EFFICACY AND SAFETY OF EPTACOG BETA (RECOMBINANT HUMAN FVIIA) ACCORDING TO AGE IN PERSONS WITH HAEMOPHILIA A/B WITH INHIBITORS UNDERGOING SURGICAL PROCEDURES

Introduction: Eptacog beta (CEVENFACTA®) is a new rFVIIa approved by the EMA for the treatment of bleeding events and prevention of bleeding during surgery in persons with haemophilia A/B with inhibitors (PwHABI) aged ≥12 years (y). Methods: PERSEPT 3 was a Phase 3 (NCT02020369) trial of eptacog beta in PwHABI who required surgical procedures. Eptacog beta was administered at an initial dose of 200μg/kg or 75μg/kg for major or minor procedures respectively. This was followed by 75μg/kg for ≥5 (major procedures) or ≥2 (minor procedures) days. Haemostatic efficacy was assessed using a 4-point scale during the intra and postoperative care period (primary efficacy endpoint was determined by the investigator at the study centre 48±4h after the last dose of eptacog beta, based on the totality of the assessments performed on the patient (pt) at each timepoint). This post-hoc analysis compared the efficacy and safety of eptacog beta by age (pts aged \u3c12 vs ≥12y). Results: Twelve pts were included (\u3c12y: n=5, 1 major and 4 minor procedures; ≥12y: n=7, 5 major and 2 minor procedures). The primary endpoint success proportion was 100% (95% CI: 39.8-100) in pts aged \u3c12y (4 successes, 1 missing) and 71.4% (95% CI: 29.0-96.3) in pts aged ≥12y (5 successes; 2 failures). The intraoperative success proportion was 100% (95% CI: 47.8-100) for pts aged \u3c12y (5 successes) and 100% (95% CI: 59.0-100) for pts aged ≥12y (7 successes). The success proportion 24h post-procedure was 100% (95% CI: 47.8-100) for pts aged \u3c12y (5 successes) and 100% (95% CI: 47.8-100) for pts aged ≥12y (5 successes; 2 missing). Two pts discontinued treatment (1 aged \u3c12y withdrew consent; 1 aged ≥12y due to an adverse event (AE): postprocedural hematoma). One pt experienced 2 serious AEs leading to death, both were considered unrelated to the treatment. No allergic or thrombotic events occurred; no neutralising antibodies were detected. Antifibrinolytics were used concomitantly with eptacog beta in 4 patients without any safety concerns. Discussion/Conclusion: This post-hoc subgroup analysis shows that eptacog beta is effective and well-tolerated in perioperative care irrespective of patient age (\u3c12 vs ≥12y), supporting the use of eptacog beta for bleed management (prevention and treatment) in major and minor surgical procedures in all PwHABI

PK-guided switch between standard half-life and extended half-life factor VII products

