von Willebrand factor/factor VIII concentrate (Wilate) prophylaxis in children and adults with von Willebrand disease.

ABSTRACT: Long-term prophylaxis with a von Willebrand factor (VWF) concentrate is recommended in patients with von Willebrand disease (VWD) who have a history of severe and frequent bleeds. However, data from prospective studies are scarce. WIL-31, a prospective, noncontrolled, international phase 3 trial, investigated the efficacy and safety of Wilate prophylaxis in severe patients with VWD. Male and female patients 6 years or older with VWD types 1, 2 (except 2N), or 3 who had completed a prospective, 6-month, on-demand, run-in study (WIL-29) were eligible to receive Wilate prophylaxis for 12 months. At baseline, patients (n = 33) had a median age of 18 years. Six (18%) patients had severe type 1, 5 (15%) had type 2, and 22 (67%) had type 3 VWD. The primary end point of a >50% reduction in mean total annualized bleeding rate (TABR) with Wilate prophylaxis vs prior on-demand treatment was met; mean TABR during prophylaxis was 5.2, representing an 84.4% reduction. The bleeding reduction was consistent across age, sex, and VWD types. The mean spontaneous ABR was 3.2, representing an 86.9% reduction vs on-demand treatment. During prophylaxis, 10 (30.3%) patients had 0 bleeding events and 15 (45.5%) patients had 0 spontaneous bleeding events. Of 173 BEs, 84.4% were minor and 69.9% treated. No serious adverse events related to study treatment and no thrombotic events were recorded. Overall, WIL-31 showed that Wilate prophylaxis was efficacious and well-tolerated in pediatric and adult patients with VWD of all types. The WIL-29 and WIL-31 trials were registered at www.ClinicalTrials.gov as #NCT04053699 and #NCT04052698, respectively.

Simoctocog alfa (Nuwiq®) in previously untreated patients with severe haemophilia A-Final efficacy and safety results from the NuProtect study.

INTRODUCTION: Simoctocog alfa (Nuwiq®) is a 4th generation recombinant FVIII with proven efficacy for the prevention and treatment of bleeding episodes (BEs) in previously treated patients with severe haemophilia A. The NuProtect study assessed the immunogenicity, efficacy and safety of simoctocog alfa in 108 previously untreated patients (PUPs). The incidence of high-titre inhibitors was 16.2% and no patients with non-null F8 mutations developed inhibitors. AIM: To report the efficacy and safety results from the NuProtect study. METHODS: PUPs received simoctocog alfa for prophylaxis, treatment of BEs, or as surgical prophylaxis. The efficacy of prophylaxis (during inhibitor-free periods) was assessed using annualised bleeding rates (ABRs). The efficacy in treating BEs and in surgical prophylaxis was assessed using a 4-point scale. Adverse events were recorded throughout the study. RESULTS: Of 108 PUPs treated with simoctocog alfa, 103 received at least one prophylactic dose and 50 received continuous prophylaxis for at least 24 weeks. In patients on continuous prophylaxis, the median ABR was 0 (mean 0.5) for spontaneous BEs and 2.5 (mean 3.6) for all BEs. In 85 patients who had BEs, efficacy of BE treatment was excellent or good for 92.9% (747/804) of rated BEs; 92.3% of BEs were treated with 1 or 2 infusions. The efficacy of surgical prophylaxis was excellent or good for 94.7% (18/19) of rated procedures. There were no safety concerns and no thromboembolic events. CONCLUSION: Simoctocog alfa was efficacious and well tolerated as prophylaxis, surgical prophylaxis and for the treatment of BEs in PUPs with severe haemophilia A.

Long-term immunogenicity, efficacy and tolerability of simoctocog alfa in patients with severe haemophilia A who had completed the NuProtect study in previously untreated patients.

BACKGROUND: The NuProtect study reported data on the immunogenicity, efficacy and tolerability of simoctocog alfa (Nuwiq® ) in 108 previously untreated patients with severe haemophilia A planned to be treated for ≥100 exposure days or up to 5 years. The NuProtect-Extension study collected long-term prophylaxis data in children with severe haemophilia A. METHODS: Patients who completed the NuProtect study according to the protocol were eligible for the NuProtect-Extension study, a prospective, multinational, non-controlled, Phase 3b study. RESULTS: Of 48 patients who entered the extension study, 47 (median age 2.8 years) received prophylaxis with simoctocog alfa for a median of 24 months, with 82%-88% on a twice-weekly or less regimen. No patient developed FVIII inhibitors during the extension study. The median (IQR) annualized bleeding rate (ABR) during prophylaxis was 0 (0-0.5) for spontaneous bleeding episodes (BEs) and 1.00 (0-1.95) for all BEs. ABRs estimated using a negative binomial model were .28 (95% CI: .15, .53) for spontaneous and 1.62 (95% CI: 1.09, 2.42) for all BEs. During the median follow-up of 24 months, 34 (72%) patients had zero spontaneous BEs and 46 (98%) had zero spontaneous joint BEs. Efficacy in treating BEs was excellent or good for 78.2% of rated BEs, and efficacy of surgical prophylaxis was excellent for two rated surgeries. No treatment-related adverse events were reported. CONCLUSION: No FVIII inhibitors developed during long-term prophylaxis in the NuProtect-Extension study. Prophylaxis with simoctocog alfa was efficacious and well-tolerated, and is therefore an attractive long-term option for children with severe haemophilia A.

