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November 13, 2011 8:05 am ET

—  TRACER did not achieve primary endpoint

—  TRA-2P results are expected to be available in early 2012

—  Merck to consider results from both studies before deciding regulatory strategy

Researchers today presented and published results from TRACER (Thrombin
Receptor Antagonist for Clinical Event Reduction in Acute Coronary
Syndrome), the first clinical outcomes trial of vorapaxar, the
investigational Protease Activated Receptor 1 (PAR-1) thrombin receptor
antagonist from Merck (NYSE:MRK) (known as MSD outside the U.S. and
Canada). The results from TRACER were presented during the late-breaking
clinical trials session at the American Heart Association (AHA) 2011
Scientific Sessions and published concurrently online in the New
England Journal of Medicine.

Merck is developing vorapaxar for the prevention of thrombosis and the
reduction of cardiovascular events, and it is being evaluated in two
major clinical outcomes studies in different patient groups: TRACER was
a study in patients with acute coronary syndrome (ACS), and TRA-2P is a
secondary prevention study in patients who have experienced a previous
heart attack or ischemic stoke or who have documented peripheral artery
disease (PAD). TRACER is being led by the Duke Clinical Research
Institute (DCRI) in Durham, N.C. and TRA-2P is being led by the
Thrombolysis in Myocardial Infarction (TIMI) academic research group at
the Brigham and Women’s Hospital in Boston, Mass.

TRACER compared vorapaxar plus standard of care to placebo plus standard
of care in 12,944 patients with ACS. At time of randomization, more than
85 percent of patients in both groups were taking both aspirin and a
P2Y12 inhibitor (mostly clopidogrel). On the primary endpoint, the
addition of vorapaxar to standard of care resulted in a non-significant
8 percent reduction in the first occurrence of any component of the
composite of cardiovascular death, myocardial infarction (MI, or heart
attack), stroke, recurrent ischemia with re-hospitalization and urgent
coronary revascularization, with a p-value of p=0.072, which means that
TRACER did not achieve its primary endpoint. On the key secondary
endpoint, the addition of vorapaxar to standard of care reduced the
composite of CV death, MI, or stroke, by 11 percent, with a p-value of
p=0.018; this finding was driven by a 12 percent relative reduction
(p=0.021) in heart attacks, primarily spontaneous heart attacks.
However, due to the pre-specified data analysis plan, superiority for
the key secondary endpoint cannot be declared because the primary
endpoint was not achieved. Rates of bleeding were approximately 40
percent greater in the group that also received vorapaxar compared to
the group that received only standard of care, and there was a
three-fold increase in intracranial hemorrhage (1.07 percent versus 0.24
percent, p<0.001).

“Because most patients in TRACER had vorapaxar added to a regimen
containing both a P2Y12 inhibitor and aspirin, we now better understand
the effect of using these three mechanisms together to prevent clots in
patients with ACS,” said Peter S. Kim, Ph.D., executive vice president,
Merck and president, Merck Research Laboratories. “Fewer patients in
TRA-2P were taking both aspirin and a P2Y12 inhibitor, so the results
from the second vorapaxar study should give us greater insight into the
effect of blocking PAR-1 in different groups of patients, including many
patients who were not taking the combination of a P2Y12 inhibitor and
aspirin.”

The TRA-2P study is in the final stage of being closed out and the
external investigators and Merck plan to submit TRA-2P for presentation
and publication in early 2012. Merck will determine its potential
regulatory strategy and consider potential additional studies for
vorapaxar when it can consider the TRACER data in ACS patients together
with the TRA-2P data in heart attack, stroke and PAD patients, once
those data are available in early 2012.

“The results of TRACER provide us with some insight into the potential
role of PAR-1 inhibition in the fight against thrombosis, and are
certainly worthy of further examination,” said Kenneth W. Mahaffey,
M.D., co-director for cardiovascular research at DCRI and senior author
of the TRACER manuscript. “We look forward to conducting more analyses
on these results, as well as seeing the results of TRA-2P when they
become available.”

Researchers also noted that results on the primary and key secondary
efficacy endpoints were generally consistent across subgroups. However,
among a subgroup of patients who were taking vorapaxar but not a P2Y12
inhibitor at randomization, the risk of bleeding was not increased, and
the observed effect on efficacy tended to be more pronounced in these
patients who received vorapaxar plus aspirin only. This analysis is
exploratory, and will be reviewed again based on the data from TRA-2P.
Additional studies may be considered to better understand the effects of
vorapaxar in different patient populations.

“Despite all of the progress that has been made, cardiovascular disease
remains the world’s leading killer. Merck thanks the researchers and the
thousands of study participants around the world for their contribution
to advancing the scientific community’s understanding of this critical
area of cardiovascular medicine,” said Dr. Kim.

Additional Information on the Vorapaxar Development Program

Vorapaxar is a novel, oral, PAR-1 antagonist that inhibits
thrombin-induced platelet activation. The vorapaxar development program
was designed to understand the potential role of blocking PAR-1 with
vorapaxar in patients with ACS and in the chronic care setting. Key
differences between the two studies are:

• Patient population: TRACER included 12,944 patients being
  admitted to the hospital with ACS. TRA-2P included 26,447 stable
  patients who had previously experienced an ischemic stroke or heart
  attack no less than 2 weeks and no more than 12 months before
  randomization, or who had PAD.
• Dosing: In TRACER, vorapaxar was administered starting with a
  40 mg loading dose, followed by a 2.5 mg daily maintenance oral dose,
  for at least one year of follow-up. In TRA-2P, patients
  received 2.5 milligrams for more than one year.
• Control arm: In both studies, vorapaxar was added to standard
  of care. In TRACER, at the time of enrollment, of the 6,743 patients
  in the vorapaxar group, 88 percent were taking clopidogrel and 96
  percent were taking aspirin, and 87 percent of the 5,639 patients in
  the placebo group were taking clopidogrel and 97 percent were taking
  aspirin. Fewer patients in the TRA-2P study received both aspirin and
  a P2Y12 inhibitor as standard of care than patients in TRACER.
• Status: TRACER has been completed and the data from TRACER have
  been shared. The TRA-2P study is in the final stage of being closed
  out and remains blinded; all final patient visits have been completed.

In January of this year, Merck and the external study investigators
announced that the combined Data and Safety Monitoring Board (DSMB) for
the two clinical trials had reviewed the available safety and efficacy
data, and recommended that patients in the TRACER trial discontinue
study drug and investigators close out the study. At that time, TRACER
had accumulated the pre-defined number of primary and major secondary
endpoints, although not all patients continued to receive study drug
through the pre-specified one-year follow up. For the TRA-2P study, the
DSMB recommended that the study drug be continued in patients who had
experienced a previous heart attack or PAD (approximately 75 percent of
the patients enrolled in the study), but immediately discontinued in
patients who experienced a stroke prior to entry into the study or
during the course of the study.

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