Key questions in the new hemophilia era: update on concomitant use of FVIII and emicizumab in hemophilia A patients with inhibitors

Introduction: Immune tolerance induction (ITI) is the primary therapeutic strategy and only proven method to eradicate inhibitors to coagulation factor VIII (FVIII) in hemophilia A. Emicizumab, a humanized bispecific monoclonal antibody that mimics the function of activated FVIII, has expanded options to treat hemophilia A. The availability of emicizumab necessitates a revisit of recommendations for managing patients with inhibitors. Areas covered: Current evidence is reviewed about the concomitant use of emicizumab and FVIII concentrates during and after ITI. Areas where data are lacking are highlighted and ongoing studies designed to address these issues are described. Expert opinion: Inhibitor eradication remains a desirable goal. All patients with inhibitors should be offered at least one attempt at ITI. Emicizumab monotherapy is an option for inhibitor patients who are not candidates for ITI. Evidence is emerging about the use of emicizumab during ITI to prevent bleeds. Studies are currently addressing the safety, efficacy, and feasibility of concomitant emicizumab and FVIII in ITI. As evidence regarding the risk of inhibitor recurrence and need for continued FVIII to maintain immune tolerance post-ITI is limited, the role of emicizumab alone or in combination with FVIII after ITI is the subject of an upcoming studyThis review is based on presentations from a Grifols-sponsored symposium at the International Society on Thrombosis and Haemostasis 2020 Virtual Congress. The paper is otherwise not funde

Valoración de la eficacia percibida de la dinamica grupal “¿qué-tal?” Para el autocuidado y aprendizaje mutuo en un equipo asistencial

The team of psychologists in Hematology Service of La Paz University Hospital, has incorporated a weekly dynamic, as a tool of self-care and mutual learning. The purpose is to share the assessment of the week in the personal and professional areas, in a formal and systematic proceeding. We call it “What’s-up?” Objective: To present the perceived effectiveness of the dynamic by those who participated in it during the last 6 years. Method: Retrospective study with a single measure in the form of semi-structured online questionnaire, developed ad-hoc. The final sample consists of 41 participants. Results: High efficiency is perceived by these professionals of this dynamic , with an average of 8 over 10 (DS=0.62). The most robust correlations turned out to be the emotional management, mutual support, group belonging and aid in the personal sphere, all of them (p<0,01). Conclusions: The greatest perceived benefits were related to the emotional level and the group relationship, followed by learning professional skills. The implementation of self-care preventive programs for professionals in contact with intense experience of suffering is considered to be beneficial.El equipo de psicólogos del Servicio de Hematología del Hospital Universitario La Paz, viene realizando una dinámica semanal, como herramienta de autocuidado y aprendizaje mutuo. La finalidad es compartir la valoración de la semana en el ámbito personal y profesional, de manera formal y sistemática. A esta dinámica grupal de enfoque interdisciplinar la denominamos “¿Qué-tal?”. Objetivo: presentar la eficacia percibida de la dinámica por parte de los participantes de los últimos 6 años. Método: estudio retrospectivo con una única medida en forma de cuestionario on-line semiestructurado, elaborado ad hoc. La muestra final consta de 41 participantes. Resultados: Se evidencia la alta eficacia percibida de esta herramienta con una media de 8 sobre 10 (DT=0,62). Las correlaciones más robustas resultaron ser la gestión emocional, apoyo mutuo, pertenencia grupal y la ayuda en el ámbito personal, (p< 0,01). Conclusiones: Los mayores beneficios percibidos se refieren al ámbito emocional y a la relación grupal, seguidos del aprendizaje de habilidades profesionales. Se considera beneficiosa la implantación de programas preventivos de autocuidado para profesionales en contacto con intensa experiencia de sufrimient

Behçet's disease: New insight into the relationship between procoagulant state, endothelial activation/damage and disease activity

Background: Behçet disease (BD) is associated with a prothrombotic state of unknown origin that may lead to life-threatening events. Calibrated Automated Thrombogram (CAT) and Rotational Thromboelastometry (ROTEM) are two global haemostasis assays that may reveal new insights into the physiopathological mechanisms of the disease and its procoagulant condition. Methods. 23 BD patients who had no signs or symptoms of current thrombosis and 33 age- and sex-matched controls were included in the study. We performed ROTEM and CAT tests and assessed erythrocyte count, platelet count, platelet contribution to clot formation and plasma levels of tissue-type plasminogen activator, plasminogen activator inhibitor type 1 (PAI-1), fibrinogen, C-reactive protein (CRP), thrombin-antithrombin III complex (TAT), D-dimer and E-selectin (ES). Results: Both ROTEM and CAT tests showed a hypercoagulable state in the BD patients. Plasma levels of PAI-1, fibrinogen, TAT, CRP and ES were significantly increased in this group compared to controls. The disease activity (DA) was significantly correlated with levels of ES and the maximum clot firmness, and this last one, in turn, correlated with rising levels of ES, PAI-1, CRP and fibrinogen. CAT parameters did not correlate with DA or ES. Conclusions: Both ROTEM and CAT tests reveal that patients with BD have a procoagulant state even in the absence of thrombosis. ROTEM test indicates that increased levels of fibrinogen and PAI-1 may be involved in the prothrombotic state of this pathology, while platelets do not significantly contribute. Moreover, CAT assay demonstrate that plasma from BD patients is able to generate more thrombin than controls in response to the same stimulus and that this effect is independent of the DA and the endothelial impairment suggesting the involvement of another factor in the hypercoagulable state observed in BD patients. This study also shows that endothelium activation/damage may be a contributing factor in both the procoagulant and clinical conditions of BD, as shown by the direct correlation between ES levels, ROTEM parameters and DAThis work was supported by grants from FIS PS09/00531 and FIS PI12/0183

