New Study Shows Prasugrel Achieves Faster Onset and Higher Levels of Platelet Inhibition than Clopidogrel at Approved or Higher Doses
INDIANAPOLIS and TOKYO, Oct. 23 /PRNewswire-FirstCall/ -- In a Phase I
study, a 60 mg loading dose of the investigational antiplatelet compound
prasugrel showed faster onset of activity and achieved greater inhibition
of platelet aggregation than either the approved 300 mg loading dose of
clopidogrel (Plavix(R)) or a higher 600 mg clopidogrel dose, researchers
with Daiichi Sankyo (TSE: 4568) and Eli Lilly and Company (NYSE: LLY)
presented today.
Thirty minutes after oral administration, the level of platelet
inhibition with a prasugrel 60 mg dose was significantly higher than
observed with either loading dose of clopidogrel. At one hour, the
antiplatelet inhibition achieved with a prasugrel loading dose was greater
than that seen at up to six hours following administration of the approved
and high loading doses of clopidogrel.
"This data shows for the first time that as early as 30 minutes after
dosing, a 60 mg prasugrel loading dose achieves greater platelet inhibition
than both the approved loading dose and high-dose clopidogrel," said
Kenneth Winters, M.D., Lilly research cardiologist.
In an earlier Phase I study with healthy volunteers, a 60 mg loading
dose of prasugrel showed a lower rate of poor responders by platelet
function testing compared with the approved 300 mg loading dose of
clopidogrel. Poor responders are defined as those who fail to reach a
specified level of platelet inhibition after receiving the drug. Findings
showed poor antiplatelet response in 17 percent to 43 percent of those
given the approved clopidogrel loading dose (depending on the definition of
poor responder used); while no poor responders were observed with
prasugrel.
Winters presented the new clinical data today in an oral presentation
at the Cardiovascular Research Foundation's 18th annual Transcatheter
Cardiovascular Therapeutics meeting in Washington, D.C. Data from the other
Phase I study appeared in a poster presentation at the meeting.
Daiichi Sankyo and Lilly are currently studying prasugrel in the Phase
III head-to-head clinical trial TRITON-TIMI 38. The TRITON-TIMI 38 study
will evaluate the safety and efficacy of prasugrel compared with
clopidogrel in reducing ischemic events such as heart attacks, stroke and
death in approximately 14,000 patients with acute coronary syndrome
undergoing percutaneous coronary intervention, including coronary stenting.
The study is expected to be completed in 2007, and, if successful,
regulatory submissions will follow in the same year.
About the studies
In the Phase I study, "Inhibition of Platelet Aggregation Following
Loading and Maintenance Dose Administration of 60/10 mg Prasugrel, 300/75
mg and 600/75 mg Clopidogrel In Healthy Subjects," loading and maintenance
doses of prasugrel (60 mg and 10 mg, respectively) were compared with 600
mg and 300 mg clopidogrel loading doses (both given with the approved
clopidogrel 75 mg maintenance dose) in a three-period crossover study in 41
aspirin-free healthy subjects. A seven-day maintenance dose schedule
followed the loading dose, followed by a 14-day washout period before the
next treatment period. Researchers used turbidometric aggregometry,
considered the gold standard of testing platelet function, to measure the
inhibition of platelet aggregation (IPA) to 20 micron ADP.
The study used a crossover design in which the same individuals
received each of the three medication regimens, on three separate
occasions, allowing researchers to compare in each individual the
antiplatelet response of prasugrel to either 300 mg or 600 mg clopidogrel.
Thirty minutes following initial oral administration of a 60 mg
prasugrel loading dose, inhibition of platelet aggregation (IPA, to 20
micron ADP) was significantly higher at 52.1 percent, compared with 4.3
percent for clopidogrel 600 mg (p<0.001) and 1.3 percent for clopidogrel
300 mg (p<0.001). Four hours after initial administration, prasugrel 60 mg
maintained significantly greater IPA versus both high-dose and
approved-dose clopidogrel: 89.7 percent for prasugrel compared with 64.1
percent for clopidogrel 600 mg (p<0.001) and 42.4 percent for clopidogrel
300 mg (p<0.001).
The study also showed that a 10 mg maintenance dose of prasugrel
resulted in higher and less variable platelet inhibition than the approved
75 mg maintenance dose of clopidogrel.
In findings from "A 60 mg Loading Dose of Prasugrel Produces a Lower
Rate of Poor Responders Compared to a 300 mg Loading Dose of Clopidogrel,"
a 60 mg loading dose of prasugrel resulted in a significantly lower rate of
poor responders as assessed by aggregometry compared with a 300 mg loading
dose of clopidogrel. Platelet aggregometry data from five studies in
healthy subjects were integrated and analyzed to compare antiplatelet
activity response rates between prasugrel (n=109) and clopidogrel (n=131).
Maximal platelet aggregation in response to ADP (20 micron) was determined
at baseline, and two hours, four to five hours (4/5), and 24 hours
following dosing.
There were significantly more poor responders, as defined by platelet
function testing using aggregometry, with clopidogrel 300 mg than for
prasugrel 60 mg (p<0.005, McNemar's test vs. prasugrel). With clopidogrel
the number of poor responders ranged from 17 percent (4/5 hours;
criteria=IPA<10 percent) to 43 percent (2 hours; criteria=IPA<20 percent).
