From human to humans: Introducing the first recombinant human FVIII product produced from a human cell line

Whilst the introduction of recombinant FVIII (rhFVIII) products was a major advance in the management of haemophilia A, opportunities for improvements remain in regard to reduced immunological challenge, improved functional properties, improved tolerability and greater levels of pathogen safety. Human-cl rhFVIII (Octapharma AG, Lachen, Switzerland) is a B-domain-deleted FVIII protein produced in a human cell line (HEK [human embryonic kidney] 293F). The human-cl rhFVIII purification process has five chromatographic steps and includes two virus inactivation/removal steps. Human-cl rhFVIII is of high purity (>99.9%), high specific activity, low DNA content and is completely free of animal-derived products. Human-cl rhFVIII, produced in cells with human posttranslational modification (PTM) machinery, is a glycosylated protein with a monosaccharide and sialic acid content and composition comparable with plasma-derived FVIII. In vitro studies have shown that human-cl rhFVIII does not contain antigenic N-glycolylneuraminic acid (NeuGc) or Galα(1,3)Gal epitopes observed with rhFVIII derived from hamster cell lines and that binding affinity for its physiological chaperone protein, von Willebrand factor, may be enhanced compared with commercially available rhFVIII preparations. In a prospective, single-centre, randomised, open-label, crossover, phase II pharmacokinetic (PK) trial in 22 patients with severe haemophilia A, initial PK data from seven patients indicated that the PK profiles of human-cl rhFVIII and Kogenate ® FS were similar. Following the PK assessment, patients are being followed for 50 exposure days and a minimum of six months on prophylactic treatment with human-cl rhFVIII. To date, no adverse events have been recorded (∼2-50 exposure days) and no FVIII inhibitors have been detected in patients (10-15 exposure days) whilst receiving human-cl rhFVIII. Preclinical and clinical evidence to date for human-cl rhFVIII are extremely encouraging and full results of the PK assessment phase and six-month efficacy, safety, tolerability and immunogenicity data are eagerly awaited.