Thromb Haemost 2017; 117(03): 508-518
DOI: 10.1160/TH16-05-0398
Coagulation and Fibrinolysis
Schattauer GmbH

Long-term safety and efficacy of extended-interval prophylaxis with recombinant factor IX Fc fusion protein (rFIXFc) in subjects with haemophilia B

K.John Pasi
1   Royal London Haemophilia Centre, Barts and The London School of Medicine and Dentistry, London, UK
,
Kathelijn Fischer
2   Van Creveldkliniek, University Medical Center, Utrecht, The Netherlands
,
Margaret Ragni
3   Hemophilia Center of Western Pennsylvania, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
,
Beatrice Nolan
4   Our Lady’s Children’s Hospital, Dublin, Ireland
,
David J. Perry
5   Addenbrookes Hospital, Cambridge, UK
,
Roshni Kulkarni
6   Michigan State University, East Lansing, Michigan, USA
,
Margareth Ozelo
7   INCT do Sangue Hemocentro UNICAMP, University of Campinas, Brazil
,
Johnny Mahlangu
8   Haemophilia Comprehensive Care Centre, Faculty of Health Sciences, University of the Witwatersrand, Charlotte Maxeke Johannesburg Academic Hospital and NHLS, Johannesburg, South Africa
,
Amy D. Shapiro
9   Indiana Hemophilia and Thrombosis Center, Indianapolis, Indiana, USA
,
Ross I. Baker
10   Western Australian Centre for Thrombosis and Haemostasis, Murdoch University, Perth, Western Australia, Australia
,
Carolyn M. Bennett
11   Emory University School of Medicine, Children’s Healthcare of Atlanta, Aflac Cancer and Blood Disorders Center, Atlanta, Georgia, USA
,
Christopher Barnes
12   The Royal Children’s Hospital, Parkville, Melbourne, Victoria, Australia
,
Johannes Oldenburg
13   Institute of Experimental Haematology and Transfusion Medicine, University of Bonn, Bonn, Germany
,
Tadashi Matsushita
14   Department of Transfusion Medicine, Nagoya University Hospital, Nagoya, Japan
,
Huixing Yuan
15   Biogen, Cambridge, Massachusetts, USA
,
Alejandra Ramirez-Santiago
15   Biogen, Cambridge, Massachusetts, USA
,
Glenn F. Pierce
15   Biogen, Cambridge, Massachusetts, USA
,
Geoffrey Allen
15   Biogen, Cambridge, Massachusetts, USA
,
Baisong Mei
15   Biogen, Cambridge, Massachusetts, USA
› Institutsangaben
Financial support: This study was funded by Biogen and Sobi.
Weitere Informationen

Publikationsverlauf

Received: 23. Mai 2016

Accepted after major revision: 02. Dezember 2016

Publikationsdatum:
22. November 2017 (online)

Summary

The safety, efficacy, and prolonged half-life of recombinant factor IX Fc fusion protein (rFIXFc) were demonstrated in the Phase 3 B-LONG (adults/adolescents ≥12 years) and Kids B-LONG (children <12 years) studies of subjects with haemophilia B (≤2 IU/dl). Here, we report interim, long-term safety and efficacy data from B-YOND, the rFIXFc extension study. Eligible subjects who completed B-LONG or Kids B-LONG could enrol in B-YOND. There were four treatment groups: weekly prophylaxis (20–100 IU/kg every 7 days), individualised prophylaxis (100 IU/kg every 8–16 days), modified prophylaxis (further dosing personalisation to optimise prophylaxis), and episodic (ondemand) treatment. Subjects could change treatment groups at any point. Primary endpoint was inhibitor development. One hundred sixteen subjects enrolled in B-YOND. From the start of the parent studies to the B-YOND interim data cut, median duration of rFIXFc treatment was 39.5 months and 21.9 months among adults/adolescents and children, respectively; 68/93 (73.1 %) adults/adolescents and 9/23 (39.1 %) children had ≥100 cumulative rFIXFc exposure days. No inhibitors were observed. Median annualised bleeding rates (ABRs) were low in all prophylaxis regimens: weekly (≥12 years: 2.3; <6 years: 0.0; 6 to <12 years: 2.7), individualised (≥12 years: 2.3; 6 to <12 years: 2.4), and modified (≥12 years: 2.4). One or two infusions were sufficient to control 97 % (adults/adolescents) and 95 % (children) of bleeding episodes. Interim data from B-YOND are consistent with data from B-LONG and Kids B-LONG, and confirm the longterm safety of rFIXFc, absence of inhibitors, and maintenance of low ABRs with prophylactic dosing every 1 to 2 weeks.

Supplementary Material to this article is available online at www.thrombosis-online.com.

