[Cost-minimization analysis of replacement therapy in the treatment of von Willebrand disease]

BACKGROUND: Replacement therapy with von Willebrand factor (VWF)/factor VIII (FVIII) concentrates represents an effective approach for patients with von Willebrand disease (VWD) who are unresponsive to desmopressin. However, various concentrates are available, with heterogeneous VWF content and VWF/FVIII ratio.AIM: To compare the costs associated to the replacement therapy with VWF/FVIII concentrates in Italy.METHODS: A cost-minimization analysis was performed to compare the pharmaceutical costs per patient of alternatives available for replacement therapy of VWD in the prospective of the Italian National Health Service. For each alternative the analysis calculated the number of vials, and relative costs, required to reach the target levels of VWF:RCo in patients who undergone to major surgery, minor surgery, spontaneous bleeding and prophylaxis.RESULTS: Haemate P® is associated with the lowest FVIII dosage, numbers of vials used and costs in all the clinical situations and at all the dosages considered. With Haemate P® the average costs in major surgery, minor surgery, spontaneous bleeding, and prophylaxis was € 710.94, € 592.45, € 473.96, and € 592.45, respectively. While the costs associated to Fanhdi®, Wilate®, and Wilfactin® was: € 1,309.28, € 1,071.23, € 952.20, and € 1,190.25; € 1,512.45, € 1,344.40, € 1,176.35, and € 1,344.40; € 3,814.09, € 3,269.22, € 3,269.22, and € 3,814.09.CONCLUSIONS: Treatment with Haemate P®, which presents a low FVIII content, allows to reach the target level of VWF:RCo with a lower number of vials and lower costs for the NHS.[Article in Italian

Gene transfer in hemophilia B: a big step forward

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Albutrepenonacog alfa (Idelvion®) for the treatment of Italian patients with hemophilia B: a budget impact model

BACKGROUND: Enhanced pharmacokinetic profile of albutrepenonacog alfa allows to prolong the interdose period in prophylaxis, maintaining higher trough level, and to reduce dosage needed for bleeding. This improvement could lead to a better efficiency of the hemophilia B treatment.OBJECTIVES: To estimate the impact of this new drug on the Italian National Health System (NHS).METHODS: A model was developed from the NHS perspective to assess the budget impact of treating severe hemophilia B with reimbursed recombinant factor IX over 3 years in Italy. Target population was based on data from the National Registry of Congenital Coagulopathies, which collects data from 54 Hemophilia Treatment Centers. Treatment options were: albutrepenonacog alfa (Idelvion®), eftrenonacog alfa (Alprolix®) and nonacog alfa (BeneFIX®). Annual bleeding rate, dose and infusions needed to treat an episode based on clinical trials data were considered.RESULTS: Mean costs per patient were calculated for prophylaxis and bleeding treatment by age groups. Applying age-specific costs to the expected new pattern of drugs utilization, the impact on the NHS budget was € 6 million of savings cumulated in 3 years. The model results most sensitive to drug dosages. Lower drug consumption in prophylaxis and reduced bleeding rate than the alternatives reduce expenditures. Main limitations of this analysis were the assumptions that all severe patients receive prophylaxis and the lack of consideration of positive effects of hemorrhagic complications reduction (with consequent lower need of physiotherapy/prosthetic substitution).CONCLUSIONS: The introduction of Idelvion® as therapeutic option for hemophilia B is expected to decrease pharmaceutical costs and improve patient’s quality of life due to less frequent infusions

Comparative Analysis Of Residual Factor VIII Expression from Recurrent F8 Nonsense Mutations Indicates that Localization in the B- domain Favours Readthrough- mediated Protein Output

