AZD6140 phase IIa data demonstrate greater and more consistent inhibition of platelet aggregation (IPA) compared with current ‘gold standard’ treatment

European Society of Cardiology (ESC), Stockholm, Wednesday 7 September 2005: Phase IIa data for the antiplatelet agent AZD6140 demonstrate greater and more consistent inhibition of platelet aggregation (IPA) compared with clopidogrel, according to results of the DISPERSE study presented today at the ESC meeting in Stockholm. DISPERSE, the first study of AZD6140 in patients, examined doses of 50 mg, 100 mg, 200 mg and 400 mg versus the standard 75 mg dose of clopidogrel and confirms the findings of earlier pre-clinical and healthy volunteer studies. AZD6140 is being developed for the prevention of thrombotic events, such as heart attack and stroke, in patients with acute coronary syndrome (ACS).

Antiplatelet drugs, such as AZD6140, work by inhibiting the aggregation of platelets in the blood, which may reduce the risk of clot formation. AZD6140 is the first oral, reversible adenosine diphosphate (ADP) receptor antagonist that selectively blocks the P2Y₁₂ receptor, a key target receptor for ADP on platelets.

AZD6140 is being studied versus clopidogrel to investigate its potential to provide superior protection against thrombotic events. DISPERSE, a Phase IIa study, was designed to assess the antiplatelet effects and tolerability of AZD6140 compared with clopidogrel in stable atherosclerotic patients. There is a growing body of evidence from clinical studies that supports the hypothesis that higher levels of inhibition of platelet aggregation could lead to a reduction in thrombotic events.

At Day 28, steady state, the higher doses of AZD6140 demonstrated an increase in mean IPA of between 28 and 35% compared to clopidogrel (final extent). The mean percentage IPAs were 88% (+/- 2.0%) 100 mg BD; 93% (+/- 1.5%); 200mg BD and 95% (+/- 1.4%) 400 mg OD when compared with 60% (+/- 3.5%) for clopidogrel 75 mg OD. In addition to the higher level of IPA reported with these doses of AZD6140, the variability of response was less than that observed with clopidogrel. AZD6140 was generally well tolerated. One major, non-fatal bleed was seen in the AZD6140 400 mg OD group. “The greater and more consistent IPA observed in DISPERSE is encouraging from a clinical perspective”, commented Professor Steen Husted, Department of Medicine and Cardiology, Århus University Hospital and DISPERSE lead investigator. “We know that there can be substantial variability of response to clopidogrel and consequently there is a need for a more consistent therapy.”

Results also showed AZD6140 to have a fast onset of action. AZD6140 rapidly inhibited ADP induced platelet aggregation (final extent) after initial dosing (day 1) with peak inhibition 2 hours post dose (96% +/- 6.1% for 400 mg OD).

Dr Gary Peters, AstraZeneca Medical Science Director for AZD6140 commented, “These encouraging results from DISPERSE show AZD6140 to have a fast onset of action, which is important in the acute hospital setting. AZD6140 was well tolerated and as we continue to expand our knowledge with further clinical trials, we hope to demonstrate the full clinical potential of AZD6140”.

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Maria Pierrou, Global PR Manager (Thrombosis), AstraZeneca
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Notes to Editors

AZD6140

AZD6140 is a new antiplatelet agent being developed for the prevention of thrombotic events in patients with ACS. Antiplatelet treatments such as AZD6140, work by inhibiting the aggregation of platelets in the blood, which may reduce the risk of clot formation. AZD6140 is the first oral, reversible ADP receptor antagonist that selectively blocks the P2Y₁₂ receptor, a key target receptor for ADP on platelets. AZD6140 is currently in phase II, which means it is not licensed in any country.

The DISPERSE study

The D ose-finding I nvestigative S tudy to assess the P harmacodynamic E ffects of AZD6140 in atherosclerotic disease study¹ was a randomised, double blind, parallel-group study, in stable atherosclerotic disease patients (n=200). Subjects received AZD6140 (50 mg BD, 100 mg BD, 200 mg BD, or 400 mg OD) or clopidogrel 75 mg OD for 28 days. All groups received aspirin 75-100 mg OD.

Acute coronary syndrome (ACS)

ACS is an umbrella term for conditions that cause chest pain due to insufficient blood supply to the heart muscle (acute myocardial ischemia). ACS includes both unstable angina (chest pain with ECG changes compatible with ischaemia) and heart attack (non ST elevation myocardial infarction). It is the most common reason for cardiac hospitalisation in the western world and is increasingly prevalent in many European countries.² Patients with ACS are at increased risk from strokes and subsequent heart attacks.

AstraZeneca

AstraZeneca is a major international healthcare business engaged in the research, development, manufacture and marketing of prescription pharmaceuticals and the supply of healthcare services. It is one of the world’s leading pharmaceutical companies with healthcare sales of over $21.4 billion and leading positions in sales of gastrointestinal, oncology, cardiovascular, neuroscience and respiratory products. AstraZeneca is listed in the Dow Jones Sustainability Index (Global) as well as the FTSE4Good Index. 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 CRESTOR^TM , EXANTA^TM , ATACAND^TM , ZESTRIL^TM , TENORMIN^TM , SELOKEN ZOK /TOPROL-XL^TM and PLENDIL^TM .

References:

1. Husted S, Emanuelsson H, Heptinstall S, Clark S, and Peters G. Greater and Less Variable Inhibition of Platelet Aggregation (IPA) with AZD6140, the First Oral Reversible ADP Receptor Antagonist, Compared with Clopidogrel in Patients with Atherosclerosis (The DISPERSE Study). Presented at European Society of Cardiology (ESC), Stockholm, 7th September 2005. 2. European Society of Cardiology. Acute Coronary Syndrome. http://www.escardio.org/knowledge/ehs/survey/ACS_II.htm