Results from Two Phase II Trials Add to Understanding of Brilinta (Ticagrelor) and How it Works in the Body

Wednesday, 18 November 2009

AstraZeneca today announced the results of the phase II studies, ONSET/OFFSET and RESPOND for ticagrelor (BRILINTA) at the annual American Heart Association (AHA) Scientific Sessions in Orlando, FL, with ONSET/OFFSET study results being simultaneously published in the medical journal Circulation.

The ONSET/OFFSET data showed that treatment with ticagrelor (BRILINTA) achieved a more rapid onset of antiplatelet effect (41% IPA vs. 8% at 30 minutes; P<0.0001), greater inhibition of platelet aggregation (IPA) that was sustained during maintenance phase of treatment (IPA; P<0.0001 at all times) and faster offset IPA compared to clopidogrel, in patients with stable coronary artery disease (CAD) on aspirin therapy.

Platelets initiate the formation of blood clots by sticking together (clumping or aggregating), a process called platelet aggregation. Inhibition of platelet aggregation (IPA) is the prevention of clumping of platelets in the blood, which reduces the risk of clot formation and subsequent thrombotic events.

These results were achieved using ticagrelor 180 mg loading dose followed by 90 mg twice daily, as studied in PLATO (A Study of Platelet Inhibition and Patient Outcomes), compared to clopidogrel 600 mg loading dose followed by 75 mg once daily dose.

Key findings:
• Greater IPA occurred with ticagrelor compared to clopidogrel at time points of 0.5, 1, 2, 4, 8 and 24 hours after patients received initial treatment dose and at 6 weeks (P<0.0001 for all)
• At 2 hours after patients received initial treatment dose a greater proportion of patients achieved >50% IPA (98% versus 31%, P<0.0001) and >70% IPA (90% versus 16%, P<0.0001) in the ticagrelor versus clopidogrel group, respectively
• A faster offset of IPA occurred with ticagrelor than clopidogrel (4 to 72 hour slope (IPA (%)/hour): -1.037 versus -0.482, p<0.0001). At 24 h after last treatment dose, mean IPA was 58% for ticagrelor versus 52% for clopidogrel (p=NS). This level of IPA with ticagrelor is equivalent to the levels patients achieved on maintenance clopidogrel therapy in the study
• IPA for ticagrelor on day 3 after the last dose was comparable to clopidogrel at day 5

In the Phase II RESPOND study, the antiplatelet effect of ticagrelor on both clopidogrel responders and non-responders were evaluated in 98 patients with stable coronary artery disease.

Among patients identified as clopidogrel responders, switching from clopidogrel to ticagrelor resulted in a mean IPA increase of 26% and switching from ticagrelor to clopidogrel resulted in a mean IPA decrease of 24%, suggesting that patients can be switched from clopidogrel to ticagrelor without interruption of antiplatelet effect.

Among patients identified as clopidogrel non-responders, the primary endpoint (difference in the proportion of non-responders on ticagrelor versus clopidogrel who achieved >10% final extent IPA) was not statistically significant. This result derives from the higher than expected response to clopidogrel after 14 days of treatment in patients initially defined as clopidogrel non-responders. However, the nominal p-values for this difference at the >30% and >50% IPA levels were both <0.001. Additional exploratory and ad-hoc analyses showed that at steady state (Day 14), the IPA response to ticagrelor was consistently higher compared with clopidogrel at all post dose assessments with nominal p-values <0.05 for all assessments. The findings from RESPOND demonstrated that due to the variability of clopidogrel response, identification of clopidogrel non-responders is difficult.

“In acute coronary syndromes, a rapid and sustained antiplatelet effect is desirable since patients are at highest risk for events soon after they present with symptoms,” commented Dr. Paul A. Gurbel, Director of the Sinai Center for Thrombosis Research, Baltimore, MD, and Principal Investigator of both the ONSET/OFFSET and RESPOND studies. “Today’s data add to the growing body of evidence to understand how ticagrelor works, and how it affects platelets in the body.”


About the ONSET/OFFSET Study
The ONSET/OFFSET trial was a randomised multicenter, double-blind, parallel-group study of patients with stable CAD on aspirin therapy. This trial was designed to assess the onset and rate of offset of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable CAD. 123 patients with stable CAD on aspirin therapy received ticagrelor (180 mg load, then 90 mg twice daily [n=57]), clopidogrel (600 mg load, then 75 mg once daily [n=54] or placebo (n=12) for 6 weeks. The total duration of the study for each patient was approximately 10 weeks.

About the RESPOND Study
The RESPOND study was a phase II, randomised, multicenter, international trial designed to assess the effect of ticagrelor in stable CAD patients (n=98) responsive and non-responsive to clopidogrel. In a 2-way crossover design, non-responders (n=41) and responders (n=57) randomly received either clopidogrel (600 mg load, then 75 mg once daily) or ticagrelor (180 mg load, then 90 mg twice daily) for 14 days during period one. In Period 2, all non-responders switched treatment and half of the responders continued with the same therapy while the remaining switched. The study set out to investigate the antiplatelet effect of ticagrelor in patients non-responsive to clopidogrel and examined the effect after switching between agents.

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:


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