111 research outputs found
Acquired bleeding disorders
Acquired bleeding disorders can accompany hematological, neoplastic, autoimmune, cardiovascular or liver diseases, but can sometimes also arise spontaneously. They can manifest as single factor deficiencies or as complex hemostatic abnormalities. This review addresses (a) acquired hemophilia A, an autoimmune disorder characterized by inhibitory autoantibodies against coagulation factor VIII; (b) acquired von Willebrand syndrome in patients with cardiovascular disorders, where shear stress abnormalities result in destruction of von Willebrand factor; and (c) liver function disorders that comprise complex changes in pro- and anti-hemostatic factors, whose clinical implications are often difficult to predict. The article provides an overview on the pathophysiology, diagnostic tests and state-of-the-art treatment strategies
On Digital Sustainability and Digital Public Goods
Several 2022 reports from government and academic organisations contain the key message that sustainable development can be achieved using digital technologies. The report âčDigital Resetâș (Digitalization for Sustainability, 2022) calls for using digital technologies to reduce greenhouse gas emissions and resource waste in the agriculture, mobility, industry, and energy sectors. The researchers see digitalisation as a means to an end for sustainable transformation. Similarly, the report by the Coalition for Digital Environmental Sustainability (CODES, 2022), presents an action plan that includes impact initiatives to «achieve a sustainable planet in the digital age». The EU argues that digital technologies must play a key role in achieving climate neutrality in the EU by 2050 (Muench et al., 2022). The authors call for a âčtwin transitionâș, managing digital and green transitions simultaneously so that they reinforce each other
Warum digitaler und nachhaltiger Wandel gleichzeitig stattfinden muss
Regierungen und akademische Organisationen sind sich sicher, dass eine nachhaltige Entwicklung mit digitaler Technologien erreicht werden kann. Auch die EU argumentiert, dass Technologie eine SchlĂŒsselrolle bei der Erreichung der KlimaneutralitĂ€t in der EU bis 2050 spielen mĂŒssen (Muench et al., 2022). Unserer Autor*innen fordern einen «doppelten Ăbergang», d. h. die gleichzeitige BewĂ€ltigung des digitalen und des grĂŒnen Wandels, so dass sie sich gegenseitig verstĂ€rken
Predictive modeling identifies total bleeds at 12-weeks postswitch to N8-GP prophylaxis as a predictor of treatment response
Predicting annualized bleeding rate (ABR) during factor VIII (FVIII) prophylaxis for severe hemophilia A (SHA) is important for long-term outcomes. This study used supervised machine learning-based predictive modeling to identify predictors of long-term ABR during prophylaxis with an extended half-life FVIII. Methods âData were from 166 SHA patients who received N8-GP prophylaxis (50 IU/kg every 4 days) in the pathfinder 2 study. Predictive models were developed to identify variables associated with an ABR of â€1 versus >1 during the trial's main phase (median follow-up of 469 days). Model performance was assessed using area under the receiver operator characteristic curve (AUROC). Pre-N8-GP prophylaxis models learned from data collected at baseline; post-N8-GP prophylaxis models learned from data collected up to 12-weeks postswitch to N8-GP, and predicted ABR at the end of the outcome period (final year of treatment in the main phase). Results âThe predictive model using baseline variables had moderate performance (AUROC = 0.64) for predicting observed ABR. The most performant model used data collected at 12-weeks postswitch (AUROC = 0.79) with cumulative bleed count up to 12 weeks as the most informative variable, followed by baseline von Willebrand factor and mean FVIII at 30 minutes postdose. Univariate cumulative bleed count at 12 weeks performed equally well to the 12-weeks postswitch model (AUROC = 0.75). Pharmacokinetic measures were indicative, but not essential, to predict ABR. Conclusion âCumulative bleed count up to 12-weeks postswitch was as informative as the 12-week post-switch predictive model for predicting long-term ABR, supporting alterations in prophylaxis based on treatment responseThis analysis and medical writing support for the article was funded by Novo Nordisk A/S (BagsvĂŠrd, Denmark
Body mass index best predicts recovery of recombinant factor VIII in underweight to obese patients with severe haemophilia A
Background Factor VIII (FVIII) products are usually dosed according to body weight
(BW). This may lead to under- or over-dosing in underweight or obese patients,
respectively.
