FDA Accepts and Grants Priority Review for AVYCAZ® (ceftazidime and avibactam) Supplemental New Drug Application (sNDA)

DUBLIN, Feb. 24, 2016 /PRNewswire/ -- Allergan plc (NYSE: AGN), a leading global pharmaceutical company, today announced the U.S. Food and Drug Administration (FDA) has accepted for filing the company's supplemental New Drug Application (sNDA) for AVYCAZ^® (ceftazidime and avibactam). This filing will add important new clinical data to the current label from two Phase 3 trials evaluating the safety and efficacy of AVYCAZ, in combination with metronidazole, for the treatment of complicated intra-abdominal infections (cIAI), including patients with infections due to ceftazidime-nonsusceptible (CAZ-NS) pathogens. The FDA granted priority review status to this application based on the previous Qualified Infectious Disease Product (QIDP) designation for AVYCAZ. Allergan expects the Agency to take action on the filing in the second quarter of 2016.

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AVYCAZ was first approved in the U.S. in February 2015 for the treatment of adult patients with cIAI, in combination with metronidazole, and complicated urinary tract infections (cUTI), including pyelonephritis, caused by designated susceptible bacteria, including certain Enterobacteriaceae and Pseudomonas aeruginosa. This original approval was based on Phase 2 data from the company's clinical development program and supporting in vitro data, and as a result, the current labeling denotes AVYCAZ should be reserved for use in cIAI and cUTI patients who have limited or no alternative treatment options.

"Since its approval, AVYCAZ has provided physicians with a treatment option to address complicated intra-abdominal infections caused by certain Gram-negative pathogens for which physicians currently have limited or no options," said David Nicholson, Ph.D., President and Executive Vice President, Global R&D, Allergan. "This acceptance is encouraging, as the inclusion of full Phase 3 clinical data to the label further demonstrates the safety and efficacy of AVYCAZ in difficult-to-treat infections and provides physicians further validation of the drug's spectrum of activity against pathogens of greatest concern."

"We look forward to working with the FDA in the coming months to add these data to the AVYCAZ label. We are committed to the ongoing development of our anti-infective portfolio to help the healthcare community respond effectively to serious infections," Nicholson said.

The application included results from two Phase 3 studies, which evaluated the efficacy and safety of AVYCAZ, in combination with metronidazole, for the treatment of patients with cIAI, including patients with infections due to Gram-negative pathogens that met pre-specified criteria for pathogens resistant to ceftazidime alone but susceptible to AVYCAZ. In these studies, clinical cure rates at the Test of Cure (TOC) time point met the primary endpoint of statistical non-inferiority to meropenem. AVYCAZ has demonstrated in vitro activity against Enterobacteriaceae in the presence of some beta-lactamases and extended-spectrum beta-lactamases (ESBLs) of the following groups: TEM, SHV, CTX-M, Klebsiella pneumoniae carbapenemase (KPCs), AmpC and certain oxacillinases (OXA). AVYCAZ also demonstrated in vitro activity against Pseudomonas aeruginosa in the presence of some AmpC beta-lactamases, and certain strains lacking outer membrane porin (OprD). AVYCAZ is not active against bacteria that produce metallo-beta lactamases and may not have activity against Gram-negative bacteria that overexpress efflux pumps or have porin mutations.

Phase 3 studies evaluating the safety and efficacy of AVYCAZ for the treatment of cUTI have been completed and the data is being analyzed for submission later this year.

Ceftazidime and avibactam is being jointly developed with AstraZeneca. Allergan holds the rights to commercialize ceftazidime and avibactam in North America, while AstraZeneca holds the rights to commercialize the combination in the rest of the world.

About AVYCAZ
AVYCAZ is an antibiotic developed to treat certain serious Gram-negative bacterial infections. It consists of ceftazidime, a third-generation cephalosporin, that is an established and respected treatment for serious Gram-negative bacterial infections, and avibactam, a non-β lactam β-lactamase inhibitor.

The addition of avibactam to ceftazidime protects ceftazidime from breakdown by certain β-lactamases. AVYCAZ offers a differentiated profile in the treatment of cIAI, (in combination with metronidazole, and cUTI through its in vitro activity against Enterobacteriaceae, including those that produce certain ESBL and KPC, and difficult-to-treat Pseudomonas aeruginosa.

INDICATIONS AND USAGE
As only limited clinical safety and efficacy data for AVYCAZ (ceftazidime and avibactam) are currently available, reserve AVYCAZ for use in patients who have limited or no alternative treatment options.

Complicated Intra-Abdominal Infections (cIAI)
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.

Complicated Urinary Tract Infections (cUTI), including Pyelonephritis
AVYCAZ is 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.

Usage
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 the components of AVYCAZ (ceftazidime and avibactam), avibactam‑containing products, 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 less than or equal 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 less than or equal 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 less than or equal 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 Gram-Negative Infections
Gram-negative bacteria are highly adaptive pathogens that can develop resistance through several mechanisms and can pass along genetic materials that allow other bacteria to become drug-resistant as well. Gram-negative bacteria are common causes of complicated intra-abdominal infections and urinary tract infections.

Complicated intra-abdominal infections are a considerable problem. The most common pathogens associated with complicated intra-abdominal infections include Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Providencia stuartii, Enterobacter cloacae, Klebsiella oxytoca and Pseudomonas aeruginosa.

Complicated urinary tract infections are also often caused by Gram-negative pathogens. Escherichia coli (E. coli) is one of the common organisms causing complicated urinary tract infections (UTIs), and is becoming increasingly resistant to available antibiotics.

According to the Centers for Disease Control and Prevention (CDC), rates of Klebsiella pneumoniae carbapenemase (KPC) producing organisms in particular have increased across the country significantly in the past 10 years. In addition, E. coli, Klebsiella (K. pneumoniae and K. oxytoca) and Pseudomonas aeruginosa are on the rise.

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 September 30, 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.

SOURCE Allergan plc

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