ASPECT-NP Clinical Trial Results
Demonstrated Non-Inferiority of ZERBAXA to Meropenem for Treating
Ventilated Nosocomial Pneumonia in Primary and Key Secondary
Endpoints
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 29th 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
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