Advances in Treatment for Haemophilia

Abstract

Traditional replacement therapy for haemophilia is limited by development of inhibitors, parenteral administration  and  short  half-life  of  the  protein. A number of new therapies are in development and reaching  the  clinic  which  can  address  all  these problems.  Firstly, modifications have been made to Factor VIII (FVIII) and Factor IX (FIX) which prolong their half-life without impairing function. The prolongation of approximately 1.5 times control for Factor VIII is relatively modest but for Factor IX it is 35-fold  which  allows  prophylactic  injections  to be given every 7-14 days. A step further is the development of a bispecific antibody which mimics 
the  cofactor  function  of  FVIII  by  binding  to  both Factor IXa and Factor X. A completely novel approach is to remedy the procoagulant deficiency in haemophilia  by  balancing  it  with  a  corresponding reduction in anticoagulant activity. All three anticoagulant pathways (TFPI, Protein C-Protein S and antithrombin) have been identified as targets for this  'rebalancing'  approach  to  therapy,  which  has been  successful  in  preliminary  trials.  These  new therapies  have  the  advantage  that  they  will  not stimulate anti-FVIII or FIX antibodies and will be able to work effectively even if they are present. Moreover, they can be given by subcutaneous injection and have much longer half-lives that FVIII or FIX.  However, they may be difficult to monitor and to combine safely with other treatments. Finally, the success of early trials with gene therapy offer the prospect of freeing patients from injections entirely and elevating their FVIII or IX levels into the range sufficient to secure normal haemostasis.