Phase I, randomized, double-blind, placebo-controlled, single-dose escalation study of the recombinant factor VIIa variant BAY 86-6150 in hemophilia

. Background: BAY similar to 86-6150 is a new human recombinant factor similar to 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 similar to 86-6150 in non-bleeding hemophilia subjects. Methods: The study included non-bleeding men (1865 similar to years of age) with moderate or severe hemophilia similar to A or B with or without inhibitors. Sixteen subjects were randomized 3 : 1 to four cohorts of escalating doses of BAY similar to 86-6150 (6.5, 20, 50 or 90 mu g 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 similar to days postdose. Results: At the tested doses, BAY similar to 86-6150 was not associated with clinically significant adverse events or dose-limiting toxicities. BAY similar to 86-6150 pharmacokinetics exhibited a linear dose response, with a half-life of 57 h. Subjects demonstrated consistent, dose-dependent thrombin generation ex similar to vivo in platelet-poor plasma (PPP) (mean peak effect, 26237 nm thrombin from 6.5 to 90 mu g kg(-1)). Peak thrombin levels over time paralleled BAY similar to 86-6150, with thrombin kinetics appearing to be slightly shorter; thus, circulating BAY similar to 86-6150 retained activity. There were corresponding decreases in activated partial thromboplastin and prothrombin times. No subject developed de similar to novo anti-BAY similar to 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 similar to 86-6150 was tolerated at the highest dose (90 mu g kg(-1)), with no safety concerns. Safety and efficacy will be further evaluated in phase similar to II/III studies.