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 pg/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 mu g/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 pharmacodynamic 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], respectively). Thirty-one of the 38 subjects who received TB-402 (82%) experienced a total of 85 treatmentemergent 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 similar to 48 hours in the >= 37.5-mu g/kg dose groups. TB-402 was associated with a prolonged APTT at doses >= 2.5 mu g/kg (similar to 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.