DUBLIN, Sept. 2, 2015 /PRNewswire/ -- (NYSE: AGN)
Allergan plc. today announced positive topline results from
RECAPTURE 1 and 2, the pivotal Phase III studies evaluating
the antibiotic AVYCAZ™ (ceftazidime-avibactam) as a treatment for
adult hospitalized patients with complicated urinary tract
infections (cUTI), including pyelonephritis.
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AVYCAZ consists of a cephalosporin, ceftazidime, an established
treatment for serious bacterial infections, and the first and only
non-beta lactam beta-lactamase inhibitor, avibactam. The addition
of avibactam protects ceftazidime from being broken down by certain
beta-lactamases that are produced by these resistant bacteria.
Ceftazidime-avibactam was approved by the US Food and Drug
Administration (FDA) as AVYCAZ in February
2015 for the treatment of cUTI including pyelonephritis and
complicated intra-abdominal infections (cIAI), in combination with
metronidazole, caused by designated susceptible bacteria,
including certain Enterobacteriaceae and Pseudomonas
aeruginosa for patients 18 years of age and older. AVYCAZ
received a priority review based on Phase II data from the
company's clinical development program and supporting in
vitro data, and as such should be reserved for use in patients
who have limited or no alternative treatment options. In the
EU, the regulatory submission seeking approval for a range of
indications, was accepted and validated by the European Medicines
Agency (EMA) in May 2015 and is
currently under review.
The global RECAPTURE 1 and 2 Phase III studies evaluated the
safety and efficacy of AVYCAZ administered intravenously as a
two-hour infusion (2000/500mg every 8 hours), compared to
doripenem, administered intravenously as a 30-minute infusion
(500mg every 8 hours), in hospitalized adult patients with cUTI,
including pyelonephritis. Data from the studies were analysed as a
single-pooled dataset with the agreement of the US FDA and the
EMA.
In the RECAPTURE 1 and RECAPTURE 2 Phase III studies, AVYCAZ met
the objective of statistical non-inferiority compared to doripenem
for both the EMA primary and FDA co-primary endpoints.
AVYCAZ was also effective in treating cUTI patients infected
with ceftazidime-resistant bacteria.
The most commonly reported adverse events were headache, nausea,
constipation and diarrhea. No new
safety concerns were identified upon review of the most frequent
events up to the late follow-up visit (45–52 calendar days after
randomization).
"We are very pleased by these results, which we plan to submit
to the FDA to further support the use of AVYCAZ as a treatment
option for patients with these serious and life-threatening
complicated urinary tract infections," said David Nicholson, Executive Vice President &
President, Global Brands R&D at Allergan.
Elisabeth Björk, Vice President, Global Medicines Development,
AstraZeneca, said: "These positive results show the efficacy of
CAZ-AVI in treating complicated urinary tract infections, including
those resistant to ceftazidime, and further support regulatory
submissions to make this medicine available to patients.
AstraZeneca is committed to addressing the public health challenge
posed by emerging infections through our portfolio of innovative
antibiotics."
Allergan plans to submit this data as a supplemental New Drug
Application (sNDA) to the Food and Drug Administration by the end
of 2015.
Ceftazidime-avibactam is being jointly developed with
AstraZeneca. Allergan holds the rights to commercialize
ceftazidime-avibactam in North
America, while AstraZeneca holds the rights to commercialize
ceftazidime-avibactam in the rest of the world.
About RECAPTURE
RECAPTURE 1 and RECAPTURE 2 are Phase III, randomized,
multi-center, double-blind, double-dummy, parallel-group,
comparative studies to determine the efficacy, safety, and
tolerability of AVYCAZ (2000 mg / 500 mg, q8h) versus doripenem
(500mg, q8h) in the treatment of complicated urinary tract
infections in hospitalized adults. As agreed with both the US FDA
and the EMA, data from the RECAPTURE 1 and 2 studies have been
analysed as single-pooled dataset. A total of 1033 patients have
been randomized to the RECAPTURE-1 and -2 trials from 30
countries.
