Download PDF
Semin Thromb Hemost 2021; 47(01): 032-042
DOI: 10.1055/s-0040-1718887
Review Article

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

Matteo Nicola Dario Di Minno
1   Department of Translational Medical Sciences, Federico II University, Naples, Italy
,
Alessandro Di Minno
2   Dipartimento di Farmacia, Università degli Studi di Napoli “Federico II,” Napoli, Italy
,
Ilenia Calcaterra
3   Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy
,
Ernesto Cimino
3   Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy
,
Francesco Dell'Aquila
3   Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy
,
Massimo Franchini
4   Department of Haematology and Transfusion Medicine, “Carlo Poma” Hospital, Mantua, Italy
› Author Affiliations
› Further Information
    Permissions and Reprints

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

© 2020. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 

  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 8 Björkman S. Population pharmacokinetics of recombinant factor IX: implications for dose tailoring. Haemophilia 2013; 19 (05) 753-757
    CrossrefPubMedGoogle Scholar
  • 9 Mancuso ME, Santagostino E. Outcome of clinical trials with new extended half-life FVIII/IX concentrates. J Clin Med 2017; 6 (04) E39
    CrossrefPubMedGoogle Scholar
  • 10 Mannucci PM, Mancuso ME. Investigational drugs for coagulation disorders. Expert Opin Investig Drugs 2013; 22 (08) 945-953
    CrossrefPubMedGoogle Scholar
  • 11 Harris JM, Chess RB. Effect of pegylation on pharmaceuticals. Nat Rev Drug Discov 2003; 2 (03) 214-221
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 14 Roopenian DC, Akilesh S. FcRn: the neonatal Fc receptor comes of age. Nat Rev Immunol 2007; 7 (09) 715-725
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    Article in Thieme ConnectPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    Article in Thieme ConnectPubMedGoogle Scholar
  • 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
    Article in Thieme ConnectPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 43 Bayer HealthCare. Indications and usage of Jivi. Available at: https://labeling.bayerhealthcare.com/html/products/pi/Jivi_PI.pdf. Accessed February 18, 2019
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar