New and Emerging Agents for the Treatment of Hemophilia: Focus on Extended Half-Life Recombinant Clotting Proteins

Drugs

Volumn 75, Issue 14, 2015, Pages 1587-1600

  Ragni, Margaret V ^a  

^a UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ACTIVATED PROTEIN C; ANTITHROMBIN; BLOOD CLOTTING FACTOR; BLOOD CLOTTING FACTOR 5A; BLOOD CLOTTING FACTOR 8; HYBRID PROTEIN; MONOCLONAL ANTIBODY; PACE FURIN CLEAVED BLOOD CLOTTING FACTOR 3; RECOMBINANT BLOOD CLOTTING FACTOR 8; RECOMBINANT BLOOD CLOTTING FACTOR 9; SMALL INTERFERING RNA; TISSUE FACTOR PATHWAY INHIBITOR; UNCLASSIFIED DRUG; ZYMOGEN LIKE FACTOR X; BLOOD CLOTTING FACTOR 9; RECOMBINANT PROTEIN;

AGING; ARTICLE; CHEMOPROPHYLAXIS; CLINICAL TRIAL (TOPIC); DRUG HALF LIFE; GROUPS BY AGE; HEMOPHILIA; HEMOSTASIS; HUMAN; PATIENT; PROTEIN TARGETING; RNA INTERFERENCE; HALF LIFE TIME; HEMOPHILIA A; METABOLISM;

FACTOR IX; FACTOR VIII; HALF-LIFE; HEMOPHILIA A; HUMANS; RECOMBINANT PROTEINS;

EID: 84942501426     PISSN: 00126667     EISSN: 11791950     Source Type: Journal    
DOI: 10.1007/s40265-015-0451-5     Document Type: Article

References (79)

1. Valentino LA. Controversies regarding the prophylactic management of adults with severe hemophilia A. Haemophilia. 2009;15(Suppl 2):5-22.
2. Ragni MV, Kessler CM, Fogarty PJ, Josephson N, Neff AT, Raffini L. Survey of current prophylaxis practices and bleeding characteristics of children with severe hemophilia A in US hemophilia treatment centers. Haemophilia. 2012;18:63-8 (PMID 21539695).
3. Rosendaal G, Lafeber FP. Pathogenesis of haemophilic arthropathy. Haemophilia. 2006;12(Suppl 3):117-21.
4. Collins PW, Blanchette VS, Fisdher K, Bjorkman S, Oh M, Fritsch S, Schroth P, Spotts G, Astermark J, Ewenstein B. Break-through bleeding in relation to predicted factor VIII level in patients receiving prophylactic treatment for severe hemophilia A. J Thromb. Haemost. 2009;7:413-20.
5. Manco-Johnson MJ, Abshire TC, Shapiro AD, Riske B, Hacker MR, Kilcoyne R, Ingram JD, Manco-Johnson L, Funk S, Jacobon L, Valentino LA, Hoots WK, Buchanan GR, DiMichele D, Recht M, Brown D, Leissinger C, Bleak S, Cohen A, Mathew P, Matsunaga A, Medeiros D, Nugent D, Thomas GA, Thompson AA, McRedmond K, Soucie JM, Austin H, Evatt BL. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med. 2007;357:535-44.
6. National Hemophilia Foundation. Medical and Scientific Advisory Council (MASAC) Recommendation No.179. MASAC Recommendation concerning prophylaxis: regular administration of clotting factor concentrate to prevent bleeding. National Hemophilia Foundation web site, at http://www.hemophilia.org/Researchers-Healthcare-Providers/Medical-and-Scientific-Advisory-Council-MASAC/MASAC-Recommendations/MASACRecommendation-Concerning-Prophylaxis. Accessed 19 Aug 2015.
7. Valentino LA. Secondary prophylaxis therapy: What are the benefits, limitations, and unknowns? Haemophilia. 2004;10:147-57.
