Safety and efficacy of sucrose-formulated full-length recombinant factor VIII: Experience in the standard clinical setting

Summary

The safety of full-length sucrose-formulated recombinant factor VIII (rFVIII-FS; KOGENATE^® FS) for up to 24 months of use was evaluated in a postmarketing observational study in Europe. Long-term safety and efficacy data were available for 212 patients with severe haemophilia A, including 13 previously untreated patients (PUPs) and 12 patients with 1–19 exposure days (EDs). Patients accumulated a mean (± SD) of 187 (121) EDs to rFVIII-FS and received a total of 39,627 infusions, mainly for prophylaxis and for the treatment of 4,283 spontaneous or trauma-related bleeds during an average observation time of 710 (136) days. Of these bleeding episodes, 85.4% were successfully treated with one or two infusions of rFVIII-FS. Haemostasis was also evaluated during 46 minor to major surgical pro- cedures, and the response to infusion was “excellent” or “good” in all cases. FVIII inhibitor formation was observed in six patients (two de novo; four persistent or recurrent). The de novo cases represent 8.0% (2 of 25) of patients who reported 0–19 previous EDs at study entry. Four of the five patients who reported possible drug-related adverse effects developed inhibitors. The results of this observational study demonstrate the efficacy and safety of rFVIII-FS during normal clinical use in the treatment of patients with severe haemophilia A. Furthermore, these findings are consistent with those of previous phase III clinical studies with rFVIII-FS, particularly with regard to its efficacy and low incidence of inhibitor formation.

Keywords

Haemophilia - recombinant factor VIII - Kogenate - inhibitors - prophylaxis

 

• References

• 1 Pool JG, Gershgold EJ, Pappenhagen AR. High-potency antihaemophilic factor concentrate prepared from cryoglobulin precipitate. Nature 1964; 203: 312.
• 2 Lee DC, Miller JL, Petteway Jr. SR. Pathogen safety of manufacturing processes for biological products: special emphasis on KOGENATE Bayer. Haemophilia 2002; 8 (Suppl. 02) 6-9.
• 3 Aygoren-Pursun E, Scharrer I. A multicenter pharmacosurveillance study for the evaluation of the efficacy and safety of recombinant factor VIII in the treatment of patients with hemophilia A. German Kogenate Study Group. Thromb Haemost 1997; 78: 1352-1356.
• 4 Seremetis S, Lusher JM, Abildgaard CF. et al. Human recombinant DNA-derived antihaemophilic factor (factor VIII) in the treatment of haemophilia A: conclusions of a 5-year study of home therapy. The KOGENATE Study Group. Haemophilia 1999; 5: 9-16.
• 5 Abshire TC, Brackmann HH, Scharrer I. et al. Sucrose formulated recombinant human antihemophilic factor VIII is safe and efficacious for treatment of hemophilia A in home therapy. International Kogenate-FS Study Group. Thromb Haemost 2000; 83: 811-816.
• 6 Kreuz W, Gill JC, Rothschild C. et al. Full-length sucrose-formulated recombinant factor VIII for treatment of previously untreated or minimally treated young children with severe haemophilia A: results of an international clinical investigation. Thromb Haemost 2005; 93: 457-467.
• 7 Luboshitz A, Lubetsky A, Maas Enriquez M. et al. Clinical evaluation of continuously infused sucroseformulated recombinant factor VIII during surgery. Poster presented at: Hemophilia 2006 World Congress. May 5-21 2006. Vancouver, BC.:
• 8 Scharrer I, Brackmann HH, Sultan Y. et al. Efficacy of a sucrose-formulated recombinant factor VIII used for 22 surgical procedures in patients with severe haemophilia A. Haemophilia 2000; 6: 614-618.
• 9 Lusher JM, Arkin S, Abildgaard CF. et al. Recombinant factor VIII for the treatment of previously untreated patients with hemophilia A. Safety, efficacy, and development of inhibitors. Kogenate Previously Untreated Patient Study Group. N Engl J Med 1993; 328: 453-459.
• 10 Schwaab R, Brackmann HH, Meyer C. et al. Haemophilia A: mutation type determines risk of inhibitor formation. Thromb Haemost 1995; 74: 1402-1406.
• 11 Hay CR, Ollier W, Pepper L. et al. HLA class II profile: a weak determinant of factor VIII inhibitor development in severe haemophilia A. UKHCDO Inhibitor Working Party. Thromb Haemost 1997; 77: 234-237.
• 12 Oldenburg J, Picard JK, Schwaab R. et al. HLA genotype of patients with severe haemophilia A due to intron 22 inversion with and without inhibitors of factor VIII. Thromb Haemost 1997; 77: 238-242.
• 13 Astermark J, Oldenburg J, Pavlova A. et al. Polymorphisms in the IL10 but not in the IL1beta and IL4 genes are associated with inhibitor development in patients with hemophilia A. Blood 2006; 107: 3167-3172.
• 14 Astermark J, Oldenburg J, Escobar M. et al. The Malmo International Brother Study (MIBS). Genetic defects and inhibitor development in siblings with severe hemophilia A. Haematologica 2005; 90: 924-931.
• 15 Lusher JM. First and second generation recombinant factor VIII concentrates in previously untreated patients: recovery, safety, efficacy, and inhibitor development. Semin Thromb Hemost 2002; 28: 273-276.
• 16 Peerlinck K, Hermans C. Epidemiology of inhibitor formation with recombinant factor VIII replacement therapy. Haemophilia 2006; 12: 579-590.
• 17 Wight J, Paisley S. The epidemiology of inhibitors in haemophilia A: a systematic review. Haemophilia 2003; 9: 418-435.
• 18 National Cancer Institute. Common Terminology Criteria for Adverse Events v3.0, August 2006. Available at: http://ctep.cancer.gov/forms/CTCAEv3.pdf.
• 19 Edwards IR, Aronson JK. Adverse drug reactions: definitions, diagnosis, and management. Lancet 2000; 356: 1255-1259.
• 20 Pollmann H, Externest D, Ganser A. et al. Efficacy, safety and tolerability of recombinant factor VIII (REFACTO) in patients with haemophilia A: interim data from a postmarketing surveillance study in Germany and Austria. Haemophilia 2007; 13: 131-143.
• 21 Mauser-Bunschoten EP, Rosendaal FR, Nieuwenhuis HK. et al. Clinical course of factor VIII inhibitors developed after exposure to a pasteurised Dutch concentrate compared to classic inhibitors in hemophilia A. Thromb Haemost 1994; 71: 703-706.
• 22 Peerlinck K, Arnout J, Gilles JG. et al. A higher than expected incidence of factor VIII inhibitors in multitransfused haemophilia A patients treated with an intermediate purity pasteurized factor VIII concentrate. Thromb Haemost 1993; 69: 115-118.
• 23 Rosendaal FR, Nieuwenhuis HK, Van den Berg HM. et al. A sudden increase in factor VIII inhibitor development in multitransfused hemophilia A patients in The Netherlands. Dutch Hemophilia Study Group. Blood 1993; 81: 2180-2186.
• 24 Astermark J. Overview of inhibitors. Semin Hematol 2006; 43 (Suppl. 24) S3-S7.