For the FDA, the co-primary analysis was conducted in the
Microbiological Modified Intent-to-Treat (mMITT) population and the
non-inferiority margin was 10%. The co-primary endpoints
were:
(1) Symptomatic resolution
of UTI-specific symptoms except flank pain
(frequency/urgency/dysuria/suprapubic pain) and resolution of, or
improvement in, flank pain based on the patient-reported symptom
assessment response at the Day 5 visit and
(2) Proportion of patients
with both a symptomatic resolution of UTI-specific symptoms at
Test of Cure (TOC) visit and a favourable microbiological response
at TOC.
The lower and upper bounds of the 95% confidence interval for
the difference (CAZ-AVI – doripenem) in the percentage of patients
for (1) were -2.39% and 10.42% respectively and for (2) were 0.30%
and 13.12% respectively.
For the EMA, the primary analysis of favourable microbiological
response was conducted at the TOC in the mMITT population and the
non-inferiority margin was 12.5%. The lower and upper bounds of the
95% confidence interval for the difference (CAZ-AVI – doripenem) in
the percentage of patients with a favourable microbiological
response were 0.3% and 12.4% respectively.
The mMITT population included all enrolled patients who met the
cUTI diagnosis criteria and were identified as carrying an eligible
baseline pathogen.
About Ceftazidime-avibactam
Ceftazidime-avibactam is an antibiotic being developed in the EU
to treat serious Gram-negative bacterial infections. It consists of
ceftazidime, a third-generation, antipseudomonal cephalosporin,
that is an established and respected treatment for serious
Gram-negative bacterial infections, and avibactam, the first and
only non-β lactam β-lactamase
inhibitor. The addition of avibactam to ceftazidime protects
ceftazidime from breakdown by certain β-lactamases.
Ceftazidime-avibactam is marketed in the U.S. as AVYCAZ™. As
only limited clinical safety and efficacy data for AVYCAZ are
currently available, AVYCAZ should be reserved for use in patients
who have limited or no alternative treatment options.
AVYCAZ, in combination with metronidazole, is indicated for the
treatment of complicated intra-abdominal infections (cIAI) caused
by the following susceptible microorganisms: Escherichia coli,
Klebsiella pneumoniae, Proteus mirabilis, Providencia stuartii,
Enterobacter cloacae, Klebsiella oxytoca, and Pseudomonas
aeruginosa in patients 18 years or older.
AVYCAZ is also indicated for the treatment of complicated
urinary tract infections (cUTI) including pyelonephritis caused by
the following susceptible microorganisms: Escherichia coli,
Klebsiella pneumoniae, Citrobacter koseri,
Enterobacter aerogenes, Enterobacter cloacae,
Citrobacter freundii, Proteus spp., and
Pseudomonas aeruginosa in patients 18 years or older.
To reduce the development of drug-resistant bacteria and
maintain the effectiveness of AVYCAZ and other antibacterial drugs,
AVYCAZ should be used only to treat infections that are proven or
strongly suspected to be caused by susceptible bacteria.
IMPORTANT SAFETY INFORMATION
CONTRAINDICATIONS
AVYCAZ is contraindicated in patients with known serious
hypersensitivity to AVYCAZ, avibactam‑containing products,
ceftazidime, or other members of the cephalosporin class.
WARNINGS AND PRECAUTIONS
- In a Phase 3 complicated intra-abdominal infections (cIAI)
trial, clinical cure rates were lower in a subgroup of patients
with baseline creatinine clearance (CrCL) of 30 to 50 mL/min
compared to those with CrCL greater than 50 mL/min. The reduction
in clinical cure rates was more marked in patients treated with
AVYCAZ plus metronidazole compared to meropenem-treated patients.
Clinical cure rates in patients with normal renal function/mild
renal impairment (CrCL greater than 50 mL/min) was 85% (322/379)
with AVYCAZ plus metronidazole vs 86% (321/373) with meropenem, and
clinical cure rates in patients with moderate renal impairment
(CrCL 30 to 50 mL/min) was 45% (14/31) with AVYCAZ plus
metronidazole vs 74% (26/35) with meropenem. Within this subgroup,
patients treated with AVYCAZ received a 33% lower daily dose than
is currently recommended for patients with CrCL 30 to 50 mL/min.
Monitor CrCL at least daily in patients with changing renal
function and adjust the dosage of AVYCAZ accordingly.
