Novo Nordisk also stopped their clinical programme of a rFVIIa analogue exhibiting a higher activity (Vatreptacog alfa), because of a high incidence of antidrug antibody development observed after vatreptacog alfa exposure [41]. Vatreptacog alfa contained a rFVIIa protein with introduced amino acid changes V158D, E296V and M298Q). Bayer has developed BAY86-6150, a biogineered rFVIIa containing two amino acid exchanges (T106N and V253N) that introduce two more N-linked glycans yielding a fivefold increased half-life extension [42]. The clinical study programme has stopped

in May 2013 because of the presence of neutralizing inhibitors in subjects. The latter two examples demonstrate that any change in amino acid sequence may increase the immunogenicity of a therapeutic protein. The increasingly diverse biochemical characteristics of the new Palbociclib in vivo products

have to be considered when determining CT99021 cell line potencies and also when monitoring treatment in patients with the various available assays. For current FVIII products, the European Medicines Agency (EMA) is asking for determination of the potency by a chromogenic assay, whereas the U.S. Food and Drug Administration (FDA) is asking for a one-stage assay based potency. Release of future products by the authorities will require product-specific assays which for most protein-based products will be the chromogenic assays. However, most haemophilia treatment centres in

USA, Europe and Japan are still applying one-stage assays which may not correspond to the biological activity of the new proteins. Some companies have performed field studies for their products to demonstrate the compatibility with the current assay procedures, e.g. for N8 and rFVIII-FC [43, 44]. Others recommend specific one-stage assay kits/activators as ellagic acid based activated partial thromboplastin time (APTT) reagents MCE [45]. Other options discussed are the use of product-specific reference standards and conversion factors. Most of the haemophilia centres have worked with their assay set up for decades and it has proven to work safely in all clinical situations that have occurred over the years. It will be a challenge to introduce new assay set ups in the routine clinical management of the patients. However, it is obviously mandatory if all the new upcoming products wanted to be included in patients’ treatment. A number of new factor concentrates and drugs based on other technologies with improved half-lifes and alternative administration routes are becoming available soon and will improve the treatment of patients with haemophilia with and without inhibitors. The advances for rFIX are significantly with half-life extensions to up to 100 h, allowing substitution intervals of 1–2 weeks.