Clinical trial data show antibiotic
candidate’s activity against problematic resistant Gram-negative
bacteria in patients with complicated infections
Cubist Pharmaceuticals, Inc. (NASDAQ: CBST) today announced the
first detailed results from positive pivotal Phase 3 clinical
trials of its antibiotic candidate ceftolozane/tazobactam in
development to treat serious infections including complicated
urinary tract infections (cUTI) and complicated intra-abdominal
infections (cIAI). Results will be presented at the 24th European
Congress of Clinical Microbiology and Infectious Diseases (ECCMID)
being held in Barcelona May 10 - 13.
These new data include additional details on
ceftolozane/tazobactam’s clinical cure and/or microbiological
eradication rates, which met or exceeded pre-specified U.S. Food
and Drug Administration (FDA) and European Medicines Agency (EMA)
non-inferiority margins, as well as details on the overall safety
profile. Additionally, for the first time Cubist is presenting data
on microbiological eradication of key problematic Gram-negative
pathogens, including Pseudomonas aeruginosa and extended-spectrum
beta-lactamase (ESBL)-producing Escherichia coli (E. coli) and
Klebsiella pneumoniae. Microbiological eradication rates for
ceftolozane/tazobactam were 84% - 100% in these pathogens across
the cUTI and cIAI clinical trials, as detailed more fully
below.
Growing antibiotic resistance poses a serious global health
threat, as highlighted in the April 30, 2014 World Health
Organization report. Collectively, the common Gram-negative
pathogens E. coli, Klebsiella pneumoniae and Pseudomonas aeruginosa
account for approximately one-third of all pathogens and 70% of all
Gram-negative pathogens causing healthcare-associated infections
(HAIs). These Gram-negative bacteria are common causes of urinary
tract and intra-abdominal infections.
“We are delighted by the growing body of evidence indicating
that ceftolozane/tazobactam may prove to be an important treatment
option to address three of the most difficult to treat
Gram-negative pathogens—specifically Pseudomonas aeruginosa and
ESBL-producing E. coli and Klebsiella pneumoniae, —in cUTI and
cIAI,” said Steven Gilman, Ph.D., Executive Vice President of
Research and Development and Chief Scientific Officer of Cubist.
“Cubist hopes to make this new tool available to physicians and
patients worldwide to help fight antimicrobial resistance, and
looks forward to next steps in our global regulatory
submissions.”
Phase 3 clinical trial in cUTI
Ceftolozane/tazobactam met its 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 end of therapy—the Test of Cure (TOC) visit.
The composite cure rates at TOC in the Microbiological Modified
Intent-to-Treat (mMITT) and Per Protocol (PP) populations were
76.9% versus (vs.) 68.4% and 83.3% vs. 75.4%, respectively.
Although this trial was not prospectively designed to demonstrate
superiority, the finding that the lower bound of the confidence
interval around the positive treatment differences in favor of
ceftolozane/tazobactam was greater than zero, indicated statistical
superiority over levofloxacin in this trial.
Results of the secondary analyses were consistent with and
supportive of the primary outcome. Microbiological eradication
rates for ceftolozane/tazobactam vs. levofloxacin were 80.4% vs.
72.1% in the mMITT population and 86.2% vs. 77.6% in the PP
population.
Clinical trial data showed the following per-pathogen
microbiological eradication rates in the Microbiologically
Evaluable (ME) population for ceftolozane/tazobactam vs.
levofloxacin:
- E. coli (n=546): 91% vs. 80%
- Klebsiella pneumoniae (n=48): 84% vs.
61%
- Pseudomonas aeruginosa (n=19): 86% vs.
58%
In the mMITT population, ceftolozane/tazobactam demonstrated a
composite cure rate of 60.0% vs. 39.3% against
levofloxacin-resistant pathogens, and 62.3% vs. 35.1% against
ESBL-producing pathogens.
Drug-related adverse events occurred in 10.3% and 12.0% of the
ceftolozane/tazobactam and levofloxacin groups, respectively. The
most commonly reported adverse event for ceftolozane/tazobactam was
headache (5.8%). Additionally, in this trial, adverse events for
ceftolozane/tazobactam included constipation (3.9%), hypertension
(3%), nausea (2.8%), and diarrhea (1.9%). This adverse event
profile is consistent with that seen with ceftolozane/tazobactam in
the prior Phase 2 trial in cUTI and comparable to levofloxacin in
this trial.
“Pseudomonas aeruginosa and ESBL-producing Enterobacteriaceae
are resistant pathogens we see in patients with complicated urinary
tract infections,” said presenting author Florian Wagenlehner,
M.D., Ph.D., Clinic for Urology, Pediatric Urology and Andrology,
Justus-Liebig University, Giessen University. “The data presented
during ECCMID demonstrate the activity of ceftolozane/tazobactam
against these problematic pathogens.”
