In Landmark Phase III Head-to-Head Study, Prasugrel Statistically Superior to Clopidogrel in Reducing Risk of Heart Attack

In Landmark Phase III Head-to-Head Study, Prasugrel Statistically Superior to Clopidogrel in Reducing Risk of Heart Attack

November 05, 2007

Investigational compound reduces risk of major
cardiovascular events by 19 percent, significantly improves
net clinical benefit despite increased bleeding


    TOKYO and INDIANAPOLIS, Nov. 5 /Xinhua-PRNewswire/ --
In the pivotal Phase III head-to-head TRITON TIMI-38
clinical trial, the investigational antiplatelet agent
prasugrel produced a highly significant 19 percent
reduction in relative risk (p=0.0004) for the composite
endpoint of cardiovascular death, non-fatal heart attack or
non-fatal stroke when compared with clopidogrel
(Plavix(R)/Iscover(R)) in the treatment of patients across
the full spectrum of acute coronary syndrome undergoing
percutaneous coronary intervention. 

    ( Logo:
http://www.newscom.com/cgi-bin/prnh/20070601/CLF003LOGO )

    A significant reduction in the risk for the composite
endpoint favoring prasugrel (60 mg loading dose/10 mg
maintenance dose) over clopidogrel (300 mg LD/75 mg MD) was
observed as early as three days. The absolute difference in
this endpoint continued to increase over the course of the
15-month, 13,608-patient trial. 

    In the important subgroup of patients with diabetes,
prasugrel reduced the relative risk of cardiovascular
death, non-fatal myocardial infarction and non-fatal stroke
by 30 percent (p<0.001). In addition, in the key
secondary endpoint of stent thrombosis, prasugrel reduced
the recurrence of stent thrombosis (a new clot that
develops at the stent site) by 52 percent (p<0.0001).

    TRITON also showed that treatment with prasugrel
significantly reduced the relative risk of cardiovascular
death, non-fatal heart attack and non-fatal stroke by 21
percent in patients with STEMI (ST-elevation myocardial
infarction, or high-risk heart attack) (p=0.02) and 18
percent in patients suffering from UA (unstable angina, or
chest pain)/NSTEMI (non-STEMI) (p=0.002).   In addition,
prasugrel-treated patients experienced a 34 percent decline
in urgent target vessel revascularization (a procedure to
reopen blocked arteries) (p<0.001) and a 42 percent
reduction in heart attack with subsequent death from
cardiovascular causes (p=0.02).

    While the overall incidence of non-CABG (coronary
artery bypass grafting) bleeding in TRITON was low in both
the prasugrel and clopidogrel treatment groups,
prasugrel-treated patients experienced a statistically
significant increase in non-CABG (coronary artery bypass
grafting) major bleeding compared to clopidogrel-treated
patients (2.4 vs. 1.8 percent, or 146 vs. 111 patients,
p=0.03), including higher rates of life-threatening
bleeding (1.4 vs. 0.9 percent, or 85 vs. 56 patients,
p=0.01). Though infrequent, fatal bleeding was
statistically more frequent among prasugrel-treated than
clopidogrel-treated patients (0.4 percent vs. 0.1 percent,
or 21 vs. five patients, p=0.002).  However, death from
cardiovascular causes occurred less frequently among
prasugrel-treated patients than clopidogrel-treated
patients (2.1 percent vs. 2.4 percent, or 133 vs. 150
patients, p=0.31), as did all-cause death (3.0 percent vs.
3.2 percent, or 188 vs. 197 patients, p=0.64).

    The study identified three distinct patient
subpopulations with a higher risk of major bleeding in both
treatment arms - patients who were 75 years of age or older,
weighed less than 60 kg (132 lbs.), or had a prior history
of transient ischemic attack (TIA) or stroke.  Researchers
are evaluating pharmacokinetic data from several prasugrel
studies, including TRITON, to determine whether a lower
dose of prasugrel might be appropriate for some patients.
Among patients without any of these risk factors (80
percent of the 13,608-patient TRITON study), there was no
significant difference in major bleeding between prasugrel-
and clopidogrel-treated patients (2 percent vs. 1.5 percent,
p=0.17). 

    Based on an analysis using the combined endpoint of
all-cause death, heart attack, stroke and major bleeding,
the net clinical benefit for prasugrel compared with
clopidogrel was a significant 13 percent reduction in
overall events (12.2 vs. 13.9, p=0.004). In the
subpopulations defined as being at greater risk of
bleeding, the net clinical benefit was not different
between prasugrel- and clopidogrel-treated patients
(p=0.43). Without the subpopulations defined as being at
greater bleeding risk, the net clinical benefit was 20
percent (10.2 vs. 12.5, p<0.001).
 
    Overall, for every 1,000 people treated with prasugrel
compared to clopidogrel in the study, there were 23 fewer
heart attacks and an additional six major bleeding
complications. 

    "Our study provides compelling evidence that the
prasugrel regimen tested is superior to standard dose
clopidogrel as an antiplatelet therapy to support patients
undergoing coronary stenting," said Elliott Antman,
M.D., senior investigator with the TIMI Study Group at
Harvard Medical School and director of the Samuel A. Levine
Cardiac Unit at Brigham and Women's Hospital in Boston.
"With the data from TRITON and other studies, we
expect to define populations at particular bleeding risk to
help establish clear guidance for using this promising
therapy." 

    Antman announced the initial study results today at the
American Heart Association's 2007 Scientific Sessions in
Orlando, Florida (abstract 07-LBCT-20660-AHA). Prasugrel is
being co-developed by Daiichi Sankyo Company, Limited (TSE:
4568) and Eli Lilly and Company (NYSE: LLY).

