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June 3, 2019 3:55 pm ET

Approval Based on Results of Phase 3 Trial Evaluating Critically Ill Patients with Pneumonia; 100% of Patients Were on Mechanical Ventilation

KENILWORTH, 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 Merck’s supplemental New Drug Application (sNDA) for the use of
ZERBAXA^® (ceftolozane and tazobactam) for the treatment of
patients 18 years and older with hospital-acquired bacterial pneumonia
and ventilator-associated bacterial pneumonia (HABP/VABP) caused by the
following susceptible Gram-negative microorganisms: Enterobacter
cloacae, Escherichia coli, Haemophilus influenzae, Klebsiella oxytoca,
Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, and
Serratia marcescens. The sNDA for ZERBAXA had previously
been designated Priority Review status by the FDA. 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 or prevent infections that are proven or strongly suspected to be
caused by susceptible bacteria.

This expanded use is based on results of the pivotal Phase 3 ASPECT-NP
trial that compared ZERBAXA 3g (ceftolozane 2g and tazobactam 1g)
intravenously every 8 hours to meropenem (1g intravenously every 8
hours) for 8 to 14 days for the treatment of adult patients with
HABP/VABP.

ZERBAXA is contraindicated in patients with known serious
hypersensitivity to the components of ZERBAXA (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.
Additionally,
Clostridium difficile-associated diarrhea
(CDAD), ranging from mild diarrhea to fatal colitis, has been reported
with nearly all systemic antibacterial agents, including ZERBAXA. See
Important Safety Information below.

“Pneumonia in ventilated patients remains a significant clinical
challenge and is associated with substantial morbidity and mortality,”
said Dr. Andrew Shorr, head of pulmonary, critical care and respiratory
services, Medstar Washington Hospital Center, Washington, D.C. “The need
to cover diverse pathogens including Pseudomonas aeruginosa and
certain Enterobacteriaceae adds to the challenge.”

According to a recent publication by the Foundation for the National
Institutes of Health Biomarkers Consortium, ventilated patients with
HABP have a higher rate of mortality (39%) than those with VABP (27%).
In addition,
Pseudomonas aeruginosa is the most
common Gram-negative pathogen in HABP/VABP and is becoming increasingly
difficult to treat.

“We are grateful to all of the patients who participated in the studies
which led to the approval of ZERBAXA for the treatment of HABP/VABP,”
said Dr. Roy Baynes, senior vice president and head of global clinical
development, chief medical officer, Merck Research Laboratories. “This
approval reflects Merck’s longstanding commitment to helping alleviate
the burden of infectious diseases, including serious infections caused
by Gram-negative pathogens.”

Clinical Data Supporting Use of ZERBAXA (Ceftolozane and Tazobactam)
in HABP/VABP

A total of 726 adult patients hospitalized with HABP/VABP were enrolled
in a multinational, double-blind study (NCT 02070757) comparing ZERBAXA
3g (ceftolozane 2g and tazobactam 1g) intravenously every 8 hours to
meropenem (1g intravenously every 8 hours) for 8 to 14 days of therapy.
All patients had to be intubated and on mechanical ventilation at
randomization.

Efficacy was assessed based on all-cause mortality at Day 28 and
clinical cure, defined as complete resolution or significant improvement
in signs and symptoms of the index infection at the test-of-cure (TOC)
visit which occurred 7 to 14 days after the end of treatment. The
analysis population was the intent-to-treat (ITT) population, which
included all randomized patients.

Of the 726 patients in the ITT population, the median age was 62 years
and 44% of the population was greater than or equal to 65 years of age,
with 22% of the population greater than or equal to 75 years of age. The
majority of patients were white (83%), male (71%) and were from Eastern
Europe (64%). The median APACHE II score was 17 and 33% of patients had
a baseline APACHE II score of greater than or equal to 20. All patients
were on mechanical ventilation and 519 (71%) had VABP. At randomization,
the majority of patients had been hospitalized for greater than or equal
to 5 days (77%) and were in an ICU (92%), with 49% of patients
ventilated for greater than or equal to 5 days. At baseline, 36% of
patients had creatinine clearance (CrCl) less than 80 mL/min. Of these,
14% had CrCl less than 50 mL/min.

Approximately 13% of patients were failing their current antibacterial
drug therapy for HABP/VABP, and bacteremia was present at baseline in
15% of patients. Key comorbidities included diabetes mellitus,
congestive heart failure, and chronic obstructive pulmonary disease at
rates of 22%, 16% and 12%, respectively.

ZERBAXA (ceftolozane and tazobactam) was non-inferior to meropenem for
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 for clinical response 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%).

In the ventilated HABP sub-group, a favorable response for ZERBAXA in
28-day all-cause mortality was observed, 24.2% (24/99) for ZERBAXA and
37.0% (40/108) for meropenem, respectively, for a weighted proportion
difference of 12.8 (stratified 95% CI: 0.18, 24.75). In the VABP
subgroup, 28-day all-cause mortality was 24.0% (63/263) for ZERBAXA and
20.3% (52/256) for meropenem, for a weighted proportion difference of
-3.6 (stratified 95% CI: -10.74, 3.52).

Adverse reactions occurring in 2% or greater of patients receiving
ZERBAXA in this study include hepatic transaminase increased 11.9%
(43/361), renal impairment/renal failure 8.9% (32/361), diarrhea 6.4%
(23/361), intracranial hemorrhage 4.4% (16/361), vomiting 3.3% (12/361),
and Clostridium difficile colitis 2.8% (10/361). Treatment
discontinuation due to adverse reactions occurred in 1.1% (4/361) of
patients receiving ZERBAXA and 1.4% (5/359) of patients receiving
meropenem.

Additional Important Safety Information about ZERBAXA (ceftolozane
and tazobactam)

Patients with changing renal function: Dose adjustment is
required for patients with CrCl 50 mL/min or less. All doses of ZERBAXA
are administered over 1 hour. 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 the components of ZERBAXA
(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 2 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 or a
prophylactic indication is unlikely to provide benefit to the patient
and risks the development of drug-resistant bacteria.

Adverse Reactions: The most common adverse reactions occurring in
≥5% of patients. in the HABP/VABP trial were increase in hepatic
transaminases (11.9%), renal impairment/renal failure (8.9%) and
diarrhea (6.4%).

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 3g dose (ceftolozane 2g and tazobactam 1g) is
approved in the United States and is indicated for treatment of patients
18 years and older with hospital-acquired bacterial pneumonia and
ventilator-associated bacterial pneumonia (HABP/VABP) caused by the
following susceptible Gram-negative microorganisms: Enterobacter
cloacae, Escherichia coli, Haemophilus influenzae, Klebsiella oxytoca,
Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, and
Serratia marcescens.

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 or prevent 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.

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
(908) 740-1871

Investors:

Teri Loxam
(908) 740-1986

Michael DeCarbo
(908) 740-1807