Comparing The AstraZeneca Investigational Drug AZD6140 To Clopidogrel For Inhibition Of Platelet Aggregation

Main Category: Cardiovascular / Cardiology
Article Date: 14 Mar 2006 - 0:00 PDT

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New Phase IIb data unveiled today reported effects of the AstraZeneca investigational antiplatelet drug AZD6140 on inhibition of platelet aggregation compared to clopidogrel in patients with non-ST elevation acute coronary syndromes (NSTE-ACS). AZD6140 is proposed to work by inhibiting the aggregation of platelets in the blood. The two sub-studies were part of the DISPERSE2 study,1 which assessed the safety and tolerability of AZD6140 plus aspirin compared with clopidogrel plus aspirin in patients with NSTE-ACS. These data were presented today at the American College of Cardiology (ACC) annual scientific sessions in Atlanta, Georgia.

AZD6140 is being studied as the first reversible oral adenosine diphosphate (ADP) receptor antagonist for acute coronary syndromes (ACS). It is proposed to selectively inhibit the P2Y12 receptor, a key target receptor for ADP on platelets.

The first sub-study,2 involving 45 patients, assessed the platelet inhibitory effect of administering AZD6140 in patients not previously treated with clopidogrel (clopidogrel-naďve). The primary measure of this sub-study was final extent ADP-induced platelet aggregation (PA), which is a recognised methodology for evaluating the effect of a drug on platelets. On Day 1, after the first dose, the mean inhibition of platelet aggregation (IPA) at two hours was 66% for the AZD6140 90 mg group, 80% for the AZD6140 180 mg group, and 82% for the AZD6140 270 mg group versus 22% for the clopidogrel 300 mg group. The subsequent 4, 8, and 12 hour time points assessed on Day 1 showed similar effects. At Week 4, at the pre-dose through 12 hour time points assessed, the mean IPA for the AZD6140 180 mg twice-daily dosing group was 87%-95% versus 52%-64% IPA for the clopidogrel 75 mg group, while mean IPA for the AZD6140 90 mg twice-daily dosing group was 73%-79%.

The second sub-study,3 involving 44 patients, assessed the effect on platelets of administering AZD6140 in patients who received clopidogrel prior to entry into the study. The primary measure of this sub-study was final extent PA as measured prior to study drug dosing and at 2, 4, 8, and 12 hours after AZD6140 or clopidogrel administration on Day 1. Mean PA prior to dosing was AZD6140 90 mg 48%, AZD6140 180 mg 34%, AZD6140 270 mg 43%, and clopidogrel 75 mg 38%. In the clopidogrel-only group, the mean decrease in PA across time points ranged from 2% to 11% while the mean decrease in PA was 37%-38% for the AZD6140 90 mg group, 28%-32 % for the AZD6140 180 mg group, and 34%-42% for the AZD6140 270 mg group.

"Oral antiplatelet agents play a key role in the management of acute coronary syndromes, but current therapies do have limitations," said Dr. Robert F. Storey, University of Sheffield, UK, and lead investigator of both DISPERSE2 sub-studies. "The data presented today add to the growing body of knowledge about AZD6140 and its effects on platelet aggregation."

These are the first sub-studies of the DISPERSE2 study to be presented. The phase IIa DISPERSE study,4 presented last year at the European Society of Cardiology (ESC) meeting in Stockholm, examined the ability of AZD6140 to inhibit platelet aggregation compared with clopidogrel. Safety and tolerability data from the phase IIb DISPERSE2 study were presented at the 2005 American Heart Association (AHA) meeting in Dallas.1

AstraZeneca also announced the name of its Phase III clinical trial for AZD6140, PLATO (A Study of Platelet Inhibition and Patient Outcomes), which will commence in 2006. PLATO is a head to head outcomes study of AZD6140 versus clopidogrel being conducted in 40 countries through 1,000 investigational centres and will include 16,000 ACS patients.

