Biotech Tracker News - Exanta and Arixtra Shine at ASH
December 10, 2002  Developmental anticoagulant therapy became a hot topic at last year’s American Society of Hematology (ASH) meeting, and continues to be one this year. Yesterday, studies presented at ASH reinforced the point that direct thrombin inhibition is the wave of the present for the primary and secondary prophylactic management of venous thromboembolism (VTE), which includes deep vein thrombosis (DVT), blood clots lodged in the deep veins typically of the legs, and pulmonary embolism (PE), their life-threatening migration to the lung circulation.  AstraZeneca’s (NYSE: AZN) Exanta (ximelagatran) continues to generate data supporting approval as an improvement to effective but clinically cumbersome warfarin formulations, such as Bristol Myers Squibb’s (NYSE: BMY) Coumadin. Sanofi (NYSE: SNY) and Organon’s Arixtra (fondaparinux), while nailing down its place in minimizing the perioperative risk of VTE, is evolving as a clear, more convenient, alternative to both unfractionated heparin and low molecular weight heparins such as Aventis’s (NYSE: AVE) Lovenox (enoxaparin). In a phase III clinical trial, Exanta’s VTE prophylactic effects were greater than those of warfarin for patients undergoing total knee replacement (TKR) surgery. Exanta reduced the risk of postoperative blood clot development by 26%, compared to warfarin, in this population. More importantly, the risk of PE or death did not significantly differ between groups, a definitely plus for the more convenient fixed-dose administration of Exanta.  A separate phase III investigation confirmed that Exanta is an anticoagulation option for extended VTE prophylaxis – the 7th through 24th months on anticoagulation – for patients who have completed a conventional six-month anticoagulation course. An approximate 84% relative VTE risk reduction was observed for extended therapy Exanta recipients compared to placebo recipients simulating outcomes of a standard 6-month anticoagulation program. EXULT (EXanta Used to Lessen Thrombosis) is a randomized, double-blind trial of 2,301 patients undergoing TKR. Study subjects were randomized to receive Exanta 24mg twice daily, Exanta 36 mg twice daily, or warfarin dose-adjusted in the standard manner requiring blood draws and laboratory assessment of biochemical coagulation parameters. Study prophylaxis was continued for 7 to 12 days. VTE incidence was 20.3% for recipients of Exanta 36 mg and 27.6% for warfarin, and there were no statistically significant differences between the two treatment groups with respect to incidence of PE, death, or clinically relevant bleeding.  THRIVE III (Oral Direct THRombin Inhibitor ximelagatran for Venous ThromboEmbolism) evaluated 1,223 study subjects in double-blind fashion. These patients had experienced VTE and had received standard secondary prophylactic anticoagulation for six months. Subjects were randomized to further, long-term, secondary prevention with either Exanta 24 mg twice daily or placebo for another 18 months without monitoring anticoagulation parameters. The estimated cumulative risk of recurrent VTE during the extension phase was 12.6% for placebo recipients and 2.8% for Exanta recipients (p<0.0001). The adverse event profile, including that related to significant bleeding, was again reassuring.  MATISSE PE is a randomized, open-label evaluation of Arixtra in 2,213 study subjects with symptomatic PE. Patients received either once-daily subcutaneous Arixtra 7.5 mg or continuous dose adjusted intravenous unfractionated heparin for at least 5 days. The incidence of symptomatic, recurrent VTE over the 3 month follow-up period was 3.8% in the Arixtra group and 5% in the unfractionated heparin group on a conservative, intent-to-treat basis. Though the comparative efficacy did not reach statistical significance, this 25% relative risk reduction represents a clinically significant magnitude of prophylactic effect. The major bleeding incidence and mortality rates were comparable and reassuring.  MATISSE DVT is a 2,205-patient, randomized, double blind trial of Arixtra for patients with symptomatic DVT and free of symptomatic PE. Patients received either once-daily subcutaneous Arixtra 7.5 mg or twice-daily weight-adjusted Lovenox 1mg/kg for at least 5 days. The incidence of symptomatic, recurrent VTE was 3.9% in the Arixtra group and 4.1% in the Lovenox group on a conservative, intent-to-treat basis. The major bleeding incidence and mortality rates were comparable and reassuring. Arixtra recipients weighing less than 50 kg received 5mg once daily, and those weighing more than 100 kg received 10mg once daily.
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