Effient (Prasugrel) Showed Significant 26 Percent Reduction in Cardiovascular Events Over Clopidogrel in New Core Clinical Cohort Population Sub-Analysis of the TRITON-TIMI 38 Pivotal Study

INDIANAPOLIS and TOKYO, Aug. 15, 2011 /PRNewswire/ — A new post-hoc
sub-analysis of an important set of patients from the TRITON-TIMI 38 study -
those identified as the “core clinical cohort” population – showed that
treatment with prasugrel (in combination with aspirin) was associated with a 26
percent relative risk reduction in the combined primary endpoint of
cardiovascular death, myocardial infarction or stroke, compared to treatment
with clopidogrel (8.3 percent vs. 11.0 percent, respectively, p<0.0001).(1) This
corresponds to a 2.7 percent absolute risk reduction for patients treated with
prasugrel. The results of this analysis, which also examined clinical outcomes
in two other cohorts of patients who were treated for acute coronary syndromes
(ACS) and underwent angioplasty with stenting, will help inform appropriate
physician prescribing of prasugrel. These data were recently published online in
theAmerican Journal of Cardiology.(1)

For this analysis, investigators analyzed three patient clinical cohorts:

— The core clinical cohort: Patients who were under 75 years of age,
weighed 60 kg or more and who had no prior history of stroke or
transient ischemic attack (TIA). This group (n=10,804, 79 percent of all
study subjects) excluded those patients considered to be at a higher
risk for bleeding by the U.S. Food and Drug Administration (FDA) and the
European Medicines Agency (EMA) in their regulatory approval of
prasugrel and as outlined in prescribing labels for prasugrel tablets in
these regions.(1)
— The non-core cohort: Patients 75 years of age or older or patients who
weighed less than 60 kg, but without known prior stroke or TIA (n=2,149;
16 percent of study participants).(1) The use of prasugrel in patients
greater than or equal to 75 years is generally not recommended. If,
after a careful individual benefit/risk evaluation by the prescribing
physician, treatment is deemed necessary in the patient age group
greater than or equal to 75 years, then following a 60 mg loading dose,
a reduced maintenance dose of 5 mg should be prescribed.(2)
— The third group were patients with a self-reported or known history of
stroke or TIA prior to enrollment (n=518; 4 percent of study
participants). Prasugrel is contraindicated in such patients.(1)
— Patients without known prior stroke but with missing baseline weight
data were excluded from the analysis as it could not be determined to
which final cohort they should be assigned to (n= 137; 1 percent of
study participants).(1)

In the core clinical cohort, there were higher bleeding rates in prasugrel
patients compared to clopidogrel patients.(1) Appropriate prescribing may help
minimize a bleeding risk. Based on the post hoc analysis reported in this paper,
in patients in the TRITON-TIMI 38 study who were younger than 75, heavier than
60 kg and with no prior stroke, the difference in the rates of certain types of
bleeding (known as non-CABG TIMI major bleeding) was reduced, without adversely
impacting the efficacy of prasugrel versus clopidogrel.

Relative bleeding rates were similar across the core and “non-core” groups. In
the core group, the rate of TIMI major bleeding was 1.9 percent in prasugrel
patients compared to 1.5 percent in clopidogrel patients, corresponding to a 0.4
percent absolute increase and a 24 percent relative increase in prasugrel
patients (p= 0.17).(1) In the non-core group, the rate of TIMI major bleeding
was 4.1 percent in prasugrel patients compared to 3.4 percent in clopidogrel
patients, corresponding to a 0.7 percent absolute increase and a 23 percent
relative increase in prasugrel patients (p= 0.40).(1) In both cases findings
were not statistically significant.

