Newer Hemostatic Agents

Abstract

The mainstay of treatment of inherited coagulation disorders is based on the infusion of the deficient clotting factor, when available. Significant advances have been made over the past two decades in the production and availability of factor replacement products. In spite of such progression, several issue are still unsolved, the most important being the need for frequent factor concentrate infusions and the development of inhibitory alloantibodies. To overcome these important limitations, several newer hemostatic agents with an extended half-life are at an advanced stage of clinical development. After a brief overview of hemostasis, this narrative review summarizes the current knowledge on the most promising novel products for hemostasis. The current status of gene therapy for hemophilia, the only therapeutic option to definitively cure this inherited bleeding disorder, is also concisely discussed.

Keywords

clotting factor concentrates - new hemostatic products - extended half-life - hemophilia - inhibitors

• References

• 1 Franchini M, Mannucci PM. Past, present and future of hemophilia: a narrative review. Orphanet J Rare Dis 2012; 7: 24
• 2 Berntorp E, Shapiro AD. Modern haemophilia care. Lancet 2012; 379 (9824) 1447-1456
• 3 Mannucci PM. Back to the future: a recent history of haemophilia treatment. Haemophilia 2008; 14 (Suppl. 03) 10-18
• 4 Mannucci PM. Hemophilia: treatment options in the twenty-first century. J Thromb Haemost 2003; 1 (7) 1349-1355
• 5 Mannucci PM, Franchini M. Present and future challenges in the treatment of haemophilia: a clinician's perspective. Blood Transfus 2013; 11 (Suppl. 04) s77-s81
• 6 Pipe SW. Recombinant clotting factors. Thromb Haemost 2008; 99 (5) 840-850
• 7 Coppola A, Tagliaferri A, Di Capua M, Franchini M. Prophylaxis in children with hemophilia: evidence-based achievements, old and new challenges. Semin Thromb Hemost 2012; 38 (1) 79-94
• 8 Franchini M, Coppola A, Tagliaferri A, Lippi G. FEIBA versus NovoSeven in hemophilia patients with inhibitors. Semin Thromb Hemost 2013; 39 (7) 772-778
• 9 Franchini M, Lippi G. Recombinant activated factor VII: mechanisms of action and current indications. Semin Thromb Hemost 2010; 36 (5) 485-492
• 10 Franchini M, Manzato F, Salvagno GL, Montagnana M, Zaffanello M, Lippi G. Prophylaxis in congenital hemophilia with inhibitors: the role of recombinant activated factor VII. Semin Thromb Hemost 2009; 35 (8) 814-819
• 11 Franchini M, Mannucci PM. Inhibitors of propagation of coagulation (factors VIII, IX and XI): a review of current therapeutic practice. Br J Clin Pharmacol 2011; 72 (4) 553-562
• 12 Lippi G, Favaloro EJ, Franchini M, Guidi GC. Milestones and perspectives in coagulation and hemostasis. Semin Thromb Hemost 2009; 35 (1) 9-22
• 13 Favaloro EJ, Franchini M, Lippi G. Aging hemostasis: changes to laboratory markers of hemostasis as we age—a narrative review. Semin Thromb Hemost 2014; 40 (6) 621-633
• 14 Lippi G, Franchini M, Targher G. Arterial thrombus formation in cardiovascular disease. Nat Rev Cardiol 2011; 8 (9) 502-512
• 15 Kenne E, Renné T. Factor XII: a drug target for safe interference with thrombosis and inflammation. Drug Discov Today 2014; 19 (9) 1459-1464
• 16 Lisman T, De Groot PG. Mechanism of action of recombinant factor VIIa. J Thromb Haemost 2003; 1 (6) 1138-1139
• 17 Pipe SW. The hope and reality of long-acting hemophilia products. Am J Hematol 2012; 87 (Suppl. 01) S33-S39
• 18 Peyvandi F, Garagiola I, Seregni S. Future of coagulation factor replacement therapy. J Thromb Haemost 2013; 11 (Suppl. 01) 84-98
• 19 Stennicke HR, Kjalke M, Karpf DM , et al. A novel B-domain O-glycoPEGylated FVIII (N8-GP) demonstrates full efficacy and prolonged effect in hemophilic mice models. Blood 2013; 121 (11) 2108-2116
• 20 Agersø H, Stennicke HR, Pelzer H , et al. Pharmacokinetics and pharmacodynamics of turoctocog alfa and N8-GP in haemophilia A dogs. Haemophilia 2012; 18 (6) 941-947
