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June 30, 2014 7:00 am ET

Merck Planning Regulatory Submissions in the U.S. for EMEND^® in Pediatric Setting Including New Suspension Formulation in Second Half of 2014

WHITEHOUSE STATION, N.J.–(BUSINESS WIRE)–Merck (NYSE:MRK), known as MSD outside the United States and Canada,
today announced results from a global, investigational Phase 3 study to
evaluate the safety and efficacy of EMEND^® (aprepitant) in
the prevention of chemotherapy-induced nausea and vomiting (CINV) in
pediatric cancer patients, aged 6 months to 17 years. In this study in
pediatric cancer patients undergoing very highly, highly, or moderately
emetogenic (vomit-inducing) chemotherapy, the use of the EMEND regimen
for CINV prevention was significantly more effective than a control
regimen in achieving Complete Response, defined as no vomiting or
retching and no use of rescue medication for nausea and vomiting, in all
phases of CINV (acute, delayed, and overall). These new data were
presented in an oral session at the Multinational Association of
Supportive Care in Cancer/International Society of Oral Oncology
(MASCC/ISOO) Annual International Symposium on Supportive Care in
Cancer (Abstract #0286) by Dr. Hyoung Jin Kang, M.D., Ph.D., lead
investigator and associate professor, Department of Pediatrics, Cancer
Research Institute, Seoul National University College of Medicine,
Seoul, Korea.

“Nausea and vomiting are common complications of cancer chemotherapy and
can be particularly distressful and debilitating to pediatric cancer
patients,” said Dr. Stuart Green, vice president, clinical research,
Merck Research Laboratories. “In this large pediatric study, adding
EMEND to a standard regimen for prevention of CINV resulted in
significant reduction of emetic events.”

Based on these data, Merck plans worldwide regulatory submissions for
EMEND (aprepitant), beginning in the United States, for use in the
prevention of CINV in pediatric and adolescent cancer patients (ages 6
months to 17 years). In the United States, Merck plans to submit a New
Drug Application (NDA) for a new pediatric formulation (powder for
suspension) and a supplemental NDA for use of the current formulation
(capsules). Both filings are planned for the second half of 2014.

EMEND, a Substance P/Neurokinin-1 (NK1) receptor antagonist approved for
use in combination with other antiemetic agents, is indicated in adults
for the prevention of acute and delayed nausea and vomiting associated
with initial and repeat courses of highly emetogenic cancer
chemotherapy, including high-dose cisplatin; and for prevention of
nausea and vomiting associated with initial and repeat courses of
moderately emetogenic cancer chemotherapy. EMEND has not been studied
for treatment of established nausea and vomiting. Chronic continuous
administration of EMEND is not recommended. Safety and efficacy of EMEND
in pediatric patients have not been established.

Efficacy and Safety Findings for Investigational, Phase 3 CINV
Prevention Study of EMEND in Pediatric Patients

The Phase 3 randomized, double-blind, active-comparator study of 302
participants evaluated EMEND for prevention of CINV in children (ages 6
months to 17 years of age). In the study, patients receiving emetogenic
chemotherapy were randomly assigned to receive an EMEND plus ondansetron
regimen (n=152) or a control regimen (placebo plus ondansetron) (n=150).
The EMEND regimen included either EMEND capsules or an investigational
powder for suspension formulation of aprepitant dosed based on weight.
Ondansetron dosing was based on the approved pediatric dose (as per the
local label). The primary endpoint of the study was complete response
(no vomiting, no retching, and no use of rescue medication for nausea
and vomiting) in the delayed phase (25 to 120 hours following initiation
of chemotherapy). The secondary endpoints were complete response in the
acute phase (0 to 24 hours) and overall phase (0-120 hours), and no
vomiting in the overall phase. In both groups, the first dose of EMEND
or placebo (plus ondansetron) was administered on day 1 of chemotherapy,
then subsequently (without ondansetron) later on days 2 and 3.
Dexamethasone could be administered intravenously per investigator
discretion (the dose was based on weight). Administration of
dexamethasone was similar in patients receiving the EMEND regimen and
the control regimen (44 vs. 42 patients, respectively).

EMEND Regimen Increased Complete Response in Days 2 through 5
(primary endpoint)

In the study, 51 percent of patients receiving the EMEND (aprepitant)
regimen achieved the primary endpoint of complete response in the
delayed phase of CINV, versus 26 percent of those in the control group
(p <0.0001). For the secondary endpoints, 66 percent of patients
receiving the EMEND regimen achieved a complete response in the acute
phase of CINV, versus 52 percent of those receiving the control regimen
(p = 0.0135). In addition, complete response in the overall phase was
higher in patients receiving the EMEND regimen versus the control
regimen (40% vs. 20%, p =0.0002). No vomiting in the overall phase was
observed in 47 percent vs. 21 percent of patients receiving the EMEND
regimen compared to the control regimen, respectively (p <0.0001).