8. Hay CRM. Prophylaxis in adults with haemophilia. Haemophilia. 2007;13(Suppl 2):10-5.
9. Walsh CE, Valentino LA. Factor VIII prophylaxis for adult patients with severe haemophilia A: results of a US survey of attitudes and practices. Haemophilia. 2009;15:1014-21.
10. Ragni MV, Ojeifo O, Hill K, Feng J, Yan J, Hill KA, Sommer SS, Trucco M, Brambilla DJ. Risk factors for inhibitor formation in hemophilia: a prevalent case-control study. Haemophilia. 2009;15:1074-82.
11. Gouw SC, van den Berg HM, Fischer K, Auerswald G, Carcao M, Chalmers E, Chambost H, Kurnik K, Liesner R, Petrini P, Platokouki H, Altisent C, Oldenburg J, Nolan B, Garrido RP, Mancuso ME, Rafowicz A, Williams M, Clausen N, Middelburg RA, Ljung R, van der Bom JG. Intensity of factor VIII treatment and inhibitor development in children with severe hemophilia A: the RODIN study. Blood. 2013;121:4046-55.
12. Gouw SC, van der Bom JG, van den Berg HM. Treatment-related risk factors of inhibitor development in previously untreated patients with severe hemophilia A: the CANAL cohort study. Blood. 2007;109:4648-54.
13. Soucie JM, Symons J, Evatt B, Brettler D, Huszti H, Linden J. Home-based infusion therapy and hospitalization for bleeding complications among males with hemophilia. Haemophilia. 2001;7:198-206.
14. Goudemand J. Pharmacoeconomic aspects of inhibitor treatment. Eur J Haematol Suppl. 1998;63:24-7.
15. Kontermann RE. Strategies to extend plasma half-lives of recombinant antibodies. BioDrugs. 2009;23:93-109.
16. Powell J, Pasi J, Ragni M, Ozelo M, Valentino L, Mahlangu J, Manco-Johnson M, Josephson N, Perry D, Apte S, Baker R, Novitzky N, Chan G, Wong R, Krassova S, Allen G, Campion M, Jiang H, Innes A, Li S, Cristiano L, Goyal J, Sommer J, Dumont JA, Nugent K, Brennan A, Vigliani G, Luk A, Pierce FG. Phase 3 study of long-acting recombinant factor IX Fc in hemophilia B. N Engl J Med. 2013;369:2313-23 (PMID 24304002).
17. Mahlangu J, Powell J, Ragni M, Chowdary P, Josephson N, Pabinger N, Hanabusa H, Gupta N, Kulkarni R, Fogarty P, Perry D, Shapiro A, Pasi J, Apte S, Krassova S, Jiang J, Li S, Cristiano LM, Neelakantan S, Greblikas F, Goyal J, Sommer J, Dumont JA, Innes A, Nugent K, Brennan A, Vigiliani G, Luk A, Pierce GF. Phase 3 study of long-acting recombinant factor VIIIFc in hemophilia A. Blood. 2014;123:317-25 PMID 24227821.
18. Dumont JA, Low SC, Peters RT, Bitonti AJ. Monomeric Fc fusions: impact on pharmacokinetic and biological activity of protein therapeutics. BioDrugs. 2006;20:151-60.
19. Roopenian DC, Akilesh S. FcRn: the neonatal Fc receptor comes of age. Nat Rev Immunol. 2007;7:715-25.
20. Shapiro AD, Ragni MV, Valentino L, Key NS, Josephson NC, Powell JS, Cheng G, Thompson A, Goyal J, Tubridy KL, Peters RT, Dumont JA, Euwart DA, Li L, Hallen B, Gozzi P, Bitonti A, Jiang H, Luk A, Pierce GF. Recombinant factor IX Fc fusion (rFIXFc) demonstrates safety and prolonged activity in hemophilia B patients. Blood. 2012;119:666-72.
