Safety and Efficacy of B-domain Deleted Third Generation Recombinant Factor VIII (GreenGene F™) in Korean Patients with Hemophilia A: Data from a Post-marketing Surveillance Study

BACKGROUND: New B-domain deleted third generation recombinant factor VIII (FVIII; GreenGene F™, beroctocog alfa) was launched in 2010. We determined safety and efficacy of GreenGene F™ during routine clinical practice in patients with hemophilia A over a period of 12 months. METHODS: From July 2010 to July 2014, a total of 136 hemophilia A patients were enrolled in a post-marketing surveillance (PMS) study. Among them, 134 patients were assessed for drug safety and 114 patients were analyzed for drug efficacy. Patients with differing hemophilia A severities and medical histories were monitored during 12 months of prophylactic and/or on-demand therapy. RESULTS: Among 134 patients evaluated, 85 (63.4%) had severe hemophilia. Ninety-two received a total of 1,266,077 units for prophylaxis, and 42 received 516,491 units for bleeding episodes. Three patients developed inhibitors. In 112 previously treated patients, one patient (0.9%) developed inhibitor after intensive FVIII treatment for surgery. Among 22 previously untreated patients, inhibitors were observed in 2 infants (9.1%). Overall, there were a total of 47 adverse events (other than inhibitors) of all types in 30 patients (22.4%), 11 in 10 patients (7.5%) of which were considered showing serious adverse events (SAEs); most of which were hemorrhages at different sites. None of the SAEs were judged as product related. An excellent/good efficacy rate of 91.3% for hemostasis and 89.4% for hemorrhage prevention was recorded. CONCLUSION: The results of this PMS study support the use of GreenGene F™ as safe and efficacious in hemorrhage prevention and treatment of hemophilia A. These results are consistent with the findings from previously published GreenGene F™ studies.

Progress of Hemophilia A Therapeutics in Korea / 임상소아혈액종양

Over the past several decades, hemophilia treatment in Korea has progressed dramatically. It has become possible to prevent hemophilia complications by maintenance treatment as well as on-demand treatment with the help of the National Health Insurance program. Treatment and prevention of hemorrhage, prevention of joint complications, treatment and prevention of infectious complications have greatly improved the quality of life and life expectancy of hemophilia patients. However, the development of inhibitor is the most serious and challenging complication of clotting factor replacement therapy, although immune tolerance regimens and bypassing agents have shown some efficacy in countering this complication. The development of novel methods of therapy, including the use of extended half-life factors and gene therapy, will further improve the outcome of hemophilia patients. Administering the right drug to the right patients with the right dose at the right time will be necessary for treating the patient. Achievement of optimal therapeutic goals will require continued cooperation between patients and medical staff.

The F309S mutation increases factor VIII secretion in human cell line

OBJECTIVES: The capacity of a human cell line to secrete recombinant factor VIII with a F309S point mutation was investigated, as was the effect of the addition of chemical chaperones (betaine and sodium-4-phenylbutyrate) on the secretion of factor VIII. METHODS: This work used a vector with a F309S mutation in the A1 domain to investigate FVIII production in the HEK 293 human cell line. Factor VIII activity was measured by chromogenic assay. Furthermore, the effects of chemical drugs on the culture were evaluated. RESULTS: The addition of the F309S mutation to a previously described FVIII variant increased FVIII secretion by 4.5 fold. Moreover, the addition of betaine or sodium-4-phenylbutyrate increased the secretion rate of FVIIIÄB proteins in HEK 293 cells, but the same effect was not seen for FVIIIÄB-F309S indicating that all the recombinant protein produced had been efficiently secreted. CONCLUSION: Bioengineering factor VIII expressed in human cells may lead to an efficient production of recombinant factor VIII and contribute toward low-cost coagulation factor replacement therapy for hemophilia A. FVIII-F309S produced in human cells can be effective in vivo.

Pharmacokinetics and Tolerability Evaluation of Human Coagulation Recombinant Factor VIII (GreenGene(TM)) in Hemophilia A Patients

BACKGROUND: GreenGene(TM) (Green Cross Corp.) is a recombinant clotting factor VIII which is used for hemophilia A. This study aimed to investigate the pharmacokinetics and safety profiles of 25 IU/kg and 50 IU/kg of GreenGene(TM) in Korean hemophilia A patients. METHODS: A dose-block randomized, single-blind, active drug-controlled, single and multiple dose, parallel-group study was conducted with 16 hemophilia A patients (25 IU/kg: 50 IU/kg = 8:8). They received GreenGene(TM) or GreenMono(TM)(active control) intravenously on day 1 and every other day from day 4 to 10. FVIII:C (Factor VIII procoagulant activity) was measured to determine the pharmacokinetics (PK) at baseline and up to 48 hours for single and multiple administration. PK parameters were determined using noncompartmental methods. RESULTS: The maximum concentration (Cmax) and the area under the concentration-time curve (AUC0-48) of the GreenGene(TM) 25 IU/kg (mean +/- SD) were 59.00 +/- 19.26 % and 774.40 +/- 380.13 %.h respectively, while those of 50 IU/kg were 131.50 +/- 39.81 % and 1462.44 +/- 397.09 %.h after single administration. The Cmax and AUC0-48 in steady state of the GreenGene(TM) 25 IU/kg were 68.17 +/- 22.75 % and 863.30 +/- 334.40 %.h, while those of 50 IU/kg were 147.17 +/- 18.47 % and 1820.08 +/- 704.42 %.h. No serious adverse event was observed. CONCLUSION: The GreenGene(TM) to hemophilia A patients appeared to be well tolerated within range of 25-50 IU/kg. The PK parameters of factor VIII showed dose-independent manner with 25 IU/kg and 50 IU/kg dose ranges.

A Case of Hemophilia A Diagnosed in a Premature Infant

Although the majority of abnormal bleeding during the neonatal period results from acquired coagulation disorders, inherited coagulation disorders can also manifest at this time. Hemophilia is the most common of inherited coagulation disorder. Although 40-70% of cases with hemophilia are diagnosed in the neonatal period, few cases have been reported in premature infants. We report a case of a premature infant born at 31 weeks of gestation, diagnosed with hemophilia A by blood coagulation test, coagulation factor assay and study of the F8 gene. The baby was treated with recombinant factor VIII (Recombinate(R), USA) because of repeated seizures and intramuscular hematoma.