- Serious and occasionally fatal hypersensitivity (anaphylactic)
reactions and serious skin reactions have been reported in patients
receiving beta-lactam antibacterial drugs. Before therapy with
AVYCAZ is instituted, careful inquiry about previous
hypersensitivity reactions to other cephalosporins, penicillins, or
carbapenems should be made. Exercise caution if this product is to
be given to a penicillin or other beta-lactam-allergic patient
because cross sensitivity among beta-lactam antibacterial drugs has
been established. Discontinue the drug if an allergic reaction to
AVYCAZ occurs.
- Clostridium difficile-associated diarrhea (CDAD) has
been reported for nearly all systemic antibacterial drugs,
including AVYCAZ, and may range in severity from mild diarrhea to
fatal colitis. Careful medical history is necessary because CDAD
has been reported to occur more than 2 months after the
administration of antibacterial drugs. If CDAD is suspected or
confirmed, antibacterials not directed against C. difficile
should be discontinued, if possible.
- Seizures, nonconvulsive status epilepticus, encephalopathy,
coma, asterixis, neuromuscular excitability, and myoclonia have
been reported in patients treated with ceftazidime, particularly in
the setting of renal impairment. Adjust dosing based on creatinine
clearance.
- Prescribing AVYCAZ 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 (incidence of ≥10% in either indication) were vomiting
(14%), nausea (10%), constipation (10%), and anxiety (10%).
Please see full Prescribing Information for AVYCAZ at
www.avycaz.com.
About ALLERGAN
Allergan plc (NYSE: AGN), headquartered in Dublin, Ireland, is a unique, global
pharmaceutical company and a leader in a new industry model—Growth
Pharma. Allergan is focused on developing, manufacturing, and
commercializing innovative branded pharmaceuticals, high-quality
generic and over-the-counter medicines, and biologic products for
patients around the world.
Allergan markets a portfolio of best-in-class products that
provide valuable treatments for the central nervous system, eye
care, medical aesthetics, gastroenterology, women's health,
urology, cardiovascular and anti-infective therapeutic categories,
and operates the world's third-largest global generics business,
providing patients around the globe with increased access to
affordable, high-quality medicines. Allergan is an industry leader
in research and development, with one of the broadest development
pipelines in the pharmaceutical industry and a leading position in
the submission of generic product applications globally.
With commercial operations in approximately 100 countries,
Allergan is committed to working with physicians, health care
providers, and patients to deliver innovative and meaningful
treatments that help people around the world live longer, healthier
lives.
For more information, visit Allergan's website at
www.allergan.com.
About AstraZeneca
AstraZeneca is a global, innovation-driven biopharmaceutical
business that focuses on the discovery, development and
commercialization of prescription medicines, primarily for the
treatment of cardiovascular, metabolic, respiratory, inflammation,
autoimmune, oncology, infection and neuroscience diseases.
AstraZeneca operates in over 100 countries and its innovative
medicines are used by millions of patients worldwide. For more
information please visit: www.astrazeneca.com
Forward-Looking Statement
Statements contained in this press release that refer to future
events or other non-historical facts are forward-looking statements
that reflect Allergan's current perspective of existing
trends and information as of the date of this release. Except as
expressly required by law, Allergan disclaims any intent
or obligation to update these forward-looking statements. Actual
results may differ materially from Allergan's current
expectations depending upon a number of factors
affecting Allergan's business. These factors include,
among others, the difficulty of predicting the timing or outcome
of FDA approvals or actions, if any; the impact of
competitive products and pricing; market acceptance of and
continued demand for Allergan's products; difficulties or
delays in manufacturing; and other risks and uncertainties detailed
in Allergan's periodic public filings with
the Securities and Exchange Commission, including but not
limited to Allergan's Quarterly Report on Form 10-Q for
the quarter ended March 31, 2015 (such periodic public
filings having been filed under the "Actavis plc" name). Except as
expressly required by law, Allergan disclaims any intent or
obligation to update these forward-looking statements.
Contacts:
Investors:
Lisa Defrancesco
862-261-7152
Media:
Mark Marmur
973-906-1526
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SOURCE Allergan plc