title: Developing the First Recombinant Factor XIII for Congenital Factor XIII Deficiency: Clinical Challenges and Successes.
abstract: Congenital factor XIII (FXIII) deficiency is a rare, autosomal recessive bleeding disorder with potentially life-threatening consequences. FXIII is composed of two subunits (A and B), and a deficiency or dysfunction of either can result in FXIII deficiency. Traditionally, FXIII deficiency has been managed by infusing plasma-derived products containing FXIII (fresh frozen plasma, cryoprecipitate, and plasma-derived FXIII concentrates), all of which contain both subunits. Despite the increased safety of plasma-derived products, concern remains regarding potential viral safety issues. This review describes the development, from concept to clinical use, of a recombinant FXIII molecule (containing subunit A only; rFXIII-A2) for congenital FXIII-A subunit deficiency. Unmet needs and ongoing challenges in congenital FXIII deficiency are also discussed. Despite the challenges in developing a product for a very rare bleeding disorder, the information gathered on efficacy, safety, and pharmacokinetics of FXIII replacement therapy represents the largest dataset on congenital FXIII-A subunit deficiency in the world. It also provides evidence for the safety and efficacy of monthly prophylaxis with 35 IU/kg of rFXIII-A2in patients with FXIII-A subunit deficiency. The issues encountered and overcome, along with lessons learned, may be applied to and encourage the development of new recombinant products for other rare bleeding disorders.
authors.affiliation: Division of Haematology/Oncology, Department of Paediatrics and Child Health Evaluative Sciences, Research Institute, Hospital for Sick Children, University of Toronto, Toronto, Canada.
authors.forename: Manuel
authors.initials: M
authors.lastname: Carcao
authors.affiliation: Department of Laboratory Medicine, Tokyo Medical University, Tokyo, Japan.
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Fukutake
authors.affiliation: Thrombosis and Hemostasis Unit, Rabin Medical Center, Petah Tikva, Israel.
authors.forename: Aida
authors.initials: A
authors.lastname: Inbal
authors.affiliation: Nationwide Children's Hospital, The Ohio State University College of Medicine, Ohio.
authors.forename: Bryce
authors.initials: B
authors.lastname: Kerlin
authors.affiliation: Coagulation Disorders Unit, Hematology and Cancer Center and Clinical Chemistry, Helsinki University Hospital, Helsinki, Finland.
authors.forename: Riitta
authors.initials: R
authors.lastname: Lassila
authors.affiliation: Institute for Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Oldenburg
authors.affiliation: Novo Nordisk A/S, Søborg, Denmark.
authors.forename: May-Lill
authors.initials: ML
authors.lastname: Garly
authors.affiliation: Children's Hospital of Orange County, UC Irvine School of Medicine, Orange, California.
authors.forename: Diane
authors.initials: D
authors.lastname: Nugent
mesh_terms: D005176:Factor XIII / Q000627:therapeutic use*; D005177:Factor XIII Deficiency / Q000188:drug therapy*; D006801:Humans; D011994:Recombinant Proteins / Q000627:therapeutic use*
chemical_list: D011994:Recombinant Proteins; D005176:Factor XIII