No poor responders to prasugrel 60 mg were observed for 20 micron ADP.
"There is room to continue to improve therapy for patients with acute
coronary syndrome," said Francis Plat, M.D., Daiichi Sankyo vice president
of Cardiovascular Development. "Our Phase III clinical program will
evaluate whether the greater, faster and more reliable platelet inhibition
seen in early studies comparing prasugrel to clopidogrel translates into
improved clinical outcomes."
Doctors use antiplatelet agents for both acute and maintenance therapy
to inhibit platelet activation and aggregation that occur in diseased
arteries and as adjunct therapy to invasive procedures such as percutaneous
coronary intervention, a procedure to open blockages in heart arteries
through placement of coronary stents. Recent studies suggest that a
relationship may exist between a poor platelet response to antiplatelet
agents in individual patients and poor clinical outcomes, which can
manifest as major adverse cardiovascular events, including heart
attacks.(i,ii,iii)
Cardiovascular disease is the leading cause of death in the U.S. and
worldwide, killing 17 million people each year.(iv) Acute heart attacks and
unstable angina, called acute coronary syndrome, affect more than 942,000
Americans each year. Despite current medical interventions, 300,000 people
experience recurrent heart attacks and 500,000 people die from heart
attacks annually in the U.S.(v)
About prasugrel
Eli Lilly and Company (NYSE: LLY) and Sankyo Company Ltd., a subsidiary
of Daiichi Sankyo Company, Limited (TSE: 4568) are developing prasugrel, an
investigational oral antiplatelet agent, as a potential treatment for
patients who have suffered a heart attack or unstable angina (heart-related
chest pain). Prasugrel is designed to inhibit platelet activation and
aggregation by blocking the P2Y12 adenosine diphosphate (ADP) receptor on
the platelet surface. Antiplatelet agents prevent platelets from clumping
or sticking together, which can cause formation of blood clots and lead to
heart attack or stroke.
About Eli Lilly and Company
Lilly, a leading innovation-driven corporation, is developing a growing
portfolio of first in class and best-in-class pharmaceutical products by
applying the latest research from its own worldwide laboratories and from
collaborations with eminent scientific organizations. Headquartered in
Indianapolis, Ind., Lilly provides answers - through medicines and
information - for some of the world's most urgent medical needs. Additional
information about Lilly is available at http://www.lilly.com. P-LLY
About Daiichi Sankyo Company, Limited
Daiichi Sankyo Company, Limited was established on Sept. 28, 2005, as
the joint holding company of two major Japanese pharmaceutical companies --
Sankyo Co., Ltd., and Daiichi Pharmaceutical Co., Ltd. Daiichi Sankyo is a
global pharmaceutical innovator, continuously generating innovative drugs
and services and maximizing its corporate value. Both companies have used
their cumulative knowledge and expertise in the field of cardiovascular
disease as a foundation for developing an abundant product lineup and R&D
pipeline. For further details, please refer to the company Web site at
http://www.daiichisankyo.co.jp/eng.
This press release contains certain forward-looking statements about
the potential of the investigational compound prasugrel (CS-747, LY640315)
and reflects Lilly's current beliefs. However, as with any pharmaceutical
compound under development, there are substantial risks and uncertainties
in the process of development and regulatory review. There is no guarantee
that the compound will receive regulatory approvals, or that the regulatory
approval will be for the indication(s) anticipated by the company. There is
also no guarantee that the compound will prove to be commercially
successful. For further discussion of these and other risks and
uncertainties, see Lilly's filing with the United States Securities and
Exchange Commission. Lilly undertakes no duty to update forward-looking
statements.
Plavix(R) is a registered trademark of Sanofi-Synthelabo Inc.
(i) Barragan, P., Bouvier, J. L., Roquebert, P. O., Macaluso, G.,
Commeau, P., Comet, B., Lafont, A., Camoin, L., Walter, U., and
Eigenthaler, M. Resistance to thienopyridines: clinical detection of
coronary stent thrombosis by monitoring of vasodilator-stimulated
phosphoprotein phosphorylation. Catheter Cardiovasc Interv 2003;
59: 295-302
(ii) Muller, I., Besta, F., Schulz, C., Massberg, S., Schonig, A., and
Gawaz, M. Prevalence of clopidogrel non-responders among patients
with stable angina pectoris scheduled for elective coronary stent
placement. Thromb Haemost 2003; 89: 783-787
(iii) Matetzky, S., Shenkman, B., Guetta, V., Shechter, M., Bienart, R.,
Goldenberg, I., Novikov, I., Pres, H., Savion, N., Varon, D., and
Hod, H. Clopidogrel resistance is associated with increased risk of
recurrent atherothrombotic events in patients with acute myocardial
infarction. Circulation 2004; 109: 3171-3175.
(iv) World Health Organization. The Atlas of Heart Disease and Stroke -
Types of Cardiovascular Disease 2005.
(v) American Heart Association. Heart Disease and Stroke Statistics
2005.
SOURCE Eli Lilly and Company; Daiichi Sankyo Company, Limited