21. Powell JS, Josephson NJ, Quon D, Ragni MV, Cheng G, McKinney B, Jiang H, Li L, Dumont JA, Joyal J, Zhang X, Sommer J, McCue J, Barbetti M, Luk A, Pierce G. Safety and prolonged activity of recombinant factor VIII Fc fusion protein in hemophilia A patients. Blood. 2012;119:3031-7.
22. Shapiro A, Ragni MV, Kulkarni R, Oldenberg J, Srivastava A, Quon D, Pasi J, Hanabusa H, Pabinger I, Mahlangu J, Fogarty P, Lillicrap D, Kulke S, Potts J, Neelakantan S, Nestorov I, Dumont J, Jiang H, Brennan A, Pierce G. Recombinant factor VIII Fc fusion protein: extended-interval dosing maintains low bleeding rates and correlates with von Willebrand factor levels. J Thromb Haemost. 2014;12:1788-800.
23. Salas J, Liu T, Lu Q, Kulman JD, Ashworth T, Kistanova E, Moore N, Pierce GF, Jiang J, Peters R. Enhance pharmacokinetics of factor VIIa as a monomeric Fc fusion. Thromb Res. 2015;. doi: 10.1016/j.thrombres.2014.12.018.
24. Peters T. Serum albumin. Adv Protein Chem. 1985;37:161-245.
25. Kim J, Bronson CL, Hayton WL. Albumin turnover: FcRn-mediated recycling saves as much albumin from degradation as the liver produces. Am J Physiol Gastrointest Liver Physiol. 2006;290:G352-60.
26. Metzner HJ, Pipe SW, Weimer T, Schulte S. Extending the pharmacokinetic half-life of coagulation factors by fusion to recombinant albumin. Thromb Haemost. 2013;110:931-9.
27. Metzner HJ, Weimer T, Kronthaler U, Lang W, Schulte S. Genetic fusion to albumin improves the pharmacokinetic properties of factor IX. Thromb Haemost. 2009;102:634-44.
28. Santagostino E, Negrier C, Klamroth R, Tiede A, Pabinger I, Voigt C, Jacobs I, Morfini M. Safety and pharmacokinetics of a novel recombinant fusion protein linking coagulation factor IX with albumin (rIX-FP) in hemophilia B patients. Blood. 2012;120:2405-11.
29. 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 2):S11-4.
30. Santagostino E, Jacobs IC, Voigt C, Feussner A, Limsakun T. Pharmacokinetic results of two phase III clinical studies of coagulation factor IX (recombinant) albumin fusion protein (rIX-FP) in previously treated patients with hemophilia B (PROLONG-9FP). Blood. 2014;14(Suppl):1491 (abstract).
31. Santagostino E, Martinowitz U, Lissitchkov T, Pan-Petesch B, Hanabusa H, Oldenburg J, Boggio L, Negrier C, Pabinger-Fasching I, von Depka Prondzinski M, Altisent C, Castaman G, Yamamoto K, Alvarez-Roman M, Voigt C, Jacobs I. Efficacy and safety results of a phase 3 pivotal clinical study or recombinant fusion protein linking coagulation factor IX with albumin (RIX-FP) in previously treated patients with hemophilia B. Int Soc Thromb Haemost. 2015;13(Suppl 2):OR347 (abstract).
32. Zollner S, Schuermann D, Raquet E, Mueller-Chors J, Weimer T, Pragst I, Dickneite G, Schulte S. Pharmacologic characteristics of a novel, recombinant fusion protein linking coagulation factor VIIa with albumin (rVIIa-FP). J Thromb Haemost. 2014;12:220-8.
33. Golor G, Bensen-Kennedy D, Haffner S, Easton R, Jung K, Moises T, Lawo JP, Joch C, Veldman A. Safety and pharmacokinetics of a recombinant fusion protein linking coagulation factor VIIa with albumin in healthy volunteers. J Thromb Haemost. 2013;11:1977-85.
34. Webster R, Didier E, Harris P, Siegel N, Stadler J, Tilbury L, Smith D. PEGylated proteins: evaluation of their safety in the absence of definitive metabolism studies. Drug Metab Dispos. 2007;35:9-16.
