Long-acting recombinant fusion protein linking coagulation factor IX with albumin (rIX-FP) in children

Summary

A global phase 3 study evaluated the pharmacokinetics, efficacy and safety of a recombinant fusion protein linking coagulation factor IX with albumin (rIX-FP) in 27 previously treated male children (1–11 years) with severe and moderately severe haemophilia B (factor IX [FIX] activity ≤2 IU/dl). All patients received routine prophylaxis once every seven days for up to 77 weeks, and treated any bleeding episodes on-demand. The mean terminal half-life of rIX-FP was 91.4 hours (h), 4.3-fold longer than previous FIX treatment and clearance was 1.11 ml/h/kg, 6.4-fold slower than previous FIX treatment. The median (Q1, Q3) annualised spontaneous bleeding rate was 0.00 (0.00, 0.91) and was similar between the <6 years and ≥6 years age groups, with a weekly median prophylactic dose of 46 IU/kg. In addition, patients maintained a median trough level of 13.4 IU/dl FIX activity on weekly prophylaxis. Overall, 97.2 % of bleeding episodes were successfully treated with one or two injections of rIX-FP (95 % CI: 92 % to 99 %), 88.7 % with one injection, and 96 % of the treatments were rated effective (excellent or good) by the Investigator. No patient developed FIX inhibitors and no safety concerns were identified. These results indicate that rIX-FP is safe and effective for preventing and treating bleeding episodes in children with haemophilia B with weekly prophylaxis. Routine prophylaxis with rIX-FP at treatment intervals of up to 14 days are currently being investigated in children with severe and moderately severe haemophilia B. Clinicaltrials.gov (NCT01662531)

Keywords

Haemophilia B - factor IX - on-demand treatment - prophylactic regimen - rIX-FP

• References

• 1 Bolton-Maggs PHB, Pasi KJ. Haemophilias A and B. Lancet 2003; 361: 1801-1809.
• 2 Srivastava A, Brewer AK, Mauser-Bunschoten EP. et al. Guidelines for the management of hemophilia. Haemophilia 2012; 19: e1-e47.
• 3 RIXUBIS Package Insert. Available at: http://www.rixubis.com/pdf/rixubis_pi.pdf Accessed 22nd February 2016
• 4 Santagostino E, Mancuso ME.. Venous access in haemophilic children: choice and management. Haemophilia 2010; 16: 20-24.
• 5 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: 2405-2411.
• 6 Martinowitz U, Lissitchkov T, Lubetsky A. et al. Results of a phase I/II open-label, safety and efficacy trial of coagulation factor IX (recombinant), albumin fusion protein in haemophilia B patients. Haemophilia 2015; 21: 784-790.
• 7 International Conference on Harmonization. Harmonized Tripartite Guideline: Guideline for Good Clinical Practice (E6). ICH. 1996 Available at: http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R1_Guideline.pdf Accessed February 22, 2016.
• 8 European Medicines Agency. Committee for medicinal products for human use (CHMP), Guideline in the Clinical Investigation of Recombinant and Human Plasma-Derived Factor IX Products. EMEA. 2009 CHMP/BPWP/144552/2009
• 9 Verbruggen B, Novakova I, Wessels H. et al. The Nijmegen modification of the Bethesda assay for factor VIII:C inhibitors: improved specificity and reliability. Thromb Haemost 1995; 73: 247-251.
• 10 Windyga J, Lissitchkov T, Stasyshyn O. et al. Efficacy and safety of a recombinant factor IX (Bax326) in previously treated patients with severe or moderately severe haemophilia B undergoing surgical or other invasive procedures: a prospective, open-label, uncontrolled, multicentre, phase III study. Haemophilia 2014; 20: 651-658.
• 11 Morfini M, Lee M, Messori A.. The design and analysis of half-life and recovery studies for factor VIII and factor IX. Factor VIII/Factor IX Scientific and Standardization Committee of the International Society for Thrombosis and Haemostasis. Thromb Haemost 1991; 66: 384-386.
• 12 Lee M, Morfini M, Schulman S. et al. Scientific and Standardization Committee Communication: The Design and Analysis of Pharmacokinetic Studies of Coagulation Factors. Available at: http://c.ymcdn.com/sites/www.isth.org/resource/group/d4a6f49a-f4ec-450f-9e0f-7be9f0c2ab2e/official_communications/fviiipharmaco.pdf Accessed February 22, 2016
• 13 Rallapalli PM, Kemball-Cook G, Tuddenham EG. et al. An interactive mutation database for human coagulation factor IX provides novel insights into the phenotypes and genetics of hemophilia B. J Thromb Haemost 2013; 11: 1329-1340.
• 14 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; 127: 1761-1769.
• 15 Alprolix Package Insert. Available at: http://www.alprolix.com/pdfs/PrescribingInformation.pdf Accessed 22nd February 2016
• 16 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.
• 17 Roth DA.. Human recombinant factor IX: safety and efficacy studies in hemophilia B patients previously treated with plasma-derived factor IX concentrates. Blood 2001; 98: 3600-3606.
• 18 Benefix Package Insert. Available at: http://labeling.pfizer.com/showlabe-ling.aspx?id=492 Accessed February 22, 2016
• 19 Journeycake JM.. Catheter-related deep venous thrombosis in children with hemophilia. Blood 2001; 98: 1727-1731.
• 20 Price VE, Carcao M, Connolly B. et al. A prospective, longitudinal study of central venous catheter-related deep venous thrombosis in boys with hemophilia. J Thromb Haemost 2004; 02: 737-742.
• 21 Ranta S, Kalajoki-Helmiö T, Pouttu J. et al. MRI after removal of central venous access device reveals a high number of asymptomatic thromboses in children with haemophilia. Haemophilia 2011; 18: 521-526.
• 22 Blanchette VS, Key NS, Ljung LR. et al. Definitions in hemophilia: communication from the SSC of the ISTH. J Thromb Haemost 2014; 12: 1935-1939.
• 23 HGVS. Nomenclature for the description of sequence variations homepage. Available at. Accessed December 10, 2015.
• 24 Goodeve AC, Reitsma PH, McVey JH.. Nomenclature of genetic variants in hemostasis. J Thromb Haemost 2011; 09: 852-855.
• 25 CDC Hemophilia B Mutation Project (CHBMP) F9 Database. Available at: http://www.cdc.gov/ncbddd/hemophilia/champs.html Accessed February 22, 2016.
• 26 Broderick CR, Herbert RD, Latimer J.. Association between physical activity and risk of bleeding in children with hemophilia. J Am Med Assoc 2012; 308: 1452-1459.