Brief Reports
Vol. 5 No. 1 (2026)
https://doi.org/10.4081/btvb.2026.413

Pharmacokinetics of extended half-life albumin-fused factor IX and heterogeneous F9 variants in hemophilia B: a retrospective cohort study

Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
Published: 2 March 2026
286
Views
154
Downloads
Hemophilia B, F9 variants, extended half-life rFIX, pharmacokinetics, clearance

Authors

Barbara Lunghi
Department of Life Sciences and Biotechnology, University of Ferrara, Italy.
Massimo Morfini
Italian Association or Hemophilia Centers (AICE), Milan, Italy.
Silvia Linari
Center for Bleeding Disorders, Careggi University Hospital, Florence, Italy.
Dario Balestra
Department of Life Sciences and Biotechnology, University of Ferrara, Italy.
Alessio Branchini
Department of Life Sciences and Biotechnology, University of Ferrara, Italy.
Lisa Pieri
Center for Bleeding Disorders, Careggi University Hospital, Florence, Italy.
Donata Belvini
Oncohematology-Oncologic Institute of Veneto, Castelfranco Veneto Hospital, Castelfranco Veneto, Italy.
Laura Banov
Thrombosis and Hemostasis Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
Cristina Santoro
Department of Hematology, University Hospital Policlinico Umberto I, Rome, Italy.
Giancarlo Castaman
Center for Bleeding Disorders, Careggi University Hospital, Florence, Italy.
Francesco Bernardi
francesco.bernardi@unife.it
https://orcid.org/0000-0003-0305-2212
Department of Life Sciences and Biotechnology, University of Ferrara, Italy.

No information is available about the influence exerted by F9 variants on extended half-life (EHL)-recombinant factor IX (rFIX) pharmacokinetics (PK). Adult patients with severe HB (n=41), infused with EHL albumin-fused-rIX-FP, were investigated for key parameters, obtained by Non-Compartmental Analysis (NCA), and for F9 variants, grouped by non-null (n=27) and null (n=14) lesions. Distribution of PK parameters did not differ between genotype groups. However, clearance in the first tertile, including favorable PK profiles, was slower (p=0.003) in patients with null (mean 0.52 mL/h/kg) than in non-null (mean 0.62 mL/h/kg) variants, and non-null genotypes were more frequent in the third tertile (p=0.046). Missense variant bioinformatics analyses predicted more severe disease features in the third than in the first tertile. These exploratory results suggest i) a moderate role of F9 variant type in inter-individual EHL-rFIX clearance variability and ii) differences in F9 genotype-PK NCA parameter association between EHL- and standard half-life-rFIX products.

Downloads

Download data is not yet available.