Objective This article evaluates the pharmacokinetics (PK) of recombinant FVIII
concentrate, particularly recovery, in relation to body mass index (BMI) and other
body composition descriptors.
Materials and Methods Thirty-five previously treated adults with severe haemophilia
A from five BMI categories (underweight, normal, overweight, obese class I and II/III)
were included. PK was evaluated after 50 IU per kilogram of BW single-dose recombinant
FVIII (turoctocog alfa). The body composition variable was based on measurements
of weight, height, bioimpedance analysis, and dual-energy X-ray
absorptiometry. A dosing model was derived to achieve similar peak FVIII activity
levels across BMI categories.
Results A statistically significant positive association between BMI and C30min,
IR30min, and AUC0âinf was observed; CL and Vss showed a significant negative association
with BMI; tœ was independent of BMI and other parameters. The dosing model
introduced a correction factor âMâ for each BMI category, based on linear regression
analysis of C30min against BMI, which ranged from 0.55 for underweight to 0.39 for
obese class II/III. This model achieved similar peak FVIII activity levels across BMI
categories, estimating an average dose adjustment of ĂŸ243.3 IU (underweight) to
â1,489.6 IU (obese class II/III) to achieve similar C30min.
Conclusion BMI appears to be the best predictor of recombinant FVIII recovery;
however, PK endpoints were also dependent on other body composition variables. The
model demonstrated that dosing can be adjusted for individual BMI to achieve better
FVIII predictability across BMI categoriesThis work was funded by Novo Nordisk A/S (BagsvĂŠrd, Denmark)
SHP656, a polysialylated recombinant factor VIII (PSA-rFVIII): First-in-human study evaluating safety, tolerability and pharmacokinetics in patients with severe haemophilia A
Introduction
SHP656 is the first factor VIII (FVIII) product developed using polysialylation (PSA) technology, in which fullâlength recombinant (r) FVIII (antiâhaemophilic factor [recombinant]) is conjugated with a 20 kDa PSA polymer.
Aim
To compare the safety, immunogenicity and pharmacokinetics of SHP656 vs the parent rFVIII (octocog alfa) after single infusions of 25â75 IU/kg in patients with severe haemophilia A (FVIII activity <1%).
Methods
Multinational, phase 1, prospective, openâlabel, twoâperiod, fixedâsequence, doseâescalation trial (clinicaltrials.gov NCT02716194). Patients received single doses of rFVIII and then SHP656 sequentially at the same dose: 25 ± 3 IU/kg (Cohort 1), 50 ± 5 IU/kg (Cohort 2) and 75 ± 5 IU/kg (Cohort 3).
Results
Forty patients received rFVIII: 11 in Cohort 1, 16 in Cohort 2 and 13 in Cohort 3. Two patients withdrew before receiving SHP656, leaving 38 patients who completed the study and received both treatments. No treatmentârelated adverse events (AEs), serious AEs, deaths, study withdrawals, thrombotic events or allergic reactions were reported; and no significant treatmentârelated changes in laboratory parameters or vital signs. No patients developed FVIII inhibitors or antibodies to PSA. FVIII activity was significantly prolonged following SHP656 administration vs rFVIII with an approximately 1.5âfold extension in mean residence time (P < .05). Exposure increased proportional to the SHP656 dose over the 25â75 IU/kg dose range
Gentherapie der HĂ€mophilie: Empfehlung der Gesellschaft fĂŒr Thrombose- und HĂ€mostaseforschung (GTH).
Gene therapy has recently become a realistic treatment perspective for patients with haemophilia. Reviewing the literature and our personal experience from clinical trials, we discuss key aspects of haemophilia A and B gene therapy with vectors derived from adeno-associated virus (AAV), including predictable results, risks, adverse events, and patient-reported outcomes. Patient selection, informed consent, administration, and monitoring of gene therapy as well as data collection are explained. We also discuss the need for interdisciplinary cooperation with hepatology and other specialties. We emphasize structural and organizational requirements for treatment centres according to the hub-and-spoke model and recommend the use of electronic diaries to ensure safe and timely collection and exchange of data. Electronic diaries will play a key role as primary source of data for pharmacovigilance, post-marketing clinical studies, national and international registries, as well as health technology and benefit assessment. Reimbursement aspects and the future of gene therapy in adolescents and children are also considered. In a rapidly evolving scientific environment, these recommendations aim to support treatment providers and payers to prepare for the implementation of gene therapy following marketing authorization
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