TRUST trial: BAY 86‐6150 use in haemophilia with inhibitors and assessment for immunogenicity

Introduction The most serious and challenging complication of haemophilia treatment is development of inhibitors to replacement factors VIII or IX . Innovative therapies currently being explored for patients with haemophilia and inhibitors include BAY 86‐6150, a modified recombinant activated factor VII ( FVII a). Immunogenicity remains a substantial barrier in this endeavour. Aim To present safety and efficacy results of the BAY 86‐6150 study in patients with inhibitors and report detailed analysis of epitope mapping in a patient who developed anti‐ BAY 86‐6150 antibodies. Methods Patients aged 12–62 years with moderate or severe haemophilia A or B were eligible for the phase 3 TRUST trial if they had a history of high‐titre inhibitors. Four escalating doses of BAY 86‐6150 (6.5, 20, 50, 90 μg kg −1 ) were planned with ≥10 patients per dose level. Bleeding episodes were treated with BAY 86‐6150. Development of anti‐ BAY 86‐6150 antibodies was considered a serious adverse event. Results TRUST was discontinued after one patient in the 6.5‐μg kg −1 cohort developed anti‐ BAY 86‐6150 neutralizing antibodies following three exposures. The anti‐ BAY 86‐6150 antibodies cross‐reacted with and neutralized wild‐type FVII a ( WT ‐ FVII a). Post hoc epitope mapping using peripheral blood mononuclear cells from the responding patient found that none of the 14 peptides unique to BAY 86‐6150 were recognized by the patient's T cells, but strong responses were detected against 2 WT ‐ FVII a peptides. Conclusion In the single patient with haemophilia A who developed anti‐ BAY 86‐6150 antibodies, results of T‐cell epitope mapping indicated BAY 86‐6150 was no more immunogenic than WT ‐ FVII a.