Introduction
Nuwiq® (Human‐cl rhFVIII) is a new‐generation recombinant factor VIII (rFVIII) protein, without chemical modification or fusion to any other protein, produced in a human cell line.
...Aim/Methods
This prospective, open‐label, multinational phase III study assessed the efficacy and safety of Human‐cl rhFVIII in 59 previously treated patients (PTPs) with severe haemophilia A aged 2–12 years (2–5 N = 29; 6–12 N = 30) during standard prophylaxis (≥50 exposure days and ≥6 months). Efficacy in treating breakthrough bleeds and during surgical prophylaxis was also assessed.
Results
An initial pharmacokinetic assessment (N = 13 per age subgroup) demonstrated comparable results with the one‐stage and chromogenic assays. Mean (SD) half‐life was 11.9 (5.4) and 13.1 (2.6) hours in children aged 2–5 years and 6–12 years respectively (one‐stage assay). Prophylactic efficacy, based on mean monthly bleeding rate, was ‘excellent’ or ‘good’ in 91.5% of children for all bleeds and in 96.6% of children for spontaneous bleeds. Mean (SD) annualized bleeding rate was 4.12 (5.22) median 1.9 for all bleeds, 1.50 (3.32) median 0 for spontaneous bleeds and 2.34 (3.54) median 1.57 for traumatic bleeds. There were no major, life‐threatening bleeds. Efficacy was ‘excellent’ or ‘good’ in the treatment of 82.4% of breakthrough bleeds. Overall efficacy during five major surgeries was rated as ‘excellent’. There were no FVIII inhibitors or treatment‐related serious adverse events.
Conclusion
These results in paediatric PTPs indicate that Human‐cl rhFVIII is effective for the prevention and treatment of bleeds.
Introduction
Nuwiq® (human‐cl rhFVIII, simoctocog alfa) is a 4th generation recombinant human FVIII, without chemical modification or fusion with any other protein, produced in a human cell line.
...Aim/Methods
This study (GENA‐13) was an extension of the GENA‐03 study in which previously treated children aged 2‐12 years with severe haemophilia A received Nuwiq® prophylaxis for ≥6 months. GENA‐13 examined long‐term tolerability, immunogenicity and efficacy of Nuwiq® prophylaxis in children.
Results
Of 59 patients enrolled in GENA‐03, 49 continued Nuwiq® prophylaxis in GENA‐13 for a median (range) of 30.0 (9.5‐52.0) months. No patient withdrew due to drug‐related adverse events or developed inhibitors. Only 2 of 20 518 infusions were associated with possibly related adverse events (dyspnoea, fever). The estimated annualized bleeding rate (ABR) was 0.67 (95% CI: 0.44, 1.02) for spontaneous and 2.88 (95% CI: 1.86, 4.46) for all bleeds. Younger children (2‐5 years) had lower ABRs than children aged 6‐12 years. Annualized bleeding rates were reduced in GENA‐13 vs GENA‐03, especially for spontaneous bleeds in younger children (71% reduction; ABR ratio 0.29 95% CI: 0.11, 0.74). Nuwiq® efficacy was rated as excellent/good in the treatment of 83.0% of 305 evaluated breakthrough bleeds. Surgical prophylaxis with Nuwiq® was rated as excellent for all 17 assessed procedures.
Conclusion
Long‐term treatment with Nuwiq® for the prevention of bleeds in children with severe haemophilia A was well tolerated, effective and reduced spontaneous bleeding by up to 70% compared with GENA‐03.
Introduction
Octanate® is a human, plasma‐derived, von Willebrand factor‐stabilized coagulation factor VIII (FVIII) concentrate with demonstrated haemostatic efficacy in previously treated patients ...with haemophilia A.
Aim
This prospective, open‐label study aimed to assess the immunogenicity of octanate® in previously untreated patients (PUPs).
Methods
The study monitored development of FVIII inhibitors in 51 PUPs. Tolerability, viral safety, FVIII recovery and efficacy of octanate® for the prevention and treatment of bleeds and in surgical procedures were also assessed.
Results
Five (9.8%) of the 51 patients developed inhibitors during the study, 4 of which (7.8%) were high titre. Three inhibitor cases (5.9%) were considered clinically relevant; 2 were transient inhibitors that disappeared during regular octanate® treatment without a change in dose or treatment frequency. Amongst 45 patients with FVIII:C <1% at baseline and who received ≥20 exposure days (EDs) or had <20 EDs but developed an inhibitor, inhibitor incidence was 11.1% (6.7% clinically relevant). All clinically relevant inhibitors developed within 20 EDs of on‐demand treatment. No inhibitors developed in PUPs receiving prophylaxis. All patients who developed inhibitors had either intron 22 inversions or large deletions. Irrespective of the reason for administration, haemostatic efficacy was rated as “excellent” in 99.6% of all infusions (4700 of 4717 infusions), and no complications were reported in 23 surgical procedures. Mean incremental in vivo recovery was 2.0%/IU/kg (±0.7) and 1.9%/IU/kg (±0.5) for the first and second assessments, respectively. Tolerability was rated “very good” in 99.9% of infusions.
Conclusion
In PUPs with severe haemophilia A, octanate® demonstrated haemostatic efficacy with a low rate of inhibitor development.
