Long-Term Safety and Efficacy of Recombinant Coagulation Factor IX Albumin Fusion Protein (rIX-FP) in Previously Treated Pediatric Patients with Hemophilia B: Results from a Phase 3b Extension Study

Abstract

Introduction A phase 3b extension study evaluated the long-term safety and efficacy of a recombinant fusion protein-linking coagulation factor IX (FIX) with albumin (rIX-FP) for the routine prophylaxis and on-demand treatment of bleeding in pediatric hemophilia B patients.

Methods Previously treated patients aged <12 years with moderate to severe hemophilia B enrolled in a 3-year extension study following a phase 3 pivotal study in which they received weekly rIX-FP prophylaxis. In the extension study, they could maintain or extend their prophylaxis interval to every 10 or 14 days if they were well controlled on the 7-day regimen.

Results Compared with their initial regimen, by the end of the study, dosing intervals were the same, extended, and shortened in 16, 4, and 4 patients, respectively. Very low annualized spontaneous bleeding rates (AsBRs) were observed; median AsBR was 0.0 for the 7- and 10-day regimens, and 1.1 for the 14-day regimen. The 7- and 14-day regimens were comparable in preventing spontaneous bleeds; mean (95% confidence interval) difference in AsBR of −1.2 (−2.6 to 0.3) bleeding episodes/year/subject. Overall, 96% of bleeding episodes were successfully treated with one or two injections of rIX-FP. Patients on a 14-day regimen maintained a mean steady-state trough FIX level of >7.2 IU/dL. No patient developed an inhibitor.

Conclusion This extension study demonstrated the long-term safety and efficacy of weekly rIX-FP in pediatric patients. Additionally, it showed that adequate bleed protection can be achieved with 10- or 14-day rIX-FP regimens in selected pediatric patients while maintaining safety.

Keywords

rIX-FP - factor IX - hemophilia B - prophylaxis - recombinant fusion protein

Note

Editorial support for the writing of this manuscript was provided by Jessica Jackson of Meridian HealthComms in accordance with good publication practice (GPP3) and was funded by CSL Behring. CSL Behring reviewed and provided feedback on the paper. The authors had full editorial control of the paper and provided their final approval of all content.

Members of the PROLONG-9FP Investigators Study Group

Australia: Christopher Barnes, Royal Children's Hospital, Victoria; Julie Curtin, The Children's Hospital Westmead, NSW; Canada: Anthony Chan, McMaster Children's Hospital, Hamilton, ON; Czech Republic: Jan Blatny, Children's University Hospital, Masaryk University, Brno; Bohumir Blazek, University Hospital Ostrava, Ostrava-Poruba; Vladimir Komrska, University Hospital Motol, Prague; Germany: Hans-Jürgen Laws, Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich-Heine Universitaet, Dusseldorf; Spain: Maria-Teresa Álvarez Román, Hospital Universitario La Paz, Madrid.

• References

• 1 Srivastava A, Brewer AK, Mauser-Bunschoten EP. , et al; Treatment Guidelines Working Group on Behalf of The World Federation Of Hemophilia. Guidelines for the management of hemophilia. Haemophilia 2013; 19 (01) e1-e47
• 2 Konkle BA, Huston H, Nakaya Fletcher S. Hemophilia B. Seattle, WA: GeneReviews(R); 1993
• 3 Bolton-Maggs PH, Pasi KJ. Haemophilias A and B. Lancet 2003; 361 (9371): 1801-1809
• 4 Clausen N, Petrini P, Claeyssens-Donadel S, Gouw SC, Liesner R. ; PedNet and Research of Determinants of Inhibitor development (RODIN) Study Group. Similar bleeding phenotype in young children with haemophilia A or B: a cohort study. Haemophilia 2014; 20 (06) 747-755
• 5 den Uijl IE, Fischer K, Van Der Bom JG, Grobbee DE, Rosendaal FR, Plug I. Analysis of low frequency bleeding data: the association of joint bleeds according to baseline FVIII activity levels. Haemophilia 2011; 17 (01) 41-44
• 6 Shapiro A, Potts J, Li S. , et al. Association of bleeding tendency with time under target FIX activity levels in severe hemophilia B patients treated with recombinant factor IX Fc fusion protein. Blood 2013; 122 (21) 2349-2350
• 7 Castaman G. The benefits of prophylaxis in patients with hemophilia B. Expert Rev Hematol 2018; 11 (08) 673-683
• 8 Santagostino E, Mancuso ME. Barriers to primary prophylaxis in haemophilic children: the issue of the venous access. Blood Transfus 2008; 6 (Suppl. 02) s12-s16
• 9 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 (04) 634-644
• 10 Kenet G, Chambost H, Male C. , et al; PROLONG-9FP Investigator Study Group. Long-acting recombinant fusion protein linking coagulation factor IX with albumin (rIX-FP) in children. Results of a phase 3 trial. Thromb Haemost 2016; 116 (04) 659-668
• 11 Mancuso M, Lubetsky A, Pan-Petesch B. , et al. Long-term safety and efficacy of rIX-FP prophylaxis with dosing intervals of 7, 10, 14 and 21 days in previously treated adults and adolescents with hemophilia B. J Thromb Haemost 2020 [in press]
• 12 World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA 2013; 310 (20) 2191-2194
• 13 Verbruggen B, Novakova I, Wessels H, Boezeman J, van den Berg M, Mauser-Bunschoten E. The Nijmegen modification of the Bethesda assay for factor VIII:C inhibitors: improved specificity and reliability. Thromb Haemost 1995; 73 (02) 247-251
• 14 Santagostino E, Martinowitz U, Lissitchkov T. , et al; PROLONG-9FP Investigators Study Group. Long-acting recombinant coagulation factor IX albumin fusion protein (rIX-FP) in hemophilia B: results of a phase 3 trial. Blood 2016; 127 (14) 1761-1769
• 15 Jiménez-Yuste V, Auerswald G, Benson G. , et al. Achieving and maintaining an optimal trough level for prophylaxis in haemophilia: the past, the present and the future. Blood Transfus 2014; 12 (03) 314-319
• 16 Carcao M, Zak M, Abdul Karim F. , et al. Nonacog beta pegol in previously treated children with hemophilia B: results from an international open-label phase 3 trial. J Thromb Haemost 2016; 14 (08) 1521-1529
• 17 Fischer K, Kulkarni R, Nolan B. , et al. Recombinant factor IX Fc fusion protein in children with haemophilia B (Kids B-LONG): results from a multicentre, non-randomised phase 3 study. Lancet Haematol 2017; 4 (02) e75-e82
• 18 Pasi KJ, Fischer K, Ragni M. , et al. Long-term safety and efficacy of extended-interval prophylaxis with recombinant factor IX Fc fusion protein (rFIXFc) in subjects with haemophilia B. Thromb Haemost 2017; 117 (03) 508-518