Enhanced Half-Life Recombinant Factor VIII Concentrates for Hemophilia A: Insights from Pivotal and Extension Studies

Abstract

The development of enhanced half-life recombinant factor VIII (EHL-rFVIII) concentrates has improved the management of hemophilia. Furthermore, the chance of maintaining higher trough levels has allowed higher protection from bleeding and, in turn, improved safely performance for certain types of physical activity. The first technology used to improve the pharmacokinetic profile of factor VIII (FVIII) was fusion with the Fc domain of immunoglobulin G. More recently, conjugation to hydrophilic polymers of polyethylene glycol (PEG) has been demonstrated to prolong plasma half-life of FVIII by means of a reduction in clearance of the molecule due to steric hindrance by PEG covering the protein. Here we report results of a systematic review of pivotal studies on EHL-rFVIII concentrates. Significant heterogeneity is observed among different studies on EHL-rFVIII concentrates, and direct comparisons should be avoided. The annualized bleeding rate has ranged between 1.2 and 1.9 in different EHL-rFVIII concentrates, with a progressive further decrease during extension phases of pivotal studies. Zero bleeding was reported by 40 to 45% of patients. Overall, the emerging treatment options seem to be highly effective and safe, associated with a decreased dosing interval to twice weekly or less, which reduces, but does not entirely eliminate, the burden of treatment. Overall, further information is needed from real-life settings to permit differentiation between EHL-FVIII concentrates and for individualizing treatment.

