Additional Data Points to Potential of XERAVA
to Treat Carbapenem-Resistant, Multidrug-Resistant Escherichia Coli
TP-6076 Demonstrates In Vivo Efficacy in
Murine Lung and Thigh Infection Models with Acinetobacter
Baumannii
Tetraphase Pharmaceuticals, Inc. (NASDAQ:TTPH), a
biopharmaceutical company focused on commercializing novel
tetracyclines to treat serious and life-threatening conditions,
announced the presentation of new data on XERAVA™ (eravacycline), a
novel, fully synthetic fluorocycline approved by the U.S. Food and
Drug Administration (FDA) and the European Medicines Agency for the
treatment of complicated intra-abdominal infections (cIAI) in
adults, and TP-6076, a clinical-stage candidate targeting
multidrug-resistant (MDR) infections, at the American Society for
Microbiology (ASM) Microbe 2019 Annual Meeting held June 20-24 in
San Francisco.
“The data presented at ASM Microbe underscore the broad
potential of XERAVA as a potent antibiotic against gram-negative
and gram-positive clinical isolates, including MDR pathogens,” said
Larry Edwards, current Chief Operating Officer of Tetraphase and
recently named President and Chief Executive Officer, effective
August 1, 2019. “As we now focus our efforts squarely on the
commercial success of XERAVA in complicated intra-abdominal
infections, we continue to be encouraged by studies that highlight
its validity as a new treatment option for serious,
life-threatening infections. Additionally, as recently announced,
we are looking to outlicense our early-stage pipeline, and we
believe that the pharmacokinetic and efficacy data of TP-6076
strengthens this asset as an attractive outlicensing
candidate.”
Studies Continue to Demonstrate the Potent In Vitro Activity
of Eravacycline Against Gram-Negative and Gram-Positive Clinical
Isolates, Including Multidrug-Resistant Pathogens
Carbapenem resistance is emerging in E. coli, including its MDR
lineage. New agents, including XERAVA, have distinctive mechanisms
that inhibit or kill many carbapenem-resistant organisms.
Accordingly, Johnson et al. tested these antibiotics against
clinical E. coli isolates, including those that are carbapenem
resistant, from surveillance systems encompassing multiple sites
across the U.S. The minimum inhibitory concentrations (MIC) of 179
U.S. clinical E. coli isolates, which were non-susceptible to one
or more carbapenems, were determined with cefiderocol,
ceftazidime-avibactam and XERAVA; three carbapenems (meropenem,
imipenem, ertapenem); and eight non-carbapenem comparators. Using
FDA/Clinical and Laboratory Standards Institute (CLSI) breakpoint
interpretations, the percent susceptible isolates was higher for
cefiderocol (96%), ceftazidime-avibactam (92%), and XERAVA (97%)
than for any carbapenem (meropenem, 75%; imipenem, 46%; ertapenem,
3%) and for all other comparators except tigecycline (98%) and
colistin (99%). These data demonstrated that cefiderocol,
ceftazidime-avibactam and XERAVA were highly active overall among
the carbapenem-resistant E. coli clinical isolates, notwithstanding
variation by phylogroup, clonal group, New Delhi
metallo-beta-lactamase genotype and geographical
region. Given these results, XERAVA may be a promising new
treatment option for infections caused by carbapenem-resistant,
multidrug-resistant E. coli.
In a large, ongoing surveillance study of XERAVA, researchers
evaluated the in vitro activity of the drug against Gram-negative
and Gram-positive global isolates collected in 2017, including MDR
pathogens. A total of 7,084 bacterial isolates were collected from
different geographic regions, including Europe (n=3,539), the U.S.
(n=2,381) and Asia/Pacific (n=1,164). Overall, XERAVA exhibited
potent in vitro activity against Enterobacteriaceae, A. baumannii
and clinically important Gram-positive organisms, including
resistant pathogens. The MICs of XERAVA against all
Enterobacteriaceae (n=3,250) were generally two- to four-fold lower
than tigecycline, including for MDR isolates.
