Treatment of Hemophilia in the Near Future

 

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Abstract

Advancements and debacles have characterized hemophilia treatment over the past 50 years. The 1970s saw the availability of plasma-derived concentrates making prophylaxis and home therapy possible. This optimistic perception changed extremely in the early 1980s, when most people with hemophilia were infected with HIV and hepatitis viruses. Then, also in the 1980s, the rapid progress in molecular biology led to the development of recombinant therapeutic products. This important advancement was a huge technological leap fresh off from the earlier 1980s disaster. Now in the 21st century, the newer bioengineering drugs open a new hopeful phase for the management of hemophilia. The current efforts are concentrated on producing novel coagulation factors with prolonged bioavailability, increased potency, and resistance to inactivation and potentially reduced immunogenicity; this phase of evolution is improving very quickly. 2014 is the year of marketing approval by the Food and Drug Administration of the first bioengineered FVIII and FIX long-acting drugs, using Fc-fusion strategy. This represents the first significant advance in the hemophilia therapy that dramatically transforms patient management by substantially reducing the frequency of injections, improving compliance, and simplifying prophylaxis and, in turn, refining the quality of life of hemophilia patients, offering them a nearly normal life expectancy, particularly to newborns with hemophilia B.

• References

• 1 Pipe SW. Recombinant clotting factors. Thromb Haemost 2008; 99 (5) 840-850
  PubMedGoogle Scholar
• 2 Pasut G, Veronese FM. State of the art in PEGylation: the great versatility achieved after forty years of research. J Control Release 2012; 161 (2) 461-472
  CrossrefPubMedGoogle Scholar
• 3 Hershfield MS. PEG-ADA replacement therapy for adenosine deaminase deficiency: an update after 8.5 years. Clin Immunol Immunopathol 1995; 76 (3 Pt 2) S228-S232
  CrossrefPubMedGoogle Scholar
• 4 Röstin J, Smeds AL, Akerblom E. B-Domain deleted recombinant coagulation factor VIII modified with monomethoxy polyethylene glycol. Bioconjug Chem 2000; 11 (3) 387-396
  CrossrefPubMedGoogle Scholar
• 5 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
  CrossrefPubMedGoogle Scholar
• 6 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
  CrossrefPubMedGoogle Scholar
• 7 Powell J, Fischer K, Kerlin BA, Shah A, Michaels LAON. BEHALF OF THE INVESTIGATORS OF THE PROTECT VIII TRIAL. Site specific PEGylated factor VIII BAY 94–9027: update on the results of the completed Phase 1 and Phase 2/3 studies. Haemophilia 2014; 20 (Suppl. 03) 187
  CrossrefPubMedGoogle Scholar
• 8 Thim L, Vandahl B, Karlsson J , et al. Purification and characterization of a new recombinant factor VIII (N8). Haemophilia 2010; 16 (2) 349-359
  CrossrefPubMedGoogle Scholar
• 9 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
  CrossrefPubMedGoogle Scholar
• 10 Ehrenforth S. N8-GP – a new long-acting factor VIII for the treatment of patients withhaemophilia A. Haemophilia 2014; 20 (Suppl. 03) 188
  CrossrefPubMedGoogle Scholar
• 11 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
  PubMedGoogle Scholar
• 12 Abbeuhl B, Ploder B, Fritsch S, Patrone L, Ewenstein B, Wong W-Y. The prolong-ate study. A phase 2/3 study evaluating the efficacy and safety of BAX 855, a pegylated full-length recombinant factor VIII (PEG-RFVIII) with extended half-life, for prophylactic and episodic treatment in severe haemophilia A. Haemophilia 2014; 20 (Suppl. 02) 62
  PubMedGoogle Scholar
• 13 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
  CrossrefPubMedGoogle Scholar
• 14 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