Introduction
Nuwiq® (Human‐cl rhFVIII) is a fourth generation recombinant FVIII, produced in a human cell line, without chemical modification or protein fusion. No inhibitors developed in studies ...with Nuwiq® in 201 previously treated patients with haemophilia A (HA). The immunogenicity, efficacy and safety of Nuwiq® in previously untreated patients (PUPs) with severe HA are being assessed in the ongoing NuProtect study.
Methods
The study, conducted across 38 centres worldwide, is evaluating 110 true PUPs of all ages and ethnicities enrolled for study up to 100 exposure days (EDs) or 5 years maximum. The primary objective is to assess the immunogenicity of Nuwiq® (inhibitor activity ≥0.6 BU) using the Nijmegen‐modified Bethesda assay at a central laboratory.
Results
Data for 66 PUPs with ≥20 EDs from a preplanned interim analysis were analysed. High‐titre (HT) inhibitors developed in 8 of 66 patients after a median of 11.5 EDs (range 6‐24). Five patients developed low‐titre inhibitors (4 transient). The cumulative incidence (95% confidence interval) was 12.8% (4.5%, 21.2%) for HT inhibitors and 20.8% (10.7%, 31.0%) for all inhibitors. During inhibitor‐free periods, median annualized bleeding rates during prophylaxis were 0 for spontaneous bleeds and 2.40 for all bleeds. Efficacy was rated as “excellent” or “good” in treating 91.8% of bleeds. Efficacy of surgical prophylaxis was “excellent” or “good” for 8 (89%) procedures and “moderate” for 1 (11%). No tolerability concerns were evident.
Conclusion
These interim data show a cumulative incidence of 12.8% for HT inhibitors and convincing efficacy and tolerability in PUPs treated with Nuwiq®.
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 4th 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.
Abstract Objectives This study examined the effects of elevated concentration hydrogen peroxide tooth whitening treatments on tooth surface and subsurface integrity. Methods Sound human molars were ...ground and polished to prepare an uniform substrate for bleaching treatments. A cycling treatment included alternating ex vivo human salivary exposures with bleaching treatments under conditions of controlled temperature and durations of treatment. Bleaching was carried out with prototype bleaching strips containing hydrogen peroxide gel at 13% and 16% concentrations. A non-bleached group was used as a control. Treatments included 28 h of total bleaching exposure in vitro . Surface color was measured prior to and following bleaching. Effects of bleach on physical properties of tooth surfaces were assessed by microhardness measures on enamel. Ultrastructural effects were examined by surface and subsurface confocal laser scanning microscopy (CLSM) and scanning electron microscopy (SEM) techniques. In addition, the effects of bleaching on tooth micro-chemical composition were studied by Raman spectroscopy combined with CLSM technique. Results Color assessments confirmed significant ex vivo tooth bleaching. Surface microhardness and VP-SEM (variable pressure SEM) measures revealed no deleterious effects on the enamel surfaces. CLSM micromorphological assessments supported the safety of hydrogen peroxide bleaching strips both on surface and subsurface enamel, DEJ and dentin ultrastructure. Raman spectroscopy analysis demonstrated no obvious effects of bleaching treatments on the micro-chemical composition of enamel and dentin. Significant effects of bleaching were seen in reducing background luminescence of Raman spectra obtained from enamel and dentin. Conclusions These results confirm that hydrogen peroxide whitening strips do not produce changes in surface/subsurface histomorphology, surface microhardness and micro-chemical composition of teeth. Effects of bleaches on tooth luminescence recorded in micro-Raman spectroscopy may serve as an internal signature to bleaching effects and warrant further study.
For patients with haemophilia A (HA), lifelong replacement therapy with factor VIII (FVIII) concentrates is the treatment of choice. Octanate® is a plasma‐derived, human, von Willebrand ...factor‐stabilized FVIII product with demonstrated haemostatic efficacy in patients with HA. The aim of this ongoing study is to assess the immunogenicity of Octanate® in previously untreated patients (PUPs), monitoring for development of FVIII inhibitors. Interim data on 39 PUPs treated for bleeding, prophylactically and for surgical coverage are reported. Two of 39 subjects (5.1%) developed clinically relevant inhibitor titres over the course of the study. Another two displayed inhibitors that disappeared spontaneously without Octanate® dose change. All inhibitors developed under on‐demand treatment and before exposure day (ED) 50. Remarkably, no inhibitor was observed in PUPs receiving prophylaxis with Octanate®. Of 39 subjects, 30 had exceeded 50 EDs at the time of this analysis. All inhibitor subjects were found to have large FVIII gene defects, either intron 22‐inversions or large deletions. Octanate® was well‐tolerated and the adverse event profile was consistent with the population studied. The haemostatic efficacy of Octanate® in prophylaxis and treatment of bleeding were generally rated as ‘excellent’, and no complication was reported for surgery. Notable FVIII activity was present in blood at 15 min postadministration, and levels remained high at 1 h. Mean incremental in vivo recovery (IVR) was 2.0 (±0.6) % IU−1kg−1. These interim results indicate Octanate® to be an efficacious, well‐tolerated human FVIII product for management of HA in PUPs, associated with a minimal risk of inhibitors.
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