ABSTRACT The novel fusion protein linking recombinant factor VIIa with recombinant albumin (rVIIa-FP) is designed to extend the half-life of recombinant factor VIIa (rFVIIa) and improve the care of ...hemophilia A or B patients with inhibitors. Preclinical studies in various animal models have demonstrated markedly improved pharmacokinetic and pharmacodynamic properties, as well as prolonged retention in the joint tissues, of rVIIa-FP compared with a commercially available rFVIIa (NovoSeven®). A phase I study in healthy volunteers – the first study in the PROLONG-7FP program – confirmed that rVIIa-FP has a good tolerability profile in doses of up to 1,000 μg/kg and has demonstrated enhanced pharmacodynamic activity relative to rFVIIa. The half-life of rVIIa-FP at the highest dose investigated in the study was 8.5 hours, which represents a 3- to 4-fold half-life extension compared with rFVIIa. Encouraging results from preclinical and phase I studies have led to the initiation of clinical studies of rVIIa-FP in patients with congenital hemophilia A or B and inhibitors, and in patients with confirmed factor VII deficiency. The results from these studies are awaited with interest by clinicians and patients alike.
Abstract Since its discovery in 1970, protein S (PS) has emerged as a key vitamin K-dependent natural anticoagulant protein at the crossroads of multiple biological processes, including coagulation, ...apoptosis, atherosclerosis, angiogenesis/vasculogenesis, and cancer progression. Following the binding to a unique family of protein tyrosine kinase receptors referred to as Tyro-3, Axl and Mer (TAM) receptors, PS can lead to regulation of coagulation, phagocytosis of apoptotic cells, cell survival, activation of innate immunity, vessel integrity and angiogenesis, and local invasion and metastasis. Because of these dynamics and multiple functions of PS, which are largely lost following invalidation of the mouse PROS1 gene, this molecule is currently intensively studied in biomedical research. The purpose of this review is to provide a brief chronicle of the discovery and current understanding of the mechanisms of PS signaling, and how PS and their signaling partners regulate various cellular functions, with a particular focus on TAM receptors.
Aims
The use of factor VIII (FVIII) prophylaxis in haemophilia A is considered the standard of care, particularly in children. Despite adjustment of doses for body weight and/or age, a large ...pharmacokinetic (PK) variability between patients has been observed. PK‐tailored prophylaxis may help clinicians adjust coagulation factor FVIII activity (FVIII:C) to the desired level, which may differ in individual patients. The objective was to develop a population PK model for simoctocog alfa based on pooled clinical trial data and to develop a Bayesian estimator to allow PK parameters in individual patients to be estimated using a reduced number of blood samples.
Methods
PK data from 86 adults and 29 children/adolescents with severe haemophilia A were analysed. The FVIII data measured using 2 different assays (chromogenic and the 1‐stage clotting assay) were fit to separate develop population PK models using nonlinear mixed‐effect models. A Bayesian estimator was then developed to estimate the time above the threshold of 1%.
Results
The PK data for chromogenic and the 1‐stage clotting assays were both best described by a 2‐compartment models. Simulations demonstrated good predictive capacity. The limited sampling strategy using blood sample at 3 and 24 hours allowed an accurate estimation of the time above the threshold of 1% FVIII:C (mean bias 0.01 and 0.11, mean precision 0.18 and 0.45 for 2 assay methods).
Conclusion
In this study, we demonstrated that a Bayesian approach can help to reduce the number of samples required to estimate the time above the threshold of 1% FVIII:C with good accuracy.
Adeno-associated viral (AAV) vector gene therapy has shown promise as a possible cure for hemophilia. However, immune responses directed against AAV vectors remain a hurdle to the broader use of this ...gene transfer platform. Both innate and adaptive immune responses can affect the safety and efficacy of AAV vector–mediated gene transfer in humans. These immune responses may be triggered by the viral capsid, the vector’s nucleic acid payload, or other vector contaminants or excipients, or by the transgene product encoded by the vector itself. Various preclinical and clinical strategies have been explored to overcome the issues of AAV vector immunogenicity and transgene-related immune responses. Although results of these strategies are encouraging, more efficient approaches are needed to deliver safe, predictable, and durable outcomes for people with hemophilia. In addition to durability, long-term follow-up of gene therapy trial participants will allow us to address potential safety concerns related to vector integration. Herein, we describe the challenges with current methodologies to deliver optimal outcomes for people with hemophilia who choose to undergo AAV vector gene therapy and the potential opportunities to improve on the results.
