Background:
Human-cl rhFVIII is the first recombinant factor VIII concentrate expressed in a human cell line (Human Embryonic Kidney 293F cells). Studies in previously treated severe haemophilia A patients demonstrated bio-equivalence to a full length rFVIII concentrate, safety and efficacy in preventing and treating bleeding episodes (BEs).
Aims:
The objectives of this GCP study were to evaluate the pharmacokinetics (PK), efficacy, safety, and immunogenicity of Human-cl rhFVIII in previously treated children between 2 and 12 years.
Methods:
First, patients were to undergo an in-vivo recovery (IVR) investigation with Human- cl rhFVIII. In a subset of patients, the PK of Human-cl rhFVIII was assessed in comparison to the patient’s previously used FVIII product. After an injection of 50 IU/kg, blood samples were collected up to 48 hours for PK analysis and up to 2 hours for IVR. IVR was repeated in patients after 3 and 6 months. FVIII coagulant activity (FVIII:C) was measured by chromogenic and one-stage assay in a central laboratory. Patients were treated prophylactically with Human-cl rhFVIII every other day or 3x weekly with 30-40 IU Human-cl rhFVIII per kg for 6 months. Human-cl rhFVIII was also used in case of breakthrough bleeds. Inhibitors were measured before, during and at the end of the study by modified Nijmegen Bethesda assay in a central laboratory. Adverse events were recorded throughout the study.
Results:
59 patients (29: 2-5 years; 30: 6-12 years) were enrolled from 15 sites in Europe. 13 children of each age group participated in the comparative PK investigation. Mean PK parameters of Human-cl rhFVIII were similar to those of the previous FVIII product, both for the chromogenic and the one-stage assay: AUCnorm 0.23 vs. 0.24 h*IU/mL/[IU/kg]); IVR 1.88 vs. 1.61% per IU/kg; T1/2 9.7 vs. 12.5 h. IVR remained stable throughout the study. There were a total of 108 BEs in 32/59 patients treated with Human-cl rhFVIII. The majority of treated BE were traumatic (60.2%) and minor (56.5%). The mean±SD monthly rate of all types of BEs/patient was 0.34±0.43 (spontaneous BEs: 0.12±0.27; traumatic BEs: 0.19±0.29). No patient discontinued the study because of an AE. Two possibly related AEs (mild headache, mild back pain) in two patients, and no inhibitor development was reported.
Conclusion:
The data indicate that Human-cl rhFVIII is efficacious and safe in preventing and treating BEs in previously treated children. The PK of Human-cl rhFVIII and the previous product was very similar.
Keywords: Recombinant factor VIII, Haemophilia A, Pharmacokinetics, Paediatric
The goal of Dr. Chen's research is to examine a method for selectively expanding hematopoietic stem cells expressing the factor VIII transgene. She will also examine the immune consequences of this approach, based on the idea that gene transfer in platelets evades immune recognition. This research has the potential to elicit important clues to developing an approach for gene therapy of hemophilia A and hemophilia A with inhibitors.
Dr. Chen earned a PhD in hematology from Fujian Medical University in China. She already has more than 27 papers published in the Chinese medical literature. Her research in hemophilia and gene therapy will be under the mentorship of Dr. Qizhen Shi, MD, PhD, Associate Investigator at the Blood Research Institute and Assistant Professor of Pediatric Hematology at the Medical College of Wisconsin.