    "The TRITON data demonstrate the statistical
superiority of this new antiplatelet therapy to prevent
heart attacks, and validate our decision to test prasugrel
head to head against clopidogrel," said J. Anthony
Ware, M.D., Lilly cardiovascular platform leader for
prasugrel.  "We are very pleased with the trial's
outcome and are excited by the potential for these results
to help us further tailor prasugrel therapy to assure the
greatest benefit from this novel treatment."

    Cardiovascular disease is the leading cause of death in
the U.S. and worldwide, killing 16.7 million people each
year(i). Acute heart attacks and unstable angina, called
acute coronary syndrome, affect more than 840,000 Americans
each year and 800,000 in Europe(i,ii). Utilizing current
medical interventions and treatments, 300,000 people
continue to experience recurrent heart attacks and 450,000
people die from heart attacks annually in the U.S(iv).

    "TRITON confirms the statistically superior
clinical benefit of prasugrel as a third-generation oral
antiplatelet that may advance cardiovascular care,"
said John Alexander, M.D., M.P.H., global head of  research
and development, Daiichi Sankyo Company, Limited.
"Given the promising TRITON results, Daiichi Sankyo
and Lilly are expeditiously finalizing our submission
package and are still hopeful to submit to the FDA by year
end."

    About the TRITON TIMI-38 study

    TRITON TIMI-38 was a Phase III, multi-center,
randomized, double blind, parallel group, head-to-head
clinical trial comparing the effects of prasugrel versus
clopidogrel in patients with acute coronary syndrome
undergoing percutaneous coronary intervention (PCI). PCI is
a procedure to open blockages in heart arteries including
the use of coronary stenting. The study enrolled 13,608
patients at 707 trial sites in 30 countries.

    The primary endpoint of the study was to compare the
effects of prasugrel to clopidogrel on the composite
incidence of cardiovascular death, non-fatal heart attack
and non-fatal stroke during a median period of at least 12
months following PCI. Key secondary objectives included
rehospitalization for a cardiac ischemic event; the need
for additional procedures to restore blood flow (urgent
target vessel revascularization) at 30 days; and stent
thrombosis. Key safety endpoints included non-CABG major,
life threatening and minor bleeding as well as the overall
safety and tolerability of prasugrel.

    Patients were randomly assigned to one of two treatment
groups and given a loading dose of either prasugrel 60 mg or
the approved loading dose of clopidogrel 300 mg anytime
between randomization and one hour after the completion of
the PCI procedure, followed by a daily maintenance dose of
either prasugrel 10 mg or clopidogrel 75 mg. All patients
also received a daily low dose of aspirin. 

    Antiplatelet agents are critical for both acute and
maintenance therapy to inhibit platelet activation and
subsequent aggregation that occur in diseased arteries and
as adjunct therapy to invasive procedures such as
percutaneous coronary intervention. 

    About prasugrel

    Daiichi Sankyo Company, Limited (TSE: 4568), and Eli
Lilly and Company (NYSE: LLY) are co-developing prasugrel,
an investigational oral antiplatelet agent invented by
Daiichi Sankyo and its Japanese research partner Ube
Industries, Ltd., as a potential treatment, initially for
patients with acute coronary syndrome undergoing PCI.
Prasugrel works by inhibiting platelet activation and
subsequent aggregation by blocking the P2Y12 adenosine
diphosphate (ADP) receptor on the platelet surface.
Antiplatelet agents prevent platelets from clumping or
sticking together, which can result in clogged arteries and
may lead to heart attack or stroke.  

    About Daiichi Sankyo Company, Limited
  
    Daiichi Sankyo Company, Limited, established in 2005
after the merger of two leading century-old Japanese
pharmaceutical companies, is a global pharmaceutical
innovator, continuously generating innovative drugs that
enrich the quality of life for patients around the world. 
The company uses its cumulative knowledge and expertise in
the fields of cardiovascular disease, cancer, metabolic
disorders, and infection as a foundation for developing an
abundant product lineup and R&D pipeline. 

    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.  

    This press release contains certain forward-looking
statements about the potential of the investigational
compound prasugrel (CS-747, LY640315) and reflects Daiichi
Sankyo's and 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 approval, that
the regulatory approval will be for the indication(s)
anticipated by the companies, or that later studies and
patient experience will be consistent with study findings
to date.  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 and Daiichi Sankyo's filings with the Tokyo
Stock Exchange.  Daiichi Sankyo and Lilly undertake no duty
to update forward-looking statements. 

    Plavix(R)/Iscover(R) are registered trademarks of
Sanofi-Synthelabo Inc.

    P-LLY

    (i) World Health Organization.  The Atlas of Heart
Disease and Stroke - Types of Cardiovascular Disease 2005.
 
    (ii) American Heart Association.  Heart Disease and
Stroke Statistics - 2006 Update.  Dallas, TX. American
Heart Association.

    (iii) Bertrand CURE study

    (iv) American Heart Association.  Heart Attack and
Angina Statistics. URL:
http://www.americanheart.org/presenter.jhtml?identifier=4591.
Last accessed July 26, 2007.


    For more information, please contact:

     Joedy Isert
     Eli Lilly and Company
     Cell: [phone] / [phone]

     Jo-ann Straat
     Daiichi Sankyo (USA)
     Tel:  [phone]

     Shigemichi Kondo
     Daiichi Sankyo (Tokyo)
     Tel:  [phone]