Phase 3 clinical trial in cIAI
Ceftolozane/tazobactam, in combination with metronidazole, met
both the FDA and EMA primary endpoints of statistical
non-inferiority compared to meropenem. The primary endpoint was a
clinical cure rate 26 - 30 days after the initiation of therapy—the
TOC visit. For the FDA, the primary analysis was conducted in the
Modified Intent-to-Treat (MITT) population where the overall
clinical cure rate was 83.0% for ceftolozane/tazobactam in
combination with metronidazole vs. 87.3% for meropenem. For the
FDA, statistical non-inferiority was defined at a pre-specified 10%
non-inferiority margin. For the EMA, the primary analysis was
conducted in the Clinically Evaluable (CE) population where the
overall clinical cure rate was 94.1% for ceftolozane/tazobactam in
combination with metronidazole vs. 94.0% for meropenem. For the
EMA, statistical non-inferiority was defined at a pre-specified
12.5% non-inferiority margin.
Results of the secondary analyses were consistent with and
supportive of the primary outcome. Per-pathogen microbiological
eradication rates for ceftolozane/tazobactam vs. meropenem were
comparable between groups. Clinical cure in patients infected with
ESBL-producing Enterobacteriaceae was achieved in 86.2% and 82.8%
of patients in the ceftolozane/tazobactam in combination with
metronidazole and meropenem treatment groups, respectively.
Clinical trial data showed the following per-pathogen
microbiological eradication rates in Gram-negative aerobes in the
ME population for ceftolozane/tazobactam in combination with
metronidazole vs. meropenem:
- E. coli (n=426): 96% vs. 95%
- Klebsiella pneumoniae (n=53): 100% vs.
88%
- Pseudomonas aeruginosa (n=53): 100% vs.
100%
The most commonly reported adverse events for
ceftolozane/tazobactam in combination with metronidazole were
nausea (7.9%), diarrhea (6.2%), and fever (5.2%). In this trial,
other adverse events for ceftolozane/tazobactam included insomnia
(3.5%) and vomiting (3.3%). This adverse event profile is
consistent with that seen with other cephalosporin antibiotics and
comparable to meropenem in this trial.
“Ceftolozane/tazobactam is a novel antibacterial candidate being
developed for the potential treatment of common and problematic
Gram-negative pathogens that cause infections in patients following
a broad range of surgical procedures,” said presenting author
Christian Eckmann, M.D., Chief of Surgery at the Department of
Visceral and Thoracic Surgery Klinikum Peine, Academic Hospital of
Medical University, Hannover. “These clinical trial data suggest
that ceftolozane/tazobactam is a potential useful treatment for
patients with complicated intra-abdominal infections.”
More information regarding presentations of
ceftolozane/tazobactam Phase 3 data in cUTI and cIAI, as well as
other Cubist presentations during ECCMID, is available on the
Congress website here. Additionally, a list of selected
presentations can be reviewed in A Guide to Sessions for Cubist
Investors.
About Ceftolozane/Tazobactam
Ceftolozane/tazobactam, an antibiotic candidate being developed
to treat certain Gram-negative infections, consists of ceftolozane,
a novel cephalosporin that has demonstrated potent in vitro
activity against Pseudomonas aeruginosa, with tazobactam, a
well-established beta-lactamase inhibitor. The addition of
tazobactam broadens coverage to include most extended-spectrum
beta-lactamase (ESBL)-producing Escherichia coli (E. coli),
Klebsiella pneumoniae, and other Enterobacteriaceae.
Ceftolozane/tazobactam is being developed for the potential
treatment of complicated urinary tract infections (cUTI) and
complicated intra-abdominal infections (cIAI).
Ceftolozane/tazobactam is also being developed for the potential
treatment of hospital-acquired bacterial pneumonia
(HABP)/ventilator-associated bacterial pneumonia (VABP).
About Gram-negative Bacteria
There has been a worldwide increase in the number of infections
caused by Gram-negative bacteria. Highly adaptive pathogens that
can develop resistance through several mechanisms, resistant
Gram-negative bacteria are a serious global public health concern.
Collectively, Escherichia coli (E. coli), Klebsiella pneumoniae (K.
pneumoniae) and Pseudomonas aeruginosa (P. aeruginosa) account for
approximately one-third of all pathogens and 70% of all
Gram-negative pathogens causing healthcare-associated infections
(HAIs). Gram-negative bacteria are common causes of intra-abdominal
infections (IAIs), urinary tract infections (UTIs), and nosocomial,
or hospital-acquired, pneumonia, as well as bacteremia (bloodstream
infections). E. coli is the most common cause of UTIs, and cases of
UTI caused by extended-spectrum beta-lactamase (ESBL)-producing E.
coli and K. pneumoniae, as well as P. aeruginosa, including
drug-resistant strains, are increasing. ESBL-producing E. coli and
K. pneumoniae are also frequently isolated in patients with
complicated IAIs (cIAIs). Additionally, P. aeruginosa is the most
common Gram-negative organism causing ventilator associated
pneumonia and the second most common cause of catheter-associated
UTIs. For more information reference a video on Gram-negative
bacteria mechanisms of resistance.