P117 Introduction: Extended half-life (EHL) factor VIII (FVIII) requires improvements in half-life (t1/2) & area under the curve (AUC) of 1.3 & 1.25 times compared to standard half-life (SHL) products. The aim of this study is compare pharmacokinetics (PK) after the switch from SHL to EHL in patients with hemophilia A (HA). Methods: Multicenter comparative, cross-sectional, prospective study analyzing PK differences after switch from SHL to EHL (ef-moroctocog alfa [rFVIII-Fc] & rurioctocog alfa pegol [PEG-rFVIII]). WAPPS- Hemo® was used to analyze PK parameters with 2-3 samples: t1/2; AUC, peak level (PL); trough level at 24, 48 & 72 hours (TL24, TL48, TL72); & time to reach FVIII levels of 1, 2, 5% (T1%, T2%, T5%). Ratio of t1/2 & AUC, the number of weekly doses & the dose/kg/week before & after the switch were compared. Wilcoxon & Kruskal-Wallis tests (SPSS®) were used to compare the PK parameters. Results: Eightythree patients from 8 Spanish hospitals were analyzed (62 rFVIII-Fc; 21 PEG-rFVIII), 79 had severe HA & 4 moderate HA. Median age was 30 years (range = 3-64) & no differences in weight were observed between both periods.Dose/kg/week & weekly infusion frequency were reduced after the switch to EHL, & significant improvements were observed in all PK parameters after the change from SHL to EHL (Table 1). The median ratios of t1/2 & AUC were 1.3 (IQR:1.2-1.6) and 1.6 (IQR:1.3-2.2) in the entire cohort. In patients with =12 years ratios of t1/2 & AUC were 1.4 (IQR:1.3-1.6) & 1.7 (IQR:1.3-2.3), and in the cohort of 16 patients <12 years treated with rFVIII-Fc were 1.3 (IQR:0.9-1.5) and 1.4 (IQR:1.1- 2.1).After the switch to EHL, median weekly dose frequency (30%, IQR:0-33.3%) & dose/kg/week (16.9%, IQR:8.7-32.8%) were reduced. In a small subset of 15 younger patients the dose/kg/week was increased a median of 28.6% (IQR:11.7-40-7%). No differences were observed in any of the PK parameters & median ratios of t1/2 & AUC in patients aged =12 years treated with rFVIII-Fc vs. PEG-rFVIII (46 rFVIII-Fc; 21 PEG-rFVIII). Discussion/Conclusion: EHL FVIII have shown significant PK improvements in clinical real practice, allowing to reduce weekly infusion number & dose/kg/week. Outside the clinical trial setting, we have observed an increase in t1/2 & AUC ratios accordingly to EHL definition. Comparisons regarding clinical outcomes (bleeding rate after switch) will be performed after a follow-up of 1 year with EHL for the full cohort

Unraveling the effect of silent, intronic and missense mutations on VWF splicing: contribution of next generation sequencing in the study of mRNA

Large studies in von Willebrand disease patients, including Spanish and Portuguese registries, led to identification of >250 different mutations. It is a challenge to determine the pathogenic effect of potential splice site mutations on VWF mRNA. This study aimed to elucidate the true effects of 18 mutations on VWF mRNA processing, investigate the contribution of next-generation sequencing to in vivo mRNA study in von Willebrand disease, and compare the findings with in silico prediction. RNA extracted from patient platelets and leukocytes was amplified by RT-PCR and sequenced using Sanger and next generation sequencing techniques. Eight mutations affected VWF splicing: c.1533+1G>A, c.5664+2T>C and c.546G>A (p.=) prompted exon skipping; c.3223-7_3236dup and c.7082-2A>G resulted in activation of cryptic sites; c.3379+1G>A and c.7473G>A (p.=) demonstrated both molecular pathogenic mechanisms simultaneously; and the p.Cys370Tyr missense mutation generated two aberrant transcripts. Of note, the complete effect of 3 mutations was provided by next generation sequencing alone because of low expression of the aberrant transcripts. In the remaining 10 mutations, no effect was elucidated in the experiments. However, the differential findings obtained in platelets and leukocytes provided substantial evidence that 4 of these would have an effect on VWF levels. In this first report using next generation sequencing technology to unravel the effects of VWF mutations on splicing, the technique yielded valuable information. Our data bring to light the importance of studying the effect of synonymous and missense mutations on VWF splicing to improve the current knowledge of the molecular mechanisms behind von Willebrand disease.info:eu-repo/semantics/publishedVersio

Unraveling the effect of silent, intronic and missense mutations on VWF splicing: contribution of next generation sequencing in the study of mRNA

