Pharmacokinetics, immunogenicity, safety, and preliminary efficacy of subcutaneous turoctocog alfa pegol in previously treated patients with severe hemophilia A (alleviate 1)

BACKGROUND: The 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. OBJECTIVES: Evaluate 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/METHODS: In 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. RESULTS: Single‐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. CONCLUSIONS: Subcutaneous 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.