Phase I, randomized, double-blind, placebo-controlled, single-dose escalation study of the recombinant factor VIIa variant BAY 86-6150 in hemophilia
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Date
2012
Authors
Mahlangu, J. N.
Coetzee, M. J.
Laffan, M.
Windyga, J.
Yee, T. T.
Schroeder, J.
Haaning, J.
Siegel, J. E.
Lemm, G.
Journal Title
Journal ISSN
Volume Title
Publisher
International Society on Thrombosis and Haemostasis
Abstract
Background: BAY 86-6150 is a new human recombinant
factor VIIa variant developed for high procoagulant
activity and longer action in people with hemophilia with
inhibitors. Objectives: To investigate the safety, tolerability,
pharmacodynamics, pharmacokinetics and immunogenicity of
BAY 86-6150 in non-bleeding hemophilia subjects. Methods:
The study included non-bleeding men (18–65 years of
age)withmoderate or severe hemophilia AorBwith or without
inhibitors. Sixteen subjects were randomized 3 : 1 to four
cohorts of escalating doses of BAY 86-6150 (6.5, 20, 50 or
90 lg kg)1 [n = 3 per cohort]) or placebo (n = 1 per cohort);
an independent data-monitoring committee reviewed previous
cohort data before the next dose escalation. Blood samplingwas
performed predose and postdose; subjects were monitored for
50 days postdose. Results: At the tested doses, BAY 86-6150
was not associated with clinically significant adverse events or
dose-limiting toxicities. BAY 86-6150 pharmacokinetics exhibited
a linear dose response, with a half-life of 5–7 h. Subjects
demonstrated consistent, dose-dependent thrombin generation
ex vivo in platelet-poor plasma (PPP) (mean peak effect, 26–
237 nMthrombin from 6.5 to 90 lg kg)1). Peak thrombin levels
over time paralleled BAY 86-6150, with thrombin kinetics
appearing to be slightly shorter; thus, circulating BAY 86-6150
retained activity. There were corresponding decreases in
activated partial thromboplastin and prothrombin times. No
subject developed de novo anti-BAY 86-6150 neutralizing
antibodies during the 50-day follow-up. Conclusions: In this
first-in-human, multicenter, randomized, double-blind, placebo-
controlled, single-dose escalation study, BAY 86-6150
was tolerated at the highest dose (90 lg kg)1), with no safety
concerns. Safety and efficacy will be further evaluated in
phase II/III studies.
Description
Keywords
Hemophilia, Recombinant factor VIIa variant, Pharmacokinetics
Citation
Mahlangu, J. N., Coetzee, M. J., Laffan, M., Windyga, J., Yee, T. T., Schroeder, J., ... & Lemm, G. (2012). Phase I, randomized, double‐blind, placebo‐controlled, single‐dose escalation study of the recombinant factor VIIa variant BAY 86‐6150 in hemophilia. Journal of Thrombosis and Haemostasis, 10(5), 773-780.