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April 13, 2019 6:00 am ET

ASPECT-NP Clinical Trial Results Demonstrated Non-Inferiority of ZERBAXA to Meropenem for Treating Ventilated Nosocomial Pneumonia in Primary and Key Secondary Endpoints

KENILWORTH, N.J.–(BUSINESS WIRE)–Merck (NYSE: MRK), known as MSD outside the United States and Canada,
today announced the first presentation of results from ASPECT-NP, a
randomized, double-blind, multi-center Phase 3 clinical trial evaluating
the efficacy and safety of ZERBAXA^® (ceftolozane and
tazobactam) for the treatment of adult patients with ventilated
nosocomial (hospital acquired) pneumonia. The results demonstrated
non-inferiority of an investigational dose of ZERBAXA to meropenem, the
active comparator, in the primary and key secondary endpoints. Based on
these results, Merck has submitted supplemental new drug applications to
the U.S. Food and Drug Administration (FDA) and European Medicines
Agency (EMA) seeking regulatory approval for ZERBAXA for this potential
new indication. The FDA Prescription Drug User Fee Act (PDUFA) date is
June 3, 2019. Detailed findings of the ASPECT-NP Phase 3 trial are
scheduled to be presented at the 29^th European Congress of
Clinical Microbiology & Infectious Diseases (ECCMID), on Monday, April
15 at 1:30 pm local time in Amsterdam, Netherlands (Poster P1917).

“ASPECT-NP is unique among registration trials for nosocomial pneumonia,
as all patients were intubated and mechanically ventilated and nearly
all were treated in the intensive care unit,” said Dr. Marin Kollef,
director of Medical Critical Care and Respiratory Care Services of
Barnes-Jewish Hospital and the Golman Professor of Medicine at
Washington University School of Medicine, St. Louis, MO. “This is a
disease state with a high mortality rate, and Merck’s commitment to this
trial provides meaningful evidence that helps expand our understanding
of the management of this patient population.”

In the U.S., ZERBAXA is currently indicated for the treatment of adult
patients with complicated urinary tract infections, including
pyelonephritis, caused by certain susceptible Gram-negative
microorganisms, and is indicated, in combination with metronidazole, for
the treatment of adult patients with complicated intra-abdominal
infections caused by certain susceptible Gram-negative and Gram-positive
microorganisms. To reduce the development of drug-resistant bacteria and
maintain the effectiveness of ZERBAXA and other antibacterial drugs,
ZERBAXA should be used only to treat infections that are proven or
strongly suspected to be caused by susceptible bacteria.

ASPECT-NP design

ASPECT-NP is a prospective, randomized, double-blind, multicenter,
non-inferiority, Phase 3 clinical trial to evaluate the safety and
efficacy of ZERBAXA compared to meropenem in ventilated patients
diagnosed with nosocomial pneumonia, including hospital-acquired and
ventilator-associated bacterial pneumonia. In the study, 726 patients
were randomized 1:1 to receive an investigational 3g dose (2g
ceftolozane/1g tazobactam) of ZERBAXA or meropenem 1g dose, administered
intravenously every eight hours for eight to 14 days. Meropenem is an
approved broad-spectrum injectable antibiotic widely used to treat
serious infections. The primary and key secondary endpoints are Day 28
all-cause mortality and Clinical Response at test-of-cure (TOC) in the
intent-to-treat (ITT) population.

“We are very grateful to the patients and healthcare professionals who
made this important trial possible,” said Dr. Joan Butterton, associate
vice president, infectious disease clinical research, Merck Research
Laboratories. “There remains an urgent need for additional treatment
options for the intubated and mechanically ventilated patient population
that was studied in ASPECT-NP. Merck is firmly committed to pursuing new
treatment options for serious infectious diseases.”

