Safety and prolonged activity of recombinant factor VIII Fc fusion protein in hemophilia A patients
Tóm tắt
Current factor VIII (FVIII) products display a half-life (t1/2) of ∼ 8-12 hours, requiring frequent intravenous injections for prophylaxis and treatment of patients with hemophilia A. rFVIIIFc is a recombinant fusion protein composed of a single molecule of FVIII covalently linked to the Fc domain of human IgG1 to extend circulating rFVIII t1/2. This first-in-human study in previously treated subjects with severe hemophilia A investigated safety and pharmacokinetics of rFVIIIFc. Sixteen subjects received a single dose of rFVIII at 25 or 65 IU/kg followed by an equal dose of rFVIIIFc. Most adverse events were unrelated to study drug. None of the study subjects developed anti-rFVIIIFc antibodies or inhibitors. Across dose levels, compared with rFVIII, rFVIIIFc showed 1.54- to 1.70-fold longer elimination t1/2, 1.49- to 1.56-fold lower clearance, and 1.48- to 1.56-fold higher total systemic exposure. rFVIII and rFVIIIFc had comparable dose-dependent peak plasma concentrations and recoveries. Time to 1% FVIII activity above baseline was ∼ 1.53- to 1.68-fold longer than rFVIII across dose levels. Each subject showed prolonged exposure to rFVIIIFc relative to rFVIII. Thus, rFVIIIFc may offer a viable therapeutic approach to achieve prolonged hemostatic protection and less frequent dosing in patients with hemophilia A. This trial was registered at www.clinicaltrials.gov as NCT01027377.
Từ khóa
Tài liệu tham khảo
Mannucci, 2001, The haemophiliac: from royal genes to gene therapy., N Engl J Med, 344, 1773, 10.1056/NEJM200106073442307
Soucie, 2000, Mortality among males with hemophilia: relationship with source of medical care. The Hemophilia Surveillance System Project Investigators., Blood, 96, 437
Manco-Johnson, 2007, Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia., New Engl J Med, 357, 535, 10.1056/NEJMoa067659
Aledort, 1994, A longitudinal study of orthopaedic outcomes for severe factor-VIII-deficient haemophiliacs. The Orthopaedic Outcome Study Group., J Intern Med, 236, 391, 10.1111/j.1365-2796.1994.tb00815.x
Petrini, 1991, Prophylaxis with factor concentrates in preventing hemophilic arthropathy., Am J Pediatr Hematol Oncol, 13, 280, 10.1097/00043426-199123000-00006
Aznar, 2000, The orthopaedic status of severe haemophiliacs in Spain., Haemophilia, 6, 170, 10.1046/j.1365-2516.2000.00397.x
Feldman, 2006, Tailored prophylaxis in severe hemophilia A: interim results from the first 5 years of the Canadian Hemophilia Primary Prophylaxis Study., J Thromb Haemost, 4, 1228, 10.1111/j.1538-7836.2006.01953.x
Kreuz, 1998, When should prophylactic treatment in subjects with haemophilia A and B start? The German experience., Haemophilia, 4, 413, 10.1046/j.1365-2516.1998.440413.x
Liesner, 1996, The impact of prophylactic treatment on children with severe haemophilia., B J Haem, 92, 973, 10.1046/j.1365-2141.1996.420960.x
Ljung, 1998, Prophylactic treatment in Sweden: overtreatment or optimal model?, Haemophilia, 4, 409, 10.1046/j.1365-2516.1998.440409.x
Löfquist, 1997, Haemophilia prophylaxis in young subjects: a long-term follow-up., J Intern Med, 241, 395, 10.1046/j.1365-2796.1997.130135000.x
Nilsson, 1992, Twenty-five years's experience of prophylactic treatment in severe haemophilia A and B., J Int Med, 232, 25, 10.1111/j.1365-2796.1992.tb00546.x
Risebrough, 2008, Cost-utility analysis of Canadian tailored prophylaxis, primary prophylaxis and on-demand therapy in young children with severe haemophilia A., Haemophilia, 14, 743, 10.1111/j.1365-2516.2008.01664.x
