FDA Approves ZONTIVITY™ (vorapaxar), First-in-Class PAR-1 Antagonist, for the Reduction of Thrombotic Cardiovascular Events in Patients with a History of Heart Attack or with Peripheral Arterial Disease


May 12, 2014 6:30 am ET

ZONTIVITY Added to Standard of Care Demonstrated Long-Term Benefit Through Three Years

Merck (NYSE:MRK),
known as MSD outside the United States and Canada, today announced that
the U.S. Food and Drug Administration (FDA) has approved ZONTIVITY™
(vorapaxar) for the reduction of thrombotic cardiovascular events in
patients with a history of heart attack (myocardial infarction) or in
patients with narrowing of leg arteries, called peripheral arterial
disease (PAD). For patients with a history of heart attack or with PAD
who had no history of stroke or transient ischemic attack (TIA),
ZONTIVITY added to standard of care produced a significant 17 percent
relative risk reduction over the three years of the study for the
combined events of cardiovascular (CV) death, myocardial infarction
(MI), stroke, and urgent coronary revascularization (UCR) [event rate
10.1 percent vs. 11.8 percent for placebo]. For the key secondary
composite efficacy endpoint of CV death, MI and stroke alone, ZONTIVITY
produced a significant 20 percent relative risk reduction in these
patients [7.9 percent vs. 9.5 percent for placebo]. These results were
driven by an 18 percent relative risk reduction in MI [5.4 percent vs.
6.4 percent for placebo] and a 33 percent relative risk reduction in
first stroke [1.2 percent vs. 1.6 percent for placebo].

The prescribing information for ZONTIVITY includes a boxed warning
regarding bleeding risk. ZONTIVITY is not for use in patients with a
history of stroke, TIA or intracranial hemorrhage (ICH), or active
pathological bleeding. Antiplatelet agents, including ZONTIVITY,
increase the risk of bleeding, including ICH and fatal bleeding.

“A significant number of Americans who have survived a heart attack or
who have PAD remain at risk for another major cardiovascular event
despite the use of existing treatments,” said Eugene Braunwald, MD, TIMI
Study Group founder and chair of the landmark TRA 2°P TIMI 50 trial that
supported the medicine’s approval. “A new treatment option like
ZONTIVITY is an important advance that can help to lower that risk for
appropriate patients taking aspirin, clopidogrel, or both.”

There is no experience with use of ZONTIVITY as the only administered
antiplatelet agent, because ZONTIVITY was studied only as an addition to
aspirin and/or clopidogrel.

“Merck has a longstanding commitment to bringing forward important new
cardiovascular medicines like ZONTIVITY to help address significant
unmet medical needs,” said Dr. Daniel Bloomfield, vice president,
Cardiovascular Diseases, Merck Research Laboratories.

First-in-Class PAR-1 Antagonist

ZONTIVITY is the first and only therapy shown to inhibit the
protease-activated receptor-1 (PAR-1), the primary receptor for
thrombin, which is considered to be the most potent activator of
platelets. The PAR-1 pathway participates in the formation of blood
clots through the activation and aggregation of platelets. ZONTIVITY
addresses this additional pathway that is not targeted by aspirin or
P2Y12 inhibitors, like clopidogrel.

Once-daily ZONTIVITY tablets contain 2.08 mg vorapaxar, equivalent to
2.5 mg vorapaxar sulfate. ZONTIVITY should be used with daily aspirin
and/or clopidogrel according to their indications or standard of care.
ZONTIVITY has not been studied as monotherapy.

Results from TRA 2°P TIMI 50 Trial

Data supporting the benefit of ZONTIVITY are from the pivotal TRA 2°P
TIMI 50 (Thrombin Receptor Antagonist in Secondary Prevention of
Atherothrombotic Ischemic Events) trial, one of the largest secondary
prevention studies of an antiplatelet medicine. In this 26,449 patient,
randomized, double-blind, placebo-controlled trial, participants had a
history of spontaneous MI within the prior two weeks to twelve months,
ischemic stroke, or documented (symptomatic) PAD. Patients were followed
for up to four years, with a median follow-up of 2.5 years. ZONTIVITY,
when used daily with standard of care that included aspirin and/or a
thienopyridine (principally clopidogrel), was superior to standard of
care alone in reducing the incidence of both the primary combined
endpoint of CV death, MI, stroke, and UCR and a key secondary composite
endpoint of CV death, MI, and stroke.

