A New Era in the Hemophilia Treatment: Lights and Shadows! - Abstract
At the beginning of 90s’, recombinant FVIII/FIX concentrates were introduced in the hemophilia therapy and in the following 20 years they underwent a progressive improvement of their characteristics, moving from 1st to 2nd and finally to 3rd generation. A new era of recombinant clotting factor concentrates has started since 2010, when new methods were implemented in their production. The most outstanding changes were: improved purification by means of more selective monoclonal antibodies or ligands, human cell lines, co-expression of Albumin or Fragment crystallizable genes, glycopeghylation, molecule modifications as B-Domain deletion and heavy and light chain fusion. These changes caused products with increased Half-life and decreased Clearance, mainly of recombinant FIX and partially of recombinant FVIII, and hopefully an increased pharmacodynamics and a lower immunogenicity. About all phase I/II studies were terminated, some of phase III are still ongoing, and few products have been licensed by Food and Drugs Administration and European Medicine Agency. The hemophilia patients, first of all children, will take advantages from the usage of the Extended Half-Life clotting factor concentrates, being possible a prophylaxis design with weekly or every two weeks infusions. The issue of immunogenicity of new concentrates is now under evaluation by means of studies in Previously Untreated Patients. On the other side of innovative therapies, a new pioneering approach to treatment of bleeding has recently arisen. The down regulation of natural anticoagulants, Tissue Factor Pathway Inhibitor and Antithrombin, by means of specific monoclonal antibodies or small small interfering Ribonucleic Acid respectively, increased thrombin generation in FVIII deficient plasma and reduced the Annualized Bleeding Rate of hemophilia patients. Similar results have been achieved by administration of a bi-specific human recombinant monoclonal antibody which mimics FVIII function by linking FIXa and FX.