Efficacy and safety of prophylaxis with once-weekly BAY 79–4980 compared with thrice-weekly rFVIII-FS in haemophilia A patients

Summary

The benefits of prophylaxis of haemophilia A patients regarding joint health and quality-of-life are well established. However, adherence to an up to every-other-day infusion regimen is a barrier to widespread adoption of prophylaxis. BAY 79–4980 is an investigational drug consisting of rFVIII-FS (sucrose-formulated recombinant FVIII) reconstituted with liposome solvent. Previous clinical studies showed extended protection from bleeding after a single injection of BAY 79–4980 (13.3 ± 6.2 days) compared with rFVIII-FS (7.2 ± 1.7 days). The effect of once-a-week prophylaxis with BAY 79–4980 (35 IU/kg) compared with three times-per-week rFVIII-FS (25 IU/kg) in previously treated, severe haemophilia A patients was evaluated in a 52-week, double-blind, two-arm, randomised, controlled study. The primary and secondary endpoints were protection from total bleeds and joint bleeds, respectively. Short- and long-term safety and tolerability of BAY 79–4980 including effects on lipid levels were assessed. A total of 139 and 131 subjects were evaluable for safety and efficacy analyses, respectively. A large difference in efficacy between treatment groups was observed with 72.1% (49/68) in the rFVIII-FS control group demonstrating <9 bleeds/year compared with 38.1% (24/63) of BAY 79–4980-treated subjects. A similar difference was seen in annualised joint bleeds, with 43 subjects (63.2%) in the control group demonstrating <5 joint bleeds/year compared with 24 subjects (38.1%) treated with BAY 79–4980. The distribution of bleeds seven days post-prophylactic treatment with BAY 79–4980 showed that 61% of bleeds occurred after day 4 post dosing. There were no safety concerns identified. The investigational treatment arm was prematurely discontinued due to failure to achieve the primary endpoint.

Keywords

Prophylaxis - haemophilia - PEGylated liposome - rFVIII-FS

• References

• 1 MASAC recommendation concerning prophylaxis (Regular administration of clotting factor concentrate to prevent bleeding). Available at: http://www.hemophilia.org/NHFWeb/MainPgs/MainNHF.aspx?menuid=57&contentid=1007 Accessed September 18, 2012 .
• 2 Berntorp E, Boulyjenkov V, Brettler D. et al. Modern treatment of haemophilia. Bull World Health Organ 1995; 73: 691-701.
• 3 Hacker MR, Geraghty S, Manco-Johnson M. Barriers to compliance with prophylaxis therapy in haemophilia. Haemophilia 2001; 7: 392-396.
• 4 Ljung R. The risk associated with indwelling catheters in children with haemophilia. Br J Haematol 2007; 138: 580-586.
• 5 Di Minno G, Cerbone AM, Coppola A. et al. Longer-acting factor VIII to overcome limitations in haemophilia management: the PEGylated liposomes formulation issue. Haemophilia 2010; 16 (Suppl. 01) 2-6.
• 6 Baru M, Carmel-Goren L, Barenholz Y. et al. Factor VIII efficient and specific non-covalent binding to PEGylated liposomes enables prolongation of its circulation time and haemostatic efficacy. Thromb Haemost 2005; 93: 1061-1068.
• 7 Powell JS, Nugent DJ, Harrison JA. et al. Safety and pharmacokinetics of a recombinant factor VIII with pegylated liposomes in severe hemophilia A. J Thromb Haemost 2008; 6: 277-283.
• 8 Spira J, Plyushch OP, Andreeva TA, Andreev Y. Prolonged bleeding-free period following prophylactic infusion of recombinant factor VIII reconstituted with pegylated liposomes. Blood 2006; 108: 3668-3673.
• 9 Spira J, Plyushch OP, Andreeva TA, Khametova RN. Evaluation of liposomal dose in recombinant factor VIII reconstituted with pegylated liposomes for the treatment of patients with severe haemophilia A. Thromb Haemost 2008; 100: 429-434.
• 10 Martinowitz U, Lalezari S, Luboshitz J, Lubetsky A, Spira J. Infusion rates of recombinant FVIII-FS with PEGylated liposomes in haemophilia A. Haemophilia 2008; 14: 1122-1124.
• 11 Musso R, Santagostino E, Faradji A. et al. Safety and efficacy of sucrose-formulated full-length recombinant factor VIII: experience in the standard clinical setting. Thromb Haemost 2008; 99: 52-58.
• 12 Den Uijl I, Mauser-Bunschoten EP, Roosendaal G, Schutgens R, Fischer K. Efficacy assessment of a new clotting factor concentrate in haemophilia A patients, including prophylactic treatment. Haemophilia 2009; 15: 1215-1218.
• 13 Blanchette VS, Shapiro AD, Liesner RJ. et al. Plasma and albumin-free recombinant factor VIII: pharmacokinetics, efficacy and safety in previously treated pediatric patients. J Thromb Haemost 2008; 6: 1319-1326.
• 14 Gilbert M. Orthopedic Advisory Committee of WFH. World Federation of Hemophilia Physical Examination Score (also called the Gilbert Score). World Federation of Hemophilia. Available at: http://www.wfh.org/2/7/7_0_Assessment_Tools_Gilbert_Score.htm Accessed May 11, 2012 .