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

DUBLIN, Oct. 11, 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), seeking the addition of new Phase 3 clinical trial data evaluating AVYCAZ in patients with complicated urinary tract infections (cUTI), including pyelonephritis, due to designated susceptible pathogens to the current product label. The FDA granted priority review status to this application based on the previous Qualified Infectious Disease Product (QIDP) designation for AVYCAZ and is expected to take action on the filing in the first quarter of 2017.

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"The initial AVYCAZ approval represented an important step forward in bringing antibiotics for difficult-to-treat infections to market, allowing us to provide physicians with earlier access to AVYCAZ for their patients in need while continuing to explore the full benefit of the drug," said David Nicholson, Ph.D., Chief R&D Officer, Allergan. "These Phase 3 data offer additional information about the efficacy of AVYCAZ in treating complicated urinary tract infections caused by certain Gram-negative pathogens and add to the complete body of clinical data."

"We look forward to working with the FDA to add these data to the AVYCAZ label and are committed to the ongoing development of our anti-infectives portfolio to ensure physicians have both the access and confidence to use the tools needed to address serious infections," Nicholson said.

AVYCAZ was first approved in the U.S. in February 2015 for the treatment of adult patients with complicated intra-abdominal infections (cIAI), in combination with metronidazole, and cUTI, including pyelonephritis, caused by designated susceptible bacteria, including certain Enterobacteriaceae and Pseudomonas aeruginosa. In June 2016, the FDA approved the addition of data from a Phase 3 cIAI clinical trial to the label that evaluated the safety and efficacy of AVYCAZ, in combination with metronidazole, for the treatment of cIAI including data from a subset of patients with infections caused by ceftazidime-nonsusceptible (CAZ-NS) pathogens and a subset of patients with pathogens producing certain extended-spectrum beta-lactamases (ESBLs).

The application included results from a Phase 3 study evaluating the efficacy and safety of AVYCAZ for the treatment of patients with cUTI, including pyelonephritis. In this study, AVYCAZ demonstrated non-inferiority to doripenem with regard to both co-primary endpoints (patient-reported symptomatic response at Day 5 and the combined patient-reported symptomatic response and microbiological eradication at the Test of Cure [TOC] visit) in the microbiologically modified intent-to treat (mMITT) population. In a subset of patients with cUTI due to CAZ-NS pathogens, as well as a subset who had pathogens that produced certain ESBLs, clinical cure rates for patients treated with AVYCAZ were similar to the overall results. The application also included data from a second open-label Phase 3 study comparing AVYCAZ to best available therapy for treating patients with cUTI due to CAZ-NS pathogens. The results of this study were consistent with the pivotal Phase 3 study evaluating the efficacy and safety of AVYCAZ for the treatment of patients with cUTI.

AVYCAZ has demonstrated in vitro activity against Enterobacteriaceae in the presence of some beta-lactamases and 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.

About AVYCAZ^®
AVYCAZ is an antibiotic developed to treat certain serious Gram-negative bacterial infections. It consists of ceftazidime, a third-generation cephalosporin and 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 caused by designated microorganisms through its in vitro activity against Enterobacteriaceae, including those that produce certain ESBLs and KPCs, and difficult-to-treat Pseudomonas aeruginosa.

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

INDICATIONS AND USAGE

Complicated Intra-Abdominal Infections (cIAI)
AVYCAZ^® (ceftazidime and avibactam), in combination with metronidazole, is indicated for the treatment of complicated intra-abdominal infections (cIAI) caused by the following susceptible Gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Enterobacter cloacae, Klebsiella oxytoca, Citrobacter freundii complex, 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.

In the treatment of cUTI, as only limited clinical safety and efficacy data for AVYCAZ are currently available, reserve AVYCAZ for use in patients with cUTI who have limited or no alternative treatment options.

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 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 of 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 in cIAI (incidence of ≥5% when used with metronidazole) were diarrhea (8%), nausea (7%), and vomiting (5%). In cUTI, the most common adverse reactions (incidence of ≥10%) were 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, Citrobacter freundii complex 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 plc
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 leading brands and best-in-class products for the central nervous system, eye care, medical aesthetics and dermatology, gastroenterology, women's health, urology and anti-infective therapeutic categories.

Allergan is an industry leader in Open Science, the Company's R&D model, which defines our approach to identifying and developing game-changing ideas and innovation for better patient care.  This approach has led to Allergan building one of the broadest development pipelines in the pharmaceutical industry with 65+ mid-to-late stage pipeline programs in development.

Our Company's success is powered by our more than 16,000 global colleagues' commitment to being Bold for Life.  Together, we build bridges, power ideas, act fast and drive results for our customers and patients around the world by always doing what is right.

With commercial operations in approximately 100 countries, Allergan is committed to working with physicians, healthcare 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 Annual Report on Form 10-K for the year ended December 31, 2015 and Quarterly Report on Form 10-Q for the quarter ended June 30, 2016 (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.

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