Recently, our group has reported a 13-bp deletion in a poly(T)-track in the F8 intron 13 as the causative variant in approximately 6% of all cases of mild haemophilia A (HA) in France. The systematic ...screening of mild HA patients for this deletion identified individuals carrying deletions from 9 to 14-bp in the same region.
To demonstrate that these highly prevalent deletions could result from a recurrent molecular mechanism and to determine the clinical significance of deletions other than 13-bp in size.
Haplotype analysis using five polymorphic markers was performed in 71 unrelated French mild hemophilia A patients. Minigene analysis was performed to study the splicing impact of deletions from 1 to 14-bp.
A peculiar haplotype (H1) was identified in 22.5% of patients carrying the 13-bp deletion. Haplotypes differing from H1 only for the two most distal markers were found in more than the half of patients. These results confirmed the founder effect origin for the 13-bp deletion. However, the 9 patients carrying other sizes of deletion had a different haplotype suggesting that these deletions arose independently. Supporting the recurrent mechanism hypothesis, similar deletions were also found in 3/19 genetically unresolved mild Canadian patients. In vitro splicing analysis confirmed that deletions larger than 9-bp had a deleterious impact on splicing of F8 transcript.
We demonstrated that the poly(T)-track in F8 intron 13 is a deletion hotspot. We recommend that deletions in this region should be specifically investigated in all genetically unresolved mild HA patients.
Long-acting recombinant factor IX (FIX) products may simplify the surgical treatment of haemophilia B patients. The impact of rIX-FP, a recombinant FIX fused to recombinant albumin, on FIX ...consumption and surgical management was assessed in patients with haemophilia B.
Male patients, ≤65 years old with severe haemophilia B (FIX activity ≤2%) requiring non-emergency surgery were enrolled in the surgical substudy of PROLONG-9FP. Dosing was based on World Federation of Hemophilia guidelines and patients' pharmacokinetics. Haemostatic efficacy was assessed on a 4-point scale. rIX-FP consumption and safety were monitored throughout the perioperative period.
This updated dataset reports on thirty (8 minor and 22 major) surgeries conducted in 21 patients. A single preoperative bolus was used in 96.7% (n = 29) of surgeries. After minor surgery, patients received a median (range) of 0 (0–3) infusions with a median (range) consumption of 0 (0–178.89) IU/kg in the 14-day postoperative period. In patients who underwent major surgery (including 15 patients undergoing joint replacement surgery), the median (range) number of infusions in the 14-day postoperative period was 5 (0−11) and median consumption was 221.7 (0–444.07) IU/kg. Haemostatic efficacy was rated as excellent or good in 87.5% (7/8) of minor surgeries and 95.5% (21/22) of major surgeries.
Surgical procedures can be performed using a single preoperative bolus of rIX-FP in nearly all patients. During postoperative care, use of rIX-FP necessitated infrequent infusions and low FIX consumption. Overall, data suggest rIX-FP simplifies perioperative care in patients with haemophilia B.
•Surgical procedures can be performed using rIX-FP with low FIX consumption.•Patients required few postoperative infusions of rIX-FP.•Outpatient care may be possible for some minor surgeries when treating with rIX-FP.•Perioperative haemostatic efficacy was good or excellent in most patients.•Overall, data suggests rIX-FP simplifies perioperative care in haemophilia B.