Additional DISPERSE2-related abstracts featured at the 2006 ACC meeting include:

-- Can Greater Inhibition of Platelet Aggregation be Tolerated? Evaluation of the Bleeding Risk of AZD6140 Compared with Clopidogrel in Patients with Acute Coronary Syndromes

-- Clinical Outcomes with AZD6140, an Oral Reversible ADP Receptor Antagonist, Compared with Clopidogrel in Patients with Acute Coronary Syndromes

-- The Effects of AZD6140, the First Oral Reversible ADP Receptor Antagonist, Compared with Clopidogrel on Biochemical Markers in Patients with Acute Coronary Syndromes

About AZD6140

AZD6140 is an investigational antiplatelet agent being studied for the prevention of thrombotic events in patients with ACS. AZD6140 is proposed to work by inhibiting the aggregation of platelets in the blood, which may reduce the risk of clot formation. AZD6140 is being studied as a reversible oral ADP receptor antagonist for acute coronary syndrome. It is proposed to selectively inhibit the P2Y12 receptor, a key target receptor for ADP on platelets. AZD6140 is currently in phase III development.

About The DISPERSE2 Study

The Dose confirmation Study assessing anti-Platelet Effects of AZD6140 vs clopidogRel in NSTEMI was a double-blind, double-dummy, parallel group, randomised dose confirmation and feasibility study of AZD6140 plus ASA compared with clopidogrel plus ASA in 990 patients with non-ST elevation acute coronary syndromes. Subjects received daily aspirin up to 325 mg first dose, then 75 to 100 mg, and heparin/LMWH and/or GP IIb/IIIa inhibition per treating physician. They were randomised to receive one of two doses of AZD6140 (90 mg or 180 mg twice daily) or clopidogrel 75 mg once daily for up to 12 weeks. Half of the AZD6140 patients were sub randomised to receive a loading dose of 270 mg while the other half started therapy with the maintenance dose. Patients randomised to clopidogrel received a 300 mg loading dose unless they had been on previous clopidogrel therapy with the option to give an additional double-blind clopidogrel 300 mg dose pre-PCI (total 600 mg dose). The primary end point studied was adjudicated total bleeding events (major plus minor) within the first four treatment weeks.

About 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 two conditions - unstable angina (chest pain with ECG changes compatible with ischemia) and heart attack (non-ST or ST-elevation myocardial infarction). Unstable angina and non-ST segment elevation myocardial infarction account for about 2.5 million hospital admissions worldwide and are a major cause of mortality and morbidity in Western countries.5

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 $23.95 billion and leading positions in sales of gastrointestinal, cardiovascular, neuroscience, respiratory, oncology and infection products. AstraZeneca is listed in the Dow Jones Sustainability Index (Global) as well as the FTSE4Good Index.

References

1- Cannon CP, Husted S, Storey RF, Harrington RA, Watkins C, Hill S, Price D, Sanders N, Emanuelsson H, and Peters G. Safety, Tolerability and Preliminary Efficacy of AZD6140, the First Oral Reversible ADP Receptor Antagonist Compared with Clopidogrel in Patients with Non-ST Segment Elevation Acute Coronary Syndrome (The DISPERSE2 Study). Presented at American Heart Association (AHA), Dallas, November 15, 2005.
2 - Storey R, Husted S, Harrington RA, Heptinstall S, Wilcox RG, Gurbel PA, Grande P, Sanders N, Peters G, Emanuelsson H, Cannon C. AZD6140 Yields Greater Inhibition of Platelet Aggregation than Clopidogrel in Patients with Acute Coronary Syndromes Without Previous Clopidogrel Treatment. Presented at American College of Cardiology (ACC), Atlanta, March 13, 2006.
3 - Storey R, Harrington RA, Husted S, Heptinstall S, Wilcox RG, Gurbel P, Grande P, Sanders N, Peters G, Emanuelsson H, Cannon C. AZD6140 Yields Additional Suppression of Platelet Aggregation in Patients with Acute Coronary Syndromes Previously Treated with Clopidogrel. Presented at American College of Cardiology (ACC), Atlanta, March 13, 2006.
4 - 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.
5 - Grech, E, Ramsdale, D. ABC of Interventional Cardiology. Acute Coronary Syndrome: Unstable Angina and Non-ST Segment Elevation Myocardial Infarction. BMJ 2003;326:1259-1261 (7 June), doi:10.1136/bmj.326.7401.1259. Accessed at http://bmj.bmjjournals.com/cgi/content/full/326/7401/1259 on March 6, 2006.

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