ASPECT-NP results

ZERBAXA was non-inferior to meropenem for the primary endpoint of 28-day
all-cause mortality in the ITT population (all randomized patients),
24.0% (87/362) and 25.3% (92/364) respectively, for a weighted
proportion difference of 1.1% (stratified 95% CI: -5.13%, 7.39%;
non-inferiority margin of 10%). In addition, ZERBAXA was non-inferior to
meropenem in the key secondary endpoint, clinical cure at Test-of-Cure
(7-14 days after the end of therapy) in the ITT population, 54.4%
(197/362) and 53.3% (194/364) respectively, for a weighted proportion
difference of 1.1% (stratified 95% CI: -6.17%, 8.29%; non-inferiority
margin of 12.5%).

Additionally, an analysis of efficacy outcomes by causative pathogens
showed that clinical and microbiologic response rates for ZERBAXA were
comparable to meropenem for Gram-negative respiratory tract pathogens,
including Pseudomonas aeruginosa and Enterobacteriaceae.
In the microbiologically evaluable (ME) population in patients with a
Gram-negative pathogen at baseline clinical cure rates were 75.2%
(85/113) and 66.7% (78/117) and microbiologic response rates were 69.9%
(79/113) and 62.4% (73/117) for ZERBAXA and meropenem respectively.
Results were consistent in the microbiologic intention-to-treat (mITT)
population with clinical cure rates of 73% (189/259) and 67.9% (163/240)
for ZERBAXA and meropenem respectively (Related mini oral ePoster O0302).

Treatment-emergent adverse events (AE) were reported in 85.9% (310/362)
of ZERBAXA versus 83.3% (299/364) of meropenem treated patients. The
incidence of treatment-related AEs was 10.5% (38/362) in the ZERBAXA
group and 7.5% (27/364) in the meropenem group. The most commonly
reported AEs with ZERBAXA were abnormal liver function tests, Clostridium
difficile colitis and diarrhea. Comparable rates of AEs were
reported for ZERBAXA and meropenem in critically ill patients (those
with high APACHE scores), and approximately 1% of patients had
treatment-related AEs leading to discontinuation of therapy.

About ZERBAXA (ceftolozane and tazobactam)

ZERBAXA is an antibacterial combination product for intravenous infusion
consisting of the cephalosporin antibacterial drug ceftolozane sulfate
and the beta-lactamase inhibitor tazobactam sodium.

ZERBAXA 1.5g (ceftolozane 1g and tazobactam 0.5g) is approved in the
United States and is indicated in adult patients for the treatment of
complicated urinary tract infections (cUTI), including pyelonephritis,
caused by the following Gram-negative microorganisms: Escherichia
coli, Klebsiella pneumoniae, Proteus mirabilis,
and Pseudomonas aeruginosa. ZERBAXA used in combination with
metronidazole is indicated in adult patients for the treatment of
complicated intra-abdominal infections (cIAI) caused by the following
Gram-negative and Gram-positive microorganisms: Enterobacter
cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella
pneumoniae, Proteus mirabilis, Pseudomonas
aeruginosa, Bacteroides fragilis, Streptococcus
anginosus, Streptococcus constellatus, and Streptococcus
salivarius.

To reduce the development of drug-resistant bacteria and maintain the
effectiveness of ZERBAXA and other antibacterial drugs, ZERBAXA should
be used only to treat infections that are proven or strongly suspected
to be caused by susceptible bacteria. When culture and susceptibility
information are available, they should be considered in selecting or
modifying antibacterial therapy. In the absence of such data, local
epidemiology and susceptibility patterns may contribute to the empiric
selection of therapy.