• 21 Tiede A, Brand B, Fischer R , et al. Enhancing the pharmacokinetic properties of recombinant factor VIII: first-in-human trial of glycoPEGylated recombinant factor VIII in patients with hemophilia A. J Thromb Haemost 2013; 11 (4) 670-678
• 22 Mei B, Pan C, Jiang H , et al. Rational design of a fully active, long-acting PEGylated factor VIII for hemophilia A treatment. Blood 2010; 116 (2) 270-279
• 23 Coyle TE, Reding MT, Lin JC, Michaels LA, Shah A, Powell J. Phase I study of BAY 94-9027, a PEGylated B-domain-deleted recombinant factor VIII with an extended half-life, in subjects with hemophilia A. J Thromb Haemost 2014; 12 (4) 488-496
• 24 Turecek PL, Bossard MJ, Graninger M , et al. BAX 855, a PEGylated rFVIII product with prolonged half-life. Development, functional and structural characterisation. Hamostaseologie 2012; 32 (Suppl. 01) S29-S38
• 25 Dumont JA, Liu T, Low SC , et al. Prolonged activity of a recombinant factor VIII-Fc fusion protein in hemophilia A mice and dogs. Blood 2012; 119 (13) 3024-3030
• 26 Peters RT, Toby G, Lu Q , et al. Biochemical and functional characterization of a recombinant monomeric factor VIII-Fc fusion protein. J Thromb Haemost 2013; 11 (1) 132-141
• 27 Powell JS, Josephson NC, Quon D , et al. Safety and prolonged activity of recombinant factor VIII Fc fusion protein in hemophilia A patients. Blood 2012; 119 (13) 3031-3037
• 28 Mahlangu J, Powell JS, Ragni MV , et al; A-LONG Investigators. Phase 3 study of recombinant factor VIII Fc fusion protein in severe hemophilia A. Blood 2014; 123 (3) 317-325
• 29 Shapiro A, Chowdary P, Quon D , et al. Recombinant factor VIII Fc fusion protein as episodic treatment for bleeding: analysis from the A-LONG Study. [Abstract] Haemophilia 2014; 20 (Suppl. 03) 16
• 30 Kulkarni R, Ragni MV, Baker RI , et al. Analysis of clinical target joint bleeding on prophylactic regimens with recombinant factor VIII Fc fusion protein in patients with severe hemophilia A. [Abstract] Haemophilia 2014; 20 (Suppl. 03) 94
• 31 Østergaard H, Bjelke JR, Hansen L , et al. Prolonged half-life and preserved enzymatic properties of factor IX selectively PEGylated on native N-glycans in the activation peptide. Blood 2011; 118 (8) 2333-2341
• 32 Negrier C, Knobe K, Tiede A, Giangrande P, Møss J. Enhanced pharmacokinetic properties of a glycoPEGylated recombinant factor IX: a first human dose trial in patients with hemophilia B. Blood 2011; 118 (10) 2695-2701
• 33 Collins PW, Møss J, Knobe K, Groth A, Colberg T, Watson E. Population pharmacokinetic modeling for dose setting of nonacog beta pegol (N9-GP), a glycoPEGylated recombinant factor IX. J Thromb Haemost 2012; 10 (11) 2305-2312
• 34 Collins PW, Colberg T, Young G , et al. Safety, efficacy and pharmacokinetics of nonacog beta pegol (N9-GP) for prophylaxis and treatment of bleeding episodes in patients with haemophilia B. J Thromb Haemost 2013; 11 (Suppl. 02) 19
• 35 Valentino LA. Recombinant FIXFc: a novel therapy for the royal disease?. Expert Opin Biol Ther 2011; 11 (10) 1361-1368
• 36 Peters RT, Low SC, Kamphaus GD , et al. Prolonged activity of factor IX as a monomeric Fc fusion protein. Blood 2010; 115 (10) 2057-2064
• 37 Shapiro AD, Ragni MV, Valentino LA , et al. Recombinant factor IX-Fc fusion protein (rFIXFc) demonstrates safety and prolonged activity in a phase 1/2a study in hemophilia B patients. Blood 2012; 119 (3) 666-672
• 38 Powell JS, Pasi KJ, Ragni MV , et al; B-LONG Investigators. Phase 3 study of recombinant factor IX Fc fusion protein in hemophilia B. N Engl J Med 2013; 369 (24) 2313-2323
• 39 Metzner HJ, Weimer T, Kronthaler U, Lang W, Schulte S. Genetic fusion to albumin improves the pharmacokinetic properties of factor IX. Thromb Haemost 2009; 102 (4) 634-644
• 40 Santagostino E, Negrier C, Klamroth R , et al. Safety and pharmacokinetics of a novel recombinant fusion protein linking coagulation factor IX with albumin (rIX-FP) in hemophilia B patients. Blood 2012; 120 (12) 2405-2411
• 41 Martinowitz U, Lubetsky A. Phase I/II, open-label, multicenter, safety, efficacy and PK study of a recombinant coagulation factor IX albumin fusion protein (rIX-FP) in subjects with hemophilia B. Thromb Res 2013; 131 (Suppl. 02) S11-S14