Concizumab restores thrombin generation potential in patients with haemophilia: Pharmacokinetic/pharmacodynamic modelling results of concizumab phase 1/1b data

Introduction: Concizumab enhances thrombin generation (TG) potential in haemophilia patients by inhibiting tissue factor pathway inhibitor (TFPI). In EXPLORER3 (phase 1b), a dose‐dependent pharmacokinetic/pharmacodynamic (PK/PD) relationship was confirmed between concizumab dose, free TFPI and TG potential. Aim: Determine the association between concizumab exposure, PD markers (free TFPI; peak TG) and bleeding episodes to establish the minimum concizumab concentration for achieving sufficient efficacy. Methods: Free TFPI predictions were generated using an estimated concizumab‐free TFPI exposure‐response (Emax) model based on concizumab phase 1/1b data for which simultaneously collected concizumab and free TFPI samples were available. Concizumab concentration at the time of a bleed was predicted using a PK model, based on available data for concizumab doses >50 μg/kg to ≤9 mg/kg. Peak TG vs concizumab concentration analyses and an Emax model were constructed based on EXPLORER3 observations. Results: The Emax model showed a tight PK/PD relationship between concizumab exposure and free TFPI; free TFPI decreased with increasing concizumab concentration. A strong correlation between concizumab concentration and peak TG was observed; concizumab >100 ng/mL re‐established TG potential to within the normal reference range. Estimated EC50 values for the identified concizumab‐free TFPI and concizumab‐TG potential models were very similar, supporting free TFPI as an important biomarker. A correlation between bleeding episode frequency and concizumab concentration was indicated; patients with a concizumab concentration >100 ng/mL experienced less frequent bleeding. The PK model predicted that once‐daily dosing would minimize within‐patient concizumab PK variability.Novo Nordis

Design of a prospective observational study on the effectiveness and real-world usage of recombinant factor VIII Fc (rFVIIIFc) compared with conventional products in haemophilia A: The A-SURE study

Introduction: Haemophilia A is a rare bleeding disorder caused by coagulation factor VIII (FVIII) deficiency. This is treated with factor VIII, conventionally using products with a half-life of 8-12 hours typically administered every 2-3 days. Recombinant FVIII Fc (rFVIIIFc) represents a new generation of products with an extended half-life allowing higher FVIII levels and longer dosing interval. The efficacy and safety of rFVIIIFc have been established in clinical studies and several years of postmarketing use. However, there remains a need to compare treatment outcome with conventional products in routine clinical use. Methods and analysis: A-SURE is an ongoing, non-interventional European study with the primary objective to compare the clinical effectiveness of rFVIIIFc with conventional factor products used for haemophilia A prophylaxis. Data covering a 24-month prospective period and a 12-month retrospective period will be collected. Three primary endpoints: bleeding rate, injection frequency and factor consumption will be used to evaluate treatment outcomes. Enrolment of 175 patients on rFVIIIFc and 175 on conventional products is planned. All eligible patients from participating centres will be invited to participate. Visits and treatments follow routine clinical practice. Bias will be reduced by patient matching for age at baseline and the last weekly prophylaxis dose of a conventional product prior to baseline. Propensity scores will be calculated based on prognostic factors and potential confounders assessed at baseline and adjusted for in the estimation of the treatment effect. Ethics and dissemination: Study approval was obtained by local independent ethics committees and/or authorities, and informed consent from patients or their legal representative is a requirement for participation. Names of ethical committees and approval numbers are provided as supplementary information. The study results will be submitted for publication in a peer-reviewed scientific journal and presented at scientific conferences.This work was fully funded by Swedish Orphan Biovitrum AB (publ

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  Data 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 ≤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  The 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  Cumulative 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 (Bagsværd, Denmark

Clinical Efficacy and Safety of Fanhdi®, a Plasma-Derived VWF/Factor VIII Concentrate, in von Willebrand Disease in Spain: A Retrospective Study

Prophylaxis; Von willebrand diseaseProfilaxis; Enfermedad de von willebrandProfilaxi; Malaltia de von willebrandObjective To evaluate the efficacy and safety of a plasma-derived factor VIII concentrate containing von Willebrand Factor (pdVWF/FVIII) in standard clinical practice in von Willebrand Disease (VWD) patients. Methods A retrospective, multicentric, observational study of VWD patients treated with Fanhdi®, a pdVWF/FVIII concentrate, from January 2011 to December 2017 was conducted at 14 centers in Spain. Efficacy and safety were evaluated for acute bleeding episodes, for prevention of bleeding in surgeries, and for secondary long-term prophylaxis. Results Seventy-two eligible patients, type 1, 2, 3 VWD (25%/38.9%/36.1%) were treated for spontaneous and traumatic bleeding (140 episodes, n = 41 patients), to prevent surgical bleeding (69 episodes, n = 43 patients); and for secondary long-term prophylaxis (18 programs, n = 13 patients). Replacement therapy with pdVWF/FVIII showed an excellent to good clinical efficacy in 96.7% of the bleeding episodes, 100% during surgical procedures and 100% during prophylaxis. No adverse events (AEs), nor serious AEs related to the product were observed. Conclusions Fanhdi® was effective, safe and well tolerated in the management of bleeding episodes, the prevention of bleeding during surgeries, and for secondary long-term prophylaxis in VWD patients.This work was supported by Grifols, manufacturer of the pdVWF/FVIII, Fanhdi®

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 AUC0–inf was observed; CL and Vss showed a significant negative association with BMI; t½ was independent of BMI and other parameters. The dosing model introduced a correction factor ‘M’ 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 þ243.3 IU (underweight) to –1,489.6 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 (Bagsværd, Denmark)