In the overall study population, patients with a history of stroke or
TIA showed an increased risk of ICH. Consequently, the approved use of
ZONTIVITY is based on the study population with a history of MI or with
PAD and without a history of stroke or TIA. Among those patients, 10,080
were randomized to treatment with ZONTIVITY and 10,090 were randomized
to treatment with placebo. High-risk patients in this group included
patients with diabetes (24 percent) and hypertension (65 percent). In
post-MI or PAD patients without a history of stroke or TIA, the study


  • A 17 percent relative risk reduction through three years for the
    composite primary efficacy endpoint of CV death, MI, stroke, and UCR.
    The composite primary efficacy endpoint occurred in 10.1 percent in
    the group taking ZONTIVITY compared with 11.8 percent in the placebo
    group (Hazard Ratio [HR]: 0.83, p<0.001). The treatment benefit was
    persistent over the course of the study and was not dependent on the
    elapsed time from prior MI to randomization. These results
    demonstrated the significant benefit of ZONTIVITY when used with
    aspirin and/or clopidogrel vs. patients using aspirin and/or
    clopidogrel alone.
  • A 20 percent relative risk reduction through three years for the key
    secondary composite efficacy endpoint of CV death, MI, and stroke. The
    findings for the key secondary efficacy endpoint showed an event rate
    of 7.9 percent in the group taking ZONTIVITY compared with 9.5 percent
    in the placebo group (HR: 0.80, p<0.001).
  • These results for the primary and secondary efficacy composites
    included an 18 percent relative risk reduction in MI (event rate: 5.4
    percent vs. 6.4 percent; HR: 0.82, 95 percent Confidence Interval
    [CI]: 0.73-0.93) and a 33 percent relative risk reduction in first
    stroke (event rate: 1.2 percent vs. 1.6 percent; HR: 0.67, 95 percent
    CI: 0.52-0.87).
  • A range of demographic differences was examined for their influence on
    outcomes. Among the 24 percent of patients with diabetes who were at a
    higher absolute risk of experiencing thrombotic cardiovascular events,
    the benefit of ZONTIVITY was consistent with the benefit seen in all
    post-MI or PAD patients without a history of stroke or TIA. Such
    analyses must be interpreted cautiously, as differences can reflect
    the play of chance among a large number of analyses.


  • Among randomized post-MI or PAD patients without a history of stroke
    or TIA who were treated with ZONTIVITY (n=10,049) or placebo
    (n=10,059), adding ZONTIVITY to standard of care (including aspirin
    and/or a thienopyridine) was associated with an increased rate of
    GUSTO moderate or severe bleeding through three years (3.7 percent)
    compared to adding placebo (2.4 percent) (HR: 1.55, 95 percent CI:
    1.30-1.86). GUSTO severe bleeding occurred at a rate of 1.3 percent
    for ZONTIVITY versus 1.0 percent for placebo (HR: 1.24, 95 percent CI:

    • Note: GUSTO severe bleeding was defined as fatal, intracranial, or
      bleeding with hemodynamic compromise requiring intervention; GUSTO
      moderate bleeding was defined as bleeding requiring transfusion of
      whole blood or packed red blood cells without hemodynamic
      compromise. (GUSTO: Global Utilization of Streptokinase and Tissue
      Plasminogen Activator for Occluded Arteries.)
  • ICH was less common in both groups compared to GUSTO moderate and
    severe bleeding. The three-year rate of ICH was numerically higher for
    patients adding ZONTIVITY to standard of care, 0.6 percent, compared
    to 0.4 percent for patients adding placebo (HR: 1.46; 95 percent CI:
    0.92-2.31). Fatal bleeding occurred at a three-year rate of 0.2
    percent in both the ZONTIVITY and placebo groups, with a hazard ratio
    of 1.15 favoring the placebo group (95 percent CI: 0.56-2.36).
  • Clinically significant bleeding occurred at a three-year rate of 15.5
    percent in the group taking ZONTIVITY, compared with 10.9 percent in
    the placebo group (HR: 1.46, 95 percent CI: 1.35-1.60).

    • Note: Clinically significant bleeding included any bleeding
      requiring medical attention including ICH, or clinically
      significant overt signs of hemorrhage associated with a drop in
      hemoglobin (Hgb) of ≥3 g/dL (or, when Hgb is not available, an
      absolute drop in hematocrit (Hct) of ≥15 percent or a fall in Hct
      of 9 to <15 percent).


ZONTIVITY (vorapaxar) will be available in the third quarter of 2014.

Additional selected safety information about ZONTIVITY

ZONTIVITY is contraindicated in patients with a history of stroke, TIA,
or ICH and in patients with active pathological bleeding such as ICH or
peptic ulcer. Discontinue ZONTIVITY in patients who experience a stroke,
TIA, or ICH.

