Results of first chronic treatment study with oral EXANTA(TM) (ximelagatran)

December 09, 2002

First chronic treatment study with oral EXANTA™ (ximelagatran) demonstrates highly significant long term benefit in preventing recurrent venous thromboembolism (VTE)

Additional data demonstrate superiority of EXANTA over both warfarin and enoxaparin in preventing VTE after major elective orthopaedic surgery

44th Annual Meeting of the American Society of Hematology (ASH), Philadelphia, USA: New results from the first chronic treatment study1 for EXANTA™ (ximelagatran), an oral direct thrombin inhibitor (Oral DTI), show that EXANTA treatment for 18 months following standard six month anticoagulation treatment is highly effective in prevention of recurrent venous thromboembolism (VTE) after an initial deep vein thrombosis (DVT) and/or pulmonary embolism (PE).

Results from the THRIVE III* study demonstrate that oral EXANTA is very effective in preventing recurrence of VTE events by 84% (relative risk reduction; RRR), compared to placebo (p<0.0001) following standard duration treatment.

THRIVE III is a multinational, randomised, multicentre, double-blind study comparing fixed dose oral EXANTA 24mg twice daily, to placebo. The study involved 1,233 patients who had been treated for six months with current standard anticoagulation therapy after an initial VTE event prior to the 18 month treatment period with EXANTA.

Notably, these long term results demonstrate that the clinical potential for EXANTA in effective secondary prevention of thromboembolic events is achieved without an increased risk of bleeding. The data show no significant increase in total bleeding events for EXANTA compared with placebo (estimated cumulative risk: 23.9% vs 21%; p=0.1703; EXANTA and placebo respectively).

"Today's exciting results from THRIVE III show that oral ximelagatran provides a convenient, well tolerated and effective solution for extending anticoagulation treatment beyond the current standard of six months warfarin treatment for patients having suffered DVT and/or PE", says Dr Henry Eriksson, THRIVE III Principal Investigator, Department of Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden. "Ximelagatran represents a potential medical breakthrough in the long-term secondary prevention and treatment of venous thromboembolism and it satisfies a clear unmet medical need for long term fixed dose oral anticoagulation treatment, without the need for coagulation monitoring or dosage titration".

Current standard anticoagulation treatment regimens to prevent recurrent DVT and PE only run for a standard six months. Physicians considering longer treatment face a risk-benefit analysis for patients, balancing the desire to prevent additional VTEs, against the risk of bleeding associated with current therapeutic options, such as warfarin (vitamin K antagonists).

The THRIVE III data show an encouraging efficacy-safety profile. Increases in alanine aminotransferase (ALT) levels were observed with EXANTA compared to placebo (estimated cumulative risk of 6.4% vs 1.2%). Importantly, however, these enzyme changes occurred within the first six months of treatment, were associated with no specific clinical symptoms and decreased with drug continuation or discontinuation.

"THRIVE III is important in confirming the efficacy and potential long-term benefits of oral EXANTA in prevention of DVT, PE or other serious medical outcomes. These results are an important step towards introducing a fundamentally new approach to oral anticoagulation", says Dr Ian Watts, Global Product Director, AstraZeneca. "Furthermore, the promise of EXANTA as a novel oral anticoagulant treatment is reinforced by other new data announced today from the EXULT A study2, showing the superior efficacy of EXANTA over warfarin in VTE prevention after orthopaedic surgery."

The EXULT A* study, also presented at ASH, demonstrates that fixed oral dose EXANTA administered post-operatively, is superior in efficacy to warfarin for total DVT and/or PE and/or all-cause mortality (20.3%, EXANTA vs 27.6%, warfarin, p=0.03). Dose-adjusted warfarin or LMWH is currently viewed as the standard treatment in the USA for VTE prophylaxis following total knee replacement surgery.

There were no statistically significant differences in incidence of major or any (major and/or minor) bleeding, perioperative indicators of bleeding, or wound drainage or appearance between the two groups in the EXULT A study.

The EXULT A results support the findings of EXPRESS*3, another study demonstrating the superior efficacy of EXANTA over enoxaparin (LMWH) in VTE prevention following major elective orthopaedic surgery. First presented at 17th International Congress on Thrombosis, Bologna on 28 October 2002, EXPRESS compares EXANTA with enoxaparin and is also presented at ASH 2002.

Thrombosis is one of the largest causes of morbidity and mortality in the western world. There are nearly four million events of thromboembolic disease (including stroke, deep vein thrombosis, pulmonary embolism and myocardial infarction) each year in the EU and Japan.4

EXANTA is the first oral direct thrombin inhibitor (Oral DTI) under phase III investigation and is the first oral anticoagulant to reach late clinical development in more than 50 years - since the development of warfarin.
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Notes to editors:

EXANTA, ATACAND, ZESTRIL, SELOKEN ZOK / TOPROL XL, PLENDIL and CRESTOR are trademarks of the AstraZeneca group of companies.
* THRIVE III: THRombin Inhibitor in Venous ThromboEmbolism Study
* EXULT A: EXanta Used to Lessen Thrombosis is a multi-centre, randomised, double-blind trial of 2,301 patients undergoing total knee replacement surgery. Patients were given oral 24mg or 36mg fixed-dose ximelagatran initiated the morning after surgery or warfarin initiated in the evening on the day of surgery.
*EXPRESS (EXpanded PRophylaxis Evaluation Surgery Study) is a randomised, double-blind study of 2,800 patients carried out in 12 European countries and South Africa. Patients received 2mg subcutaneous melagatran immediately before surgery, followed by 3mg subcutaneous melagatran in the evening after surgery, and then 24mg oral ximelagatran as a fixed dose.

AstraZeneca is a major international healthcare business engaged in the research, development, manufacture and marketing of ethical (prescription) pharmaceuticals and the supply of healthcare services. It is one of the top five pharmaceutical companies in the world with healthcare sales of over $16.4 billion and leading positions in sales of gastrointestinal, oncology, anaesthesia including pain management, cardiovascular, central nervous system (CNS) and respiratory products.

AstraZeneca has more than 40 years experience in cardiovascular medicine and aims to increase lifespan and improve quality of life by reducing the risk, prevalence and impact of cardiovascular disease. AstraZeneca has a comprehensive cardiovascular portfolio including ATACAND, ZESTRIL, SELOKEN ZOK / TOPROL XL and PLENDIL. This heritage is complemented by an innovative pipeline including CRESTOR, a new highly effective treatment for dyslipidaemia, the first oral direct thrombin inhibitor, EXANTA, and GALIDA, a novel treatment for type 2 diabetes / insulin resistance.

Ketchum UK

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