Citations

Crossref
Scopus
Google Scholar
Europe PMC
1. Björkman S, Berntorp E. Pharmacokinetics of coagulation factors: clinical relevance for patients with haemophilia. Clin Pharmacokinet 2001;40:815-32. DOI: https://doi.org/10.2165/00003088-200140110-00003
2. Santagostino E, Martinowitz U, Lissitchkov T, et al. Long-acting recombinant coagulation factor IX albumin fusion protein (rIX-FP) in hemophilia B: results of a phase 3 trial. Blood 2016;127:1761-9. DOI: https://doi.org/10.1182/blood-2015-09-669234
3. Björkman S, Shapiro AD, Berntorp E. Pharmacokinetics of recombinant factor IX in relation to age of the patient: implications for dosing in prophylaxis. Haemophilia 2001;7:133-9. DOI: https://doi.org/10.1046/j.1365-2516.2001.00465.x
4. Roth DA, Kessler CM, Pasi KJ, et al. Human recombinant factor IX: safety and efficacy studies in hemophilia B patients previously treated with plasma-derived factor IX concentrates. Blood 2001;98:3600-6. DOI: https://doi.org/10.1182/blood.V98.13.3600
5. Morfini M, Dragani A, Paladino E, et al. Correlation between FIX genotype and pharmacokinetics of Nonacog alpha according to a multicentre Italian study. Haemophilia 2016;22:537-42. DOI: https://doi.org/10.1111/hae.12916
6. Cooley B, Broze GJ, Mann DM, et al. Dysfunctional endogenous FIX impairs prophylaxis in a mouse hemophilia B model. Blood 2019;133:2445-51. DOI: https://doi.org/10.1182/blood.2018884015
7. Branchini A, Morfini M, Lunghi B, et al. F9 missense mutations impairing factor IX activation are associated with pleiotropic plasma phenotypes. J Thromb Haemost 2022;20:69-81. DOI: https://doi.org/10.1111/jth.15552
8. Metzner HJ, Weimer T, Kronthaler U, et al. Genetic fusion to albumin improves the pharmacokinetic properties of factor IX. Thromb Haemost 2009;102:634-44. DOI: https://doi.org/10.1160/TH09-04-0255
9. Lyseng-Williamson KA. Coagulation factor IX (recombinant), albumin fusion protein (Albutrepenonacog Alfa; Idelvion®): a review of its use in haemophilia B. Drugs 2017;77:97-106. DOI: https://doi.org/10.1007/s40265-016-0679-8
10. Escobar M, Mancuso ME, Hermans C, et al. IDELVION: a comprehensive review of clinical trial and real-world data. J Clin Mrd 2022;11:1071. DOI: https://doi.org/10.3390/jcm11041071
11. Rousseeuw PJ. Silhouettes: A graphical aid to the interpretation and validation of cluster analysis. J Comput Appl Math 1987;20:53-65. DOI: https://doi.org/10.1016/0377-0427(87)90125-7
12. Reva B, Antipin Y, Sander C. Determinants of protein function revealed by combinatorial entropy optimization. Genome Biol 2007;8:R232. DOI: https://doi.org/10.1186/gb-2007-8-11-r232
13. Carter H, Douville C, Stenson PD, et al. Identifying Mendelian disease genes with the variant effect scoring tool. BMC Genomics 2013;14:S3. DOI: https://doi.org/10.1186/1471-2164-14-S3-S3
14. Choi Y, Chan AP. PROVEAN web server: a tool to predict the functional effect of amino acid substitutions and indels. Bioinformatics 2015;31:2745-7. DOI: https://doi.org/10.1093/bioinformatics/btv195
15. Stafford DW. Extravascular FIX and coagulation. Thrombosis J 2016;14:S35. DOI: https://doi.org/10.1186/s12959-016-0104-2
16. Miller GJ, Howarth DJ, Attfield JC, et al. Haemostatic factors in human peripheral afferent lymph. Thromb Haemost 2000;83:427-32. DOI: https://doi.org/10.1055/s-0037-1613832
17. Gui T, Lin HF, Jin DY, et al. Circulating and binding characteristics of wild-type factor IX and certain Gla domain mutants in vivo. Blood 2002;100:153-8. DOI: https://doi.org/10.1182/blood.V100.1.153
18. Zhang H, Chen C, Wu X, et al. Effects of 14 F9 synonymous codon variants on hemophilia B expression: Alteration of splicing along with protein expression. Hum Mutat 2022;43:928-39. DOI: https://doi.org/10.1002/humu.24377

Ethics Approval

Patients with severe HB were enrolled in a global phase 3 study (www.clinicaltrials.gov, #NCT0101496274), Italian Association of Hemophilia Centres (AICE) initiatives (Genotype-Phenotype PK Study, GePKHIS, EudraCT ID2017‐003902–42)

CRediT authorship contribution

Massimo Morfini, Giancarlo Castaman, Francesco Bernardi, conception and design; Barbara Lunghi, Silvia Linari, Dario Balestra, Alessio Branchini, Lisa Pieri, Donata Belvini, Laura Banov, Cristina Santoro, data analysis and interpretation; Barbara Lunghi, Massimo Morfini, Giancarlo Castaman, Francesco Bernardi, writing – manuscript drafting; all authors, writing – manuscript review for important intellectual content. All authors have read and approved the final version of the manuscript and agreed to be accountable for all aspects of the work.

Supporting Agencies

European Union – NextGenerationEU

Data Availability Statement

All relevant data are included in the manuscript. Further original data will be made available by contacting the corresponding author within the regulations of the ethical approval.  

How to Cite



1.
Lunghi B, Morfini M, Linari S, Balestra D, Branchini A, Pieri L, et al. Pharmacokinetics of extended half-life albumin-fused factor IX and heterogeneous F9 variants in hemophilia B: a retrospective cohort study. Bleeding Thromb Vasc Biol [Internet]. 2026 Mar. 2 [cited 2026 Jun. 24];5(1). Available from: https://www.btvb.org/btvb/article/view/413
Copyright (c) 2026 The Author(s) Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.


Most read articles by the same author(s)

<< < 1 2