Much has been achieved in treatment of haemophilia in the last few decades. While it is to be hoped that gene therapy will ultimately provide a definitive cure for haemophilia the prospect still remains some way off
PLF Giangrande BSc MD FRCP FRCPath FRCPCH
Consultant Haematologist Oxford Haemophilia and Thrombosis Centre Churchill Hospital Oxford, UK
Haemophilia is an inherited bleeding disorder caused by deficiency of coagulation factor VIII (or IX) in the blood. The hallmark of the severe form is recurrent and spontaneous bleeding, typically into joints, although internal bleeding may occur. Death in infancy is common in the absence of effective treatment. However, safe and effective treatment is now available, and there has been a dramatic improvement in prognosis in recent decades. A recent study from the UK showed that almost 25% of patients with severe haemophilia survive to the age of 75, and no doubt the outlook will continue to improve. Recombinant coagulation factor concentrates are now widely used, and these offer freedom from the risk of transmission of viral infections such as hepatitis and HIV. The availability of safer products has helped to drive the adoption of prophylactic treatment, in which children receive infusions two or three times a week to prevent bleeds developing.
It is to be hoped that gene therapy will ultimately provide a definitive cure for haemophilia. Six clinical trials have already been conducted in a limited number of patients, with some promising initial results. However, the general consensus is that some 15–20 years are likely to pass before gene therapy will be available as a routine treatment.
The application of recombinant technology has hitherto been limited to simply copying the normal factor VIII and IX molecules. The next goal is to develop coagulation factor concentrates with longer duration of action or other enhanced properties, and several companies have already embarked on such development projects. Possible strategies for increasing the duration of activity of factor VIII in the circulation include generating forms of factor VIII with mutations at the sites that are the natural targets for specific proteolytic inactivation. Bayer has developed two candidate molecules in which the introduction of disulphide bonds linking the A2 and A3 domains results in a molecule with both increased potency and duration of action.[2,3] An alternative strategy has been to apply protective coating in the form of polyethylene glylol to coagulation factors, a technique (“pegylation”) applied by Baxter in their development of longeracting factor VIII and IX molecules. Recent data obtained in haemophilic mice indicate that the half-life of factor VIII treated in this way is doubled. It remains to be established whether tinkering with the structure of these proteins alters their immunogenicity and thus the likelihood of developing inhibitory antibodies.
Attachment of biologically active molecules to albumin through molecular engineering has been promoted as a natural alternative to pegylation (AlbafuseTM: www.novozymes. com). CSL Behring recently reported that this technique resulted in the extension of the halflife of recombinant factor VII six- to nine-fold in experimental animals.
Clearance of factor VIII in the circulation is normally mediated by low-density lipoprotein receptor-related protein (LRP), a hepatic clearance receptor with a broad ligand specificity. Suppression of the interaction between factor VIII and these catabolic receptors could thus theoretically prolong the half-life of factor VIII. Receptor-associated protein (RAP) is one such chemical, and this has been shown to prolong the plasma half-life of factor VIII in mice.
A completely different approach is being pursued by Syntonix in collaboration with Biovitrum to develop a long-acting factor IX molecule (www.syntnx.com/synfusion.php). This exploits the process of endothelial recycling, in which drug molecules attached to fragments of immunglobulins are protected from degradation. They bind to receptors in endothelial cells and are then transported back to the lumen of blood vessels and then into the bloodstream. Etanercept (“Enbrel”), already licensed for the treatment of rheumatoid arthritis and related conditions, works in exactly this way and demonstrates that the theory can be translated into practice. Experiments in haemophilic mice demonstrated a half-life of the novel factor IX–immunoglobulin monomer construct of 41 hours, which compared very favourably with the half-life of normal recombinant factor IX (“Benefix”) of just 13 hours. The FDA approved a phase I/IIa clinical study of this novel agent in March 2008. The trial will be conducted in previously treated patients in two centres in the United States.