About Cubist’s Commitment to Antibiotic R&D
Cubist has a growing commitment to global public health through
its leadership in the discovery, development and commercialization
of novel antibiotics to treat serious and life-threatening
infections caused by a broad range of increasingly drug-resistant
bacteria. The Company hopes to deliver at least four new
antibiotics in support of the Infectious Diseases Society of
America (IDSA) goal of 10 new antibiotics by 2020. Cubist expects
to invest approximately $400M USD in 2014 on antibacterial R&D
and approximately 75% of its employee base is focused on the
research, development, commercialization and support of
antibiotics.
About Cubist
Cubist Pharmaceuticals, Inc. is a global biopharmaceutical
company focused on the research, development, and commercialization
of pharmaceutical products that address significant unmet medical
needs in the acute care environment. Cubist is headquartered in
Lexington, Massachusetts, with a central international office
located in Zurich, Switzerland. Additional information can be found
at Cubist’s web site at www.cubist.com. Also, connect with Cubist
on Twitter @cubistbiopharma and @cubistcareers, LinkedIn, or
YouTube.
Forward Looking Statements
This press release contains forward-looking statements. Any
statements contained herein which do not describe historical facts,
including but not limited to, statements regarding: the therapeutic
potential of ceftolozane/tazobactam; positive results from our
Phase 3 clinical trials of ceftolozane/tazobactam, including that
the cUTI Phase 3 clinical trial data indicated that
ceftolozane/tazobactam was statistically superior to levofloxacin;
next steps in our global regulatory submissions for
ceftolozane/tazobactam; our aspirations to achieve a portion of the
IDSA goal of 10 new antibiotics by 2020; and the level of our
financial and personnel commitments towards antibiotic research,
development and commercialization, are forward-looking statements
which involve risks and uncertainties that could cause actual
results to differ materially from those discussed in such
forward-looking statements. Such risks and uncertainties include,
among others: regulatory developments, including the risk that the
FDA, and foreign regulatory authorities, may not respectively
accept for filing, or approve on a timely basis or at all, our New
Drug Application for ceftolozane/tazobactam, or any future
marketing approval applications that we may submit for
ceftolozane/tazobactam outside the U.S., may not agree with our
interpretation of the results from the clinical studies of
ceftolozane/tazobactam, or may require additional data, analysis,
information or further studies that may not be clinically feasible
or financially practicable; any marketing approval for
ceftolozane/tazobactam may impose significant limitations on its
use and additional post-marketing requirements; our ability to
obtain adequate pricing and reimbursement levels for
ceftolozane/tazobactam; our ability to successfully commercialize
ceftolozane/tazobactam, including as a result of regulatory
authorities’ decisions regarding labeling and other matters,
including adverse side effects, that could affect its availability
or commercial potential; our ability to maintain and enforce
intellectual property protection for ceftolozane/tazobactam;
competitive risks from current and future therapeutic alternatives
to ceftolozane/tazobactam; additional clinical trials of
ceftolozane/tazobactam may not be successful or initiated or
conducted in a timely manner; technical difficulties or excessive
costs relating to the manufacture or supply of
ceftolozane/tazobactam, including our ability to work with our
third party contract manufacturers that manufacture and supply
ceftolozane/tazobactam on our behalf; our ability to work with, and
the performance of our third party contract research organizations
that help us conduct our clinical trials; we may encounter other
unanticipated or unexpected risks with respect to the development
or manufacture of ceftolozane/tazobactam; our ability to achieve
our strategic goals, including as a result of our ability to
continue to grow revenues from the sale of CUBICIN® (daptomycin for
injection), DIFICID® (fidaxomicin) and ENTEREG® (alvimopan),
generic and other competition, manufacturing issues, our ability to
successfully develop, gain marketing approval for and commercially
launch our product candidates for their planned indications and on
their expected timelines, and our ability to discover, in-license
or acquire new products and product candidates and those additional
factors discussed in our most recent annual report on Form 10-K and
subsequent quarterly reports on Form 10-Q filed with the Securities
and Exchange Commission. We caution investors not to place
considerable reliance on the forward-looking statements contained
in this press release. These forward-looking statements speak only
as of the date of this press release, and we undertake no
obligation to update or revise any of these statements.
INVESTORS:Cubist Pharmaceuticals,
Inc.Eileen C. McIntyre, 781-860-8533Vice President, Investor
Relationseileen.mcintyre@cubist.comorMEDIA:US Media:Cubist Pharmaceuticals,
Inc.Jennifer BairdMobile: 781-708-2309Director of Product
Communicationsjennifer.baird@cubist.comorEurope Media:Weber
ShandwickNivey NocherMobile: +44 (0) 779-617-5609Account Director,
Healthnnocher@webershandwick.com