Large studies in von Willebrand disease patients, including Spanish and Portuguese registries, led to the identification of >250 different mutations. It is a challenge to determine the pathogenic effect of potential splice site mutations on VWF mRNA. This study aimed to elucidate the true effects of 18 mutations on VWF mRNA processing, investigate the contribution of next-generation sequencing to in vivo mRNA study in von Willebrand disease, and compare the findings with in silico prediction. RNA extracted from patient platelets and leukocytes was amplified by RT-PCR and sequenced using Sanger and next generation sequencing techniques. Eight mutations affected VWF splicing: c.1533+1G>A, c.5664+2T>C and c.546G>A (p.=) prompted exon skipping; c.3223-7_3236dup and c.7082-2A>G resulted in activation of cryptic sites; c.3379+1G>A and c.7437G>A) demonstrated both molecular pathogenic mechanisms simultaneously; and the p.Cys370Tyr missense mutation generated two aberrant transcripts. Of note, the complete effect of three mutations was provided by next generation sequencing alone because of low expression of the aberrant transcripts. In the remaining 10 mutations, no effect was elucidated in the experiments. However, the differential findings obtained in platelets and leukocytes provided substantial evidence that four of these would have an effect on VWF levels. In this first report using next generation sequencing technology to unravel the effects of VWF mutations on splicing, the technique yielded valuable information. Our data bring to light the importance of studying the effect of synonymous and missense mutations on VWF splicing to improve the current knowledge of the molecular mechanisms behind von Willebrand disease. clinicaltrials.gov identifier:02869074

A multi-stakeholder multicriteria decision analysis for the reimbursement of orphan drugs (FinMHU-MCDA study)

Background: Patient access to orphan medicinal products (OMPs) is limited and varies between countries, reimbursement decisions on OMPs are complex, and there is a need for more transparent processes to know which criteria should be considered to inform these decisions. This study aimed to determine the most relevant criteria for the reimbursement of OMPs in Spain, from a multi-stakeholder perspective, and using multicriteria decision analysis (MCDA). Methods: An MCDA was developed in 3 phases and included 28 stakeholders closely related to the field of rare diseases (6 physicians, 5 hospital pharmacists, 7 health economists, 4 patient representatives and 6 members from national and regional health authorities). Initially [phase A], a bibliographic review was conducted to identify the potential reimbursement criteria. Then, a reduced advisory board (8 members) proposed, selected, and defined the final list of criteria that could be relevant for reimbursement. A discrete choice experiment (DCE) [phase B] was developed to determine the relevance and relative importance weight of such criteria according to the stakeholders’ preferences by choosing between pairs of hypothetical financing scenarios. A multinomial logit model was fitted to analyze the DCE responses. Finally [phase C], the advisory board review the results using a deliberative process. Results: Thirteen criteria were selected, related to 4 dimensions: patient population, disease, treatment, and economic evaluation. Nine criteria were deemed relevant for decision-making and associated with a higher relative importance: Health-related quality of life (HRQL) (23.53%), treatment efficacy (14.64%), availability of treatment alternatives (13.51%), disease severity (12.62%), avoided costs (11.21%), age of target population (7.75%), safety (seriousness of adverse events) (4.72%), quality of evidence (3.82%) and size of target population (3.12%). The remaining criteria had a < 3% relative importance: economic burden of disease (2.50%), cost of treatment (1.73%), cost-effectiveness (0.83%) and safety (frequency of adverse events) (0.03%). Conclusion: The reimbursement of OMPs in Spain should be determined by its effect on patient’s HRQL, the extent of its therapeutic benefit from efficacy and the availability of other therapeutic options. Furthermore, the severity of the rare disease should also influence the decision along with the potential of the treatment to avoid associated costs

Análisis del switch guiado por farmacocinética de factores VIII de semivida estándar a factores de semivida extendida

