Phase I Clinical Trial of a Novel, Long-Acting Antithrombotic Drug: A Human Monoclonal Antibody Partially Inhibiting FVIII Activity.

Abstract

Current treatments for preventing thrombotic disease are still inconvenient and associated with a high risk of bleeding. Improved anticoagulant agents are therefore required. TB-402 is a monoclonal antibody (fully human IgG4-antibody) that targets factor VIII (FVIII) and represents a novel type of anticoagulant agent. In vitro, TB-402 only partially inhibits human FVIII even when TB-402 is in excess over FVIII. Preclinical studies confirmed this plateau inhibition and also established the antithrombotic efficacy of TB-402 (Jacquemin M, et al. J Thromb Haemost. 2006; 4:1047). Plateau inhibition even in setting of excess TB-402 may allow for improved safety with decreased risk of overdose and decreased need for monitoring. The long half-life of the antibody creates the possibility for a once a month administration. TB-402 may therefore represent a safer and more convenient agent than other available anticoagulants. A Phase I study has completed enrolment of 56 healthy male volunteers. This randomised, double-blind, placebo-controlled, single dose, dose escalation study evaluated the safety and the pharmacokinetic/pharmacodynamic profile of TB-402. Volunteers were treated with a single intravenous administration of placebo or TB-402 at doses of 0.015, 0.1, 0.5, 2.5, 12.5, 37.5, 188, 620 or 1,860 μg/kg. All doses were evaluated in 18–45 year old volunteers, with the highest dose also evaluated in an older age, 55–75 years, cohort. Study drug has been well tolerated in both the young and the older age cohorts, with no safety issues observed. A plateau effect in terms of FVIII level inhibition has been observed. At plateau, FVIII levels were generally decreased by 1/3 to 2/3 from baseline. aPTT prolongation (generally 1.1–1.2 times baseline) was also observed whereas the Prothrombin time (PT) was not modified. aPTT prolongations at doses of ≥ 620 μg/kg were generally maintained for at least 4 weeks. Long half-life of drug and associated anticoagulant effect are supported by the finding of consistent and prolonged effect on aPTT. In conclusion, this study demonstrates that in healthy young and older volunteers a single administration of TB-402 results in a prolonged anticoagulation effect without the risk of overdosing or spontaneous hemorrhage. TB-402 will next be evaluated in patients at risk for venous thromboembolism.