrointestinal (GI) or rectal surgery ( n = 6), synovectomy/osteotomy ( n = 8), hernia repair ( n = 4), central catheter insertion ( n = 3), ENT surgery ( n = 4), dental procedures ( n = 14), biopsies ( n = 2), gynaecological procedures ( n = 4), ophthalmological surgery ( n = 4), spinal surgery ( n = 4), urogenital surgery ( n = 2), other orthopaedic surgery ( n = 4) or other miscellaneous procedures ( n = 10). All patients demonstrated haemostasis rated as 'excellent' by the investigators. No patients experienced clinically evident thromboembolic complications during treatment with MAb factor IX. These results, from a large and varied random group of patients, demonstrate that this highly purified factor IX concentrate is safe and effective for surgical prophylaxis in patients with haemophilia B, including those patients who have experienced thromboembolic complications during prior treatment with prothrombin complex concentrates.     

Consequences of factor IX mutations in 26 families with haemophilia B

Haemophilia B is due to a variety of mutations within the factor IX gene. In the Seattle series, 26 additional unrelated families have had a mutation identified within the past 2 years. Of these, 11 were common recurrent point mutations identifiable by rapid restriction digest screening; eight of these probably represent founder mutations. 15 others were identified by sequencing amplified coding region fragments; eight are novel. Two each had frameshift and donor splice mutations and 11 had missense mutations. Five of these mutations associated with normal levels of circulating dysfunctional factor IX were computer modelled into coordinates for factor IXa.