35. Hamidi M, Azadi A, Rafiei P. Pharmacokinetic consequences of pegylation. Drug Deliv. 2006;13:399-409.
36. Collins PW, Young G, Knobe K, Karim FA, Angchaisuksiri P, Banner C, Gürsel T, Mahlangu J, Matsushita T, Mauser-Bunschoten EP, Oldenburg J, Walsh CE, Negrier C. Recombinant long-acting glycoPEGylated factor IX in hemophilia B: a multinational randomized phase 3 trial. Blood. 2014;124:3880-6.
37. Escobar M, Colberg T, Karim F, Caliskan U, Chowdary P, Giangrande P, Giermasz A, Mancuso ME, Serban M, Tsay W, Zak M, Mahlangu J. perioperative hemostatic management of major surgery in hemophilia B with long-acting recombinant glycopegylated factor IX: results from the paradigm 3 clinical trial. Int Soc Thromb Haemost. 2015;13(Suppl 2):OR348 (abstract).
38. Negrier C, Karim FA, Hanabusa H, Collins P, Colberg T, Goldman B, Walsh C. Recombinant long-acting glycopegylated factor IX (nonacog beta pegol) in hemophilia B: assessment of target joints in the multinational randomized phase 3 clinical trial. Int Soc Thromb Haemost. 2015;13(Suppl 2):PO149 (abstract).
39. Tiede A, Brand B, Fischer R, Kavakli K, Lentz SR, Matsushita T, Rea C, Knobe K, Viuff D. Enhancing the pharmacokinetic properties of recombinant factor VIII: first-in-human properties of glycoPEGylated recombinant factor VIII in patients with hemophilia A. J Thromb Haemost. 2013;11:670-8.
40. Giangrande P, Chowdary P, Ehrenforth S, Hanabusa H, Leebeek FE, Lentz SR, Nemes L, Poulsen LH, Santagostino E, You CW, Clausen WHO, Oldenburg J. Clinical evaluation of novel recombinant glycopegylated FVIII (turoctocog alfa pegol, N8-GP): efficacy and safety in previously treated patients with severe hemophilia. A - results of a pathfinder 2 international trial. Int Soc. Thromb Haemost. 2015;13(Suppl 2):OR212 (abstract).
41. Lentz SR, Misgav M, Ozelo M, Salek SZ, Veljkovic D, Recht M, Cerqueira M, Tiede A, Brand B, Mancuso ME, Seremetis S, Lindblom A, Martinowitz U. Results from a large multinational clinical trial (guardian 1) using prophylactic treatment with turoctocog alfa in adolescent and adult patients with severe hemophilia A: safety and efficacy. Haemophilia. 2013;19:691-7.
42. Coyle T, 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;12:488-96.
43. Boggio LN, Hong W, Wang M, Eyster ME, Michaels LA. Bleeding phenotype with various BAY 94-9027 dosing regimens: sub-analyses from the Protect VIII study. Blood. 2014;124:1526 (abstract).
44. Baxter. Baxter announces positive top-line results from its phase 3 study of BAX 855, extended half-life recombinant FVIII for haemophilia A patients [media release] 21 Aug 2014. http://www.baxter.com/news-media/newsroom/pres-releases/2014/08-21-14-ba855.page. Accessed 19 Aug 2015.
45. Brand B, Gruppo R, Wynn TT, Griskevicius L, Fernandez MFL, Greblikas F, Dvorak T, Patrone L, Fuerlinger M, Abbuehl BE. Initial results of a clinical trial evaluation a full-length pegylated recombinant factor FVIII with extended half-life for the perioperative control of hemostasis in hemophilia A. Int Soc Thromb Haemost. 2015;13(Suppl 2):PO242 (abstract).