Keywords

hemophilia - enhanced half-life recombinant FVIII concentrates - bleeding

Publication History

Article published online:
21 December 2020

• References

• 1 Darby SC, Kan SW, Spooner RJ. et al. Mortality rates, life expectancy, and causes of death in people with hemophilia A or B in the United Kingdom who were not infected with HIV. Blood 2007; 110 (03) 815-825
• 2 Soucie JM, Nuss R, Evatt B. et al; The Hemophilia Surveillance System Project Investigators. Mortality among males with hemophilia: relations with source of medical care. Blood 2000; 96 (02) 437-442
• 3 Plug I, Van Der Bom JG, Peters M. et al. Mortality and causes of death in patients with hemophilia, 1992-2001: a prospective cohort study. J Thromb Haemost 2006; 4 (03) 510-516
• 4 Tagliaferri A, Rivolta GF, Iorio A. et al; Italian Association of Hemophilia Centers. Mortality and causes of death in Italian persons with haemophilia, 1990-2007. Haemophilia 2010; 16 (03) 437-446
• 5 Manco-Johnson MJ, Abshire TC, Shapiro AD. et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med 2007; 357 (06) 535-544
• 6 Gringeri A, Lundin B, von Mackensen S, Mantovani L, Mannucci PM. ESPRIT Study Group. A randomized clinical trial of prophylaxis in children with hemophilia A (the ESPRIT Study). J Thromb Haemost 2011; 9 (04) 700-710
• 7 Björkman S, Folkesson A, Jönsson S. Pharmacokinetics and dose requirements of factor VIII over the age range 3-74 years: a population analysis based on 50 patients with long-term prophylactic treatment for haemophilia A. Eur J Clin Pharmacol 2009; 65 (10) 989-998
• 8 Björkman S. Population pharmacokinetics of recombinant factor IX: implications for dose tailoring. Haemophilia 2013; 19 (05) 753-757
• 9 Mancuso ME, Santagostino E. Outcome of clinical trials with new extended half-life FVIII/IX concentrates. J Clin Med 2017; 6 (04) E39
• 10 Mannucci PM, Mancuso ME. Investigational drugs for coagulation disorders. Expert Opin Investig Drugs 2013; 22 (08) 945-953
• 11 Harris JM, Chess RB. Effect of pegylation on pharmaceuticals. Nat Rev Drug Discov 2003; 2 (03) 214-221
• 12 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 (01) 132-141
• 13 Rath T, Baker K, Dumont JA. et al. Fc-fusion proteins and FcRn: structural insights for longer-lasting and more effective therapeutics. Crit Rev Biotechnol 2015; 35 (02) 235-254
• 14 Roopenian DC, Akilesh S. FcRn: the neonatal Fc receptor comes of age. Nat Rev Immunol 2007; 7 (09) 715-725
• 15 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 (03) 317-325
• 16 Shapiro AD, Ragni MV, Kulkarni R. et al. 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 (11) 1788-1800
• 17 Young G, Mahlangu J, Kulkarni R. et al. Recombinant factor VIII Fc fusion protein for the prevention and treatment of bleeding in children with severe hemophilia A. J Thromb Haemost 2015; 13 (06) 967-977
• 18 Nolan B, Mahlangu J, Perry D. et al. Long-term safety and efficacy of recombinant factor VIII Fc fusion protein (rFVIIIFc) in subjects with haemophilia A. Haemophilia 2016; 22 (01) 72-80
• 19 Konkle B, Young G, Liesner R. et al. Long-term efficacy and safety of prophylactic treatment with recombinant factor VIII Fc fusion protein (rFVIIIFc) in subjects with severe haemophilia A: final longitudinal analysis of A-LONG/ kids A-LONG and ASPIRE. Haemophilia 2019; 25 (Suppl. 01) 55
• 20 Nolan B, Konkle BA, Mahlangu J. et al. Efficacy and safety of rFVIIIFc prophylaxis in pediatric, adolescent, and adult subjects with severe hemophilia A over 3–4 years: the ASPIRE study. Res Pract Thromb Haemost PB 1774 2017; 1 (Suppl. 01) 781
• 21 Nolan B, Mahlangu J, Young G. et al. ASPIRE final results confirm established safety and sustained efficacy for up to 4 years of treatment with rFVIIIFc in previously treated subjects with severe hemophilia A. Blood 2018; 132: 1192
• 22 Königs C, Liesner R, Ozelo MC. et al. Incidence of inhibitors in previously untreated patients with severe haemophilia a treated with rFVIIIFc: the PUPs A-LONG study C. Haemophilia 2019; 25 (Suppl. 01) 32
• 23 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
• 24 Konkle BA, Stasyshyn O, Chowdary P. et al. Pegylated, full-length, recombinant factor VIII for prophylactic and on-demand treatment of severe hemophilia A. Blood 2015; 126 (09) 1078-1085
• 25 Mullins ES, Stasyshyn O, Alvarez-Román MT. et al. Extended half-life pegylated, full-length recombinant factor VIII for prophylaxis in children with severe haemophilia A. Haemophilia 2017; 23 (02) 238-246
• 26 Mullins ES, Konkle BA, McGuinn CE, Engl W, Tangada SD. Efficacy and safety results from a phase 3b, open-label, multicenter, continuation study of rurioctocog alfa pegol for prophylaxis in previously treated patients with severe hemophilia A. Blood 2018; 132: 2483