 
  • References

  • 1 Srivastava A, Brewer AK, Mauser-Bunschoten EP. et al. Guidelines for the management of hemophilia. Haemophilia 2013; 19: e1-e47.
  • 2 Mannucci PM, Tuddenham EG. The hemophilias - from royal genes to gene therapy. N Engl J Med 2001; 344: 1773-1779.
  • 3 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: 535-544.
  • 4 Khawaji M, Astermark J, Berntorp E. Lifelong prophylaxis in a large cohort of adult patients with severe haemophilia: a beneficial effect on orthopaedic outcome and quality of life. Eur J Haematol 2012; 88: 329-335.
  • 5 Iorio A, Marchesini E, Marcucci M. et al. Clotting factor concentrates given to prevent bleeding and bleeding-related complications in people with hemophilia A or B. Cochrane Database Syst Rev. 2011: CD003429.
  • 6 National Hemophilia Foundation. MASAC Recommendation Concerning Prophylaxis (Regular Administration of Clotting Factor Concentrate to Prevent Bleeding). MASAC Document #179. Available at: http://www.hemophilia.org/NHFWeb/Resource/StaticPages/menu0/menu5/menu57/masac179.pdf Accessed September 21, 2015
  • 7 Zappa S, McDaniel M, Marandola J. et al. Treatment trends for haemophilia A and haemophilia B in the United States: results from the 2010 practice patterns survey. Haemophilia 2012; 18: e140-e153.
  • 8 Petrini P. Identifying and overcoming barriers to prophylaxis in the management of haemophilia. Haemophilia 2007; 13 (Suppl. 02) 16-22.
  • 9 Hacker MR, Geraghty S, Manco-Johnson M. Barriers to compliance with prophylaxis therapy in haemophilia. Haemophilia 2001; 07: 392-396.
  • 10 Schrijvers LH, Uitslager N, Schuurmans MJ. et al. Barriers and motivators of adherence to prophylactic treatment in haemophilia: a systematic review. Haemophilia 2013; 19: 355-361.
  • 11 Fogarty PF. Biological rationale for new drugs in the bleeding disorders pipeline. Hematology Am Soc Hematol Educ Program 2011; 2011: 397-404.
  • 12 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: 235-254.
  • 13 Peters RT, Low SC, Kamphaus GD. et al. Prolonged activity of factor IX as a monomeric Fc fusion protein. Blood 2010; 115: 2057-2064.
  • 14 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: 666-672.
  • 15 Powell JS, Pasi J, Ragni MV. et al. Phase 3 study of recombinant factor IX Fc fusion protein in hemophilia B. N Engl J Med 2013; 369: 2313-2323.
  • 16 Powell JS, Apte S, Chambost H. et al. Long-acting recombinant factor IX Fc fusion protein (rFIXFc) for perioperative management of subjects with haemophilia B in the phase 3 B-LONG study. Br J Haematol 2015; 168: 124-134.
  • 17 Powell J, Shapiro A, Ragni M. et al. Switching to recombinant factor IX Fc fusion protein prophylaxis results in fewer infusions, decreased factor IX consumption and lower bleeding rates. Br J Haematol 2015; 168: 113-123.
  • 18 Fischer K, Kulkarni R, Nolan B. et al. Safety, efficacy and pharmacokinetics of rFIXFc in children with haemophilia B: results of the Kids B-LONG study. Presented at: 25th Annual International Society on Thrombosis and Haemostasis Congress; June 20-25,. 2015. Toronto; Canada:
  • 19 European Medicines Agency. Guideline on clinical investigation of recombinant and human plasma-derived factor IX products. 2015 http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2015/06/WC500187413.pdf Accessed September 1, 2016
  • 20 Urasinski T, Stasyshyn O, Andreeva T. et al. Recombinant factor IX (BAX326) in previously treated paediatric patients with haemophilia B: a prospective clinical trial. Haemophilia 2015; 21: 196-203.
  • 21 Windyga J, Lissitchkov T, Stasyshyn O. et al. Pharmacokinetics, efficacy and safety of BAX326, a novel recombinant factor IX: a prospective, controlled, multicentre phase I/III study in previously treated patients with severe (FIX level <1?%) or moderately severe (FIX level =2?%) haemophilia B. Haemophilia 2014; 20: 15-24.
  • 22 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: 3880-3886.
  • 23 Young G, Collins PW, Colberg T. et al. Nonacog beta pegol (N9-GP) in haemophilia B: a multinational phase III safety and efficacy extension trial (paradigm4). Thromb Res 2016; 141: 69-76.
  • 24 Santagostino E, Martinowitz U, Lissitchkov T. et al. Long acting recombinant coagulation factor IX albumin fusion protein (rIX-FP) in hemophilia B: results of a phase 3 trial. Blood 2016 Epub ahead of print.