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Merck & Co., Inc. (MRK) Release: 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



5/12/2014 7:01:14 AM

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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

WHITEHOUSE STATION, N.J.--(BUSINESS WIRE)-- 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 showed:

EFFICACY:

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
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
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.

SAFETY:

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: 0.92-1.66).
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

Availability

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, Facebook 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 http://www.merck.com/product/usa/pi_circulars/z/zontivity/zontivity_pi.pdf and Medication Guide for ZONTIVITY at http://www.merck.com/product/usa/pi_circulars/z/zontivity/zontivity_mg.pdf.

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

Contact:
Merck
Media:
Pamela Eisele, 267-305-3558
or
Patrick Witmer, 267-305-4910
or
Investors:
Carol Ferguson, 908-423-4465
or
Justin Holko, 908-423-5088

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