Important Safety Information about ZERBAXA (ceftolozane and
tazobactam)

Patients with renal impairment: Decreased efficacy of ZERBAXA has
been observed in patients with baseline creatinine clearance (CrCl) of
30 to ≤50 mL/min. In a clinical trial, patients with cIAIs with CrCl >50
mL/min had a clinical cure rate of 85.2% when treated with ZERBAXA
(ceftolozane and tazobactam) plus metronidazole vs. 87.9% when treated
with meropenem. In the same trial, patients with CrCl 30 to ≤50 mL/min
had a clinical cure rate of 47.8% when treated with ZERBAXA plus
metronidazole vs. 69.2% when treated with meropenem. A similar trend was
also seen in the cUTI trial. Monitor CrCl at least daily in patients
with changing renal function and adjust the dose of ZERBAXA accordingly.

Hypersensitivity: ZERBAXA is contraindicated in patients with
known serious hypersensitivity to ceftolozane/tazobactam,
piperacillin/tazobactam, or other members of the beta-lactam class.
Serious and occasionally fatal hypersensitivity (anaphylactic) reactions
have been reported in patients receiving beta-lactam antibacterials.
Before initiating therapy with ZERBAXA, make careful inquiry about
previous hypersensitivity reactions to cephalosporins, penicillins, or
other beta-lactams. If an anaphylactic reaction to ZERBAXA occurs,
discontinue use and institute appropriate therapy.

Clostridium difficile

-associated diarrhea (CDAD), ranging
from mild diarrhea to fatal colitis, has been reported with nearly all
systemic antibacterial agents, including ZERBAXA. Careful medical
history is necessary because CDAD has been reported to occur more than
two months after the administration of antibacterial agents. If CDAD is
confirmed, antibacterial use not directed against C. difficile should
be discontinued, if possible.

Development of drug-resistant bacteria: Prescribing ZERBAXA in
the absence of a proven or strongly suspected bacterial infection is
unlikely to provide benefit to the patient and increases the risk of the
development of drug-resistant bacteria.

Adverse reactions: The most common adverse reactions occurring in
≥5% of patients were headache (5.8%) in the cUTI trial, and nausea
(7.9%), diarrhea (6.2%) and pyrexia (5.6%) in the cIAI trial.

Merck’s commitment to infectious diseases

For more than 100 years, Merck has contributed to the discovery and
development of novel medicines and vaccines to combat infectious
diseases. In addition to a combined portfolio of vaccines and
antibacterial, antiviral and antifungal medicines, Merck has multiple
programs that span discovery through late-stage development. To learn
more about Merck’s infectious diseases pipeline, visit www.merck.com.

About Merck

For more than a century, Merck, a leading global biopharmaceutical
company known as MSD outside of the United States and Canada, has been
inventing for life, bringing forward medicines and vaccines for many of
the world’s most challenging diseases. Through our prescription
medicines, vaccines, biologic therapies 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 health care through far-reaching policies, programs
and partnerships. Today, Merck continues to be at the forefront of
research to advance the prevention and treatment of diseases that
threaten people and communities around the world – including cancer,
cardio-metabolic diseases, emerging animal diseases, Alzheimer’s disease
and infectious diseases including HIV and Ebola. For more information,
visit www.merck.com and
connect with us on Twitter, Facebook, Instagram, YouTube and
LinkedIn.

Forward-Looking Statement of Merck & Co., Inc., Kenilworth, N.J., USA

This news release of Merck & Co., Inc., Kenilworth, N.J., USA (the
“company”) includes “forward-looking statements” within the meaning of
the safe harbor provisions of the U.S. Private Securities Litigation
Reform Act of 1995. These statements are based upon the current beliefs
and expectations of the company’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 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; the company’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 the company’s patents
and other protections for innovative products; and the exposure to
litigation, including patent litigation, and/or regulatory actions.

The company 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 the company’s 2018 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 ZERBAXA (ceftolozane and
tazobactam) at 

http://www.merck.com/product/usa/pi_circulars/z/zerbaxa/zerbaxa_pi.pdf

Media:
Pam Eisele
(267) 305-3558

Sarra Herzog
(201) 669-6570

Investor:
Teri Loxam
(908) 740-1986

Michael DeCarbo
(908) 740-1807