  CrossrefPubMedGoogle Scholar
• 15 Collins PW, Young G, Knobe K , et al. Recombinant long-acting glycoPEGylated factor IX in hemophilia B: a multinational randomized phase 3 trial. Blood 2014; 124 (26) 3880-3886
  CrossrefPubMedGoogle Scholar
• 16 Sim DS, Brooks A, Mallari C , et al. Glycopegylated Factor IX enables prolonged efficacy after subsutaneous injection but requires a higher than expected plasma activity to prevent bleeding in hemophilia B mice. Blood 2013; 122: 1104
  CrossrefPubMedGoogle Scholar
• 17 Chang J, Jin J, Lollar P , et al. Changing residue 338 in human factor IX from arginine to alanine causes an increase in catalytic activity. J Biol Chem 1998; 273 (20) 12089-12094
  CrossrefPubMedGoogle Scholar
• 18 Stennicke HR, Ostergaard H, Bayer RJ , et al. Generation and biochemical characterization of glycoPEGylated factor VIIa derivatives. Thromb Haemost 2008; 100 (5) 920-928
  PubMedGoogle Scholar
• 19 Ljung R, Karim FA, Saxena K , et al; Pioneer™1 Investigators. 40K glycoPEGylated, recombinant FVIIa: 3-month, double-blind, randomized trial of safety, pharmacokinetics and preliminary efficacy in hemophilia patients with inhibitors. J Thromb Haemost 2013; 11 (7) 1260-1268
  CrossrefPubMedGoogle Scholar
• 20 Pasut G, Veronese FM. PEGylation for improving the effectiveness of therapeutic biomolecules. Drugs Today (Barc) 2009; 45 (9) 687-695
  CrossrefPubMedGoogle Scholar
• 21 Fruijtier-Pölloth C. Safety assessment on polyethylene glycols (PEGs) and their derivatives as used in cosmetic products. Toxicology 2005; 214 (1-2) 1-38
  CrossrefPubMedGoogle Scholar
• 22 Bendele A, Seely J, Richey C, Sennello G, Shopp G. Short communication: renal tubular vacuolation in animals treated with polyethylene-glycol-conjugated proteins. Toxicol Sci 1998; 42 (2) 152-157
  CrossrefPubMedGoogle Scholar
• 23 Young MA, Malavalli A, Winslow N, Vandegriff KD, Winslow RM. Toxicity and hemodynamic effects after single dose administration of MalPEG-hemoglobin (MP4) in rhesus monkeys. Transl Res 2007; 149 (6) 333-342
  CrossrefPubMedGoogle Scholar
• 24 Armstrong JK, Hempel G, Koling S , et al. Antibody against poly(ethylene glycol) adversely affects PEG-asparaginase therapy in acute lymphoblastic leukemia patients. Cancer 2007; 110 (1) 103-111
  CrossrefPubMedGoogle Scholar
• 25 Ivens IA, Baumann A, McDonald TA, Humphries TJ, Michaels LA, Mathew P. PEGylated therapeutic proteins for haemophilia treatment: a review for haemophilia caregivers. Haemophilia 2013; 19 (1) 11-20
  CrossrefPubMedGoogle Scholar
• 26 Bjoernsdottir I, Watson E, Sternebring O, Kornoe HT, Kristensen JB, Bagger MA. Pharmacokinetics, tissue distribution, excretion of 40 kDa PEG and pegylated rFIX (N9-GP) in FIX KO mice. Haemophilia 2014; 20 (Suppl. 02) 47
  PubMedGoogle Scholar
• 27 Brambell FW, Hemmings WA, Morris IG. A theoretical model of gamma-globulin catabolism. Nature 1964; 203: 1352-1354
  CrossrefPubMedGoogle Scholar
• 28 Roopenian DC, Akilesh S. FcRn: the neonatal Fc receptor comes of age. Nat Rev Immunol 2007; 7 (9) 715-725
  CrossrefPubMedGoogle Scholar
• 29 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
  CrossrefPubMedGoogle Scholar
• 30 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
  CrossrefPubMedGoogle Scholar
• 31 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
  CrossrefPubMedGoogle Scholar
• 32 Salas J, Liu T, Kistanova E , et al. Enhanced pharmacokinetics of factor VIIA as a monomeric FC fusion. J Thromb Haemost 2011; 9: 268
  PubMedGoogle Scholar
• 33 Sleep D, Cameron J, Evans LR. Albumin as a versatile platform for drug half-life extension. Biochim Biophys Acta 2013; 1830 (12) 5526-5534
  CrossrefPubMedGoogle Scholar
• 34 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
  PubMedGoogle Scholar