• 42 Martinowitz U, Lubetsky A, Santagostino E , et al. Efficacy, PK and safety results of a Phase I/II clinical study of recombinant fusion protein linking coagulation factor IX with albumin (rIX-FP) in previously treated patients with hemophilia B. J Thromb Haemost 2013; 11 (Suppl. 02) 240-241
• 43 Salas J, Liu T, Kistanova E , et al. Enhanced pharmacokinetics of factor VIIA as a monomeric FC fusion. J Thromb Haemost 2011; 9 (Suppl. 02) 268
• 44 Weimer T, Wormsbächer W, Kronthaler U, Lang W, Liebing U, Schulte S. Prolonged in-vivo half-life of factor VIIa by fusion to albumin. Thromb Haemost 2008; 99 (4) 659-667
• 45 Golor G, Bensen-Kennedy D, Haffner S , et al. Safety and pharmacokinetics of a recombinant fusion protein linking coagulation factor VIIa with albumin in healthy volunteers. J Thromb Haemost 2013; 11 (11) 1977-1985
• 46 Powell J, Martinowitz U, Windyga J , et al; LipLong Study Investigators. Efficacy and safety of prophylaxis with once-weekly BAY 79-4980 compared with thrice-weekly rFVIII-FS in haemophilia A patients. A randomised, active-controlled, double-blind study. Thromb Haemost 2012; 108 (5) 913-922
• 47 Mahlangu JN, Coetzee MJ, Laffan M , et al. Phase I, randomized, double-blind, placebo-controlled, single-dose escalation study of the recombinant factor VIIa variant BAY 86-6150 in hemophilia. J Thromb Haemost 2012; 10 (5) 773-780
• 48 Møss J, Rosholm A, Laurén A. Safety and pharmacokinetics of a glycoPEGylated recombinant activated factor VII derivative: a randomized first human dose trial in healthy subjects. J Thromb Haemost 2011; 9 (7) 1368-1374
• 49 Mahlangu J, Karim FA, Gorska-Kosicka M , et al. Anti-drug antibody formation in hemophilia patients with inhibitors after receiving recombinant activated FVII analogue (vatreptacog alfa). Haemophilia 2013; 19 (Suppl. 02) 26
• 50 Parunov LA, Fadeeva OA, Balandina AN , et al. Improvement of spatial fibrin formation by the anti-TFPI aptamer BAX499: changing clot size by targeting extrinsic pathway initiation. J Thromb Haemost 2011; 9 (9) 1825-1834
• 51 Gorczyca ME, Nair SC, Jilma B , et al. Inhibition of tissue factor pathway inhibitor by the aptamer BAX499 improves clotting of hemophilic blood and plasma. J Thromb Haemost 2012; 10 (8) 1581-1590
• 52 Dockal M, Pachlinger R, Hartmann R , et al. Biological Explanation of Clinically Observed Elevation of TFPI Plasma Levels After Treatment with TFPI-Antagonistic Aptamer BAX 499 Blood (ASH Annual Meeting Abstracts), November 2012;120:1104
• 53 Toschi V. OBI-1, porcine recombinant Factor VIII for the potential treatment of patients with congenital hemophilia A and alloantibodies against human Factor VIII. Curr Opin Mol Ther 2010; 12 (5) 617-625
• 54 Kempton CL, Abshire TC, Deveras RA , et al. Pharmacokinetics and safety of OBI-1, a recombinant B domain-deleted porcine factor VIII, in subjects with haemophilia A. Haemophilia 2012; 18 (5) 798-804
• 55 Skinner MW. Gene therapy for hemophilia: addressing the coming challenges of affordability and accessibility. Mol Ther 2013; 21 (1) 1-2
• 56 Lippi G, Franchini M, Saenko EL. Gene therapy for hemophilia A. Friend or foe?. Blood Coagul Fibrinolysis 2009; 20 (6) 395-399
• 57 Nathwani AC, Tuddenham EG, Rangarajan S , et al. Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. N Engl J Med 2011; 365 (25) 2357-2365
• 58 Du LM, Nurden P, Nurden AT , et al. Platelet-targeted gene therapy with human factor VIII establishes haemostasis in dogs with haemophilia A. Nat Commun 2013; 4: 2773
• 59 Monahan PE, Gui T. Gene therapy for hemophilia: advancing beyond the first clinical success. Curr Opin Hematol 2013; 20 (5) 410-416
• 60 Viuff D, Barrowcliffe T, Saugstrup T, Ezban M, Lillicrap D. International comparative field study of N8 evaluating factor VIII assay performance. Haemophilia 2011; 17 (4) 695-702
• 61 Sommer JM, Moore N, McGuffie-Valentine B , et al. Comparative field study evaluating the activity of recombinant factor VIII Fc fusion protein in plasma samples at clinical haemostasis laboratories. Haemophilia 2014; 20 (2) 294-300