rFIX

The precise measurement of very low levels of factor IX activity (FIX:C < 1 IU/dL) is essential for understanding clinical severity and risk of inhibitor development in patients with severe hemophilia B (Pw-SHB). However, such measurement sensitivity has not yet been achieved. We aimed to establish a measurement method using clot waveform analysis (CWA). Residual FIX:C by adding anti-FIX monoclonal antibody, FIX:C by adding recombinant (r)FIX to the commercial Pw-SHB plasmas, and FIX:C in our Pw-SHB were determined by CS-2000i™ /CS-2400™ , followed by analysis of CWA parameters...

Extended half-life FIX (EHL-FIX) concentrates have been developed with the purpose of reducing the frequency of infusions in patients with severe or moderate hemophilia B. We describe the case of a 63-year-old patient with severe hemophilia B (sHB) treated with FIX-Fc fusion protein (rFIXFc) who underwent neurosurgery.

Background: The Canadian Bleeding Disorders Registry (CBDR) captures data from 24 hemophilia treatment centers and patients directly. Nonacog beta pegol (N9-GP) was approved in Canada in 2018. Objectives: To assess treatment outcomes following switching to N9-GP in a real-world setting. Methods: CBDR data for Canadian male patients (aged 7-72 years) with hemophilia B receiving prophylactic N9-GP for ≥6 months as of March 31, 2021, were included...

Water soluble polymers and their derivatives bound to proteins can dramatically favor the biological activity of new drugs and vaccines. Quantification of the modification degree of the protein is crucial during the development and licensing phase and later in order to monitor the industrial production process and to match product specification. In this work, we describe an innovative way to measure directly the modification degree of polysialylated proteins using proton NMR (Nuclear Magnetic Resonance) spectroscopy...

Progress in hemophilia therapy has been remarkable in the first 20 years of the third millennium, but the innovation began with the description the fractionation of plasma in 1946. The first concentrates followed the discovery of FVIII in the cryoprecipitate of frozen plasma and FIX in the supernatant in the early 1960s, which led to the initial attempts at replacement therapy. Unfortunately, the lack of screening methods for viral pathogens resulted in people with hemophilia (PWH) receiving concentrates contaminated by hepatitis A virus, hepatitis C virus, and human immunodeficiency virus, as these concentrates were made from large industrial pools of plasma derived from thousands of donors...

INTRODUCTION: In 2017, all people with severe haemophilia B (PWSHB) in Ireland switched from standard half-life (SHL) recombinant FIX (rFIX) to rFIX Fc fusion protein (rFIXFc) prophylaxis. AIMS: To evaluate prophylaxis regimens, bleeding rates and factor usage for two years of rFIXFc prophylaxis in a real-world setting. METHODS: Data collected retrospectively from electronic diaries and medical records of PWSHB for a two-year period on rFIXFc prophylaxis were compared with paired baseline data on SHL rFIX treatment...

Recently, the Chinese hamster ovary (CHO) cell-based clustering assay replaced the in vivo Histamine Sensitisation Test (HIST) in mice in European Pharmacopoeia (Ph. Eur.) general chapter 2.6.33. ‘Residual pertussis toxin’ as the recommended method to test for residual pertussis toxin in acellular pertussis vaccine intermediates. To support the standardised CHO clustering assay, availability of a reference standard is critical. Ph. Eur. pertussis toxin Biological Reference Preparation (BRP) batch 1 was first calibrated in International Units in 2008 for the HIST and subsequently also calibrated for the CHO clustering assay in 2017...

BACKGROUND: The anti-tissue factor plasma inhibitor monoclonal antibody concizumab is under clinical investigation for subcutaneous prophylaxis of hemophilia A/B (HA/HB) with or without inhibitors. Breakthrough bleeds while on concizumab prophylaxis may be treated with bypassing agents (recombinant activated factor VIIa [rFVIIa] and activated prothrombin complex concentrate [APCC]), or with factor VIII (FVIII) or factor IX (FIX). OBJECTIVES: To evaluate the effect of combining concizumab with rFVIIa, APCC, rFVIII, and rFIX on thrombin generation (TG) potential...

A joint World Health Organization (WHO) - European Directorate for the Quality of Medicines & HealthCare (EDQM) study was run to calibrate the WHO 5th International Standard (IS) for Blood Coagulation Factor IX (FIX), Concentrate, and European Pharmacopoeia (Ph. Eur.) Human Coagulation Factor IX concentrate Biological Reference Preparation (BRP) Batch 3. The suitability of the 4th IS as a potency standard for purified full-length recombinant FIX (rFIX) was also investigated. Forty-nine laboratories contributed data for the calibration of 2 plasma-derived FIX candidates, relative to the 4th IS, from clotting and chromogenic assays...

Coagulation factor IX (FIX) is a complex post-translationally modified human serum glycoprotein and high-value biopharmaceutical. The quality of recombinant FIX (rFIX), especially complete γ-carboxylation, is critical for rFIX clinical efficacy. Bioreactor operating conditions can impact rFIX production and post-translational modifications (PTMs). With the goal of optimizing rFIX production, we developed a suite of Data Independent Acquisition Mass Spectrometry (DIA-MS) proteomics methods and used these to investigate rFIX yield, γ-carboxylation, other PTMs, and host cell proteins during bioreactor culture and after purification...

