The prospect of

viral safety associated with FVIII produced from recombinant DNA technology was the main advantage, but additionally, rFVIII could – at least theoretically – become available in unlimited supply. These accomplishments, published in a single issue of ‘Nature’ in 1984 [12–15], were remarkable in view of the size and complexity of the FVIII gene which encompassed 186,000 base pairs and represented 0.1% of the human X chromosome. In a very short time thereafter, in collaboration with scientists at Genentech and the Genetics Institute, two U.S. Pharmaceutical Companies (Miles, Inc./Cutter Biological, Berkeley, CA, and Baxter/Hyland Div., Glendale, CA) accomplished scale-up, purification and standardization of two CP-673451 molecular weight rFVIII products for clinical use. Following preclinical in vitro studies,

and studies in animals, prelicensure clinical trials in patients with haemophilia A began in 1987 [16]. Safety and efficacy in treatment of bleeding episodes and in controlling bleeding in major surgery was documented in adults [17,18]. Recombinate was licensed for use in the U.S. in 1992 and Kogenate was licensed for use in early 1993. In January 1989, a study in previously untreated patients (PUPs) was begun with Kogenate [19], and in July, 1990, the PUP study with Recombinate began [20,21]. Clinicians involved in these early trials with rFVIII products found that it was relatively easy to enrol subjects, all of whom had heard about AIDS and hepatitis with plasma-derived products. In both NVP-BGJ398 concentration of the PUP trials, haemostatic responses were excellent and the products were well tolerated. However, inhibitor antibodies developed early (after a median of 9–11 EDs) in 20–25% of study subjects. Approximately half of the inhibitors in both PUP studies were ‘high responding’ (>5 BU), whereas the remainder were ‘low responding’ and most of these were transient [22–24]. Nevertheless, some clinicians became concerned that recombinant FVIII was causing a higher incidence of inhibitors. ADAMTS5 However, earlier studies in infants and children with severe haemophilia A published in 1992 and 1993 had documented a higher incidence of inhibitor development

with plasma-derived FVIII (25–50%) [25,26] than previously thought. It had become increasingly apparent that, if one looks for inhibitors prospectively, with laboratory monitoring at frequent intervals, 25–35% (or even 50%) of PUPs will develop inhibitors after a median of 9–11 EDs. Roughly one-third of these will disappear despite continued exposure to FVIII given for episodic treatment. In addition, it was becoming increasingly apparent that such findings were not related to a particular type of product, but were seen with plasma-derived as well as rFVIII products [27]. Other analyses were documenting that patient-related factors, such as the severity of haemophilia, FVIII gene mutation causing the person’s haemophilia, race, etc.