Efficacy, Immunogenicity, Pharmacokinetics, and Safety Of Human-cl rhFVIII – a GCP Study In Children With Severe Haemophilia A

Abstract

IntroductionHuman-cl rhFVIIIis the first recombinant factor VIII concentrate expressed in a human cell line (Human Embryonic Kidney 293F cells). Studies in adolescent and adult pre-treated patients with severe haemophilia A showed a favorable PK profile with a median half-life of 17.1 hours (one stage assay) and indicated safety and efficacy in preventing and treating bleeding episodes (BE). AimsThe objectives of this international GCP study were to evaluate the efficacy, safety, immunogenicity and pharmacokinetic (PK) properties of Human-cl rhFVIIIin previously treated children between 2 and 12 years of age. MethodsAll patients started with an in-vivo recovery (IVR) investigation and 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 all patients after 3 and 6 months. FVIII plasma levels were 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, injecting 30-40 IU Human-cl rhFVIIIper kg for at least 6 months and > 50 exposure days. 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. Results59 patients (29: 2-5 years; 30: 6-12 years) were enrolled from 15 specialized sites in Europe. 13 children of each age group participated in the comparative PK investigation. Mean PK parameters of Human-cl rhFVIII were similar in both age groups for both 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. A total of 108 BEs in 32/59 patients were treated with Human-cl rhFVIII. The majority of treated BEs were traumatic (60.2%) and minor (56.5%). The mean ± SD monthly bleeding 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 inhibitor development was reported; no patient discontinued the study because of an AE. ConclusionThe 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 was comparable in both studied age groups. Disclosures:Liesner:Octapharma AG: Consultancy, Investigator Other. Jansen:Octapharma AG: Employment. Klukowska:Octapharma AG: Investigator Other. Vdovin:Octapharma AG: Investigator Other. Szczepanski:Octapharma AG: Investigator Other. Knaub:Octapharma AG: Employment.