CO-170 Introducción y objetivos: Los factores VIII (FVIII) de semivida extendida (EHL) han mostrado en los ensayos clínicos mejoras de al menos 1, 3 veces la semivida plasmática (t1/2) y 1, 25 veces el área bajo la curva (AUC) respecto a los FVIII estándar (SHL). Herramientas basadas en modelos farmacocinéticos (PK) poblacionales permiten estimar los parámetros PK individuales y ajustar la profilaxis. El objetivo de este estudio es analizar el switch PK-guiado de SHL a EHL en pacientes con hemofilia A (HA). Métodos: Estudio multicéntrico comparativo, cruzado, prospectivo que analiza las diferencias PK tras el cambio de factores SHL a EHL (Elocta® y Adynovi®) en pacientes con HA grave/moderada en profilaxis. Se ha empleado el PopPK WAPPS-Hemo® con 2-3 muestras para realizar un perfil PK individualizado de los valores de FVIII. Los parámetros PK analizados son: t1/2, AUC, nivel pico (NP), nivel valle a las 24, 48 y/o 72 h (NV24/NV48/NV72) y tiempo para alcanzar niveles de FVIII del 5%, 2% y 1% (T5%/T2%/T1%). También analizamos los ratios de t1/2 y AUC, el nº dosis semanales y la dosis/kg/semana. Para comparar los parámetros PK entre ambos periodos empleamos los test de Wilcoxon y Kruskal-Wallis (SPSS®). Los resultados se expresaron con la mediana y el rango o rango intercuartílico (RIC). Resultados: Se han analizado 64 pacientes procedentes de 8 hospitales españoles (48 switch a Elocta® y 16 a Adynovi®), 62 con HA grave y 2 con HA moderada, con una mediana de edad de 32 años (rango=5-64) y sin diferencias en el peso entre ambos periodo [71, 0 (rango=12-116) vs 72, 0 (16, 9- 116) kg; p=0, 156]. La dosis/kg/semana se redujo tras el switch a EHL [74, 5 (RIC:59, 2-108, 1) vs 69, 2 (RIC:46, 2-96, 7) UI/kg/semana; p<0, 0001], así como ..

Timing and severity of inhibitor development in recombinant versus plasma-derived factor VIII concentrates: a SIPPET analysis

Essentials Recombinant factor VIII (rFVIII) was contrasted with plasma-derived FVIII (pdFVIII). In previously untreated patients with hemophilia A, rFVIII led to more inhibitors than pdFVIII. Inhibitors with rFVIII developed earlier, and the peak rate was higher than with pdFVIII. Inhibitors with rFVIII were more severe (higher titre) than with pdFVIII. Summary: Background The development of neutralizing antibodies (inhibitors) against factor VIII (FVIII) is the most severe complication in the early phases of treatment of severe hemophilia A. Recently, a randomized trial, the Survey of Inhibitors in Plasma-Product Exposed Toddlers (SIPPET) demonstrated a 2-fold higher risk of inhibitor development in children treated with recombinant FVIII (rFVIII) products than with plasma-derived FVIII (pdFVIII) during the first 50 exposure days (EDs). Objective/Methods In this post-hoc SIPPET analysis we evaluated the rate of inhibitor incidence over time by every 5 EDs (from 0 to 50 EDs) in patients treated with different classes of FVIII product, made possible by a frequent testing regime. Results The highest rate of inhibitor development occurred in the first 10 EDs, with a large contrast between rFVIII and pdFVIII during the first 5 EDs: hazard ratio 3.14 (95% confidence interval [CI], 1.01\ue2\u80\u939.74) for all inhibitors and 4.19 (95% CI, 1.18\ue2\u80\u9314.8) for high-titer inhibitors. For patients treated with pdFVIII, the peak of inhibitor development occurred later (6\ue2\u80\u9310 EDs) and lasted for a shorter time. Conclusion These results emphasize the high immunologic vulnerability of patients during the earliest exposure to FVIII concentrates, with the strongest response to recombinant FVIII products

Radiosynoviorthesis in the treatment of recurrent hemarthrosis in patients with haemophilia: experience in a single center

Resumen de ponencia presentada al: 10th Annual Congress of the European Association for Haemophilia and Allied Disorders 2017, 1–3 February 2017, Paris, Franc