By Brian O’Mahony
There are broad similarities between both haemophilia A and haemophilia B. They have an identical inheritance pattern, similar bleeding pattern into joints and muscles, and the same requirement for comprehensive care.
There are differing opinions in relation to the relative severity of the bleeding pattern.
Some studies and clinicians have concluded that the bleeding pattern in haemophilia B is clinically less severe on average where other studies have demonstrated no significant difference. The longer half life of FIX compared to FVIII may have an influence on the efficacy of on demand treatment in treating bleeding episodes or on prophylactic treatment for preventing bleeding episodes. Despite the fact that prophylaxis with FIX can typically be carried out with infusions twice per week, compared to three times per week for FVIII deficiency, prophylaxis is less commonly used in FIX deficiency in many countries. The risk of inhibitor development is substantially less for FIX deficiency but if inhibitors occur, treatment is much more difficult and less successful than for FVIII inhibitors.
The economics of treatment are relatively poised against FIX treatment. It is necessary to use two IU of FIX to achieve the same increase in factor levels as one IU of FVIII. Currently available recombinant FIX has a significantly lower recovery in a proportion of people with haemophilia B, and the fact that there is only one recombinant FIX on the market leads to higher median prices than for recombinant FVIII. The combination of higher unit use, lower recovery and higher median prices means that in many countries treatment of haemophilia B is significantly more expensive per patient than for haemophilia A. This is of greater consequence in countries where economic resources are strictly limited and where the relative prevalence is higher.
Ireland, for example, has the highest reported prevalence of FIX deficiency in the world and also the highest per capita use of FIX at 2.66 IU per capita. In the past, developments in FIX lagged behind developments in FVIII treatment by a significant degree. When cryoprecipitate was available for FVIII deficiency, plasma continued as the main therapy for FIX. FVIII concentrates were available from the 1970’s while those with FIX deficiency had to rely on prothrombin complex concentrates with their attendant risk of thrombogenicity. FIX concentrates were not available until the early 1990’s. Recombinant FVIII was available several years before recombinant FIX.
This situation will change in the future. The development of longer acting concentrates will be of greater benefit to those with FIX deficiency due to the longer half life and it also appears likely that they will be licensed and available earlier than the FVIII equivalents. The smaller size of the FIX gene has greatly assisted progress in the development of gene therapy and the early clinical trial results from the United Kingdom using an adenovirus vector are very promising with long term expression being achieved at a significant factor level. The success of this approach is underlined by the fact that there are now five clinical trials underway for gene therapy for haemophilia B. There seems little doubt that gene therapy will be available for treatment of haemophilia B significantly before a similar therapeutic option for haemophilia A.
The relative neglect and marginalisation of haemophilia B in the past increasingly looks likely to give way to a situation where haemophilia B is the forerunner in a bright new therapeutic future, hopefully leading to access to more therapeutic options and better and more economically viable therapies for all with haemophilia B and haemophilia A.