46. Konkle B, Stasyshn O, Wynn T, Manco-Johnson M, Gruppo R, Chowdary P, Komrska V, Griskevicius L, Eyster ME, Chojnowski K, Engl W, Patrone L, Abbuehl B. Bleeding patterns evaluated during prophylaxis with a full-length pegylated recombinant factor VIII (Bax 855) with extended half-life in hemophilia A. Int Soc Thromb Haemost. 2015;13(Suppl 2):PO260 (abstract).
47. Ljung R, Karim FA, Saxena K, Suzuki T, Arkhammar P, Rosholm A, Giangrande P. 40K GlycoPEGylated, recombinant VIIa: 3-month, double-blind, randomized trial of safety, pharmacokinetics and preliminary efficacy in hemophilia patients with inhibitors. J Thromb Haemost. 2013;11:1260-8.
48. Borel Y. Haptens bound to self IgG induce immunologic tolerance, while when coupled to syngeneic spleen cells they induce immune suppression. Immunol Rev. 1980;50:71-104.
49. Ephrem A, Chamat S, Miquel C, Fisson S, Mouthon L, Calguiri G, Delignat S, Elluru S, Bayry J, Lacroix-Desmazes S, Cohen JL, Salomon BL, Kazatchkine MD, Kaveri SV, Misra N. Expansion of experimental autoimmune encephalomyelitis. Blood. 2008;111:715-22.
50. DeGroot AS, Moise L, McMurry JA, Wambre E, van Overtvelt L, Moingeon P, Scott DW, Martin W. Activation of natural regulatory T cells by IgG Fc-derived peptide "Tregitopes". Blood. 2008;112:3303-11.
51. Lei TC, Scott DW. Induction of tolerance to factor VIII inhibitor by gene therapy with immunodominant A2 and C2 domains presented by B cells as Ig fusion proteins. Blood. 2005;105:4865-70.
52. Rath T, Baker K, Dumont JA, Peters RT, Jian H, Qiao SW, Lencer Wi WI, Pierce GF, Blumberg RS. Fc-fusion proteins and FcRn: structural insights for longer-lasting and more effective therapeutics. Crit Biotechnol. 2013;. doi: 10.3109/07388551.2013.834293 (Online 24 Oct 2013).
53. Basto AP, Badenes M, Almeida SCP, Martins C, Duarte A, Santos DM, Leitao A. Immune response profile elicited by the model antigen ovalbumin expressed in fusion with the bacterial OprI lipoprotein. Mol Immunol. 2015;64:36-45.
54. Chapman AP. PEGylated antibodies and antibody fragments for improved therapy: a review. Adv Drug Deliv Reviews. 2002;54:531-45.
55. Hershfield MS. Biochemistry and poly (ethylene glycol)-modified adenosine deaminase (PEG-ADA). In: Harris JM, Zolipsky S, editors. Poly (ethylene glycol): Chemistry and Biological Applications. Washington, DC: ACS Books; 1997. p. 134-44.
56. Liu T, Hoehn T, Hoehn S, Patarroyo-White S, Pierce G, Jiang H. Evaluation of antibody response to rFVIIIFc compared to Xyntha and Advate in hemophilia A mice. Haemophilia. 2012;18(Suppl S3):41 (abstract).
57. Spotts G, Pipe SW, Berntorp E, Collins PW, Blanchette VS, Fischer K, Oh, Valentino LA. Modelling minimally-effective trough levels in hemophilia A patients on PI-guided prophylaxis. Blood. 2014;14(Suppl):689 (abstract).
58. Kitazawa T, Igawa T, Samprei Z, Muto A, Kohima T, Soeda T, Yoshihashi K, Okuyam-Nishida Y, Saito H, Tsunoda H, Suzuki T, Adachi H, Miyazaki T, Ishii S, Kamata-Sakurai M, Iida T, Jarada A, Keido Esaki K, Funaki M, Moriyama C, Tanaka E, Kikuchi Y, Wakabayashi T, Wada M, Goto M, Toyoda T, Ueyama A, Suzuki S, Haraha K, Tachibana T, Kawabe Y, Shima M, Yoshioka A, Hattori K. A bispecific antibody to factors IXa and X restores factor VIII hemostatic activity in a hemophilia A model. Nat Med. 2012;18:1570-5.
