AIM: These post hoc analyses investigated the bleeding patterns in target joints.
METHODS: Patients randomized to 40 or 10 IU kg(-1) once weekly prophylaxis who had at least one target joint were included. Baseline demographics and disease-specific data were collected. Bleeding patterns were assessed, and an International Society on Thrombosis and Haemostasis (ISTH) definition of target joints was used.
RESULTS: A total of 67% and 8% of patients in the 40 and 10 IU kg(-1) arm, respectively, did not experience target joint bleeds during the paradigm(™) 2 trial. Twenty-four target joints were recorded in each prophylaxis arm at baseline. During the paradigm(™) 2 trial, no bleeds were reported in 17 (71%) and 7 (29%) target joints in the 40 and 10 IU kg(-1) arms respectively. All target joint bleeds in the 40 IU kg(-1) once weekly prophylaxis arm were controlled with a single injection of 40 IU kg(-1) nonacog beta pegol. By the latest ISTH definition, 90% and 58% of target joints in the 40 and 10 IU kg(-1) arms, respectively, were no longer considered target joints at the end of the paradigm(™) 2 trial. At the end of the paradigm(™) 4 extension trial, all target joints in the 40 IU kg(-1) arm were no longer considered target joints.
CONCLUSION: Routine prophylaxis with 40 IU kg(-1) once weekly nonacog beta pegol has the potential for effective management of target joint bleeds in haemophilia B patients.
AIM: This is a planned interim analysis of pathfinder™3, an international, open-label, Phase 3 trial evaluating the efficacy and safety (including immunogenicity) of N8-GP administered before, during and after major surgery in severe haemophilia A patients aged ≥12 years.
METHODS: Sixteen patients who underwent 18 major surgical procedures (including synovectomy, joint replacement and ankle arthrodesis) were included here. Postoperative assessments were conducted daily for days 1-6, and once for days 7-14. Primary endpoint was N8-GP haemostatic efficacy, assessed after completion of surgery using a four-point scale ('excellent', 'good', 'moderate', 'none').
RESULTS: Haemostasis was successful (rated 'excellent' or 'good') on completion of surgery in 17 (94.4%) procedures and rated as 'moderate' (5.6%) for one surgery in a patient with multiple comorbidities who needed an intraoperative N8-GP dose (20.7 IU kg-1 ). In the postoperative period, three bleeds occurred (one during days 1-6; two during days 7-14); all were successfully treated with N8-GP. Mean N8-GP consumption on day of surgery was 80.0 IU kg-1 ; patients received a mean of 1.7 doses (median: 2, range: 1-3). No safety concerns were identified.
CONCLUSION: The data showed that N8-GP was effective and well tolerated for the prevention and treatment of bleeds during major surgery; such FVIII products with extended half-lives may modify current treatment schedules, enabling fewer infusions and earlier patient discharge.
AIM: The aim of this study was to evaluate the pharmacokinetics (PK) of N9-GP.
METHODS: Data from 41 previously treated haemophilia B patients, enrolled globally (16 adolescents/adults and 25 children; FIX activity ≤0.02 IU mL-1) with no history of FIX inhibitors, were included. N9-GP was administered once-weekly as 10 IU kg-1or 40 IU kg-1in adolescents/adults and 40 IU kg-1in children. Blood was sampled up to 168 h (1 week) post dose. Standard PK was estimated on the basis of plasma FIX activity vs. time (PK profiles) using non-compartmental methods. Furthermore, a population PK analysis and FIX activity predictions were performed.
RESULTS: Incremental recoveries were 0.02 (IU mL-1)/(IU kg-1) in both adolescents/adults and children. The extended half-life resulted in mean trough levels of 0.27 IU mL-1for adolescents/adults and 0.17 IU mL-1for children at steady-state after weekly dosing at 40 IU kg-1. The population PK analysis confirmed a mono-exponential decay in FIX activity and allowed for predictions of FIX activity for adolescents/adults above 0.15 IU mL-1at all times and 6.4 days week-1in children.
CONCLUSION: N9-GP has the potential to shift previously treated haemophilia B patients from a severe/moderate disease state into a mild- or non-haemophilic range for most of the dosing interval, which is expected to reduce the number of bleeding episodes.
AIMS: To determine immunogenicity, pharmacokinetics (PK), efficacy, safety and quality of life of prophylaxis with a polyethylene glycol (peg)-ylated FVIII (BAX 855) based on full-length recombinant FVIII (ADVATE) in paediatric previously treated patients (PTPs) with severe haemophilia A.
METHODS: PTPs <12 years without history of FVIII inhibitors received twice-weekly infusions of 50 ± 10 IU kg(-1) BAX 855 for ≥50 exposure days. Prophylactic dose increases to ≤80 IU kg(-1) were allowed under predefined conditions. PK was evaluated after single infusions of 60 ± 5 IU kg(-1) .
