Recombinant FXIII (rFXIII-A2) Prophylaxis Prevents Bleeding and Allows for Surgery in Patients with Congenital FXIII A-Subunit Deficiency

Manuel Carcao; Carmen Altisent; Giancarlo Castaman; Katsuyuki Fukutake; Bryce A. Kerlin; Craig Kessler; Riitta Lassila; Diane Nugent; Johannes Oldenburg; May-Lill Garly; Anders Rosholm; Aida Inbal

doi:10.1055/s-0038-1624581

Thrombosis and Haemostasis, Table of Contents

CC BY-NC-ND 4.0 · Thromb Haemost 2018; 118(03): 451-460
DOI: 10.1055/s-0038-1624581

Coagulation and Fibrinolysis

Schattauer GmbH Stuttgart

Recombinant FXIII (rFXIII-A₂) Prophylaxis Prevents Bleeding and Allows for Surgery in Patients with Congenital FXIII A-Subunit Deficiency

Manuel Carcao

¹Division of Haematology/Oncology and Child Health Evaluative Sciences, Research Institute, Hospital for Sick Children, University of Toronto, Toronto, Canada

,

Carmen Altisent

²Haemophilia Unit, Vall d'Hebron University Hospital, Barcelona, Spain

,

Giancarlo Castaman

³Department of Oncology, Careggi University Hospital, Center for Bleeding Disorders and Coagulation, Firenze, Italy

,

Katsuyuki Fukutake

⁴Department of Laboratory Medicine, Tokyo Medical University, Tokyo, Japan

,

Bryce A. Kerlin

⁵Ohio State University College of Medicine, Nationwide Children's Hospital, Columbus, Ohio, United States

,

Craig Kessler

⁶Georgetown University Medical Center, Washington, DC, United States

,

Riitta Lassila

⁷Coagulation Disorders Unit, Hematology and Comprehensive Cancer Center, University of Helsinki, Helsinki University Hospital, Helsinki, Finland

,

Diane Nugent

⁸Center for Inherited Blood Disorders and UC Irvine Medical School, Children's Hospital of Orange County, Orange, California, United States

,

Johannes Oldenburg

⁹Institute for Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany

,

May-Lill Garly

¹⁰Medical & Science, Biopharm, Global Development, Novo Nordisk A/S, Søborg, Denmark

,

Anders Rosholm

¹¹Biostatistics, Biopharm, Global Development, Novo Nordisk A/S, Søborg, Denmark

,

Aida Inbal

¹²Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

› Author Affiliations

Abstract

Recombinant factor XIII-A₂ (rFXIII-A₂) was developed for prophylaxis and treatment of bleeds in patients with congenital FXIII A-subunit deficiency. mentor™2 (NCT00978380), a multinational, open-label, single-arm, multiple-dosing extension to the pivotal mentor™1 trial, assessed long-term safety and efficacy of rFXIII-A₂ prophylaxis in eligible patients (patients with severe [<0.05 IU/mL] congenital FXIII subunit A deficiency) aged ≥6 years. Patients received 35 IU/kg rFXIII-A₂ (exact dosing) every 28 ± 2 days for ≥52 weeks. Primary endpoint was safety (adverse events including immunogenicity); secondary endpoints were rate of bleeds requiring FXIII treatment, haemostatic response after one 35 IU/kg rFXIII-A₂ dose for breakthrough bleeds and withdrawals due to lack of rFXIII-A₂ efficacy. Steady-state pharmacokinetic variables were also summarized. Elective surgery was permitted during the treatment period. Sixty patients were exposed to rFXIII-A₂; their median age was 26.0 years (range: 7.0–77.0). rFXIII-A₂ was well tolerated without any safety concerns. No non-neutralizing or neutralizing antibodies (inhibitors) against FXIII were detected. Mean annualized bleeding rate (ABR) was 0.043/patient-year. Mean spontaneous ABR was 0.011/patient-year. No patients withdrew due to lack of efficacy. Geometric mean FXIII trough level was 0.17 IU/mL. Geometric terminal half-life was 13.7 days. rFXIII-A₂ prophylaxis provided sufficient haemostatic coverage for 12 minor surgeries without the need for additional FXIII therapy; eight procedures were performed within 7 days of the patient's last scheduled rFXIII-A₂ dose, and four were performed 10 to 21 days after the last dose.

Keywords

recombinant FXIII-A₂ - safety - congenital FXIII deficiency - prophylaxis - surgery

Full Text

References

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