The next generation of anti - haemophilia

Thromb Haemost 2008; 100: 365–366 Haemophilia A is an X-linked bleeding disorder caused by a deficiency of factor VIII (FVIII), a necessary cofactor for the generation of thrombin. The life expectancy of a child born with severe haemophlia A has improved dramatically over the past 30 years, from less than 20 years to nearly normal, primarily due to the development of FVIII concentrates, but also due to the efforts of comprehensive haemophlia centers that provide speciality medical care. However, as so clearly documented in the 2006 world survey of haemophlia care by the World Federation of Haemophlia, major challenges remain for the haemophlia community. Haemophlia A is the most common inheritable coagulation protein deficiency, and occurs with equal frequency in every population studied (1). However, in this age of globalization, discrepancies in the provision of haemophlia care among geographic regions have become glaringly apparent (2). Despite optimal medical care and the availability of recombinant FVIII preparations, individuals with haemophlia A still face major medical complications. Spontaneous bleeding into joints can lead to orthopedic problems even after only a few such bleeds (3). Spontaneous intracranial bleeding occurs all too often in individuals with severe haemophliaA, and can lead to death or neurological deficits, even when treated promptly after clinical symptoms appear. In addition, some individuals suffer from the development of neutralizing antibodies to infused FVIII, rendering the therapeutic infusions of FVIII no longer useful for coagulation (1). The half-life of FVIII protein is only 8–12 hours, and therefore, therapeutic intravenous infusion of FVIII protein concentrates must be administered frequently for haemostasis after serious bleeding episodes, or to sustain prophylactic FVIII concentrations, infusions are often administered every other day. Such treatment regimens are very expensive. Clearly, the development of a preparation of FVIII that would prevent spontaneous bleeding and could be infused once every two weeks would represent a major breakthrough for treating haemophlia A. In this issue of Thrombosis and Haemostasis, Spira et al. (4) add to the clinical data that support the view that such a breakthrough may be developing. The initial goal of their research was to extend the time in circulation of infused FVIII. A commonly used method for prolongation of the circulating half-life of recombinant proteins is the covalent incorporation of polyethylene glycol (PEG). Another commonly used method to extend the half-life of pharmacological compounds is to incorporate the compound into liposomes. Use of these proven technologies should safely provide benefit for FVIII also. Previously, Spira et al. (5) reported initial results with the use of PEGylated liposomes with recombinant FVIII (Kogenate FS). Such a formulation for FVIII has at least two potentially significant advantages. First, FVIII is a complex protein that has to interact precisely in order to fulfill its cofactor function in coagulation reactions. Second, a major clinical risk with currently available therapeutic FVIII is the development of an immune response and neutralizing antibodies. The addition of the PEG moiety to the FVIII protein directly would incur the risk of altering unfavorably the precise cofactor interactions, and simultaneously incur the risk of boosting the immune response. Baru et al. (5) avoided these potential risks by incorporating the PEG with the liposome rather than the FVIII protein directly. Spira et al. (6) previously reported results using PEGylated liposome formulated FVIII in subjects with severe haemophliaA that showed prolonged intervals to the next spontaneous bleeding episode after infusion of PEG-liposomal FVIII compared to infusion of recombinant FVIII alone. The mean number of days without spontaneous bleeding was 13.3 ± 4.8 days after infusion of PEG-liposomal FVIII at FVIII dose of 35 IU/kg compared with 7.2 days ± 1.7 days after infusion of a standard FVIII dose of 35 IU/kg (p < 0.05). These exciting results generated much discussion in the haemophlia community, and raised a number of interesting questions for further study, as reported in the current publication. One of the important issues raised in the previous studies involved how to account for the mechanism of action that led to the prolongation of the bleeding free interval. Initially the assumption was that the PEG and liposome prolonged the circulating half-life of the infused FVIII. However, in clinical trials the half life of PEG-liposomal FVIII was not different from standard FVIII (5, 7). Several interesting hypotheses to explain the prolonged efficacy in the absence of prolongation of the circulating half-life of FVIII will need to be addressed in animal studies and