Inhibition of Tissue Factor Pathway Inhibitor (TFPI) as a Treatment for Haemophilia: Rationale with Focus on Concizumab

Drugs
P Chowdary

Abstract

Replacement therapy with missing factor (F) VIII or IX in haemophilia patients for bleed management and preventative treatment or prophylaxis is standard of care. Restoration of thrombin generation through novel mechanisms has become the focus of innovation to overcome limitations imposed by protein replacement therapy. Tissue factor pathway inhibitor (TFPI) is a multivalent Kunitz-type serine protease inhibitor that regulates tissue factor (TF)-induced coagulation through a FXa-dependent feedback inhibition of the TF.FVIIa complex in plasma and on endothelial surfaces. Concizumab is a monoclonal, humanised antibody, specific for the second Kunitz domain of TFPI that binds and inhibits FXa, abolishing the inhibitory effect of TFPI. Concizumab restored thrombin generation in FVIII and FIX deficient plasmas and decreased blood loss in a rabbit haemophilia model. Phase 1 single and multiple dose escalation studies in haemophilia patients demonstrated a dose dependent decrease in TFPI levels and a pro-coagulant effect with increasing d-dimers and prothrombin fragment 1 + 2. A dose dependent increase in peak thrombin and endogenous thrombin potential was observed with values in the normal range when plasma TFPI levels were nearly un...Continue Reading

References

Jul 1, 1992·Journal of Internal Medicine·I M NilssonH Pettersson
Nov 1, 1990·Proceedings of the National Academy of Sciences of the United States of America·M S BajajS P Bajaj
Apr 1, 1985·British Journal of Haematology·S A Larsson
Sep 1, 1994·Clinical Pharmacology and Therapeutics·G Levy
Jul 1, 1995·Blood Coagulation & Fibrinolysis : an International Journal in Haemostasis and Thrombosis·E ErhardtsenO Nordfang
Mar 21, 1998·The Journal of Biological Chemistry·R J BaughS Krishnaswamy
Jun 9, 2001·The New England Journal of Medicine·P M Mannucci, E G Tuddenham
Jul 11, 2003·Pathophysiology of Haemostasis and Thrombosis·H Coenraad HemkerSuzette Béguin
Oct 29, 2005·Arteriosclerosis, Thrombosis, and Vascular Biology·Dougald M Monroe, Maureane Hoffman
Feb 14, 2006·Biochemical Pharmacology·Donald E Mager
Feb 21, 2006·Proceedings of the National Academy of Sciences of the United States of America·Tilman M HackengJan Rosing
Feb 12, 2008·Transfusion and Apheresis Science : Official Journal of the World Apheresis Association : Official Journal of the European Society for Haemapheresis·Susan A Maroney, Alan E Mast
Aug 30, 2008·The New England Journal of Medicine·Bruce Furie, Barbara C Furie
May 9, 2009·Journal of Thrombosis and Haemostasis : JTH·S A MaroneyA E Mast
Jul 9, 2010·Haemophilia : the Official Journal of the World Federation of Hemophilia·U Hedner, C A Lee
Nov 4, 2011·The New England Journal of Medicine·Cindy LeissingerLorenzo Mantovani
Dec 29, 2011·Frontiers in Bioscience (Landmark Edition)·George J Broze, Thomas J Girard
Feb 23, 2012·Proceedings of the National Academy of Sciences of the United States of America·Susan A MaroneyAlan E Mast
Jun 29, 2012·Haemophilia : the Official Journal of the World Federation of Hemophilia·P W Collins
Jul 11, 2012·Haemophilia : the Official Journal of the World Federation of Hemophilia·A SrivastavaUNKNOWN Treatment Guidelines Working Group on Behalf of The World Federation Of Hemophilia
Oct 11, 2012·JAMA : the Journal of the American Medical Association·Carolyn R BroderickSimon A Brown
Nov 20, 2012·British Journal of Haematology·Peter W CollinsUNKNOWN UK Haemophilia Centre Doctors
Sep 12, 2013·Seminars in Thrombosis and Hemostasis·Matteo Nicola Dario Di MinnoGiovanni Di Minno
Oct 16, 2013·Proceedings of the National Academy of Sciences of the United States of America·Jeremy P WoodAlan E Mast
Feb 27, 2014·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Henrik AgersøIda Hilden
Mar 13, 2014·Blood·Jeremy P WoodAlan E Mast
Apr 10, 2014·Haemophilia : the Official Journal of the World Federation of Hemophilia·L A Valentino
Jul 26, 2014·Journal of Thrombosis and Haemostasis : JTH·V S BlanchetteA Srivastava
Mar 31, 2015·British Journal of Haematology·Rolf Ljung, Nadine Gretenkort Andersson
Nov 26, 2015·Arteriosclerosis, Thrombosis, and Vascular Biology·Alan E Mast
Feb 18, 2016·Haemophilia : the Official Journal of the World Federation of Hemophilia·K VaradiP L Turecek
Jul 12, 2017·The New England Journal of Medicine·Johannes OldenburgMidori Shima
Jul 12, 2017·The New England Journal of Medicine·K John PasiMargaret V Ragni
Dec 6, 2017·Therapeutic Advances in Hematology·Muriel Giansily-Blaizot, Jean-François Schved

❮ Previous
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Citations

Sep 29, 2018·Journal of Thrombosis and Haemostasis : JTH·A D ShapiroS Nasr
Nov 20, 2018·Expert Review of Hematology·Johnny Mahlangu
May 2, 2020·Haemophilia : the Official Journal of the World Federation of Hemophilia·Johnny N Mahlangu
Jun 24, 2020·Expert Review of Hematology·Leonard A Valentino, Kate Khair
Sep 17, 2020·Haemophilia : the Official Journal of the World Federation of Hemophilia·Carmen Escuriola-EttingshausenJohannes Oldenburg
Nov 16, 2018·Blood Coagulation & Fibrinolysis : an International Journal in Haemostasis and Thrombosis·Saravanan SubramaniamCraig Fletcher
Nov 30, 2019·Blood·Robert F Sidonio, Karen L Zimowski
Feb 6, 2020·Expert Opinion on Investigational Drugs·Massimo FranchiniGiancarlo Maria Liumbruno
Nov 21, 2020·Haemophilia : the Official Journal of the World Federation of Hemophilia·Steven W PipeUNKNOWN Coagulation Products Safety, Supply and Access (CPSSA) Committee of the World Federation of Hemophilia
Dec 18, 2019·Molecular Therapy : the Journal of the American Society of Gene Therapy·John S S ButterfieldRadoslaw Kaczmarek
May 1, 2021·International Journal of Molecular Sciences·Max LiuYolanda M Fortenberry
May 1, 2021·International Journal of Molecular Sciences·Cristina LupuFlorea Lupu
May 18, 2021·Molecular Therapy. Nucleic Acids·Wen-Yi LinLiang Tang
Oct 22, 2020·Journal of Cardiothoracic and Vascular Anesthesia·Jenny KwakKenichi A Tanaka

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Methods Mentioned

BETA
ELISA

Clinical Trials Mentioned

NCT03196284
NCT03196297
NCT02571569
NCT02974855

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