59. Muto A, Yoshihashi K, Takeda M, Kitazawa T, Soeda T, Igawa T, Sampei Z, Kuramochi T, Sakamoto A, Haraya K, Adachi K, Kawabe Y, Nogami K, Shima M, Hattori K. Anti-factor IXa/X bispecific antibody ACE910 prevents joint bleeds in a long-term primate model of acquired hemophilia A. Blood. 2014;124:3165-71.
60. Shima M, Hanabusa H, Tald M, Matsuchita T, Sato T, Fukutake K, Fukazawa N, Marsawa S, Yoneyama K, Hogami K. Safety and prophylactic efficacy profiles of ACE910, a humanized bispecific antibody mimicking the FVIII cofactor function, in Japanese hemophilia A patients with and without inhibitors. Blood. 2014;14(Suppl):691 (abstract).
61. Shima M, Nanbusa H, Taki M, Matsushita T, Sato T, Fukutake K, Fukazawa N, Yoneyama K, Yoshida H, Takahashi H, Nogami K. Long-term safety and prophylactic efficacy of once-weekly subcutaneous administration of ACE910 in Japanese hemophilia A patients with and without FVIII inhibitors: interim results of the extension study of a phase 1 study. Int Soc Thromb Haemost. 2015;13(Suppl 2):AS017 (abstract).
62. Siner JS, Crudele JM, Connolly CT, Zhou S, Merricks EP, Nichols TC, Camire RM, Arruda VR. Unexpected role of PACE/Furin cleavage site in FVIII biology: implications for hemophilia A therapy. Blood. 2014;14(Suppl):105 (abstract).
63. Siner JI, Samelson-Jones B, Crudele JM, Zhou S, Merricks E, Nichols T, Camire RM, Arruda VR. Enhanced factor VIII gene therapy for hemophilia A dogs with a novel furin-evading factor VIII variant. Int Soc Thromb Haemost. 2015;13(Suppl 2):AS120 (abstract).
64. superFVa and recombinant human FVIIa in vivo suggest a novel bypassing strategy for hemophilia patients with inhibitors. Blood. 2014;14(Suppl):692 (abstract).
65. von Drygalski A, Bhat V, Gale AJ, Burnier L, Cramer TJ, Griffen JH, Mosnier LO. An engineered factor FVa prevents bleeding induced by anticoagulant wt activated protein C. PLOS One. 2014;9:e104304.
66. von Drygalski A, Cramer TJ, Bhat V, Griffin JH, Gale AJ, Mosnier LO. Improved hemostasis in hemophilia mice by means of an engineered factor Va mutant. J Thromb Haemost. 2014;12:363-72.
67. Reema J, Patel-Hett S, Camire RM, Fruebis J, Pittman D. A zymogen-like factor Xa improves hemostasis in a murine bleeding model. Blood. 2014;14(Suppl):1476 (abstract).
68. Ivanciu L, Toso R, Margaritis P, Pavani G, Kim H, Schlacterman A, Liiu JH, Clerin V, Pittman DD, Rose-Miranda R, Shields KM, Erbe DV, Tobin JF, Arruda VR, Camire RM. A zymogen-like factor Xa variant corrects the coagulation defect in hemophilia. Nat Biotechnol. 2011;29:1028-35.
69. Bunce MW, Toso R, Camire RM. Zymogen-like factor Xa variants restore thrombin generation and effectively bypass the intrinsic pathway in vitro. Blood. 2011;117:290-8.
70. Ivanciu L, Camire RM. Hemostatic agents of broad applicability produced by selective tuning of factor Xa zymogenicity. Blood. 2015;126:94-102.
