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Alternative therapies for the management of inhibitors
Author(s) -
Shima M.,
Lillicrap D.,
KruseJarres R.
Publication year - 2016
Publication title -
haemophilia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.213
H-Index - 92
eISSN - 1365-2516
pISSN - 1351-8216
DOI - 10.1111/hae.13005
Subject(s) - medicine , haemophilia , haemophilia a , antibody , immunology , immune tolerance , gene silencing , mechanism (biology) , mutation , monoclonal antibody , factor ix , transfection , recombinant dna , bioinformatics , immune system , gene , genetics , pediatrics , biology , philosophy , epistemology
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 (rp FVIII , Obixur, OBI ‐1, BAX 801) 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, rp FVIII reduced or stopped bleeding in all patients within 24 h. The cross‐reactivity of anti‐human FVIII antibodies to rp FVIII 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 FVIII a function by maintaining a suitable interaction between FIX a and FX (Emicizumab, ACE 910), and small interfering RNA s (si RNA , ALN ‐ AT 3) 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.