A formulation suitable for oral or intranasal administration would be a great advance, eliminating the need for intravenous injections. Natural forms of factors VIII and IX cannot be given this way, of course, as they are proteins that are readily degraded by proteolytic enzymes. A company with a track record of developing hormonal preparations by nasal insufflation is now working to develop a nasal spray formulation of factor IX (www.nastech.com). The secret lies in developing drugs that serve as molecular “keys” to open up “tight junctions” between adjacent epithelial cells, allowing large proteins to pass from a mucosal surface directly though to blood vessels.
The World Federation of Hemophilia estimates that there are approximately 400,000 patients with haemophilia around the world and two-thirds of these still receive no treatment. One positive consequence of the progressive switch to recombinant products in developed countries is that this will help to secure effective and safe treatment for people in developing countries. As patients in more affluent parts of the world such as North America, Europe, Australia and Japan convert to recombinant products, manufacturers of plasma-derived products will be forced to seek new markets in the developing world and these will also have to be competitively priced. It is clear that there will continue to be a global requirement for plasma-derived as well as recombinant coagulation factor concentrates for many years to come. There will also be new opportunities for existing manufacturers to offer contract fractionation facilities or to assist appropriate countries to set up their own fractionation plants. The development of transgenic animals also offers the potential of production of large quantities of recombinant products at low cost. Transgenic factor IX extracted from the milk of pigs is already under development in India, through a partnership signed in early 2007 between US-based scientist Dr William Velander and Intas Pharmaceuticals.
Products used in the treatment of haemophilia are very expensive and account for around 85% of the cost of care delivery for this condition. An editorial that accompanied the publication of a study confirming the efficacy of prophylaxis in preventing the development of joint damage commented that “this study puts a harsh light on cost–benefit issues … the estimated annual cost for prophylactic treatment of one patient with recombinant factor VIII was US$300,000”.
It is most unlikely that the newer products discussed above, most being developed by the very same companies that market both recombinant and plasma-derived products, will turn out to be any cheaper than current licensed brands. Initial hopes in the late 1980s that recombinant factor VIII would be cheaper than plasma-derived products were soon dashed, with manufacturers claiming that their research and development costs justified a doubling of the price. Tendering exercises in a number of countries have been successful in forcing down prices in recent years. For example, a tendering exercise in 2006 confined to England yielded estimated savings of £55m spread over two years. Whilst such significant savings are to be welcomed, there are concerns that continuing pressure on manufacturers could lead to loss of choice in future years. For example, products may be withdrawn from certain markets if a contract is not secured, and also the balance of power in the decision- making process may shift to lay healthcare managers and away from expert physicians involved in haemophilia care.
It is also clear that attention will focus in the next few years on the current model of healthcare delivery. At present, patients with haemophilia and related disorders in the UK have access to a network of 26 comprehensive care centres that are staffed by multidisciplinary teams. A study from the USA has shown that the outcome in terms of survival was significantly better among patients attending comprehensive care centres than for those who were looked after by nonspecialist physicians. Haemophilia centres have tended to be established where doctors have developed an interest in the condition, rather than where there is a real need for treatment. Careful consideration therefore needs to be given to planning a network, both in terms of the overall number of centres as well as their location within a country. A related question is whether it is really necessary to duplicate treatment facilities in paediatric and adult hospitals in the same city. A review is already underway in London to determine just how many centres are needed in the capital, and the conclusions will have major repercussions for the rest of the country.
In summary, it is clear that much has been achieved with regard to the treatment of haemophilia in the last few decades but, equally, the prospect of a true cure through gene therapy for this disorder remains some way off. Advances in the next few years are likely to be based on application of genetic engineering to develop products with enhanced properties such as prolonged half-life and reduced immunogenicity. Perhaps the current position is best summed up in words borrowed from Sir Winston Churchill: “Now this is not the end. It is not even the beginning of the end. But it is, perhaps, the end of the beginning.”
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