Switching to recombinant factor IX Fc fusion protein prophylaxis results in fewer infusions,decreased factor IX consumption and lower bleeding rates

In the phase 3 B‐LONG [Recombinant Factor IX Fc Fusion Protein (rFIXFc) in Subjects with Haemophilia B] study, rFIXFc dosed every 1–2 weeks was safe and efficacious in previously treated subjects with haemophilia B. To date, there are no evaluations of transitioning from conventional to long‐acting factor IX (FIX) prophylaxis. This post‐hoc analysis of B‐LONG subjects compared prophylaxis with other FIX products and rFIXFc. Pre‐ and on‐study data were analysed to assess dosing regimen, weekly FIX consumption and annualized bleeding rates (ABRs). Population pharmacokinetics models were used to generate FIX activity profiles with rFIXFc and recombinant FIX prophylaxis. Thirty‐nine subjects, previously treated prophylactically, were evaluated. Prior to study, most subjects (69·2%) received twice‐weekly FIX infusions; on study, subjects infused rFIXFc once every 1–2 weeks with c. 30–50% reductions in weekly consumption. On‐study estimated mean ABRs were lower than pre‐study estimated mean ABRs. Models predicted that rFIXFc administered 50 iu/kg weekly and 100 iu/kg every 10 d would maintain steady‐state FIX trough levels ≥1 iu/dl in 95·4% and 89·2% of subjects, respectively. These results indicate that patients receiving rFIXFc prophylaxis can markedly reduce infusion frequency and FIX consumption, have a greater likelihood of maintaining FIX activity >1 iu/dl and experience fewer bleeding episodes compared with prior FIX prophylaxis.     

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.     

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.     

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.     

Patterns of tertiary prophylaxis in Canadian adults with severe and moderately severe haemophilia B

From a young age patients with severe and moderately severe FIX deficiency (haemophilia B) can experience spontaneous or traumatic bleeding and joint destruction may result. The use of coagulation factor IX concentrate to prevent anticipated bleeding, as primary or secondary prophylaxis, has become a common and recommended practice in children. The current practice of using tertiary prophylaxis, in the presence of established joint arthropathy, in adults with haemophilia B is not well characterized. This observational study was conducted to gain a better understanding of the recent Canadian experience with tertiary prophylaxis in adults with severe and moderately severe haemophilia B. Data were collected from all eligible adult (≥ 18 years of age) males with baseline FIX:C ≤ 2% from seven Canadian Hemophilia Treatment centres over a 2‐year observation period from 2009 to 2011. Thirty‐four per cent of the 67 subjects with moderately severe haemophilia B were exposed to prophylaxis with the majority as continuous prophylaxis (≥45 weeks year^‐1). The severe subgroup (FIX:C < 1%) demonstrated a 52% exposure rate. None had primary prophylaxis exposure in childhood. Eighty‐one per cent used once or twice weekly infusion regimens and reported a median annual bleeding rate of five bleeds per year versus four bleeds per year for those using on‐demand treatment. Annual median factor utilization for all subjects using prophylaxis was 196 283 U year^‐1 compared to 46 361 U year^‐1 for on demand. Approximately 50% of adults with severe haemophilia B are using continuous tertiary prophylaxis in Canada, a practice likely to increase which warrants further study.     

Interpreting important health‐related quality of life change using the Haem‐A‐QoL