Van Den Berg, 2003, Comparing outcomes of different treatment regimens for severe haemophilia., Haemophilia, 9, 27, 10.1046/j.1365-2516.9.s1.10.x
Van Den Berg, 2004, Issues surrounding therapeutic choices for haemophilia patients., Haematologica, 89, 645
Blanchette, 2010, Prophylaxis in the haemophilia population., Haemophilia, 16, 181, 10.1111/j.1365-2516.2010.02318.x
Molho, 2000, Epidemiological survey of the orthopaedic status of severe haemophilia A and B patients in France., Haemophilia, 6, 23, 10.1046/j.1365-2516.2000.00358.x
Coppola, 2008, Primary prophylaxis in children with haemophilia., Blood Transfus, 6, 4
Geraghty, 2006, Practice patterns in haemophilia A therapy: global progress towards optimal care., Haemophilia, 12, 75, 10.1111/j.1365-2516.2006.01189.x
Hacker, 2001, Barriers to compliance with prophylaxis therapy in haemophilia., Haemophilia, 7, 392, 10.1046/j.1365-2516.2001.00534.x
Lillicrap, 2010, Improvements in factor concentrates., Curr Opin Hematol, 17, 393, 10.1097/MOH.0b013e32833c06c6
Dumont, 2006, Monomeric Fc fusions: impact on pharmacokinetic and biological activity of protein therapeutics., BioDrugs, 20, 151, 10.2165/00063030-200620030-00002
Dumont, 2012, Monomeric Fc fusion technology: an approach to create long lasting clotting factors., Therapeutic Proteins: Strategies to Modulate Their Plasma Half-Lives, 10.1002/9783527644827.ch10
Roopenian, 2007, FcRn: the neonatal Fc receptor comes of age., Nat Rev Immunol, 7, 715, 10.1038/nri2155
Lencer, 2005, A passionate kiss, then run: exocytosis and recycling of IgG by FcRn., Trends Cell Biol, 15, 5, 10.1016/j.tcb.2004.11.004
Huang, 2009, Receptor-Fc fusion therapeutics, traps, and MIMETIBODY technology., Curr Opin Biotechnol, 20, 692, 10.1016/j.copbio.2009.10.010
Schmidt, 2009, Fusion-proteins as biopharmaceuticals-applications and challenges., Curr Opin Drug Discov Devel, 12, 284
Dumont, 2012, Prolonged activity of a recombinant factor VIII-Fc fusion protein in hemophilia A mice and dogs., Blood, 119, 3024, 10.1182/blood-2011-08-367813
Rosen, 1984, Assay of factor VIII:C with chromogenic substrate., Scand J Haematol Suppl, 40, 139, 10.1111/j.1600-0609.1984.tb02556.x
Lee, 1999, Pharmacokinetics of recombinant factor VIII (recombinate) using one-stage clotting and chromogenic factor VIII assay., Thromb Haemost, 82, 1644
Mikaelsson, 2002, Assaying the circulating factor VIII activity in hemophilia A patients treated with recombinant factor VIII products., Semin Thromb Hemost, 28, 257, 10.1055/s-2002-32659
Stroobants, 2011, Differences between one-stage clotting and chromogenic FVIII assay results., J Thromb Haemost, 9
Lenting, 2007, Clearance mechanisms of von Willebrand factor and factor VIII., J Thromb Haemost, 5, 1353, 10.1111/j.1538-7836.2007.02572.x
Smith, 2010, Novel associations of multiple genetic loci with plasma levels of factor VII, factor VIII, and von Willebrand factor: the CHARGE (Cohorts for Heart and Aging Research in Genome Epidemiology) Consortium., Circulation, 121, 1382, 10.1161/CIRCULATIONAHA.109.869156
Terraube, 2010, Factor VIII and von Willebrand factor interaction: biological, clinical and therapeutic importance., Haemophilia, 16, 3, 10.1111/j.1365-2516.2009.02005.x
Mei, 2010, Rational design of a fully active, long-acting PEGylated factor VIII for hemophilia A treatment., Blood, 116, 270, 10.1182/blood-2009-11-254755
Liu, 2008, Site-specific PEGylation of factor VIII (PEG-FVIII) preserves full clotting activity and extends therapeutic efficacy in hemophiliaA dogs [abstract]., Blood, 112, 10.1182/blood.V112.11.511.511
Agersoe, 2011, Prolonged effect of N8-GP in haemophilia A dogs supports less frequent dosing., J Thromb Haemost, 9, 115