• 27 Chowdary P, Mullins E, Stasyshyn O, Zhang J, Engl W, Tangada S. Results from a phase 3B, open-label, multicenter, continuation study of rurioctocog alfa pegol for prophylaxis in previously treated patients with severe hemophilia A: Analysis by age group. Haemophilia 2019; 25 (Suppl. 01) 158-159
• 28 Klamroth R, Windyga J, Radulescu V. et al. Results from a phase 3, randomized, multicenter study of rurioctocog alfa pegol PK-guided prophylaxis targeting 2 FVIII trough levels in patients with severe hemophilia A (PROPEL study). Haemophilia 2019; 25 (Suppl. 01) 162
• 29 Mullins E, Kefurt C, Engl W, Tangada S. Design of a phase 3, prospective, multicenter, open-label study of safety and hemostatic efficacy of rurioctocog alfa pegol in previously untreated patients <6 years of age with severe hemophilia A. Haemophilia 2019; 25 (Suppl. 01) 83
• 30 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 (02) 270-279
• 31 Reding MT, Ng HJ, Poulsen LH. et al. Safety and efficacy of BAY 94-9027, a prolonged-half-life factor VIII. J Thromb Haemost 2017; 15 (03) 411-419
• 32 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 (04) 488-496
• 33 Santagostino E, Saxena K, Kenet G. et al. PROTECT VIII Kids Trial Results: BAY 94–9027 safety and efficacy in previously treated children with severe hemophilia A. Haemophilia 2016; 22 (Suppl. 04) 41
• 34 Lalezari S, Reding MT, Pabinger I. et al. BAY 94-9027 prophylaxis is efficacious and well tolerated for up to >5 years with extended dosing intervals: PROTECT VIII extension interim results. Haemophilia 2019; 25 (06) 1011-1019
• 35 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
• 36 Giangrande P, Andreeva T, Chowdary P. et al; Pathfinder™2 Investigators. Clinical evaluation of glycoPEGylated recombinant FVIII: efficacy and safety in severe haemophilia A. Thromb Haemost 2017; 117 (02) 252-261
• 37 Meunier S, Alamelu J, Ehrenforth S. et al. Safety and efficacy of a glycoPEGylated rFVIII (turoctocog alpha pegol, N8-GP) in paediatric patients with severe haemophilia A. Thromb Haemost 2017; 117 (09) 1705-1713
• 38 Curry N, Albayrak C, Escobar M. et al. Once-weekly prophylaxis with glycoPEGylated recombinant factor VIII (N8-GP) in severe haemophilia A: safety and efficacy results from pathfinder 2 (randomized phase III trial). Haemophilia 2019; 25 (03) 373-381
• 39 Chowdary P, Poulsen LH, Escobar MA. et al. Efficacy of an extended half-life glycoPEGylated rFVIII (N8-GP): pooled analysis of ABR (results from two clinical trials). Blood 2018; 132: 1177
• 40 Ruiz-Sáez A, Boadas A, Echenagucia M. Use of extended half-life rFVIII-Fc or rFIX-Fc in previously treated patients with hemophilia A or B. A single center experience. Haemophilia 2019; 25 (Suppl. 01) 50-51
• 41 Tortella BJ, Chhabra A, Fogarty P, Rubinstein E, Young L, Alvir J. Long-term real-world health care comparison of expenditures and international units dispensed for haemophilia A patients switching to extended from standard half-life recombinant factor VIII products. Haemophilia 2019; 25 (Suppl. 01) 56
• 42 Delmotte GN, Roche M, Giraud R. et al. Recombinant factor VIII Fc (rFVIIIFc) in real life: clinical and economic outcomes. Haemophilia 2019; 25 (Suppl. 01) 102
• 43 Bayer HealthCare. Indications and usage of Jivi. Available at: https://labeling.bayerhealthcare.com/html/products/pi/Jivi_PI.pdf. Accessed February 18, 2019
• 44 Mullins ES, Konkle BA, McGuinn CE, Engl W, Tangada SD. Efficacy and safety results from a phase 3b, open-label, multicenter, continuation study of rurioctocog alfa pegol for prophylaxis in previously treated patients with severe hemophilia A. Blood 2018; 132: 2483
• 45 Curry N, Albayrak C, Escobar M. et al. Once-weekly prophylaxis with GlycoPEGylated recombinant factor VIII (N8-GP) in severe haemophilia A: safety and efficacy results from a randomised phase 3 trial (pathfinder™2). Res Pract Thromb Haemost PB 493 2017; 1 (Suppl. 01) 730
• 46 Valentino LA, Mamonov V, Hellmann A. et al; Prophylaxis Study Group. A randomized comparison of two prophylaxis regimens and a paired comparison of on-demand and prophylaxis treatments in hemophilia A management. J Thromb Haemost 2012; 10 (03) 359-367
• 47 Khair K, Mazzucconi MG, Parra R. et al. Pattern of bleeding in a large prospective cohort of haemophilia A patients: a three-year follow-up of the AHEAD (Advate in HaEmophilia A outcome Database) study. Haemophilia 2018; 24 (01) 85-96
• 48 Seth Chhabra E, Liu T, Kulman J. et al. Developing BIVV001, a new class of factor VIII replacement for hemophilia A that is von Willebrand factor-independent. Blood 2020; 135 (17) 1484-1496