Overall, 79 percent of patients receiving the EMEND regimen and 77
percent receiving the control regimen experienced one or more adverse
events. The most common adverse events (across all grades) with the
EMEND regimen compared to the control regimen included anemia (17% vs.
25%), febrile neutropenia (16% for both groups), vomiting (15% for both
groups), neutropenia (14% vs. 12%), thrombocytopenia (10% vs. 11%),
decreased neutrophil count (9% vs. 13%), nausea (9% vs. 11%), and a
decreased platelet count (8% vs. 10%). Treatment-related adverse events
were observed in 3 percent (5/152) of patients receiving the EMEND
regimen and in 2 percent (3/150) of patients receiving the control
regimen. Serious treatment-related adverse events were observed in 1
percent (2/152) of patients on an EMEND regimen and in 0 percent (0/150)
of patients receiving the control regimen.

Selected important safety information for EMEND (aprepitant)

EMEND is contraindicated in patients who are hypersensitive to any
component of the product. EMEND is a dose-dependent inhibitor of
cytochrome P450 isoenzyme 3A4 (CYP3A4). EMEND should not be used
concurrently with pimozide, terfenadine, astemizole, or cisapride.
Inhibition of CYP3A4 by aprepitant could result in elevated plasma
concentrations of these drugs, potentially causing serious or
life-threatening reactions.

EMEND should be used with caution in patients receiving concomitant
medications, including chemotherapy agents, that are primarily
metabolized through CYP3A4. Inhibition of CYP3A4 by EMEND could result
in elevated plasma concentrations of these concomitant medications.
Conversely, when EMEND is used concomitantly with another CYP3A4
inhibitor, aprepitant plasma concentrations could be elevated. When
EMEND is used concomitantly with medications that induce CYP3A4
activity, aprepitant plasma concentrations could be reduced, and this
may result in decreased efficacy of aprepitant.

Chemotherapy agents that are known to be metabolized by CYP3A4 include
docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide, imatinib,
vinorelbine, vinblastine, and vincristine. In clinical studies, EMEND
(aprepitant) was administered commonly with etoposide, vinorelbine, or
paclitaxel. The doses of these agents were not adjusted to account for
potential drug interactions. In separate pharmacokinetic studies, EMEND
did not influence the pharmacokinetics of docetaxel or vinorelbine.

Because a small number of patients in clinical studies received the
CYP3A4 substrates vinblastine, vincristine, or ifosfamide, particular
caution and careful monitoring are advised in patients receiving these
agents or other chemotherapy agents metabolized primarily by CYP3A4 that
were not studied.

Coadministration of EMEND with warfarin (a CYP2C9 substrate) may result
in a clinically significant decrease in International Normalized Ratio
(INR) of prothrombin time. In patients on chronic warfarin therapy, the
INR should be closely monitored in the 2-week period, particularly at 7
to 10 days, following initiation of fosaprepitant with each chemotherapy
cycle.

The efficacy of hormonal contraceptives (including birth control pills,
skin patches, implants, and certain IUDs) may be reduced upon
coadministration and for 28 days following the last dose of EMEND.
Alternative or back-up methods of contraception should be used during
treatment with and for 1 month following the last dose of EMEND.

Chronic continuous use of EMEND for prevention of nausea and vomiting is
not recommended because it has not been studied and because the drug
interaction profile may change during chronic continuous use.

In clinical trials of EMEND in patients receiving highly emetogenic
chemotherapy, the most common adverse events reported at a frequency
greater than with standard therapy, and at an incidence of 1% or
greater, were hiccups (4.6% EMEND (aprepitant) vs. 2.9% standard
therapy), asthenia/fatigue (2.9% vs. 1.6%), increased ALT (2.8% vs.
1.5%), increased AST (1.1% vs. 0.9%), constipation (2.2% vs. 2.0%),
dyspepsia (1.5% vs. 0.7%), diarrhea (1.1% vs. 0.9%), headache (2.2% vs.
1.8%), and anorexia (2.0% vs. 0.5%).

In clinical trials of EMEND in patients receiving moderately emetogenic
chemotherapy, the most common adverse events reported at a frequency
greater than with standard therapy were eructation (1.0% EMEND vs. 0.1%
standard therapy) and fatigue (1.4% vs. 0.9%).

About CINV

Chemotherapy Induced Nausea and Vomiting (CINV) is a common side effect
of chemotherapy caused by injured stomach cells that start the process
of nausea and vomiting and can directly activate the area of the brain
responsible for producing nausea and vomiting.

The two main types of CINV are acute and delayed. Acute happens within
the first 24 hours of receiving chemotherapy. Delayed happens from day 2
to day 5 after chemotherapy. The amount and timing of CINV can vary.
Some chemotherapies cause acute nausea and vomiting. Others cause acute
nausea and vomiting followed by another period of delayed nausea and
vomiting.

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
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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. There can be no
guarantees with respect to pipeline products that the products will
receive the necessary regulatory approvals or that they will prove to be
commercially successful. 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 healthcare legislation in the
United States and internationally; global trends toward healthcare 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’s 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 for EMEND (aprepitant) at http://www.merck.com/product/usa/pi_circulars/e/emend/emend_pi.pdf
and Patient Information for EMEND (aprepitant) at http://www.merck.com/product/usa/pi_circulars/e/emend/emend_ppi.pdf

EMEND® is a registered trademark of Merck & Co., Inc., Whitehouse
Station, N.J., USA

Merck
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