Safety and efficacy of a new recombinant FVIII formulated with sucrose (rFVIII–FS) in patients with haemophilia A: a long‐term, multicentre clinical study in Japan

Abstract

The recombinant full-length FVIII product Kogenate has been reformulated using sucrose (rFVIII-FS) instead of human serum albumin as a stabiliser in purification and formulation. The in vivo recovery, haemostatic efficacy, and safety of rFVIII-FS were investigated in 20 previously treated patients with severe or moderate haemophilia A for > or = 24 weeks. In vivo recoveries of 73.5 +/- 16.3%, 78.4 +/- 16.1%, and 82.8 +/- 23.9% after the initial infusion of 50 IU kg(-1) rFVIII-FS and at weeks 12 and 24, respectively, showed no significant changes over time. A total of 1115 infusions (mean dose 24.1 +/- 8.4 IU kg(-1)) were included in the analysis of haemostatic efficacy. One (80.5%) or two (8.2%) infusions achieved adequate haemostasis in 88.7% of all bleeding episodes, and haemostatic efficacy was judged 'excellent' or 'good' in 749 of 764 episodes (98.0%). The haemostatic efficacy was judged as 'excellent' or 'good' in 924 of 1115 (82.9%) infusions. Twenty-one adverse events were observed in 12 patients in the total 1541 infusions included in the safety analysis. Causality with respect to rFVIII-FS could not be ruled out in three events in one HIV-negative patient: elevated CD4(%), decreased CD8(%), and elevated CD4/CD8 ratio. No FVIII inhibitor development was observed in any patient. ELISA assay testing for antibodies to rFVIII, baby hamster kidney cell (BHK) protein, and murine IgG were all negative. These results show that rFVIII-FS is a safe and effective for long-term treatment of patients with haemophilia A.

Safety and efficacy of a sucrose‐formulated recombinant factor VIII product for the treatment of previously treated patients with haemophilia A in China

“…None of the 49 patients developed a FVIII neutralizing inhibitor during the study, supporting the findings of the studies conducted with rFVIII-FS in Japan [16], North America and Europe [13] that showed de novo inhibitor formation rates of zero in 20 and 71 PTPs respectively. The absence of an inhibitor is of particular relevance, considering that only 36.7% of the patients in this trial had accumulated more than 100 EDs to infused FVIII at the time of the study entry.…”

“…These findings are comparable with those in the clinical trials conducted in previously treated haemophilic patients in North America and Europe, where 93.5% of 2585 bleeds were successfully managed with one or two infusions of rFVIII-FS and 80.5% of the patients rated control of their bleeding as ÔExcellentÕ or ÔGoodÕ [13]. Ten-min postinfusion in vivo FVIII incremental recovery in this study (1.9% per IU kg )1 ) was similar to that reported in Japanese PTPs treated with rFVIII-FS [16].…”

Factor VIII products and inhibitor development in previously treated patients with severe or moderately severe hemophilia A: a systematic review

“…Eighty‐two unique articles were reviewed in full; of these, 52 articles were excluded. Thirty articles were selected for the analysis, and four additional articles were included after monthly searches on PubMed. Most articles reported on a single cohort of patients using one brand of rFVIII product, whereas three articles provided information on multiple cohorts.…”

Preclinical experiment of auxiliary partial orthotopic liver transplantation as a curative treatment for hemophilia

“…Liver transplantation is sometimes performed for other lethal metabolic liver diseases; however, the indication of liver transplantation for cure of hemophilia itself is controversial, because coagulopathy of hemophilia can be controlled by replacement with external factor VIII and the risk of whole liver transplantation is too high in this situation. Nevertheless, repetitive replacement therapy induces inhibitor against factor VIII in the patients, which makes it difficult to control bleeding even with a large amount of factor VIII concentrates 8, 9. Together with hazard of viral infection via the factor VIII concentrates,10 induction of inhibitor deteriorates quality of life in patients with hemophilia.…”