The rate of TIMI major or minor bleeding was statistically significantly greater
with prasugrel than clopidogrel in the core group (3.9 percent vs. 3.0 percent
respectively, p=0.033), but not in the non-core group (9.8 percent prasugrel vs.
7.5 percent clopidogrel, p=0.08), although the relative increase in bleeding
within these groups were similar.(1)

“This analysis showed that the use of prasugrel in a clinically identifiable
population of ACS patients undergoing PCI in the TRITON-TIMI 38 trial
significantly improved cardiovascular outcomes,” said Stephen D Wiviott, M.D.,
at the TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital
and Harvard Medical School, Boston, and lead author of the paper.(1)

The analysis found that in >=75 year old and low body weight (<60kg) patients
(the non-core cohort), event rates were high in both treatment arms (15.3 vs.
16.3 percent, p=0.61, HR=0.94) compared to the core cohort group.(1) Patients
taking prasugrel in the third group (described above) had non-favorable results
with regard to both efficacy and safety compared to clopidogrel, with a higher
rate of primary efficacy events (19.1 percent vs. 14.4 percent, p=0.15) driven
by an increase in stroke and a higher rate of bleeding, including more
intracranial hemorrhage (2.3 percent vs. 0 percent, p=0.02).(1) Prasugrel is
contraindicated in patients who have had a prior transient ischemic attack (TIA)
or stroke.

The TRITON-TIMI 38 trial was sponsored by Daiichi Sankyo Co., Ltd. and Eli Lilly
and Company.

Study Methodology

TRITON-TIMI 38 was a head-to-head study comparing prasugrel (60-mg loading dose
[LD], followed by a 10-mg once-daily maintenance dose) plus aspirin (ASA) with
clopidogrel (300-mg LD, followed by a 75-mg once-daily maintenance dose) plus
ASA in 13,608 patients with ACS managed with percutaneous coronary intervention
(PCI), a procedure to open blockages in heart arteries, including the use of
coronary stenting. The median duration of study treatment was 14.5 months.(3)

The primary endpoint of the study was the combined incidence of cardiovascular
death, non-fatal heart attack or non-fatal stroke in patients followed for 6 -
15 months following PCI. The study showed that prasugrel taken with ASA had a 19
percent relative risk reduction of the combined endpoint of cardiovascular
death, non-fatal heart attack or non-fatal stroke versus clopidogrel taken with
ASA (9.9 percent vs. 12.1 percent respectively, p<0.001).(3) This corresponds to
a 2.2 percent absolute risk reduction for ACS patients treated with prasugrel.
In TRITON-TIMI 38, patients treated with prasugrel also experienced a 50 percent
relative risk reduction (corresponding to 1.1 percent absolute risk reduction)
in stent-related clots when compared with clopidogrel, regardless of stent type
(1.1 percent vs. 2.4 percent respectively, p<0.001).(3) In TRITON, the risk of
non-coronary artery bypass graft (non-CABG) major bleeding, including fatal
bleeding, was higher with prasugrel (2.4 percent incidence) compared with
clopidogrel (1.8 percent incidence) (p=0.03). The rate of TIMI major or minor
bleeding was significantly greater with prasugrel than clopidogrel (5.0 percent
vs. 3.8 percent respectively, p=0.002). The risk of coronary artery bypass graft
(CABG) major bleeding, including fatal bleeding, was higher with prasugrel (13.4
percent incidence) than clopidogrel (3.2 percent incidence) (p<0.001).(3) In
TRITON-TIMI 38, the loading dose of clopidogrel was delayed relative to the
placebo-controlled trials that supported its approval for ACS.

Compared with the overall study population, a higher risk of serious bleeding
among prasugrel patients was most evident in three distinct patient populations
that are readily identifiable: patients who weighed less than 60 kg, patients
who were 75 years of age or older and patients who have had a prior transient
ischemic attack (TIA) or stroke.(3) A 5 mg maintenance dose should be used for
patients who weigh less than 60 kg.(2) Prasugrel is generally not recommended
for use in patients 75 years or older.(2) If, after a careful individual
benefit/risk evaluation by the prescribing physician treatment is deemed
necessary a 5 mg maintenance dose should be prescribed.(2) Patients with prior
TIA or stroke should not be treated with prasugrel.(2)

In this study, survival analysis methods were used to compare outcomes by
treatment assignment (prasugrel vs. clopidogrel) and to compare outcomes by
whether subjects were included in the core clinical cohort, non-core cohort or
contraindicated cohort. The principal limitation of this analysis is that the
subgroups examined were identified in a post-hoc fashion.