71. Sorensen B, Mant T, Akinc A, Simon A, Melton L, Lynam C, Strahs A, Sehgal A, Hutabarat R, Chaturveth P, Barros S, Vaishnaw A. A subcutaneously administered RNAi therapeutic (ALN-AT3) targeting antithrombin for treatment of hemophilia: interim phase 1 study results in healthy volunteers and patients with hemophilia A and B. Blood. 2014;14(Suppl):693 (abstract).
72. Sehgal A, Barros S, Ivanciu L, Cooley B, Qin J, Racie T, Hettinger J, Carioto M, Jiang Y, Brodsky J, Prabhala H, Zhang X, Attarwala J, Hutabarat R, Foster D, Milstein S, Charisse K, Kuchimanchi S, Maier MA, Nechev L, Kandasamy P, Kelin AV, Nair JK, Rajeev KG, Manoharan M, Meyers R, Sorensen B, Simon AR, Dargaud Y, Negrier C, Camire RM, Akinc A. An RNAi therapeutic targeting antithrombin to rebalance the coagulation system and promote hemostasis in hemophilia. Nat Med. 2015;21:492-9.
73. Sorensen B, Mant T, Georgiev P, Rangarajan S, Pasi J, Creagh D, Bevan DH, Austin S, Hay C, Brand B, Simon A, Melton L, Lynam C, Strahs A, Sehgal A, Hutabarat R, Chaturvedi P, Barros S, Garg P, Vaishnaw A, Akinc A. A subcutaneously administered investigational RNAi therapeutic (ALN-AT3) targeting antithrombin for treatment of hemophilia: interim phase 1 study results in patients with hemophilia A or B. Int Soc Thromb Haemost. 2015;13(Suppl 2):OR213 (abstract).
74. Dockal M, Hartmann R, Polakowski T, Pahnolzer E, Kammlander W, Osterkamp F, Reineke U, Schiviz A, Hoellriegl W, Scheiflinger F. A TFPI inhibitory half-life-extended fusion peptide proves efficacious in FVIII knockout mice and Marmoset monkeys. Blood. 2014;14(Suppl):1469 (abstract).
75. Hilden I, Lauritzen B, Sorensen BB, Clausen JT, Jespersgaard C, Krogh BO, Bowler AN, Breinholt J, Gruhler A, Svensson LA, Petersen HH, Petersen LC, Balling K, Hansen L, Hermit MB, Egebjerg T, Friederischen B, Ezban M, Bjorn SE. Hemostatic effect of a monoclonal antibody mAb 2021 blocking the interaction between FXa and TFPI in a rabbit hemophilia model. Blood. 2012;119:5871-8.
76. Chowdary P, Lethagen S, Friedrich U, Brand B, Hay C, Karim A, Klamroth R, Knoebl P, Laffan M, Mahlangu J, Miesbach W, Nielsen Dalsgaard J, Martin-Salces M, Angchaisuksiri P. Safety and pharmacokinetics of anti-TFPI antibody (concizumab) in healthy volunteers and patients with hemophilia: a randomized first human dose trial. J Thromb Haemost. 2015;13:743-54.
77. Dockal M, Hartmann R, Fries M, Christella M, Thomassen LGD, Heinzmann A, Ehrlich H, Rosing J, Osterkamp F, Polakowski T, Reineke U, Griessner A, Brandstetter H, Scheiflinger F. Small peptides blocking inhibition of factor Xa and tissue factor-factor VIIa by tissue factor pathway inhibitor (TFPI). J Biol Chem. 2014;289:1732-41.
78. Peraramelli S, Thomassen S, Heinzmann A, Rosing J, Jackeng TM, Hartmann R, Scheiflinger F, Dockal M. Inhibition of tissue factor:factor VIIa-catalyzed factor IX and factor X activation by TFPI and TFPI constructs. J Thromb Haemost. 2014;12:1826-37.
79. Versteeg HH, Heemskerk JWM, Levi M, Rietsma PH. New fundamentals in hemostasis. Physiol Rev. 2013;93:327-58.