Background: Nonsense mutations, inserting premature termination codons (PTCs), might undergo, with low frequency (<0.01%), spontaneous suppression (readthrough) with production of full-length proteins upon amino acid insertion at the PTC. This process, dictated by nucleotide/protein sequence features, might have implications for hemophilia A (HA) patients. Aims: To investigate residual factor VIII (FVIII) expression through complementary studies in HA patients’ plasma and exploiting a sensitive in-vitro expression platform. Methods: Detection of plasma FVIII levels (ELISA, aPTT), and expression studies (HEK293 cells) with a highly-sensitive naturally-secreted luciferase (Gaussia, GL) fused to FVIII (FVIII-GL). Results: Plasma samples from HA patients affected by six nonsense mutations (p.R446X, p.R814X, p.K1289X, p.W1726X, p.R1985X, p.R2135X) revealed traces of FVIII. Strikingly, the two B-domain variants (p.R814X, p.K1289X) showed the highest FVIII levels, suggesting a position-dependent effect. Expression studies with the FVIII-GL variants showed that those of the B-domain produced the highest luciferase activity levels, thus supporting in vivo findings. Accordingly, the predicted readthrough-deriving amino acid changes (R446W, R814W, K1289Q/Y, W1726Y, R1985W, R2135W) showed a minor impact for those affecting the B-domain. To verify further our hypothesis, the panel of F8 mutations was rationally expanded to be representative of the majority of patients with nonsense mutations (60%), including the most frequent (50% of patients) in the B-domain. Through our sensitive platform we observed that all F8 nonsense variants led to detectable luciferase activity (0.4-6%). Strikingly, when categorized in two groups (B-domain, n=21; other domains, n=26), secreted luciferase activity of B-domain variants was significantly higher (p<0.0001) as compared with variants located in the other FVIII domains. Conclusions: Our findings for the first time indicate that nonsense mutations in the B-domain, known to tolerate missense changes as those potentially arising from readthrough, are favoured in terms of readthrough-mediated protein output, which might have pathophysiological implications for HA patients

New opportunities in Haemophilia treatment: Efmoroctocog Alfa for patients with Haemophilia A

Recently new opportunities are emerging for improving the way patients with Haemophilia A are treated. Among these opportunities, efmoroctocog alfa is a first-in-class recombinant factor VIII-Fc fusion protein (rFVIIIFc) produced by recombinant DNA technology with an extended half-life compared with conventional FVIII preparations. The available evidence coming from an Italian HTA report indicates that efmoroctocog alfa provides an effective alternative to conventional FVIII preparations (including standard rFVIIIs) for the management of Haemophilia A. Moreover, by reducing the frequency of injections required, it has the potential to reduce treatment burden, and hence improve adherence to prophylaxis and patient Quality-of-Life.&nbsp

An electronic patient-reported outcome mobile app for data collection in type a hemophilia:Design and usability study

BACKGROUND: There is currently limited evidence on the level and intensity of physical activity in individuals with hemophilia A. Mobile technologies can offer a rigorous and reliable alternative to support data collection processes but they are often associated with poor user retention. The lack of longitudinal continuity in their use can be partly attributed to the insufficient consideration of stakeholder inputs in the development process of mobile apps. Several user-centered models have been proposed to guarantee that a thorough knowledge of the end user needs is considered in the development process of mobile apps. OBJECTIVE: The aim of this study is to design and validate an electronic patient-reported outcome mobile app that requires sustained active input by individuals during POWER, an observational study that aims at evaluating the relationship between physical activity levels and bleeding in patients with hemophilia A. METHODS: We adopted a user-centered design and engaged several stakeholders in the development and usability testing of this mobile app. During the concept generation and ideation phase, we organized a need-assessment focus group (FG) with patient representatives to elicit specific design requirements for the end users. We then conducted 2 exploratory FGs to seek additional inputs for the app’s improvement and 2 confirmatory FGs to validate the app and test its usability in the field through the mobile health app usability questionnaire. RESULTS: The findings from the thematic analysis of the need-assessment FG revealed that there was a demand for sense making, for simplification of app functionalities, for maximizing integration, and for minimizing the feeling of external control. Participants involved in the later stages of the design refinement contributed to improving the design further by upgrading the app’s layout and making the experience with the app more efficient through functions such as chatbots and visual feedback on the number of hours a wearable device had been worn, to ensure that the observed data were actually registered. The end users rated the app highly during the quantitative assessment, with an average mobile health app usability questionnaire score of 5.32 (SD 0.66; range 4.44-6.23) and 6.20 (SD 0.43; range 5.72-6.88) out of 7 in the 2 iterative usability testing cycles. CONCLUSIONS: The results of the usability test indicated a high, growing satisfaction with the electronic patient-reported outcome app. The adoption of a thorough user-centered design process using several types of FGs helped maximize the likelihood of sustained retention of the app’s users and made it fit for data collection of relevant outcomes in the observational POWER study. The continuous use of the app and the actual level of engagement will be evaluated during the ongoing trial. TRIAL REGISTRATION: ClinicalTrials.gov NCT04165135; https://clinicaltrials.gov/ct2/show/NCT0416513

