Results From Two Phase II Trials Add to Understanding of Ticagrelor (BRILINTA(TM)) and How it Works in the Body
Ticagrelor data presented at the American Heart Association Scientific Sessions
ORLANDO, Fla., Nov. 18 /PRNewswire-FirstCall/ -- AstraZeneca
(NYSE:AZN) today announced the results of the
phase II studies, ONSET/OFFSET and RESPOND for ticagrelor
(BRILINTA(TM)) at the annual American Heart Association (AHA)
Scientific Sessions in Orlando, FL,(1,2) with ONSET/OFFSET study
results being simultaneously published in the medical journal
Circulation.(3)
The ONSET/OFFSET data showed that treatment with ticagrelor
(BRILINTA(TM)) 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.(1)
Key findings:(1)
-- 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% vs. 31%, P<0.0001) and
>70% IPA (90% vs. 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 vs. -0.482, P<0.0001). At 24 h
after last treatment dose, mean IPA was 58% for ticagrelor vs. 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(1)
The ONSET/OFFSET trial was a randomized 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(2)
The RESPOND study was a phase II, randomized, 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 Coronary Artery Disease (CAD)
Coronary artery disease, also called coronary heart disease, is
most often caused by atherosclerosis, and can lead to acute
coronary syndrome (ACS).
About Ticagrelor
Ticagrelor (BRILINTA(TM)) is an investigational oral
antiplatelet treatment for acute coronary syndromes (ACS) and the
first in a new chemical class, the CPTPs
(cyclo-pentyl-triazolo-pyrimidines). Ticagrelor is chemically
distinct from the thienopyridines, such as clopidogrel and
prasugrel.
AstraZeneca has proposed the name BRILINTA(TM) in the US. If
approved by the FDA, it will serve as the trade name for
ticagrelor. BRILINTA is a trademark of the AstraZeneca group of
companies.
About AstraZeneca
AstraZeneca is engaged in the research, development,
manufacturing and marketing of meaningful prescription medicines
and in the supply of healthcare services. AstraZeneca is one of the
world's leading pharmaceutical companies with global healthcare
sales of $31.6 billion and is a leader in gastrointestinal,
cardiovascular, neuroscience, respiratory, oncology and infectious
disease medicines. In the United States, AstraZeneca is a $13.5
billion dollar healthcare business.
For more information about AstraZeneca in the US or our
AZ&Me(TM) Prescription Savings programs, please visit:
www.astrazeneca-us.com.
References
(1.) Gurbel P et al, Randomised Double-Blind Study to Assess the
Onset and Offset of the Antiplatelet Effects of Ticagrelor versus
Clopidogrel in Patients with Stable Coronary Artery Disease.
Presentation at AHA 2009.
(2.) Gurbel P et al, The Effect of Ticagrelor in Stable Coronary
Artery Disease Patients Nonresponsive to Clopidogrel: The RESPOND
Study. Presentation at AHA 2009.
Source: AstraZeneca
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Posted: November 2009