Factor VIII protein (FVIII) as a coagulation replacement factor has for decades been used as the standard of care for management of people with haemophilia A. It is effective for treatment of ...bleeding events, as prophylaxis to prevent bleeding events and preserve joint function, and to support surgery in people with haemophilia A. Despite long experience in treating haemophilia A, we are only beginning to understand the functions of FVIII beyond its established role as a coenzyme to factor IXa to expedite thrombin generation through the intrinsic pathway of coagulation. Here, we review the current role of FVIII coagulant (FVIII:C) in haemophilia A management and emerging evidence for the role of FVIII across multiple systems, including the cardiovascular system, angiogenesis and maintenance of bone health. For instance, supraphysiological FVIII levels are a risk factor for venous thromboembolism. von Willebrand factor (VWF), which forms a non-covalent complex with circulating FVIII, is an established marker and regulator of angiogenesis. In a mouse model of haemophilia, treatment with FVIII decreased expression of receptor activator of nuclear factor kappa-Β ligand (RANKL), a marker for bone turnover. Longitudinal follow-up data in people with haemophilia A are needed to confirm and extend these observations.
Abstract Introduction Pneumatic tube system (PTS) in hospitals is commonly used for the transport of blood samples to clinical laboratories, as it is rapid and cost-effective. The aim was to compare ...the effects on haematology samples of a newly acquired ~ 2 km-long PTS that links 2 hospitals with usual transport (non-pneumatic tube system, NPTS). Methods Complete blood cell count, routine coagulation assays, platelet function tests (PFT) with light-transmission aggregometry and global coagulation assays including ROTEM® and thrombin generation assay (TGA) were performed on blood samples from 30 healthy volunteers and 9 healthy volunteers who agreed to take aspirin prior to blood sampling. Results The turnaround time was reduced by 31% (p < 0.001) with the use of PTS. No statistically significant difference was observed for most routine haematology assays including PFT, and ROTEM® analysis. A statistically significant, but not clinically relevant, shortening of the APTT after sample transport by PTS was found (mean ± SD: 30 s ± 1.8 vs. 29.5 s ± 2.1 for NPTS). D-dimer levels were 7.4% higher after transport through PTS but were not discordant. A statistically significant increase of thrombin generation was found in both platelet poor- and platelet rich- plasma samples after PTS transport compared to NPTS transport. Conclusion PTS is suitable for the transport of samples prior to routine haematology assays including PFT, but should not be used for samples intended for thrombin generation measurement.
Background:
The bypassing agent, activated prothrombin complex concentrate aPCC, FEIBA (factor VIII inhibitor bypass activity); Baxalta US Inc, a Takeda company, Lexington, MA, USA, is indicated for ...the treatment of bleeding episodes, perioperative management, and routine prophylaxis in patients with hemophilia A or B with inhibitors. In certain countries, aPCC is also indicated for the treatment of bleeding episodes and perioperative management in patients with acquired hemophilia A.
Objectives:
To describe long-term, real-world effectiveness, safety, and quality-of-life outcomes for patients with congenital hemophilia A or B and high-responding inhibitors receiving aPCC treatment in routine clinical practice.
Design:
FEIBA Global Outcome (FEIBA GO; EUPAS6691) was a prospective, observational study.
Methods:
Investigators determined the treatment regimen and clinical monitoring frequency. The planned patient observation period was 4 years. Data are from the safety analysis set (patients who received ⩾1 aPCC infusion).
Results:
Overall, 50 patients received either aPCC prophylaxis (n = 37) or on-demand therapy (n = 13) at screening hemophilia A, n = 49; hemophilia B, n = 1; median (range) age, 16.5 2–71 years). Mean ± standard deviation overall annualized bleeding rate and annualized joint bleeding rate for patients receiving prophylaxis were 6.82 ± 11.52 and 3.77 ± 5.71, respectively, and for patients receiving on-demand therapy were 10.94 ± 11.27 and 6.94 ± 7.39, respectively. Overall, 177 and 31 adverse events (AEs) were reported in 28 of 40 and 10 of 13 patients receiving prophylaxis or on-demand therapy, respectively. Two serious AEs were considered possibly related to aPCC: acute myocardial infarction due to coronary artery embolism in one patient receiving prophylaxis. No thrombotic microangiopathy was reported. No AEs resulted in death.
Conclusion:
This study demonstrated the long-term, real-world effectiveness and consistent safety profile of aPCC as on-demand therapy and prophylactic treatment in patients with hemophilia and high-responding inhibitors.
Trial registry:
FEIBA Global Outcome Study; EUPAS6691
https://www.encepp.eu/encepp/viewResource.htm?id=32774
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