Design of the HEM-POWR study:A prospective, observational study of real-world treatment with damoctocog alfa pegol in patients with haemophilia A

INTRODUCTION: Haemophilia A is a rare bleeding disorder caused by defects in coagulation factor VIII (FVIII). Damoctocog alfa pegol (BAY 94–9027, Jivi, Bayer, Germany) is a site-specifically PEGylated, extended-half-life, recombinant FVIII, approved for use in previously treated patients (PTPs) aged ≥12 years with haemophilia A. However, a real-world evidence regarding routine clinical use of damoctocog alfa pegol is limited. METHODS AND ANALYSIS: HEM-POWR is a multinational, multicentre, non-interventional, prospective, postmarketing cohort study evaluating the effectiveness and safety of real-world treatment with damoctocog alfa pegol. Estimated enrolment is ≥200 PTPs with haemophilia A, receiving damoctocog alfa pegol (on-demand, prophylaxis or intermittent prophylaxis (as per local label)), observed for 36 months. Primary outcomes are total bleeding events and annualised bleeding rate; secondary outcomes include long-term safety, joint health, pharmacokinetics, patient-reported outcomes (PROs) from validated questionnaires and perioperative haemostasis. Where applicable, reasons for switching to damoctocog alfa pegol, choice of treatment regimen and dose will also be captured. Exploratory and descriptive statistical analyses will be performed, and will be stratified by parameters including, but not limited to, prophylaxis regimen and haemophilia severity. Patients can record bleeds and consumption in electronic (e) Diaries, ePROs, and can access non-promotional study information (videos explaining study procedures) via an online patient portal. Optionally, patients can enrol in the LIFE-ACTIVE substudy designed to investigate the relationship between activity (measured by the ActiGraph CP Insight watch) and effectiveness parameters collected from HEM-POWR. ETHICS AND DISSEMINATION: Study approval was obtained by local independent ethics committees and authorities in participating study centres across Europe, the Americas and Asia. Informed consent from patients or their legal representative is a requirement for participation. The study results will be submitted for publication in a peer-reviewed scientific journal and presented at scientific conferences. TRIAL REGISTRATION NUMBERS: NCT03932201, EUPAS26416. PROTOCOL VERSION AND DATE: V.1.2, 27 September 2019

TNF-α/TNF-R System May Represent a Crucial Mediator of Proliferative Synovitis in Hemophilia A

Hemophilic arthropathy (HA) typically begins with proliferative synovitis that shares some similarities with inflammatory arthritides, in which the proinflammatory cytokine tumor necrosis factor (TNF)-α has a crucial pathogenetic role. Inappropriate release of TNF-α was shown to contribute to arthropathy development following intra-articular bleeding in hemophilic mice. Here, we were interested in determining whether systemic levels of TNF-α and synovial tissue expression of the TNF-α/TNF receptor (TNF-R) system could be increased and related to joint damage in hemophilia A patients with severe HA. Serum levels of TNF-α measured by quantitative enzyme-linked immunosorbent assay (ELISA) were significantly increased in HA patients (n = 67) compared to healthy controls (n = 20). In HA patients, elevated TNF-α levels were significantly associated with the number of hemarthroses, the grade of synovial hypertrophy, and both the clinical World Federation of Hemophilia score and ultrasound score. The expression of TNF-α, TNF-R1, and TNF-R2 was strongly increased in HA synovium (n = 10) compared to the non-inflamed osteoarthritis control synovium (n = 8), as assessed by both immunohistochemistry and Western blotting. Increased protein levels of TNF-α, TNF-R1, and TNF-R2 were retained in vitro by HA fibroblast-like synoviocytes (n = 6) with respect to osteoarthritis control fibroblast-like synoviocytes (n = 6). Stimulation with TNF-α resulted in a significant increase in HA fibroblast-like synoviocyte proliferation quantified by the water-soluble tetrazolium (WST)-1 assay, while it had no relevant effect on osteoarthritis fibroblast-like synoviocytes. Quantification of active/cleaved caspase-3 by ELISA demonstrated that TNF-α did not induce apoptosis either in HA or in osteoarthritis fibroblast-like synoviocytes. The TNF-α/TNF-R system may represent a crucial mediator of proliferative synovitis and, therefore, a new attractive target for the prevention and treatment of joint damage in HA patients. Our findings provide the groundwork for further clinical investigation of anti-TNF-α therapeutic feasibility in hemophiliacs