Merck (NYSE:MRK), known as MSD outside the United States and
Canada, today announced that The Lancet and Clinical Infectious
Diseases have published online the results from the pivotal Phase 3
clinical studies of ZERBAXA™ (ceftolozane/tazobactam) for Injection
(1 g/0.5 g) in complicated urinary tract infections (cUTI) and
complicated intra-abdominal infections (cIAI), respectively. The
results will also appear in forthcoming print issues of the
journals. Merck acquired ZERBAXA as a part of its purchase of
Cubist Pharmaceuticals, Inc.
The publications report the results of two large, global, Phase
3 clinical studies of ZERBAXA – a study in patients with cUTI and a
study in patients with cIAI. Both studies met the pre-specified
primary endpoints, and results of the secondary analyses for the
studies were consistent with and supportive of the primary
outcomes.
“Physicians are in need of new treatment options to address
complicated infections caused by serious Gram-negative bacteria.
Publication of the ZERBAXA Phase 3 clinical study results in The
Lancet and Clinical Infectious Diseases provides additional
information to the infectious disease community and continues to
support ZERBAXA as a new treatment for certain complicated urinary
tract and complicated intra-abdominal infections,” said René Russo,
Pharm.D, BCPS, vice president, global medical affairs, Cubist
Pharmaceuticals.
Approved in the U.S., ZERBAXA is indicated for use in
combination with metronidazole in adult patients for the treatment
of complicated intra-abdominal infections 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. ZERBAXA also is indicated in adult
patients for the treatment of complicated urinary tract infections,
including pyelonephritis, caused by the following Gram-negative
microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus
mirabilis and Pseudomonas aeruginosa.
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.
About the study of ZERBAXA in cUTI
As described in The Lancet, the cUTI study was a multicenter,
double-blind trial in which 1,083 hospitalized adult patients with
cUTI, including pyelonephritis, were randomized to receive either
intravenous (I.V.) ZERBAXA (1.5 g q8h) or high-dose I.V.
levofloxacin (750 mg qd) for seven days. In this study, treatment
with ZERBAXA was shown to be effective in patients with cUTI and
pyelonephritis, including a majority of infections caused by
levofloxacin-resistant pathogens. The comparator levofloxacin is a
common treatment option for cUTI and pyelonephritis, and is
included in international clinical practice guidelines for
cUTI.
ZERBAXA met the study’s primary endpoint of statistical
non-inferiority compared to levofloxacin (10% non-inferiority
margin). The primary endpoint was a composite of microbiological
eradication and clinical cure rate (composite cure rate) at 5-9
days after the end of therapy (the test of cure visit). The 95%
confidence interval around the treatment difference had lower and
upper bounds of 2.3% and 14.6%, respectively.
“These clinical trial results are important because
ceftolozane/tazobactam is a new treatment option for patients
facing complicated urinary tract infections caused by certain
susceptible Gram-negative bacteria,” said The Lancet publication
lead author Florian M. Wagenlehner, M.D., Ph.D., Clinic for
Urology, Pediatric Urology and Andrology, Justus-Liebig University,
and faculty member of the German Center for Infection Research,
Gießen-Marburg-Langen site. “Gram-negative bacteria are prevalent
globally and know no geographic boundaries. With the increasing
challenge of antibiotic resistance, the treatment of complicated
urinary tract infections has become more difficult to manage, and
new therapies are needed.”
About the study of ZERBAXA in cIAI
As described in Clinical Infectious Diseases, the cIAI study was
a multicenter, double-blind trial in which 993 hospitalized adult
patients with cIAI were randomized to receive either I.V. ZERBAXA
(1.5 g q8h) plus metronidazole (0.5 g q8h) or I.V. meropenem (1 g
q8h) for four to 10 days. Treatment could be continued for up to 14
days in patients who had one of the following: multiple abscesses;
non-appendix–related diffuse peritonitis, failure of prior
antimicrobial therapy, or hospital-acquired infection. Treatment
with ZERBAXA plus metronidazole was shown to be effective in
patients with cIAI, including those infections caused by certain
resistant pathogens, such as extended-spectrum beta-lactamase
(ESBL) producing Enterobacteriacae. The comparator meropenem is a
common treatment option for cIAI and is included in international
clinical practice guidelines for cIAI.
The primary endpoint of this study was the clinical cure rate
24-32 days after the initiation of therapy (the test of cure
visit). For the U.S. Food and Drug Administration, the primary
analysis was conducted in the microbiological intent-to-treat
population; the non-inferiority margin was 10%; and the lower and
upper bounds of the 95% confidence interval were -8.9% and 0.5%,
respectively. For the European Medicines Agency (EMA), the primary
analysis population was clinically evaluable patients; the
non-inferiority margin was 12.5%; and the lower and upper bounds of
the 99% confidence interval were -4.2% and 4.3%, respectively.
“Complicated intra-abdominal infections are tissue-invasive
infections that can lead to abscess formation or generalized
peritonitis. Having new antibiotics to address these types of
serious infections, particularly those caused by Gram-negative
pathogens, has been a major medical need,” said the Clinical
Infectious Diseases publication lead author Joseph Solomkin, M.D.,
professor of surgery emeritus, Department of Surgery, University of
Cincinnati College of Medicine. “These clinical trial results
reinforce that ZERBAXA is an effective new treatment for adult
patients with complicated intra-abdominal infections.”
About ZERBAXA (ceftolozane/tazobactam)
ZERBAXA, approved in the U.S., is an antibacterial combination
product consisting of the cephalosporin antibacterial drug
ceftolozane sulfate and the beta-lactamase inhibitor tazobactam
sodium for intravenous administration. The recommended dosage
regimen of ZERBAXA is 1.5 g (1 g/0.5 g) administered every eight
hours by intravenous infusion over one hour in patients 18 years or
older and with normal renal function or mild renal impairment.
Dosage adjustment is required for patients whose creatinine
clearance is 50 mL/min or less.
In the European Union, the EMA has accepted for review the
Marketing Authorization Application for ZERBAXA for the treatment
of cUTI and cIAI. A decision from the European Commission is
expected during the second half of 2015.
Important Safety Information about ZERBAXA
Patients with renal impairment: Decreased efficacy of
ZERBAXA has been observed in patients with baseline 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 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.
About Gram-negative bacteria and certain complicated
infections
Gram-negative bacteria are a serious global public health
concern. The U.S. Centers for Disease Control and Prevention has
categorized certain Gram-negative bacteria among the most serious
threats to public health. Gram-negative bacteria are common causes
of cIAI and cUTI. E. coli is the most common cause of cUTIs, and
cases of cUTI caused by Pseudomonas aeruginosa are increasing.
Additionally, Pseudomonas aeruginosa is the second most common
cause of catheter-associated UTIs. Major pathogens in cUTIs are
Enterobacteriaceae, including Escherichia coli (E. coli) and
Klebsiella pneumoniae.
About Merck
Today's Merck is a global healthcare leader working to help the
world be well. Merck is known as MSD outside of the United States
and Canada. 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 healthcare through far-reaching policies, programs and
partnerships. For more information, visit www.merck.com and connect
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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.
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conditions; manufacturing difficulties or delays; financial
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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 2014 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/tazobactam) at
http://zerbaxa.com/pdf/PrescribingInformation.pdf.
MerckMedia Contacts:Pam Eisele, 267-305-3558Robert Consalvo,
908-295-0928orInvestor Contacts:Joseph Romanelli,
908-740-1986Justin Holko, 908-740-1879
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