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