In clinical studies the half-life was 93 h, which was five times higher than the patient’s previous product. The incremental recovery

of N9-GP was 94% and 20% higher compared with recombinant and plasma-derived products respectively [12]. Data from the clinical C646 in vitro studies phase 3 will be published in 2014. Two main technologies, one using Fc of Immunoglobulin G (IgG) and the other using Albumin as a fusion partner are established. Both, IgG as well as albumin, are abundantly expressed in humans and known to exhibit a half-life of about 20 days. Both, human albumin and the Fc-part of IgG bind to the neonatal Fc-receptor (FcRn) residing, e.g. on endothelial cells. The FcRn recycles its cargo protein back to the cell surface membrane to be released into the

bloodstream [13]. An overview of clotting factors with fusion technology in current clinical studies is given in Table 2. rFVIII-Fc is a recombinant fusion of a B-domain deleted FVIII molecule and the dimeric constant region (Fc) of IgG1 [14, 15]. The product will be likely licenced in the USA by the middle of 2014. A large data set of the phase 3 clinical studies have already been published. The terminal half-life of rFVIIIFc (19.0 h) was extended 1.5-fold vs. rFVIII (12.4 h; P < 0.001). Median annualized bleeding rates (ABR) observed in the prophylactic arms 1 (individualized prophylaxis Histone Methyltransferase inhibitor (25–65 IU kg−1 every 3–5 days) and arm 2 (weekly prophylaxis (65 IU kg−1), were 1.6 and 3.6, MCE respectively, compared to 33.6 in the arm 3 with episodic treatment [16]. At the end of study, subjects were dosed every 3 days (n = 29), twice-weekly (n = 23), every 4 days (n = 4) or every 5 days (n = 24). The corresponding on-study ABR (last 3 months) dosed with rFVIIIFc every 3 days, twice-weekly, every 4 days and every 5 days was 0.0, 0.0, 2.0 and 2.0, respectively [17]. rFIX-Fc is a recombinant fusion of a FIX molecule to the Fc-domain of human IgG1 [18]. The product

will be licenced in the USA in the second quarter of 2014. A large data set of the phase 1–3 clinical studies have been published [19, 20]. As compared with recombinant factor IX (rFIX), rFIXFc exhibited a prolonged terminal half-life (82.1 h). The median annualized bleeding rates in groups 1 (weekly dose-adjusted prophylaxis, 50 IU kg−1 to start), 2 (interval-adjusted prophylaxis, 100 IU kg−1 every 10 days to start and 3 (episodic treatment) were 3.0, 1.4 and 17.7, respectively. In group 2, 53.8% of participants had dosing intervals of 14 days or more during the last 3 months of the study [20]. Recombinant fusion of albumin and to FIX was achieved by a linker sequence that contains a cleavable sequence identical to the activation site of FIX. Upon activation of the fusion protein (rFIX-FP, CSL654), albumin and the linker is cleaved off, leaving a native-activated FIXa molecule [21, 22].