Antiplatelet agents, including ZONTIVITY, increase the risk of bleeding,
including ICH and fatal bleeding. ZONTIVITY increases the risk of
bleeding in proportion to the patient’s underlying bleeding risk.
Physicians should consider the underlying risk of bleeding before
initiating ZONTIVITY.

General risk factors for bleeding include older age, low body weight,
reduced renal or hepatic function, and history of bleeding disorders.
Use of certain concomitant medications (e.g., anticoagulants,
fibrinolytic therapy, chronic nonsteroidal anti-inflammatory drugs,
selective serotonin reuptake inhibitors, selective norepinephrine
reuptake inhibitors) also increases the risk of bleeding. Avoid
concomitant use of warfarin or other anticoagulants. ZONTIVITY is not
recommended in patients with severe hepatic impairment.

Withholding ZONTIVITY for a brief period will not be useful in managing
an acute bleeding event because, due to its long half-life, significant
inhibition of platelet aggregation remains four weeks after
discontinuation. There is no known treatment to reverse the antiplatelet
effect of ZONTIVITY.

Strong CYP3A inhibitors increase and inducers decrease ZONTIVITY
exposure. Avoid concomitant use of ZONTIVITY with strong CYP3A4
inhibitors or inducers.

Bleeding, including life-threatening and fatal bleeding, is the most
commonly reported adverse reaction with ZONTIVITY.

About heart attack and PAD

Heart attacks are generally caused by atherosclerotic plaque disruption
and thrombus (blood clot) formation in a coronary artery. There are
approximately 7.6 million Americans who have survived a heart attack.
Each year, about 720,000 Americans have a new (515,000) or recurrent
(205,000) heart attack.

Peripheral arterial disease (PAD) is generally defined as obstruction of
arteries supplying the lower or upper extremities, most commonly due to
atherosclerosis and much more commonly involving the lower extremities.
About 8.5 million individuals in the U.S. have PAD, of whom
approximately 10 percent have classic claudication symptoms (i.e., calf
muscle pain on exertion), and another 50 percent have other leg
symptoms. People with PAD are at increased risk for heart attack, stroke
and cardiovascular death.

About Merck

Today’s Merck is a global healthcare leader working to help the world be
well. Merck is known as MSD outside the United States and Canada.
Through our prescription medicines, vaccines, biologic therapies, and
consumer care and animal health products, we work with customers and
operate in more than 140 countries to deliver innovative health
solutions. We also demonstrate our commitment to increasing access to
healthcare through far-reaching policies, programs and partnerships. For
more information, visit www.merck.com
and connect with us on Twitter,
and YouTube.

Forward-Looking Statement

This news release includes “forward-looking statements” within the
meaning of the safe harbor provisions of the United States Private
Securities Litigation Reform Act of 1995. These statements are based
upon the current beliefs and expectations of Merck’s management and are
subject to significant risks and uncertainties. If underlying
assumptions prove inaccurate or risks or uncertainties materialize,
actual results may differ materially from those set forth in the
forward-looking statements.

Risks and uncertainties include but are not limited to, general industry
conditions and competition; general economic factors, including interest
rate and currency exchange rate fluctuations; the impact of
pharmaceutical industry regulation and health care legislation in the
United States and internationally; global trends toward health care cost
containment; technological advances, new products and patents attained
by competitors; challenges inherent in new product development,
including obtaining regulatory approval; Merck’s ability to accurately
predict future market conditions; manufacturing difficulties or delays;
financial instability of international economies and sovereign risk;
dependence on the effectiveness of Merck patents and other protections
for innovative products; and the exposure to litigation, including
patent litigation, and/or regulatory actions.

Merck undertakes no obligation to publicly update any forward-looking
statement, whether as a result of new information, future events or
otherwise. Additional factors that could cause results to differ
materially from those described in the forward-looking statements can be
found in Merck’s 2013 Annual Report on Form 10-K and the company’s other
filings with the Securities and Exchange Commission (SEC) available at
the SEC’s Internet site (www.sec.gov).

Please see Prescribing Information, including Boxed Warning, for
ZONTIVITY (vorapaxar) at
and Medication Guide for ZONTIVITY at

ZONTIVITYTM is a trademark of Merck, Sharp &
Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station,
N.J., USA.

Pamela Eisele, 267-305-3558
Patrick Witmer, 267-305-4910
Carol Ferguson, 908-423-4465
Justin Holko, 908-423-5088

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