• 35 Schulte S. Half-life extension through albumin fusion technologies. Thromb Res 2009; 124 (Suppl. 02) S6-S8
  CrossrefPubMedGoogle Scholar
• 36 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
  CrossrefPubMedGoogle Scholar
• 37 Veldman A, Jacobs I, Bensen Kennedy A, Santagostino E. CSL Behring's recombinant coagulation portfolio: Clinical trials and results of rIX-FP and rVIII SingleChain. Haemophilia 2014; 20 (Suppl. 03) 188
  CrossrefPubMedGoogle Scholar
• 38 Schulte S. Use of albumin fusion technology to prolong the half-life of recombinant factor VIIa. Thromb Res 2008; 122 (Suppl. 04) S14-S19
  PubMedGoogle Scholar
• 39 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
  PubMedGoogle Scholar
• 40 Herzog E, Harr S, Mcewen A , et al. Biodistribution of the recombinant fusion protein linking factor rVIIa with albumin. Haemophilia 2014; 20 (Suppl. 03) 23
  CrossrefPubMedGoogle Scholar
• 41 Gregoriadis G, Jain S, Papaioannou I, Laing P. Improving the therapeutic efficacy of peptides and proteins: a role for polysialic acids. Int J Pharm 2005; 300 (1-2) 125-130
  CrossrefPubMedGoogle Scholar
• 42 Rottensteiner H, Turecek PL, Pendu R , et al. PEGylation or polysialylation reduces FVIII binding to LRP resulting in prolonged half-life in murine models. ASH Annual Meeting Abstracts. 2007; 110: 3150
  PubMedGoogle Scholar
• 43 Fogarty PF. Biological rationale for new drugs in the bleeding disorders pipeline. Hematology Am Soc Hematol Edu Program 2011; 2011: 397-404
  PubMedGoogle Scholar
• 44 Schellenberger V, Wang C-W, Geething NC , et al. A recombinant polypeptide extends the in vivo half-life of peptides and proteins in a tunable manner. Nat Biotechnol 2009; 27 (12) 1186-1190
  CrossrefPubMedGoogle Scholar
• 45 Seth Chhabra S, Liu T, Kulman J , et al. Engineering a novel rFVIII-VWF D'D3 fusion protein to enhance stability and improve pharmacokinetic properties of FVIII. J Thromb Haemost 2013; 11 (Suppl. 02) 170
  CrossrefPubMedGoogle Scholar
• 46 Liu T, Seth Chhabra S, Kulman J , et al. Prolonged efficacy in hemophilia A mouse bleeding models of a recombinant FVIII-XTEN/D'D3 heterodimer with four-fold extended half-life in circulation. Haemophilia 2014; 20 (Suppl. 03) 76
  CrossrefPubMedGoogle Scholar
• 47 Tan S, Salas J, Chen K , et al. Improving pharmacokinetic properties of the platelet-targeted coagulation factor VIIa by an unstructured polypeptide XTEN. Haemophilia 2014; 20 (Suppl. 03) 76
  CrossrefPubMedGoogle Scholar
• 48 Fares F, Guy R, Bar-Ilan A, Felikman Y, Fima E. Designing a long-acting human growth hormone (hGH) by fusing the carboxyl-terminal peptide of human chorionic gonadotropin beta-subunit to the coding sequence of hGH. Endocrinology 2010; 151 (9) 4410-4417
  CrossrefPubMedGoogle Scholar
• 49 Moschcovich L, Zakar M, Zur Y, Felikman Y, Hart G, Hershkovitz O. Fed-batch manufacturing process of long acting FVIIA-CTP in CHO cells. Haemophilia 2014; 20 (Suppl. 02) 56
  PubMedGoogle Scholar
• 50 Har G, Bar Ilan A, Hershkovitz O, Binder L, Zakar M, Fima E. Factor VIIA-CTP, a novel long-acting coagulation factor proposing an improved prophylactic treatment of hemophilic patients following SC administration – extensive evaluation in animal models. Haemophilia 2014; 20 (Suppl. 02) 37
  PubMedGoogle Scholar
• 51 Schulte S. Innovative coagulation factors: albumin fusion technology and recombinant single-chain factor VIII. Thromb Res 2013; 131 (Suppl. 02) S2-S6
  CrossrefPubMedGoogle Scholar
• 52 Zollner S, Raquet E, Claar P , et al. Non-clinical pharmacokinetics and pharmacodynamics of rVIII-SingleChain, a novel recombinant single-chain factor VIII. Thromb Res 2014; 134 (1) 125-131
  CrossrefPubMedGoogle Scholar
• 53 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
  CrossrefPubMedGoogle Scholar
