Results of a Phase III clinical trial comparing AstraZeneca's investigational oral anticoagulant Exanta (ximelagatran) with the current standard, warfarin, showed that treatment with Exanta reduced by 26 per cent the risk of blood clots after total knee replacement (TKR) surgery compared with warfarin. In addition, results of a second Phase III clinical trial in patients who had completed a conventional six-month course of treatment for blood clots showed that treatment with Exanta for an additional 18 months resulted in about an 84 per cent relative risk reduction of developing recurrent events compared with placebo.

The objective of EXULT A was to optimize the dosage of Exanta and compare its efficacy and safety with those of warfarin for the prevention of deep vein thrombosis (DVT) and pulmonary embolism (PE) in TKR patients. Results showed a 20.3 per cent incidence with Exanta 36 mg vs. a 27.6 per cent incidence with warfarin (statistically significant at p=0.003) in total DVT and/or PE and/or all-cause mortality. There were no statistically significant differences between the two treatment groups with respect to incidence of PE or death. The incidence of major bleeding on treatment was 0.8 per cent for Exanta 24 mg and for Exanta 36 mg, and 0.7 per cent for warfarin. Any (major and/or minor) bleeding on treatment was 4.8 per cent and 5.3 per cent for Exanta 24 mg and 36 mg respectively, and 4.5 per cent for warfarin.

EXULT A was a multicenter, randomized, double-blind, double-dummy trial that included 2,301 patients undergoing TKR surgery at 116 trial sites in five countries. Patients were given an oral, fixed dose of Exanta 24 mg (n=614) or 36 mg (n=629) BID, initiated the morning after surgery or dose-adjusted warfarin (n=608) at a target INR of 2.5 initiated the evening of the day of surgery. Study treatment was continued for 7-12 days. Incidence of DVT or PE was confirmed by bilateral venography or other objective means by the final treatment day; DVT or PE and bleeding were determined by an independent central adjudication committee.

THRIVE III, the second Phase III study presented at ASH, evaluated the efficacy, safety and tolerability of Exanta for extended (18 months) secondary prevention of DVT and PE, following six months of standard anticoagulation. Results showed that in patients treated with a fixed 24-mg dose of Exanta, the risk of developing a blood clot was about 84 per cent lower than in those receiving placebo. Specifically, the estimated cumulative risk of a recurring DVT or PE during 18 months of treatment was 12.6 per cent for placebo vs. 2.8 per cent for EXANTA (p<0.0001).

THRIVE III was an international, multicenter, double-blind trial with 1,223 patients with DVT and PE who had received standard anticoagulation treatment for six months. Patients were randomized to long-term secondary prevention with either oral Exanta 24 mg BID (n=612) or placebo (n=611) for another 18 months, without coagulation monitoring.

In THRIVE III, six patients on Exanta experienced major bleeding events compared with five on placebo during the 18-month period. Increases in alanine aminotransferase (ALAT) levels were observed with Exanta compared to placebo (estimated cumulative risk of 6.4 per cent vs.1.2 per cent). These enzyme changes occurred within the first six months of treatment, were associated with no specific clinical symptoms, and decreased with or without drug continuation or discontinuation.

Exanta is the first oral direct thrombin inhibitor under Phase III investigation and the first investigational oral anticoagulant to reach Phase III in more than 50 years. The intended mechanism of action of Exanta is to inhibit the activity of an enzyme called thrombin, which is critical to the final step in the formation of blood clots. Ongoing clinical studies with Exanta utilize a fixed dose without routine coagulation monitoring.

AstraZeneca submitted a filing for a European license on July 24, 2002 for the prevention of DVT/PE in major elective orthopedic surgery. This was the first regulatory submission for Exanta.