The Haemophilia Quality of Life Questionnaire for Adults (Haem‐A‐QoL) measures health‐related quality of life (HRQoL) in adults with haemophilia; however, change score thresholds for identifying individuals experiencing a HRQoL benefit have not been appropriately investigated. The objective of this analysis was to derive appropriate HRQoL responder definitions (RDs) for two Haem‐A‐QoL domains that reflect key impairments, ‘Physical Health’ and ‘Sports & Leisure,’ and the Haem‐A‐QoL ‘Total Score’ using anchor‐ and distribution‐based methods. In this analysis, data from adults in A‐LONG and B‐LONG, two Phase 3 clinical studies of rFVIIIFc in haemophilia A and rFIXFc in haemophilia B, respectively, were used. The anchor‐based approach identified Haem‐A‐QoL changes corresponding to EQ‐5D item improvements between baseline and 6 months; the distribution‐based methods examined the magnitude at baseline of one‐half standard deviation and the standard error of measurement. Through triangulation, the most appropriate RDs were derived. Of the 133 A‐LONG and 73 B‐LONG subjects with baseline Haem‐A‐QoL scores, 67 and 51 subjects, respectively, completed the Haem‐A‐QoL questionnaire at both baseline and 6 months follow‐up. Triangulation of anchor‐ and distribution‐based estimates with the observed Haem‐A‐QoL change scores identified a 10‐point reduction in the ‘Physical Health’ and ‘Sports & Leisure’ domains, and a 7‐point reduction in ‘Total Score’ as the RD thresholds most indicative of HRQoL benefit. These empirically derived RDs for two key Haem‐A‐QoL domains and ‘Total Score’ are reasonable and practical thresholds for identifying subjects with notable improvements in HRQoL, and provides HRQoL RDs that can be used for further analysis and interpretation of data from haemophilia clinical trials.     

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

Current factor IX (FIX) products display a half-life (t(1/2)) of ～ 18 hours, requiring frequent intravenous infusions for prophylaxis and treatment in patients with hemophilia B. This open-label, dose-escalation trial in previously treated adult subjects with hemophilia B examined the safety and pharmacokinetics of rFIXFc. rFIXFc is a recombinant fusion protein composed of FIX and the Fc domain of human IgG(1), to extend circulating time. Fourteen subjects received a single dose of rFIXFc; 1 subject each received 1, 5, 12.5, or 25 IU/kg, and 5 subjects each received 50 or 100 IU/kg. rFIXFc was well tolerated, and most adverse events were mild or moderate in intensity. No inhibitors were detected in any subject. Dose-proportional increases in rFIXFc activity and Ag exposure were observed. With baseline subtraction, mean activity terminal t(1/2) and mean residence time for rFIXFc were 56.7 and 71.8 hours, respectively. This is ～ 3-fold longer than that reported for current rFIX products. The incremental recovery of rFIXFc was 0.93 IU/dL per IU/kg, similar to plasma-derived FIX. These results show that rFIXFc may offer a viable therapeutic approach to achieve prolonged hemostatic protection and less frequent dosing in patients with hemophilia B. The trial was registered at www.clinicaltrials.gov as NCT00716716.     

Improvement in health‐related quality of life with recombinant factor IX prophylaxis in severe or moderately severe haemophilia B patients: results from the BAX326 Pivotal Study

Little is known about the health‐related quality of life (HRQoL) burden of haemophilia B. The aim of this study was to assess HRQoL burden of haemophilia B, the benefit of recombinant factor IX (rFIX) prophylaxis and the HRQoL benefit of achieving a zero annual bleed rate. Subjects receiving rFIX (BAX326) prophylaxis or on‐demand completed the SF‐36 survey. Baseline SF‐36 scores were compared to the general US population scores to understand the HRQoL burden. Changes in SF‐36 scores between baseline and follow‐up were tested using t‐tests. Subgroup analysis was conducted to examine SF‐36 change among subjects who switched to BAX326 prophylaxis. SF‐36 scores were also compared between those with zero bleeds and those who bled during the study. Compared to the US norms, subjects reported lower average scores in all physical and several mental HRQoL domains. At follow‐up, prophylaxis subjects reported statistically significant and clinically meaningful improvements in overall physical HRQoL, as measured by the Physical Component Score (PCS) (mean change 2.60, P = 0.019), Bodily Pain (BP) (3.45, P = 0.015) and Role Physical (RP) domains (3.47, P = 0.016). Subjects who switched to prophylaxis from intermittent prophylaxis or on‐demand experienced more pronounced improvements not only in the PCS (3.21, P = 0.014), BP (3.71, P = 0.026), RP (4.43, P = 0.008) but also in Vitality (3.71, P = 0.04), Social Functioning (5.06, P = 0.002) and General Health domains (3.40, P = 0.009). Subjects achieving zero bleeds reported lower BP (P = 0.038). Prophylaxis with BAX326 significantly improved HRQoL in patients with moderately severe or severe haemophilia B by reducing bleeds.     

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.     