• 54 Mahlangu JN, Koh PL, Ng HJ, Lissitchkov T, Hardtke M, Schroeder J. The TRUST trial: anti-drug antibody formation in patient with hemophilia with inhibitors after receiving the activated Factor VII product Bay 86–6150. Blood 2013; 122: 573
  PubMedGoogle Scholar
• 55 Keefe AD, Pai S, Ellington A. Aptamers as therapeutics. Nat Rev Drug Discov 2010; 9 (7) 537-550
  CrossrefPubMedGoogle Scholar
• 56 Waters EK, Genga RM, Schwartz MC , et al. Aptamer ARC19499 mediates a procoagulant hemostatic effect by inhibiting tissue factor pathway inhibitor. Blood 2011; 117 (20) 5514-5522
  CrossrefPubMedGoogle Scholar
• 57 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. ASH Annual Meeting Abstracts 2012; 120: 1104
  PubMedGoogle Scholar
• 58 Dockal M, Hartmann R, Polakowski T , et al. Design of a most efficient inhibitor of TFPI by molecular fusion of two inhibitor peptides. Blood 2013; 122: 3564
  PubMedGoogle Scholar
• 59 Hartmann R, Polakowski T, Brandstetter H , et al. Design of an efficient inhibitor of TFPI by molecular fusion of two inhibitory peptides improves coagulation in hemophilia. Haemophilia 2014; 20 (Suppl. 03) 77
  PubMedGoogle Scholar
• 60 Chan AC, Carter PJ. Therapeutic antibodies for autoimmunity and inflammation. Nat Rev Immunol 2010; 10 (5) 301-316
  CrossrefPubMedGoogle Scholar
• 61 Hilden I, Lauritzen B, Sørensen BB , et al. Hemostatic effect of a monoclonal antibody mAb 2021 blocking the interaction between FXa and TFPI in a rabbit hemophilia model. Blood 2012; 119 (24) 5871-5878
  CrossrefPubMedGoogle Scholar
• 62 Agersø H, Overgaard RV, Petersen MB , et al. Pharmacokinetics of an anti-TFPI monoclonal antibody (concizumab) blocking the TFPI interaction with the active site of FXa in Cynomolgus monkeys after iv and sc administration. Eur J Pharm Sci 2014; 56 (56) 65-69
  CrossrefPubMedGoogle Scholar
• 63 Kitazawa T, Igawa T, Sampei Z , et al. A bispecific antibody to factors IXa and X restores factor VIII hemostatic activity in a hemophilia A model. Nat Med 2012; 18 (10) 1570-1574
  CrossrefPubMedGoogle Scholar
• 64 Sampei Z, Igawa T, Soeda T , et al. Identification and multidimensional optimization of an asymmetric bispecific IgG antibody mimicking the function of factor VIII cofactor activity. PLoS ONE 2013; 8 (2) e57479
  CrossrefPubMedGoogle Scholar
• 65 Muto A, Yoshihashi K, Takeda M , et al. Anti-factor IXa/X bispecific antibody (ACE910): hemostatic potency against ongoing bleeds in a hemophilia A model and the possibility of routine supplementation. J Thromb Haemost 2014; 12: 206-213
  CrossrefPubMedGoogle Scholar
• 66 Shima M, Uchida N, Sanbe T , et al. The safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of ACE910, a humanized bispecific antibody mimicking the FVIIIcofactor function, demonstrated in healthy adults. Haemophilia 2014; 20 (Suppl. 03) 76
  CrossrefPubMedGoogle Scholar
• 67 Carthew RW, Sontheimer EJ. Origins and Mechanisms of miRNAs and siRNAs. Cell 2009; 136 (4) 642-655
  CrossrefPubMedGoogle Scholar
• 68 Bennett CF, Swayze EE. RNA targeting therapeutics: molecular mechanisms of antisense oligonucleotides as a therapeutic platform. Annu Rev Pharmacol Toxicol 2010; 50: 259-293
  CrossrefPubMedGoogle Scholar
• 69 Akinc A, Querbes W, De S , et al. Targeted delivery of RNAi therapeutics with endogenous and exogenous ligand-based mechanisms. Mol Ther 2010; 18 (7) 1357-1364
  CrossrefPubMedGoogle Scholar
• 70 Akinc A, Sehgal A, Barros S , et al. An RNAi Therapeutic Targeting Antithrombin Increases Thrombin Generation in Nonhuman Primates. ASH Annual Meeting Abstracts 2012; 120: 3370
  PubMedGoogle Scholar
• 71 Sehgal A, Qin J, Racie T , et al. ALN-AT3: an RNAi therapeutic targeting antithrombin for the treatment of hemophilia. Haemophilia 2014; 20 (Suppl. 03) 82-91
  PubMedGoogle Scholar