Safety and dose-dependency of eptacog beta (activated) in a dose escalation study of non-bleeding congenital haemophilia A or B patients, with or without inhibitors.

Introduction: Varying initial doses of activated eptacog beta (recombinant human FVIIa, rhFVIIa) may provide therapeutic options when treating bleeding in patients with congenital haemophilia who have developed inhibitory antibodies to factor VIII (FVIII) or factor IX (FIX). This study evaluated escalated doses of a new rhFVIIa product as a prelude to selecting the doses for clinical efficacy evaluation in haemophilia patients.

Aim: To assess the safety, pharmacokinetics, and laboratory pharmacodynamics of 3 doses of rhFVIIa in non-bleeding patients with congenital haemophilia A or B with or without inhibitors.

Methods: Adult male patients (18-75 years old) with congenital haemophilia A or B (with or without inhibitors) received infusions of rhFVIIa at doses of 25, 75 or 225 μg/kg body weight. Ten patients were treated at each dose level, and each patient received 2 different dose levels. Descriptive methods were used to analyse the data.

Results: Administration of rhFVIIa at all doses was well tolerated. Pharmacokinetic analyses showed that peak FVIIa plasma levels (C ) were approximately proportional to dose and correlated well with peak thrombin generation. Total AUC also was approximately dose proportional. Clot formation and duration correlated with FVIIa activity. Repeat doses did not produce an immunological response.

Conclusion: In the first dose-escalation study of rhFVIIa to support product registration, eptacog beta at doses of 25, 75, and 225 μg/kg was pharmacodynamically active and well tolerated in non-bleeding patients with congenital haemophilia A or B.