Evaluation of Factor VIII Polysialylation: Identification of a Longer-Acting Experimental Therapy in Mice and Monkeys

The Journal of Pharmacology and Experimental Therapeutics
Helmut GlantschnigWerner Höllriegl

Abstract

Extended half-life (EHL) factor therapies are needed to reduce the burden of prophylaxis and improve treatment adherence in patients with hemophilia. BAX 826 is a novel polysialylated full-length recombinant factor VIII [polysialyic acid (PSA) rFVIII] with improved pharmacokinetics (PK), prolonged pharmacology, and maintained safety attributes to enable longer-acting rFVIII therapy. In factor VIII (FVIII)-deficient hemophilic mice, PSArFVIII showed a substantially higher mean residence time (>2-fold) and exposure (>3-fold), and prolonged efficacy in tail-bleeding experiments (48 vs. 30 hours) compared with unmodified recombinant FVIII (rFVIII), as well as a potentially favorable immunogenicity profile. Reduced binding to a scavenger receptor (low-density lipoprotein receptor-related protein 1) and von Willebrand factor (VWF) as well as a largely VWF-independent circulation time in mice provide a rationale for prolonged BAX 826 activity. The significantly improved PK profile versus rFVIII was confirmed in cynomolgus monkeys [mean residence time: 23.4 vs. 10.1 hours; exposure (area under the curve from time 0 to infinity): 206 vs. 48.2 IU/ml⋅h] and is in line with results from rodent studies. Finally, safety and toxicity evaluati...Continue Reading

References

Aug 1, 1986·Proceedings of the National Academy of Sciences of the United States of America·J J TooleR J Kaufman
Jan 11, 1993·FEBS Letters·G GregoriadisR Lifely
Feb 24, 2001·Cellular and Molecular Life Sciences : CMLS·G GregoriadisB McCormack
Apr 9, 2001·International Journal of Pharmaceutics·A I Fernandes, G Gregoriadis
Dec 12, 2001·Clinical Pharmacokinetics·S Björkman, E Berntorp
Jun 28, 2003·Biochimica Et Biophysica Acta·Sanjay JainGregory Gregoriadis
Nov 1, 1959·Journal of Applied Physiology·S WESSLERM C SHEPS
Jul 28, 2005·International Journal of Pharmaceutics·Gregory GregoriadisPeter Laing
Aug 17, 2005·Journal of Thrombosis and Haemostasis : JTH·S W Pipe
Mar 1, 2008·Bioconjugate Chemistry·Antony ConstantinouMahendra P Deonarain
May 1, 2009·Bioconjugate Chemistry·A ConstantinouM P Deonarain
Mar 29, 2013·Haemophilia : the Official Journal of the World Federation of Hemophilia·L TangJ E Murphy
Jul 17, 2013·Journal of Thrombosis and Haemostasis : JTH·F PeyvandiS Seregni
Nov 15, 2013·Blood·Johnny MahlanguUNKNOWN A-LONG Investigators
Aug 19, 2014·Journal of Thrombosis and Haemostasis : JTH·A SchivizUNKNOWN Subcommittee on Animal Models of the Scientific and Standardization Committee of the International Society on Thrombosis and
Jul 8, 2015·Journal of Thrombosis and Haemostasis : JTH·A Tiede
Oct 13, 2015·British Journal of Haematology·Mike Laffan
Oct 17, 2017·Patient Preference and Adherence·Courtney D Thornburg, Natalie A Duncan
Oct 21, 2017·Therapeutic Advances in Hematology·Lorraine A Cafuir, Christine L Kempton
Feb 2, 2018·Therapeutic Advances in Hematology·Pauline Balkaransingh, Guy Young
Apr 11, 2018·Haemophilia : the Official Journal of the World Federation of Hemophilia·J MahlanguE Santagostino
May 8, 2018·Haemophilia : the Official Journal of the World Federation of Hemophilia·C HermansE Berntorp

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Citations

Nov 30, 2019·Haemophilia : the Official Journal of the World Federation of Hemophilia·Andreas TiedeShouryadeep Srivastava
Oct 20, 2019·Journal of Pharmaceutical Sciences·Alfred WeberPeter L Turecek

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