Recombinant factor IX (BAX326) in previously treated paediatric patients with haemophilia B: a prospective clinical trial

A newly developed recombinant factor IX (BAX326¹) was investigated for prophylactic use in paediatric patients aged <12 years with severe (FIX level <1%) or moderately severe (FIX level 1–2%) haemophilia B. The aim of this prospective clinical trial was to assess the safety, haemostatic efficacy and pharmacokinetic profile of BAX326 in previously treated paediatric patients. BAX326 was administered as prophylaxis twice a week for a period of 6 months, and on demand for treatment of bleeds. Safety was assessed by the occurrence of related AEs, thrombotic events and immunologic assessments. Efficacy was evaluated by annualized bleeding rate (ABR), and by treatment response rating (excellent, good, fair, none). PK was assessed over 72 h. None of the 23 treated paediatric subjects had treatment‐related SAEs or AEs. There were no thrombotic events, inhibitory or specific binding antibodies against FIX, rFurin or CHO protein. Twenty‐six bleeds (19 non‐joint vs. 7 joint bleeds) occurred (mean ABR 2.7 ± 3.14, median 2.0), of which 23 were injury‐related. Twenty subjects (87%) did not experience any bleeds of spontaneous aetiology. Haemostatic efficacy of BAX326 was excellent or good for >96% of bleeds (100% of minor, 88.9% of moderate and 100% of major bleeds); the majority (88.5%) resolved after 1–2 infusions. Longer T_1/2 and lower IR were observed in younger children (<6 years) compared to those aged 6 to 12 years. BAX326 administered as prophylactic treatment as well as for controlling bleeds is efficacious and safe in paediatric patients aged <12 years with haemophilia B.     

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.     

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.     

Randomized comparison of prophylaxis and on‐demand regimens with FEIBA NF in the treatment of haemophilia A and B with inhibitors

Factor replacement therapy for the treatment of moderate to severe haemophilia A and B can be complicated by the production of inhibitory alloantibodies to factor VIII (FVIII) or factor IX. Treatment with the nanofiltered anti‐inhibitor coagulant complex, Factor Eight Inhibitor Bypassing Activity (FEIBA NF), is a key therapeutic option for controlling acute haemorrhages in patients with high‐titre inhibitors or low‐titre inhibitors refractory to replacement therapy. Given the high risk for morbidity and mortality in haemophilia patients with inhibitors to FVIII or FIX, we conducted this Phase 3 prospective study to evaluate whether prophylaxis with FEIBA NF is a safe and effective treatment option. Over a 1‐year period, 17 subjects were treated prophylactically (85 ± 15 U kg^?1 every other day) while 19 subjects were treated on demand. The median (IQR) annualized bleeding rate (ABR) during prophylaxis was 7.9 (8.1), compared to 28.7 (32.3) during on‐demand treatment, which amounts to a 72.5% reduction and a statistically significant difference in ABRs between arms (P = 0.0003). Three (17.6%) subjects (ITT) on prophylaxis experienced no bleeding episodes, whereas none treated on demand were bleeding episode‐free. Total utilization of FEIBA NF for the treatment of bleeding episodes was significantly higher during on‐demand therapy than prophylaxis (P = 0.0067). There were no differences in the rates of related adverse events between arms. This study demonstrates that FEIBA prophylaxis significantly reduces all types of bleeding compared with on‐demand treatment, and the safety of prophylaxis is comparable to that of on‐demand treatment.     

Improved joint health in subjects with severe haemophilia A treated prophylactically with recombinant factor VIII Fc fusion protein

Introduction

Joint arthropathy is the long‐term consequence of joint bleeding in people with severe haemophilia.

Aim

This study assessed change in joint health over time in subjects receiving recombinant factor VIII Fc fusion protein (rFVIIIFc) prophylaxis.

Methods

ALONG is the phase 3 pivotal study in which the benefit of rFVIIIFc as a prophylactic treatment for bleeding control was shown in previously treated severe haemophilia patients ≥12 years of age (arm 1: 25‐65 IU/kg every 3‐5 days, arm 2: 65 IU/kg weekly and arm 3: episodic). After completing ALONG, subjects had the option to enrol into the extension study (ASPIRE). This interim, post hoc analysis assessed changes in joint health over ~2.8 years in these patients.

