FDA Accepts for Review New Drug Application (NDA) for Merck’s Investigational Combination of Imipenem/Cilastatin and Relebactam, and Supplemental NDA (sNDA) for ZERBAXA® (Ceftolozane and Tazobactam)


February 5, 2019 6:45 am ET

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
accepted for review regulatory filings for two antibacterial agents.
These filings are: (1) a NDA accepted for Priority Review for the
combination of relebactam, the company’s investigational beta-lactamase
inhibitor, with imipenem/cilastatin (MK-7655A, IMI/REL), for the
treatment of complicated urinary tract infections (cUTI) and complicated
intra-abdominal infections (cIAI) caused by certain susceptible
Gram-negative bacteria, in adults with limited or no alternative
therapies available; and (2) a sNDA accepted for Priority Review for
ZERBAXA® (ceftolozane and tazobactam) to treat adult patients
with nosocomial pneumonia, including ventilator-associated pneumonia
caused by certain susceptible Gram-negative microorganisms. The
Prescription Drug User Fee Act (PDUFA) target action date for IMI/REL is
July 16, 2019, while the PDUFA target action date for ZERBAXA is June 3,

In the U.S., ZERBAXA is currently indicated for the treatment of adult
patients with cUTI, including pyelonephritis, caused by certain
susceptible Gram-negative microorganisms, and is also indicated, in
combination with metronidazole, for the treatment of adult patients with
cIAI caused by certain susceptible Gram-negative and Gram-positive

Corresponding applications for both medicines have been filed with the
European Medicines Agency (EMA) and are currently under review.

“There is a major unmet need for new treatment options to address the
growing danger of serious and potentially life-threatening infections
caused by Gram-negative bacteria,” said Dr. Nicholas Kartsonis, senior
vice president, head of clinical research for infectious diseases and
vaccines, Merck Research Laboratories. “In a space where there are
currently very few treatment options, these filings underscore Merck’s
ongoing commitment to delivering new antibacterial agents to healthcare
practitioners and patients.”

The IMI/REL (MK-7655A) NDA is based on the results of the pivotal Phase
3 RESTORE-IMI 1 trial, which were presented at the 28th European
Congress of Clinical Microbiology and Infectious Diseases (ECCMID)
meeting in Madrid, Spain, in April 2018. The ZERBAXA sNDA is based on
the pivotal Phase 3 ASPECT-NP trial in adults with ventilated
hospital-acquired bacterial pneumonia or ventilator-associated bacterial
pneumonia. Merck plans to present results from the ASPECT-NP study at a
future scientific conference.

About imipenem, cilastatin and relebactam

Relebactam is an investigational, intravenous, class A and C
beta-lactamase inhibitor currently being evaluated in combination with
imipenem/cilastatin for the treatment of certain Gram-negative bacterial
infections. The FDA has designated the combination of relebactam with
imipenem/cilastatin for intravenous use as a Qualified Infectious
Disease Product (QIDP) with Fast Track status for the treatment of
complicated urinary tract infections (cUTI), complicated intra-abdominal
infections (cIAI) and hospital-acquired bacterial
pneumonia/ventilator-associated bacterial pneumonia (HABP/VABP).

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
Klebsiella pneumoniaeProteus 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
Escherichia coliKlebsiella oxytocaKlebsiella
Proteus mirabilisPseudomonas
Bacteroides fragilis, Streptococcus
Streptococcus constellatus, and Streptococcus

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

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
(ceftolozane and tazobactam) 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

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,
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 2017 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 


Pam Eisele
(267) 305-3558

Sarra Herzog
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