RESULTS: T1/2 and mean residence time were extended 1.3- to 1.5-fold compared to ADVATE (n = 31), depending on the analysis used. The point estimate for the mean annualized bleeding rate in 66 subjects receiving a median of 1.9 weekly infusions of 51.3 IU kg(-1) of BAX 855 each was 3.04 (median 2.0); 1.10 (median 0) for joint and 1.16 (median 0) for spontaneous bleeds. Overall, 38% of subjects had zero bleeds. No bleeds were severe. Haemostatic efficacy was rated excellent or good for 90% of bleeds; 91% were treated with one or two infusions. In 8/14 subjects all target joints resolved. No subject developed FVIII inhibitors or persistent binding antibodies that affected safety or efficacy. No adverse reactions occurred.
CONCLUSION: Twice-weekly prophylaxis with BAX 855 was safe and efficacious in paediatric PTPs with severe haemophilia A.
AIM: Evaluate the efficacy and safety of turoctocog alfa pegol treatment for major and minor surgeries in the pathfinder 3 and 5 phase III trials.
METHODS: Adults/adolescents aged ≥12 years with severe haemophilia A (FVIII <1%) received perioperative turoctocog alfa pegol treatment planned to achieve FVIII activity levels >80% during major surgery (pathfinder 3). The primary end point was haemostatic efficacy during surgery; secondary end points were blood loss, haemostatic effect postsurgery, consumption, transfusions, safety and health economics. Children (0-11 years) undergoing minor surgeries received 20-75 IU/kg turoctocog alfa pegol at Investigator's discretion (pathfinder 5).
RESULTS: pathfinder 3 included 35 patients undergoing 49 major surgeries. Haemostasis was successful in 47/49 (95.9%) surgeries; two had moderate haemostatic responses. Median (mean) blood loss during major surgery was 75 (322.6) mL. Four bleeds were reported postsurgery; three were successfully treated with turoctocog alfa pegol (one was not evaluated). On the day of surgery, overall mean (median) dose was 75.5 (74.5) IU/kg and mean (median) number of doses was 1.7 (2.0). Five procedures required 11 transfusions on the day of surgery or days 1-6. No safety concerns or inhibitors were identified. Forty-five minor surgeries in 23 children were performed without complications.
CONCLUSION: Turoctocog alfa pegol was effective for perioperative haemostatic management of major and minor surgeries in patients across age groups with severe haemophilia A.
METHODS: An advisory board meeting was conducted with experts in haemophilia care from Asia to understand the heterogeneity in clinical practices and care provision in the region.
FINDINGS: The overall prevalence of haemophilia in Asia ranges between 3 and 8.58/100,000 patients. Haemophilia A was more prevalent as compared to haemophilia B with a ratio of around 5:1. There is under-diagnosis in the region due to lack of diagnosis, registries and/or lack of appropriate facilities in suburban areas. Most patients are referred to the haematologists by their families or primary care physicians, while some are identified during bleeding episodes. Genetic testing faces obstacles like resource constraints, services available at limited centres and unwillingness of patients to participate. Prophylaxis is offered for people with haemophilia (PWH) with a severe bleeding phenotype. Recombinant factors are approved in most countries across the region and are the preferred therapy. The challenges highlighted for not receiving a high standard of care include patients' reluctance to use an intravenous treatment, poor patient compliance due to frequency of infusions, budget constraints and lack of funding, insurance, availability and accessibility of factor concentrates. Prevalence of neutralizing antibodies ranged from 5% to 20% in the region. Use of immune tolerance induction and bypassing agents to treat inhibitors depends on their cost and availability.
CONCLUSION: Haemophilia care in Asia has evolved to a great extent. However, some challenges remain for which a strategic approach along with multi-stakeholder involvement are needed.
METHODS: We reviewed the literature on prophylaxis in haemophilia since its inception in the 1950s to the present, the development of more and less intense factor prophylaxis regimens and their outcomes and additionally the published outcomes of prophylaxis with low dose emicizumab.
RESULTS: What these experiences collectively show is that low dose emicizumab does result in significant benefits to patients whilst being much less expensive than a "one size fits all" emicizumab prophylaxis approach. We also took note that some non-factor therapies still in development are individualized given that high doses of these can potentially put patients at risk.
CONCLUSIONS: Prophylaxis is now clearly accepted as standard of care for PWH with a severe phenotype but now in a very short time a large assortment of different treatment options for prophylaxis have become/are becoming available and the haemophilia community will need to determine how to best use these recognizing that no 'one treatment fits all'.