Results

Forty‐seven subjects had modified Haemophilia Joint Health Score (mHJHS) data at A‐LONG baseline, ASPIRE baseline and ASPIRE Year 1 and Year 2. Compared with A‐LONG baseline (23.4), mean improvement at ASPIRE Year 2 was ?4.1 (95% confidence interval [CI], ?6.5, ?1.8; P = .001). Regardless of prestudy treatment regimen, subjects showed continuous improvement in mHJHS from A‐LONG baseline through ASPIRE Year 2 (prestudy prophylaxis: ?2.4, P = .09; prestudy episodic treatment: ?7.2, P = .003). Benefits were seen in subjects with target joints (?5.6, P = .005) as well as those with severe arthropathy (?8.8, P = .02). The mHJHS components with the greatest improvement at ASPIRE Year 2 were swelling (?1.4, P = .008), range of motion (?1.1, P = .03) and strength (?0.8, P = .04).

Conclusions

Prophylaxis with rFVIIIFc may improve joint health over time regardless of prestudy prophylaxis or episodic treatment regimens.     

Efficacy and safety of Nuwiq® (human‐cl rhFVIII) in patients with severe haemophilia A undergoing surgical procedures

Introduction

Haemophilia A patients are at a high risk of excess bleeding during surgeries. The aim of haemostatic therapy during the perioperative period is to normalize FVIII level perioperatively and postoperatively to maintain normal haemostasis until wound healing is complete.

Aims/Methods

To examine the efficacy of Nuwiq^® (simoctocog alfa, human‐cl rhFVIII), a 4^th generation recombinant FVIII produced in a human cell line, for surgical prophylaxis in patients with severe haemophilia A. This analysis assessed the efficacy of Nuwiq^® during surgical procedures and in the postoperative period in seven clinical studies of previously treated patients (PTPs) with severe haemophilia A.

Results

Thirty‐six patients, aged 3‐55 years, received surgical prophylaxis with Nuwiq^® for 60 surgeries (28 major and 32 minor). Efficacy was evaluated for 52 surgeries (25 major and 27 minor). The success rate of Nuwiq^® treatment was 98.1% (51 of 52 evaluated surgeries); haemostatic efficacy was assessed as “excellent” or “good” in all but one major surgery (assessed as “moderate”). The number of infusions ranged from 1 to 19 for minor surgeries and from 3 to 76 for major surgeries. The median (range) daily doses were 42.0 (28.2‐100.9) IU kg^?1 for minor surgeries and 69.3 (43.3‐135.6) IU kg^?1 for major surgeries. There were no serious treatment‐related adverse events, and none of the patients developed FVIII inhibitors.

Conclusions

The results of this pooled analysis show that Nuwiq^® was efficacious in maintaining haemostasis during and after major and minor surgical procedures in PTPs with severe haemophilia A.     

Perioperative haemostatic management of haemophilic mice using normal mouse plasma

Intense haemostatic interventions are required to avoid bleeding complications when surgical procedures are performed on haemophilia patients. The objective of this study was to establish an appropriate protocol for perioperative haemostatic management of haemophilic mice. We assessed the prophylactic haemostatic effects of normal mouse plasma (NMP) on haemophilia B (HB) mice for both a skin flap procedure and a laparotomy. When 500 μL of NMP was administered to the mice, plasma factor IX (FIX:C) levels peaked at 15.1% immediately after intravenous (IV) administration, at 6.1% 2 h after intraperitoneal (IP) administration and at 2.7% 6 h after subcutaneous administration. Administering 500 μL of NMP via IP or IV 30 min in advance enabled the skin flap procedure to be performed safely without any complications. After the laparotomy procedure, several mice in the IP administration group exhibited lethal bleeding, but all mice survived in the IV administration group. Anti‐mouse FIX inhibitors did not develop, even after repetitive administrations of NMP. However, human FIX concentrates, especially plasma‐derived concentrates, elicited the anti‐human FIX inhibitors. The results show that administering 500 μL of NMP via IV or IP 30 min in advance enables surgical procedures to be safely performed on HB mice, and that IV administration is more desirable than IP if the procedure requires opening of the abdominal wall.     

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.     

