Alternative therapies for the management of inhibitors

Haemophilia. 2016 Jul;22 Suppl 5:36-41. doi: 10.1111/hae.13005.

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.

Keywords: ACE910; anti-TFPI antibody; antithrombin RNAi; haemophilia; immune tolerance; inhibitor.

MeSH terms

  • Antibodies, Bispecific / therapeutic use
  • Antibodies, Monoclonal, Humanized / biosynthesis
  • Antibodies, Monoclonal, Humanized / genetics
  • Antibodies, Monoclonal, Humanized / therapeutic use
  • Antibodies, Neutralizing / blood
  • Factor VIII / immunology*
  • Factor VIII / therapeutic use
  • Factor X / immunology
  • Factor X / metabolism
  • Factor Xa / immunology
  • Factor Xa / metabolism
  • Hemophilia A / drug therapy
  • Hemophilia A / immunology
  • Humans
  • Immune Tolerance
  • RNA Interference

Substances

  • Antibodies, Bispecific
  • Antibodies, Monoclonal, Humanized
  • Antibodies, Neutralizing
  • concizumab
  • emicizumab
  • Factor VIII
  • Factor X
  • Factor Xa