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Phase I, randomized, double‐blind, placebo‐controlled, single‐dose escalation study of the recombinant factor VIIa variant BAY 86‐6150 in hemophilia
Author(s) -
MAHLANGU J. N.,
COETZEE M. J.,
LAFFAN M.,
WINDYGA J.,
YEE T. T.,
SCHROEDER J.,
HAANING J.,
SIEGEL J. E.,
LEMM G.
Publication year - 2012
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/j.1538-7836.2012.04667.x
Subject(s) - tolerability , medicine , pharmacokinetics , pharmacodynamics , placebo , bay , cohort , adverse effect , partial thromboplastin time , prothrombin time , pharmacology , gastroenterology , platelet , pathology , civil engineering , alternative medicine , engineering
Summary. 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) with moderate or severe hemophilia A or B with 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 μg 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 sampling was 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 n m thrombin from 6.5 to 90 μg 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 μg kg −1 ), with no safety concerns. Safety and efficacy will be further evaluated in phase II/III studies.