COVID-19-induced coagulopathy: Experience, achievements, prospects.

The presence of coagulopathy as part of the systemic inflammatory response syndrome is a characteristic feature of severe coronavirus disease 2019 (COVID-19). Hematological changes (increased D-dimer [DD], prolonged activated partial thromboplastin clotting time [APTT] and prothrombin time [PT], high fibrinogen levels) have been observed in hospitalized patients with COVID-19, which characterize the risk of thrombotic events. Against the background of COVID-19 there is endothelial dysfunction, hypoxia and pulmonary congestion, mediated by thrombosis and microvascular occlusion. Up to 71.4% of patients who died from COVID-19 had disseminated intravascular coagulation syndrome, compared with only 0.6% of survivors. The main manifestation of COVID-19-associated coagulopathy is a significant increase in DD without a decrease in platelet count or prolongation of APTT and PT, indicating increased thrombin formation and the development of local fibrinolysis. An increase in DD levels of more than 3-4 times was associated with higher in-hospital mortality. Therefore, COVID-19 requires assessment of the severity of the disease for further tactics of thromboprophylaxis. The need for continued thromboprophylaxis, or therapeutic anticoagulation, in patients after inpatient treatment for two weeks using imaging techniques to assess of thrombosis assessment.

Unfriendly Fire: How the Tobacco Industry is Destroying the Future of Our Children.

Tobacco has long been known to be one of the greatest causes of morbidity and mortality in the adults, but the effects on the foetus and young children, which are lifelong, have been less well appreciated. Developing from this are electronic nicotine delivery systems or vapes, promulgated as being less harmful than tobacco. Nicotine itself is toxic to the foetus, with permanent effects on lung structure and function. Most vapes contain nicotine, but they also contain many other compounds which are inhaled and for which there are no toxicity studies. They also contain known toxic substances, whose use is banned by European Union legislation. Accelerating numbers of young people are vaping, and this does not reflect an exchange of vapes for cigarettes. The acute toxicity of e-cigarettes is greater than that of tobacco, and includes acute lung injury, pulmonary haemorrhage and eosinophilic and lipoid pneumonia. Given the worse acute toxicity, it should be impossible to be complacent about medium and long term effects of vaping. Laboratory studies have demonstrated changes in lung proteomics and the innate immune system with vaping, some but not all of which overlap with tobacco. It would be wrong to consider vapes as a weaker form of tobacco, they have their own toxicity. Children and young people are being targeted by the vaping industry (which is largely the same as the tobacco industry), including on-line, and unless an efficient legislative program is put in place, a whole new generation of nicotine addicts will result.

Simoctocog Alfa (Nuwiq) in Previously Untreated Patients with Severe Haemophilia A: Final Results of the NuProtect Study.

INTRODUCTION: FVIII inhibitor development is the most serious contemporary treatment complication in haemophilia A, particularly in previously untreated patients (PUPs). No inhibitors developed in clinical trials in previously treated patients treated with simoctocog alfa (Nuwiq), a fourth-generation recombinant FVIII produced in a human cell line. METHODS: The NuProtect study investigated the immunogenicity of simoctocog alfa in PUPs. NuProtect was a prospective, multinational, open-label, non-controlled, phase III study. PUPs with severe haemophilia A (FVIII:C <1%) of any age and ethnicity were treated with simoctocog alfa for 100 exposure days or a maximum of 5 years. Patients were true PUPs without prior exposure to FVIII concentrates or blood components. Inhibitor titres were measured with the Nijmegen-modified Bethesda assay; cut-off for positivity was 0.6 BU mL-1 (≥0.6 to <5 low-titre, ≥5 high titre). RESULTS: A total of 108 PUPs with a median age at first treatment of 12.0 months (interquartile range: 8.0-23.5) were treated with simoctocog alfa. F8 mutation type was known for 102 patients (94.4%) of whom 90 (88.2%) had null F8 mutations and 12 (11.8%) had non-null mutations. Of 105 PUPs evaluable for inhibitor development, 28 (26.7%) developed inhibitors; 17 high titre (16.2%) and 11 low titre (10.5%). No PUPs with non-null F8 mutations developed inhibitors. CONCLUSION: In the NuProtect study, the rate of inhibitor development in PUPs with severe haemophilia A treated with simoctocog alfa was lower than the rate reported for hamster-cell-derived recombinant factor VIII products in other recent clinical trials. No inhibitors were reported in PUPs with non-null F8 mutations.