Anti-Factor VIII

A Novel Long-Acting Anticoagulant

In 2004, ThromboGenics entered into a strategic collaborative research and licensing agreement with BioInvent to co-develop our novel antibody-based drugs. Currently, we are jointly developing TB-402 (anti-factor VIII) and TB-403 (anti-placental growth factor [anti-PlGF]).

TB-402 is a novel human antibody binding to factor VIII, an essential blood clotting factor. TB-402 is being developed as an anticoagulant for the prevention of venous thromboembolism (VTE) and as a treatment of VTE and stroke prevention in patients with atrial fibrillation. For the former, the United States has put out a  call for action.

In 2007, we successfully completed aTB-402 Phase I dose-escalation trial in healthy male volunteers. The objective of the trial was to investigate safety, tolerability, and pharmacokinetic properties of the drug candidate. In total, 56 volunteers were enrolled into the trial, both young and old. The trial demonstrated that TB-402 was safe, well tolerated, and had the desired pharmacokinetic profile and pharmacodynamic effects. TB-402 has a long half-life, allowing for single-dose treatment in orthopedic surgery patients and once-a-month administration for long-term anticoagulation. Importantly, the findings confirm that TB-402 achieves only partial inhibition of factor VIII, thus maintaining partial hemostasis. Furthermore, monitoring of the intensity of anticoagulation is not needed.

In addition, the effect of recombinant human FVIII administration on coagulation parameters in healthy male volunteers treated with a single dose of TB-402 was studied (trial TB-402-002). The results of this trial demonstrated it is possible to counteract the anticoagulant activity of TB-402 with administration of rhFVIII.

In a third Phase I study, the pharmacodynamic interactions between TB-402 and warfarin, and between TB-402 and enoxaparin, were evaluated. This study demonstrated that administration of TB-402 to patients treated with warfarin with an INR between 2 and 3, and administration of low molecular weight heparin (LMWH) (enoxaparin 1 mg/kg) to patients 48 hours after TB-402 administration, maintained an effective and safe level of anticoagulation. The results of this study suggest it may be possible to switch patients from warfarin to TB-402 and that receiving a single dose of TB-402, patients can be treated with a LMWH such as enoxaparin.

Based on these encouraging results, TB-402 has moved into Phase II clinical development. The first Phase II trial evaluated a single intravenous administration of TB-402 for the prophylaxis of VTE after total knee replacement surgery. This study included 316 patients randomly allocated to 3 doses of TB-402 administered as a single bolus 18 to 24 hours after knee replacement surgery, or to standard treatment with enoxaparin. For the pooled TB-402 treatment group, 22% experienced VTE vs 39% of  those treated with enoxaparin, a significant absolute risk reduction of 17%. Furthermore, the safety profile of TB-402 and enoxaparin  was similar.