Safety And Tolerability Data From A Large Phase II Trial Presented For Investigational Oral Direct Thrombin Inhibitor AZD0837

Main Category: Blood / Hematology
Also Included In: Cardiovascular / Cardiology
Article Date: 30 Mar 2009 - 4:00 PDT

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New data reports that in patients with atrial fibrillation (AF) the investigational once daily oral anticoagulant AZD0837 demonstrated similar or lower total bleeding rates at a comparable level of anticoagulation (as measured by biomarkers) compared to current anticoagulants (vitamin K antagonists (VKAs)). This was seen in the 300mg od, 450 mg od and 200 mg bid AZD0837 treatment groups. These new phase II trial results were presented at the 58th Annual Scientific Sessions of the American College of Cardiology (ACC), in Orlando, Florida.1

AZD0837 is converted to a selective and reversible direct thrombin inhibitor. It is being studied as a treatment to lower the risk of stroke in addition to reducing the risk of bleeding compared to standard VKA anticoagulant therapy in patients with AF.

In the phase II dose-guiding study presented today, 955 AF patients with ≥1 additional risk factor for stroke were randomised to receive one of four doses of AZD0837 (150, 300 or 450 mg once daily or 200 mg twice daily, blinded treatment) or VKA (titrated for INR 2-3, open treatment) for 3-9 months.

AZD0837 was associated with a similar suppression of blood clot formation (thrombogenesis), as judged by biomarkers, as well-controlled VKA in the 300mg od, 450 mg od and 200 mg bid treatment groups. The study demonstrated that AZD0837 is generally well tolerated. Total bleeding events were similar or less in all AZD0837 groups (5.3% - 14.1%, mean exposure: 138 - 145 days) compared with VKA (14.5% mean exposure: 160 days). Clinically relevant bleeding events (i.e. major + clinically relevant minor) in the whole cohort and the VKA-naïve sub-group were numerically less common in the AZD0837 150 mg od and 300 mg od groups versus the AZD0837 450 mg od and 200 mg bid and VKA group. A similar frequency of serum alanine aminotransferase (ALT) > 3 x the upper limit of normal was seen with AZD0837 compared to VKA (2.3% vs 1.6% respectively).

In this open study, percentages of adverse events leading to discontinuation of AZD0837 were 6.7%-12.5% versus 1.6% for VKA in this predominately VKA-experienced population. The most common adverse events with AZD0837 were GI disorders (23% versus 14% in the VKA group) such as diarrhoea, flatulence, or nausea.

"Patients with AF are at least five times more likely to experience a stroke, but although existing treatments can reduce the risk of stroke in these patients, they are associated with limitations, particularly in terms of bleeding risk and convenience," said lead investigator Dr Gregory YH Lip of City Hospital, Birmingham, England. "These data add to an encouraging body of evidence supporting the clinical development of AZD0837."

The results of today's study have provided robust data for selecting the phase III dose regimen for AZD0837. The phase III clinical trial programme is expected to be initiated in the second half of 2009 and will be designed to fully investigate the potential of AZD0837 in this area of unmet medical need.

About AZD0837

AZD0837 is an investigational once daily oral anticoagulant. It is converted into a direct thrombin inhibitor and is being investigated as a treatment to lower the risk of stroke while reducing the risk of bleeding events compared to standard anticoagulant therapy, in patients with atrial fibrillation. AZD0837 has been investigated to date in pre-clinical, phase I and phase II trials, which support its ongoing development. A programme of work aimed at resolving the stability issue related to AZD0837 tablets remains under way, and we estimate the phase III trial programme in AF will start the second half of 2009.

About Atrial Fibrillation

Atrial fibrillation (AF) is the most common arrhythmia in adults and its prevalence rises with age,2 affecting nearly 4% of people age 60 and older.3 AF is an independent risk factor for stroke.3 In AF, the irregular contractions of the left atrium cause stagnant blood, which may result in the formation of blood clots. These clots can break loose and travel through the bloodstream to the brain, causing a stroke or to the rest of the body causing a systemic embolic event. Patients with AF are at least five times more likely to experience a stroke,4 but treatment with currently available anticoagulants, VKAs, is effective in reducing the risk of stroke in patients with AF.4

About AstraZeneca

AstraZeneca is a major international healthcare business engaged in the research, development, manufacturing and marketing of meaningful prescription medicines and supplier for healthcare services. AstraZeneca is one of the world's leading pharmaceutical companies with healthcare sales of US$ 31.6 billion and is a leader in gastrointestinal, cardiovascular, neuroscience, respiratory, oncology and infectious disease medicines. For more information about AstraZeneca, please visit: http://www.astrazeneca.com

The statements contain herein include forward-looking statements. Although we believe our expectations are based on reasonable assumptions, any forward-looking statements, by their very nature, involve risks and uncertainties and may be influenced by factors that could cause actual outcomes and results to be materially different from those predicted. The forward-looking statements reflect knowledge and information available at the date of the preparation of this press release and the Company undertakes no obligation to update these forward-looking statements. Important factors that could cause actual results to differ materially from those contained in forward-looking statements, certain of which are beyond our control, include, among other things, those risk factors identified in the Company's Annual Report/Form 20-F for 2008. Nothing contained herein should be construed as a profit forecast.

References

1. Lip GYH, et al. The Oral Direct Thrombin Inhibitor AZD0837 for the Prevention of Stroke and Systemic Embolism in Patients with Atrial Fibrillation: A Phase II Randomized Dose-Guiding, Safety and Tolerability Study. Abstract 1021 presented at the 58th Annual Scientific Sessions of the American College of Cardiology (ACC), in Orlando, Florida, 29-31 March 2009

2. Olsson B, et al. Safety and tolerability of the oral direct thrombin inhibitor AZD0837 in prevention of stroke and other thromboembolic complications associated with atrial fibrillation (AF). Journal of Thrombosis and Haemostasis 2007;5 (Suppl 2):Abs O-W-053

3. Singer DE, et al. Antithrombotic therapy in atrial fibrillation. The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126:429S-456S.

4. Go AS, et al. Prevalence of diagnosed atrial fibrillation in adults. National implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA. 2001;285:2370-2375

5. Lip GYH, et al. ABC of antithrombotic therapy: Antithrombotic therapy for atrial fibrillation.BMJ 2002; 325:1022-1025

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