In an additional XERAVA study, up to 15 hospitals submitted
pathogens collected from 2014-2018 from patients attending hospital
clinics, emergency rooms, medical and surgical wards, and intensive
care units as part of CANWARD, an ongoing national Health Canada
and Canadian Antimicrobial Resistance Alliance (CARA) partnered
surveillance program in Canadian hospitals. The in vitro activity
of XERAVA was compared to a variety of other antibiotics against a
total of 15,887 Gram-negative and Gram-positive pathogens and
showed that XERAVA was more active than meropenem and
piperacillin-tazobactam against methicillin-resistant
Staphylococcus aureus (MRSA), Enterococcus faecalis, Enterococcus
faecium, vancomycin-resistant enterococci (VRE), Stenotrophomonas
maltophilia and Acinetobacter baumannii.
Additional posters highlighted ways to evaluate XERAVA using the
Beckman Coulter MicroScan Dried Gram-Negative MIC Panels and the
bioMérieux ETEST®. The ETEST strip and the MicroScan Dried
Gram-Negative MIC panel containing XERAVA were each shown to
correlate well with MICs obtained by broth microdilution reference
method (BMD). Both methods could represent a valuable tool for
XERAVA susceptibility testing and an alternative to the BMD
reference method.
New Data on the Pharmacokinetics and Efficacy of TP-6076 in
the Murine Lung and Thigh Infection Models with A.
baumannii
In addition to the XERAVA findings, new data on TP-6076,
Tetraphase’s Phase 2 ready candidate for MDR Gram-negative
bacteria, such as carbapenem-resistant Enterobacteriaceae and
carbapenem-resistant Acinetobacter baumanii, were presented. These
resistant organisms, particularly MDR A. baumannii, are of
increasing concern in association with ventilator-associated
pneumonia with high morbidity and mortality rates, especially in
immunocompromised patients.
Studies were performed to evaluate the efficacy of TP-6076 in
murine lung infection and murine thigh infection models against MDR
A. baumannii clinical isolates. TP-6076 demonstrated high potency
against MDR A. baumannii clinical isolates that were used in these
in vitro models, with MICs that ranged from <0.008 - 0.25 ug/mL (MIC 90 = 0.0625
ug/mL).
Results of the first study indicated TP-6076’s ability to
penetrate the lung. Single IV doses of TP-6076 (0.25 – 40 mg/kg)
were administered to neutropenic (or immunocompromised) mice, and
epithelial-lining fluid (ELF) was subsequently evaluated. TP-6076
resulted in statistically significant reductions in bacterial lung
titers in the murine lung infection model, with A. baumannii lung
colony forming units (CFU) decreasing by 2.4 – 6.2 log10 CFU when
compared to the untreated control group. In comparison, tigecycline
resulted in a 0.2 – 4.2 log10 CFU reduction in mean lung
titers.
TP-6076’s in vivo efficacy was also demonstrated in an
immunocompromised murine thigh infection model with A. baumannii.
Female neutropenic mice were infected intramuscularly with MDR A.
baumannii clinical isolates into their right hind-limb thighs.
TP-6076 doses resulted in a statistically significant reduction
(p<0.0001) in mean thigh CFU to 3.0 – 3.8 log10 CFU, compared to
the untreated controls. Doses of tigecycline resulted in less than
a 2 log10 CFU reduction observed for most isolates, which was not
statistically significant.
The results of these studies demonstrated in vitro activity of
TP-6076 against MDR A. baumannii isolates with statistically
significant reductions in bacterial tissue titers in the murine
thigh and lung infection models and suggest that TP-6076 has the
potential to treat life-threatening multi-drug resistant A.
baumannii infections, including ventilator-associated
pneumonia.
About XERAVA™
XERAVA (eravacycline for injection) is a tetracycline class
antibacterial indicated for the treatment of complicated
intra-abdominal infections (cIAI) in patients 18 years of age and
older. XERAVA was investigated for the treatment of cIAI as part of
the Company's IGNITE (Investigating
Gram-Negative Infections Treated with
Eravacycline) Phase 3 program. In the first pivotal Phase 3
trial in patients with cIAI, twice-daily intravenous (IV) XERAVA
met the primary endpoint by demonstrating statistical
non-inferiority of clinical response compared to ertapenem and was
well-tolerated. In the second Phase 3 clinical trial in patients
with cIAI, twice-daily IV XERAVA met the primary endpoint by
demonstrating statistical non-inferiority of clinical response
compared to meropenem and was well-tolerated. In both trials,
XERAVA achieved high cure rates in patients with Gram-negative
pathogens, including resistant isolates.
