title: Alternative therapies for the management of inhibitors.
abstract: The development of inhibitors to factor VIII (FVIII) or factor IX (FIX) remains a major treatment complication encountered in the treatment of haemophilia. Not all patients with even the same severity and genotype develop inhibitors suggesting an underlying mechanism of tolerance against FVIII- or FIX-related immunity. One mechanism may be central tolerance observed in patients in whom the FVIII mutation enables some production of the protein. The other is a peripheral tolerance mechanism which may be evident in patients with null mutation. Recently, recombinant porcine FVIII (rpFVIII, Obixur, OBI-1, BAX801) has been developed for the haemostatic treatment of both congenital haemophilia with inhibitor (CHAWI) and acquired haemophilia A (AHA). In 28 subjects with AHA with life-/limb-threatening bleeding, rpFVIII reduced or stopped bleeding in all patients within 24 h. The cross-reactivity of anti-human FVIII antibodies to rpFVIII remains around 30-50%. Recently, new therapeutics based on the quite novel concepts have been developed and clinical studies are ongoing. These are humanized asymmetric antibody mimicking FVIIIa function by maintaining a suitable interaction between FIXa and FX (Emicizumab, ACE910), and small interfering RNAs (siRNA, ALN-AT3) suppress liver production of AT through post-transcriptional gene silencing and a humanized anti-TFPI monoclonal antibody (Concizumab). Their main advantages are longer half-life, subcutaneous applicability and efficacy irrespective of the presence of inhibitors which will make it easier to initiate more effective treatment especially early childhood.
authors.affiliation: Department of Pediatrics, Nara Medical University, Kashihara, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Shima
authors.affiliation: Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, Canada.
authors.forename: D
authors.initials: D
authors.lastname: Lillicrap
authors.affiliation: Washington Center for Bleeding Disorders at Bloodworks NW, University of Washington, Seattle, WA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Kruse-Jarres
mesh_terms: D018033:Antibodies, Bispecific / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000096:biosynthesis / Q000235:genetics / Q000627:therapeutic use; D057134:Antibodies, Neutralizing / Q000097:blood; D005169:Factor VIII / Q000276:immunology* / Q000627:therapeutic use; D005170:Factor X / Q000276:immunology / Q000378:metabolism; D015951:Factor Xa / Q000276:immunology / Q000378:metabolism; D006467:Hemophilia A / Q000188:drug therapy / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance; D034622:RNA Interference
chemical_list: D018033:Antibodies, Bispecific; D061067:Antibodies, Monoclonal, Humanized; D057134:Antibodies, Neutralizing; C574488:concizumab; C000608208:emicizumab; D005169:Factor VIII; D005170:Factor X; D015951:Factor Xa
keywords: ACE910; anti-TFPI antibody; antithrombin RNAi; haemophilia; immune tolerance; inhibitor