Treatment burden,haemostatic strategies and real world inhibitor screening practice in non‐severe haemophilia A

Inhibitor formation in non‐severe haemophilia A is a life‐long risk and associated with morbidity and mortality. There is a paucity of data to understand real‐world inhibitor screening practice. We evaluated the treatment burden, haemostatic strategies, F8 genotyping and inhibitor screening practices in non‐severe haemophilia A in seven London haemophilia centres. In the 2‐year study period, 44% (377/853) patients received at least one haemostatic treatment. Seventy‐nine percent of those treated (296/377) received factor VIII (FVIII) concentrate. F8 genotype was known in 88% (331/377) of individuals. Eighteen per cent (58/331) had ‘high‐risk’ F8 genotypes. In patients with ‘standard‐risk’ F8 genotypes treated on‐demand with FVIII concentrate, 51·3% episodes (243/474) were screened within 1 year. However, poor screening compliance was observed after ‘high‐risk’ treatment episodes. In patients with ‘standard‐risk’ F8 genotypes, 12·3% (28/227) of treatment episodes were screened in the subsequent 6 weeks after surgery or a bleed requiring ≥5 exposure days. Similarly, in the context of ‘high‐risk’ F8 genotypes after any FVIII exposure, only 13·6% (12/88) of episodes were screened within 6 weeks. Further study is required to assess optimal practice of inhibitor screening in non‐severe haemophilia A to inform subsequent clinical decisions and provide more robust prevalence data to further understand the underlying immunological mechanism.     

First analysis of 10‐year trends in national factor concentrates usage in haemophilia: data from CHARMS,the Canadian Hemophilia Assessment and Resource Management System

The Canadian Hemophilia Assessment and Resource Management System (CHARMS) tracks factor concentrates (FC) from the sole suppliers, Canadian Blood Services (CBS) and Hema‐Quebec (HQ), to hospitals and to patients’ homes. Patients FC infusion data are entered into CHARMS at Canadian Hemophilia Treatment Centres (HTCs) then exported to the national database (CentrePoint). From 2000 to 2009, 2260 registered haemophilia A or B patients received FVIII (1 009 097 765 IU) and FIX (272 406 859 IU). Over 91% of FVIII and over 84% of FIX was infused at home. Utilization of FVIII progressively increased; this was accounted for by an increase in the number of patients treated (r = 0.97; P < 0.001), there being a linear relationship between the increase in utilization and the increase in number of patients treated (P < 0.001). There was also a correlation with the annual amount used per patient (r = 0.95; P < 0.001). Utilization of FIX did not increase over time. The highest proportional utilization of both FVIII and FIX was for prophylaxis, and this proportion progressively increased being, in year 10 (2009), 77% and 66% for FVIII and FIX respectively. The proportion used for bleeding remained steady; in year 10 that proportion was 14% for FVIII and 26% for FIX, the use per patient for bleeding decreasing. The HTC‐based CHARMS tracking system is essential, in Canada, for analysing indications for infusion, for predicting utilization and planning for future needs.     

Intracranial haemorrhage in children and adolescents with severe haemophilia A or B – the impact of prophylactic treatment

The discussion of prophylactic therapy in haemophilia is largely focused on joint outcomes. The impact of prophylactic therapy on intracranial haemorrhage (ICH) is less known. This study aimed to analyse ICH in children with haemophilia, with a focus on different prophylaxis regimens and sequelae of ICH. We conducted a multicentre retrospective and prospective study that included 33 haemophilia centres from 20 countries. Inclusion criteria were children and adolescents born between 1993 and 2014, with severe haemophilia A or B without inhibitors. Participants were categorized by prophylaxis regimen: full, partial or none, based on dose and dose frequency of regular infusions. The cohort study included 1515 children: 29 cases of ICH over 8038 patient years were reported. The incidence of ICH in the prophylaxis group, 0·00033 cases of ICH/patient year, was significantly lower compared to the no prophylaxis group, 0·017 cases of ICH/patient year (RR 50·06; P < 0·001) and the partial prophylaxis group, 0·0050 cases of ICH/patient year (RR 14·92; P = 0·007). In the on‐demand‐group, 8% (2/24) children with ICH died and 33% had long‐term sequelae, including intellectual and behavioural problems, paresis and epilepsy. Children on regular, frequent prophylaxis have a low risk of ICH compared to those using non‐frequent or no prophylaxis.