Tolerability and pharmacokinetics of TB-402 in healthy male volunteers.

BACKGROUND: TB-402, a human monoclonal antibody that partially inhibits Factor VIII activity (FVIII:C), is being developed as a long-acting antithrombotic agent. OBJECTIVES: The primary goal of this study was to investigate the tolerability of TB-402 in healthy male volunteers. Secondary objectives were to determine the pharmacokinetics and pharmacodynamics of TB-402. METHODS: In this ascending-dose study, healthy subjects aged 18 to 45 years were randomly assigned in a 2:1 ratio to receive TB-402 administered as a single intravenous bolus at 0.015, 0.1, 0.5, 2.5, 12.5, 37.5, 188, 620, or 1860 microg/kg or matching inactive vehicle (placebo). An older group (55-75 years) was also administered the highest dose that was well tolerated in the younger group (1860 microg/kg). Adverse events (AEs) were obtained from spontaneous reporting and from answers to nonleading questions asked by the principal investigator and study staff during follow-up visits on days 4, 7 (+/-1 day), 14 (+/-1 day), 21 (+/-2 days), 28 (+/-3 days), 42 (+/-3 days), and 56 (+/-3 days) after TB-402 administration. AEs were monitored up to the last study visit on day 56 after the administration of TB-402 or placebo, with special attention to bleeding events. The pharma-codynamic assessment of TB-402 included changes in FVIII:C, activated partial thromboplastin time (APTT), and prothrombin time (PT). RESULTS: The study enrolled 56 subjects (mean ages: younger group, 28 years [range, 20-45 years]; older group, 65 years [range, 58-76 years]; weight, 79 kg [range, 60-104 kg] and 81 kg [range, 64-94 kg], re-spectively). Thirty-one of the 38 subjects who received TB-402 (82%) experienced a total of 85 treatment-emergent AEs (TEAEs), and 14 of 18 subjects who received placebo (78%) experienced 35 TEAEs. A total of 34 bleeding events were reported in 13 of 38 subjects (34%) who received TB-402 and 7 of 18 subjects (39%) who received placebo. Most common AEs reported in subjects who received TB-402 were headache (11 [29%]), vessel puncture-site hematoma (7 [18%]), and traumatic hematoma (5 [13%]); with placebo, these AEs were vessel puncture-site hematoma (4 [22%]), headache (3 [17%]), vasovagal reaction (3 [17%]), and hematuria (3 [17%]). No serious AEs considered to be related to TB-402 were reported, and no dose-dependent increases in bleeding events were observed. On pharmacokinetic analysis of TB-402, the t(1/2) values across doses were 22.9 days (age 18-45 years) and 19.5 days (age 55-75 years). TB-402 was associated with a reduction in FVIII:C over a period of approximately 48 hours in the d37.5-microg/kg dose groups. TB-402 was associated with a prolonged APTT at doses >or=2.5 microg/kg approximately 1.1-1.2-fold predose APTT). Administration of a higher dose of TB-402 was associated with an extended duration of APTT prolongation. No significant effect on PT was found. CONCLUSIONS: In this study in healthy male volunteers, TB-402 was well tolerated in the population studied. Based on the findings from this study, the long t(1/2) of TB-402 may allow a pharmacodynamic effect over a prolonged period after single-dose administration. Further trials are needed to address the tolerability and efficacy of this agent in preventing thromboembolism. Clinicaltrials.gov identifier: NCT00612196.

Neutralization of alpha(2)-antiplasmin by microplasmin: a randomized, double-blind, placebo-controlled, ascending-dose study in healthy male volunteers.

BACKGROUND: Microplasmin is the isolated proteinase domain of plasmin. Administration of microplasmin has been found to neutralize alpha(2)-antiplasmin (alpha(2)-AP) activity, which has been associated with reduced infarct size in various preclinical models of stroke. OBJECTIVES: The goals of this first-in-man study were to investigate the ability of microplasmin to neutralize alpha(2)-AP activity and to monitor its tolerability in healthy male volunteers. METHODS: This Phase I, double-blind, placebo-controlled, ascending-dose study included 10 groups, each containing 6 subjects who were randomized to receive microplasmin or placebo in a 2:1 ratio. The study had 3 parts. In part 1, subjects received a single intravenous bolus of microplasmin 0.1, 0.5, 1, 1.5, or 2 mg/kg or placebo over 15 minutes. In part 2, subjects received a bolus of microplasmin 1 mg/kg or placebo, followed by an infusion of 1, 2, 3, or 4 mg/kg or placebo over 60 minutes. In part 3, subjects, all of whom were aged >55 years, received a bolus of mi-croplasmin 1 mg/kg or placebo, followed by an infusion of 1 mg/kg or placebo. The primary pharmaco-dynamic end point was the change in alpha(2)-AP activity, measured at different time points up to 4 days after dosing using a chromogenic assay. All adverse events were monitored based on spontaneous reports and nondirected questioning at study visits up to the post-study visit 21 days after administration of study drug. RESULTS: The mean (SD) age of subjects in parts 1, 2, and 3 was 30 (8), 30 (8), and 64 (8) years, respectively. All groups receiving microplasmin had a dose-dependent decrease in alpha(2)-AP activity. In part 1, the mean maximal inhibition of alpha(2)-AP was 11.8% (6.0%), 27.7% (4.3%), 53.0% (4.8%), 65.3% (4.3%), and 84.0% (6.0%) after bolus administration of microplasmin 0.1, 0.5, 1, 1.5, and 2 mg/kg, respectively, and 7.4% (6.9%) after administration of placebo. In part 2, the mean maximal inhibition of alpha(2)-AP was 74.6% (11.2%), 95.5% (3.3%), 99.0% (1.0%), and 88.0% (12.5%) after bolus administration of microplasmin 1 mg/kg followed by an infusion of 1, 2, 3, and 4 mg/kg, respectively, compared with 12.9% (6.8%) after administration of placebo. In part 3, the mean maximal inhibition was 69.7% (3.4%) after bolus administration of microplasmin 1 mg/kg followed by an infusion of 1 mg/kg, compared with 8.8% (4.1%) with placebo. One subject in the highest dose group in part 1 (2 mg/kg) and 2 subjects in the highest dose group in part 2 (1 + 4 mg/kg) had an urticarial reaction. All 3 subjects also had a decrease in total hemolytic complement and an increase in complement 5a. CONCLUSIONS: Neutralization of alpha(2)-AP activity by microplasmin was feasible in these healthy male volunteers. The urticarial reactions observed in the highest dose groups were considered dose-limiting adverse events. Further trials are needed to investigate the tolerability of this therapy and whether it is neuroprotective in patients with acute ischemic stroke.