Indications and Usage
XERAVA is indicated for the treatment of complicated
intra-abdominal infections (cIAI) caused by susceptible
microorganisms: Escherichia coli, Klebsiella pneumoniae,
Citrobacter freundii, Enterobacter cloacae, Klebsiella oxytoca,
Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus,
Streptococcus anginosus group, Clostridium perfringens, Bacteroides
species, and Parabacteroides distasonis in patients 18 years or
older.
Limitations of Use
XERAVA is not indicated for the treatment of complicated urinary
tract infections (cUTI).
Usage
To reduce the development of drug-resistant bacteria and
maintain the effectiveness of XERAVA and other antibacterial drugs,
XERAVA 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.
Important Safety Information
XERAVA is contraindicated for use in patients with known
hypersensitivity to eravacycline, tetracycline-class antibacterial
drugs, or to any of the excipients. Life-threatening
hypersensitivity (anaphylactic) reactions have been reported with
XERAVA.
The use of XERAVA during tooth development (last half of
pregnancy, infancy and childhood to the age of eight years) may
cause permanent discoloration of the teeth (yellow-gray-brown) and
enamel hypoplasia.
The use of XERAVA during the second and third trimester of
pregnancy, infancy and childhood up to the age of eight years may
cause reversible inhibition of bone growth.
Clostridium difficile associated diarrhea (CDAD) has been
reported with use of nearly all antibacterial agents and may range
in severity from mild diarrhea to fatal colitis.
The most common adverse reactions observed in clinical trials
(incidence ≥3%) were infusion site reactions (7.7%), nausea (6.5%),
and vomiting (3.7%).
XERAVA is structurally similar to tetracycline-class
antibacterial drugs and may have similar adverse reactions. Adverse
reactions including photosensitivity, pseudotumor cerebri, and
anti-anabolic action which has led to increased BUN, azotemia,
acidosis, hyperphosphatemia, pancreatitis, and abnormal liver
function tests, have been reported for other tetracycline-class
antibacterial drugs, and may occur with XERAVA. Discontinue XERAVA
if any of these adverse reactions are suspected.
To report SUSPECTED ADVERSE REACTIONS, contact Tetraphase
Pharmaceuticals Inc., at 1-833-7-XERAVA (1-833-793-7282) or FDA at
1-800-FDA-1088 or www.fda.gov/medwatch.
Please see full Prescribing Information for XERAVA at
www.XERAVA.com.
About Tetraphase Pharmaceuticals, Inc.
Tetraphase Pharmaceuticals, Inc., is a biopharmaceutical company
using its proprietary chemistry technology to create novel
tetracyclines for serious and life-threatening conditions,
including infections caused by many of the multidrug-resistant
bacteria highlighted as urgent public health threats by the World
Health Organization and the Centers for Disease Control and
Prevention. The Company has created more than 3,000 novel
tetracycline compounds using its proprietary technology platform.
Tetraphase's lead product XERAVA™ is approved for the treatment of
complicated intra-abdominal infections by the U.S. Food and Drug
Administration and the European Medicines Agency. The Company’s
pipeline also includes TP-271 and TP-6076, which are Phase 2 ready,
and TP-2846, which is in preclinical testing for acute myeloid
leukemia. The Company intends to outlicense its pipeline
candidates. Please visit www.tphase.com for more company information.
Forward-Looking Statements
Any statements in this press release about our future
expectations, plans and prospects, including statements regarding
our strategy, future operations, prospects, plans and objectives,
and other statements containing the words "anticipates,"
"believes," "expects," "plans," "will" and similar expressions,
constitute forward-looking statements within the meaning of The
Private Securities Litigation Reform Act of 1995. Actual results
may differ materially from those indicated by such forward-looking
statements as a result of various important factors, including
whether preclinical data is indicative of expected clinical data;
our cash resources and the expected revenue will be sufficient to
fund our operations in the future; our product candidates will
succeed in clinical trials; even if such clinical trials are
successful, whether we may ever achieve regulatory approval of such
product candidates; and other clinical, regulatory and commercial
risk factors discussed in the "Risk Factors" section of our
quarterly report on Form 10-Q for the period ended March 31, 2019,
filed with the Securities and Exchange Commission on May 8, 2019.
In addition, the forward-looking statements included in this press
release represent our views as of June 24, 2019. We anticipate that
subsequent events and developments will cause our views to change.
However, while we may elect to update these forward-looking
statements at some point in the future, we specifically disclaim
any obligation to do so.
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Argot Partners Maeve Conneighton 212-600-1902
maeve@argotpartners.com
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