PURPOSE: Pharmacokinetic (PK) differences between the extended half-life (EHL) factor IX (FIX) concentrates for hemophilia B exist, which may influence hemostatic efficacy of replacement therapy in patients. Therefore, we aimed to evaluate the PK properties of three EHL-FIX concentrates and compare them to a standard half-life (SHL) recombinant FIX (rFIX) concentrate. METHODS: Activity-time profiles of PEGylated FIX (N9-GP), FIX linked with human albumin (rIX-FP), FIX coupled to human IgG1 Fc-domain (rFIXFc), and SHL rFIX were simulated for 10,000 patients during steady-state dosing of 40 IU/kg once weekly (EHL-FIX) and biweekly (rFIX) using published concentrate specific population PK models...

BACKGROUND: Few have assessed physical activity (PA) and annual bleed rates (ABRs) among people with hemophilia on extended half-life (EHL) factors (recombinant factor VIII Fc [rFVIIIFc]/recombinant factor IX Fc [rFIXFc]) and conventional factors (recombinant factor VIII [rFVIII]/recombinant factor IX [rFIX]). OBJECTIVE: To assess changes in PA and ABR at consecutive annual visits in individuals with severe hemophilia A and B (HA/HB) on prophylactic treatment with rFVIIIFc/rFIXFc versus rFVIII/rFIX...

Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder that is known to have a polygenic (i.e., many genes of individually small effects) architecture. Polygenic scores (PGS), which characterize this polygenicity as a single score for a given individual, are considered the state-of-the-art in psychiatric genetics research. Despite the proliferation of ADHD studies adopting this approach and its clinical implications, remarkably little is known about the predictive utility of PGS in ADHD research to date, given that there have not yet been any systematic or meta-analytic reviews of this rapidly developing literature...

A 57-year-old man with mild haemophilia B was admitted for coronary artery bypass graft surgery. His factor IX (FIX) activity was 15% on admission. Our goal was to maintain his FIX activity at 80%-100% for post-op days (PODs) 0-3, and at 60%-80% for PODs 4-14. Preoperatively, the patient was given recombinant FIX (rFIX) bolus using the formula:Dosage needed=%(desired FIX level-current level of FIX)×weight (kg)×1.3.This increased his activity to 100%. One IU of rFIX increased FIX activity by 0.8%; the half-life of rFIX is 18-24 hours...

Eftrenonacog-alfa is a recombinant factor IX-Fc fusion protein increasingly prescribed in hemophilia B patients. We aimed to assess its pharmacodynamics (PD) in real-life setting via FIX activity measurement and thrombin generation assay (TGA). Sixty samples from 15 severe hemophilia B treated patients were collected at different time points. FIX activity was measured using product-specific one-stage clotting assay (reference method) and two chromogenic assays (CSA) (Biophen FIX and Rox FIX). TGA was triggered with 1 pM tissue factor...

INTRODUCTION: In sub-Saharan Africa, access to clotting factor concentrates (CFCs) is often extremely limited and published data on people with haemophilia on prophylaxis are almost not existent. AIMS AND METHODS: To assess the feasibility, barriers and outcomes of a low-dose and low-frequency prophylaxis with extended half-life (EHL) recombinant Fc fusion FVIII and FIX in Ivorian children on a two-year period in the setting of the World Federation of Hemophilia's (WFH) humanitarian aid programme...

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Extended half-life of factor IX (FIX) demonstrated clinical benefit and lower treatment burden than standard half-life FIX products in clinical trials. We analysed the impact in efficacy, pharmacokinetics (PKs) and costs of the switch from nonacog alfa (rFIX) to albutrepenonacog alfa (rFIX-FP) in the first patient with haemophilia B (HB) treated in Spain outside clinical trials. A 7-year-old boy presented with HB with poor venous access and repetition infections using rFIX, which was switched to rFIX-FP. Prophylaxis was adjusted by PKs using WAPPS-Hemo tailoring from 100 IU/kg/week of rFIX to 80 IU/kg/3 weeks of rFIX-FP...

BACKGROUND: Hemophilia B is caused by coagulation factor IX (FIX) deficiency. Recombinant fusion protein linking coagulation FIX with recombinant albumin (rIX-FP; Idelvion® ) is used for replacement therapy with an extended half-life. A previous quantitative whole-body autoradiography (QWBA) study investigating the biodistribution of rIX-FP indicated equal biodistribution, but more prolonged tissue retention compared with a marketed recombinant FIX product. OBJECTIVES: To complete and confirm the QWBA study data by directly measuring rIX-FP protein and activity levels in tissues following intravenous (i...

The effect of the GlycoPEGylation process used for prolonging the half-life of recombinant factor IX (rFIX) has no impact on the primary and higher order structure of activated factor IX. Characterisation work performed on recombinant factor IX and on the GlycoPEGylated form of rFIX (N9-GP), confirm that the primary structure as well as the post translational modifications (PTMs) (disulphide bonds, γ-carboxylation, β-hydroxylation, sulphation and O- and N-linked glycan structures) were comparable for rFIX and N9-GP...