title: Phase I, randomized, double-blind, placebo-controlled, single-dose escalation study of the recombinant factor VIIa variant BAY 86-6150 in hemophilia.
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.
  
  
  OBJECTIVE
  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 nm 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.
authors.affiliation: Hemophilia Comprehensive Care Center, Charlotte Maxeke Johannesburg Academic Hospital and University of Witwatersrand, Johannesburg, South Africa. johnny.mahlangu@nhls.ac.za
authors.forename: J N
authors.initials: JN
authors.lastname: Mahlangu
authors.forename: M J
authors.initials: MJ
authors.lastname: Coetzee
authors.forename: M
authors.initials: M
authors.lastname: Laffan
authors.forename: J
authors.initials: J
authors.lastname: Windyga
authors.forename: T T
authors.initials: TT
authors.lastname: Yee
authors.forename: J
authors.initials: J
authors.lastname: Schroeder
authors.forename: J
authors.initials: J
authors.lastname: Haaning
authors.forename: J E
authors.initials: JE
authors.lastname: Siegel
authors.forename: G
authors.initials: G
authors.lastname: Lemm
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D057134:Antibodies, Neutralizing / Q000097:blood; D003029:Coagulants / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D016903:Drug Monitoring / Q000379:methods; D005060:Europe; D015942:Factor VIIa / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology / Q000493:pharmacokinetics; D006207:Half-Life; D006467:Hemophilia A / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D002836:Hemophilia B / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D006801:Humans; D008297:Male; D008875:Middle Aged; D010314:Partial Thromboplastin Time; D010919:Placebos; D011517:Prothrombin Time; D011994:Recombinant Proteins / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology / Q000493:pharmacokinetics; D013019:South Africa; D013917:Thrombin / Q000378:metabolism; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D057134:Antibodies, Neutralizing; D003029:Coagulants; D010919:Placebos; D011994:Recombinant Proteins; C103587:recombinant FVIIa; C574607:BAY 86-6150; D015942:Factor VIIa; D013917:Thrombin