Notes to Editors

About prasugrel

Daiichi Sankyo Company, Limited, and Eli Lilly and Company co-developed
prasugrel, an oral antiplatelet agent discovered by Daiichi Sankyo and its
Japanese research partner, Ube Industries, Ltd. Prasugrel helps keep blood
platelets from clumping together and developing a blockage in an artery. The
European Commission granted marketing authorization for prasugrel for the
prevention of atherothrombotic events in patients with ACS undergoing PCI, in
combination with ASA.(2) To date prasugrel has been approved in more than 65
countries worldwide.

About Acute Coronary Syndromes

Acute coronary syndrome includes heart attacks and unstable angina (chest pain).
Coronary heart disease, which can result in ACS, is the single most common cause
of death in the European Union, accounting for more than 741,000 deaths in the
EU each year.(4) Acute coronary syndrome (ACS), which includes heart attack and
type of chest pain called unstable angina, affects more than 1 million people in
the United States annually.(5) The annual incidence of new heart attacks is
estimated to be approximately 610,000 and about 325,000 people will have a
recurrent attack.(5) Heart attack is a major manifestation of coronary heart
disease, which occurs when the arteries become narrowed or clogged by
cholesterol and fat deposits. In some cases the plaque can rupture, resulting in
a blood clot, which may partially or totally block the blood supply to portions
of the heart, resulting in ACS.(6) Many ACS patients undergo PCI to re-open the
artery, which usually includes a stent placement.

About Daiichi Sankyo

The Daiichi Sankyo Group is dedicated to the creation and supply of innovative
pharmaceutical products to address the diversified, unmet medical needs of
patients in both mature and emerging markets. While maintaining its portfolio of
marketed pharmaceuticals for hypertension, hyperlipidemia, and bacterial
infections, the Group is engaged in the development of treatments for thrombotic
disorders and focused on the discovery of novel oncology and
cardiovascular-metabolic therapies. Furthermore, the Daiichi Sankyo Group has
created a “Hybrid Business Model,” which will respond to market and customer
diversity and optimize growth opportunities across the value chain. For more
information, please visit www.daiichisankyo.com.

About Eli Lilly and Company

Lilly, a leading innovation-driven corporation, is developing a growing
portfolio of 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 www.lilly.com.

This press release contains certain forward-looking statements about prasugrel
for the reduction of thrombotic cardiovascular events (including stent
thrombosis) in patients with acute coronary syndromes who are managed with
percutaneous coronary intervention and reflects Daiichi Sankyo’s and Lilly’s
current beliefs. However, as with any pharmaceutical product, there are
substantial risks and uncertainties in the process of development and
commercialization. There is no guarantee that future study results and patient
experience will be consistent with study findings to date or that the product
will 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.

Effient® is a registered trademark of Eli Lilly and Company.

(1) Wiviott, S.D. et al. Efficacy and Safety of Intensive Antiplatelet Therapy
with Prasugrel from TRITON – TIMI 38 in a Core Clinical Cohort Defined by
Worldwide Regulatory Agencies. The American Journal of Cardiology 2011.
Published online 4 Aug 2011. Available at:
http://www.ajconline.org/article/S0002-9149(11)01906-0/abstract. Accessed 8 July
2010.

(2) European Medicines Agency. Efient Summary of Product Characteristics.
Electronic Medicines Compendium website.

(3) Wiviott, S.D. et al. Prasugrel versus Clopidogrel in Patients with Acute
Coronary Syndromes. New England Journal of Medicine 2007 Vol 357 (20);
2001-2015.

(4) British Heart Foundation Health Promotion Research Group. European
Cardiovascular Disease Statistics 2008. Accessed 8 July 2010.

(5) Roger VL, Go AS, Lloyd-Jones DM et al. for the American Heart Association
Statistics Committee and Stroke Statistics Subcommittee. Heart disease and
stroke statistics – 2011 update. Circulation. 2011;123:e1-e192.

(6) WebMD Medical Reference in Collaboration with the Cleveland Clinic. Heart
Disease: Coronary Artery Disease. Accessed 8 July 2010.

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SOURCE Eli Lilly and Company