• Robert Klamroth, Clemens Feistritzer, Ute Friedrich, Steven R Lentz, Kirsten Reichwald, Marek Zak, and Pratima Chowdary.
• Department of Internal Medicine, Hemophilia Treatment Centre, Vivantes Klinikum im Friedrichshain, Berlin, Germany.
• J. Thromb. Haemost. 2020 Feb 1; 18 (2): 341-351.

BackgroundThe current standard of care for patients with hemophilia A is regular prophylaxis with factor VIII (FVIII) administered intravenously. Interest in subcutaneous (s.c.) administration, to potentially increase convenience, reduce the treatment burden and improve compliance, is increasing.ObjectivesEvaluate the pharmacokinetics (PK), immunogenicity, safety, and preliminary efficacy of s.c. administration of turoctocog alfa pegol (s.c. N8-GP) in adult or adolescent previously treated patients (PTPs) with severe hemophilia A (alleviate 1; NCT02994407).Patients/MethodsIn part A, 24 PTPs received a single dose of s.c. N8-GP (12.5, 25, 50, or 100 IU/kg) with 6 patients per cohort. PK modelling of data from part A supported a suitable dose for part B. Part B comprised a multiple dose trial in 26 PTPs; patients <60 kg received 2000 IU and patients ≥60 kg received 4000 IU s.c. N8-GP daily for 3 months.ResultsSingle-dose s.c. N8-GP supported dose linearity. Daily prophylaxis with s.c. N8-GP appeared well tolerated and efficacious, achieving a mean trough FVIII activity close to 10% at steady state. Five patients developed anti-N8-GP binding antibodies after 42 to 91 exposure days, one of whom developed an inhibitor to FVIII. Anti-N8-GP antibody appearance was associated with a decline in FVIII plasma activity in four of the five patients. Five patients reported a total of nine treatment-requiring bleeding episodes during prophylaxis.ConclusionsSubcutaneous administration of N8-GP is associated with a high incidence of antibodies in PTPs with severe hemophilia A. Further clinical development of s.c. N8-GP has been suspended.© 2019 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.

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