FDA Approves Allergan's sNDA for AVYCAZ® (ceftazidime and avibactam) to include new Phase III data in Patients with Complicated Urinary Tract Infections (cUTI), Including Pyelonephritis

DUBLIN, Jan. 30, 2017 /PRNewswire/ -- Allergan plc (NYSE: AGN), a leading global pharmaceutical company, today announced the U.S. Food and Drug Administration (FDA) has approved the company's supplemental New Drug Application (sNDA) to update the label for AVYCAZ^® (ceftazidime and avibactam) with clinical data from two Phase 3 trials supporting the indication to treat patients with complicated urinary tract infections (cUTI), including pyelonephritis, caused by designated susceptible Gram-negative microorganisms.

In Trial 1, known as RECAPTURE, AVYCAZ was non-inferior to doripenem with regard to both primary endpoints. In Trial 2, known as REPRISE, AVYCAZ demonstrated a higher combined clinical and microbiological cure rate vs. best available therapy (BAT), including meropenem, imipenem, doripenem, and colistin. Additionally, both trials included a subset of patients with infections caused by pathogens producing certain ESBL groups and AmpC beta-lactamases in which the clinical and microbiological cure rates were similar to the overall results.

The prevalence of infections caused by resistant Gram-negative bacteria, specifically extended spectrum beta-lactamase (ESBL) and Klebsiella pneumoniae carbapenamase (KPC)-producing carbapenem-resistant Enterobacteriaceae (CRE), and resistant Pseudomonas aeruginosa have steadily increased in recent years; this has led the U.S. Centers for Disease Control and Prevention (CDC) to classify these pathogens as urgent and serious public health threats, as there are very limited treatment options.   

"Gram-negative pathogens are among the most urgent antibiotic resistance threats and cause more than 40,000 resistant infections in the U.S. alone each year," said David Nicholson, Ph.D., Chief R&D Officer, Allergan. "This new sNDA approval for AVYCAZ is based on a large clinical database, comprising data from more than 1,300 patients with cUTI across Phase 3 studies, including a number of patients with infections due to ceftazidime non-susceptible (CAZ-NS) pathogens. It provides physicians with further clinical evidence that will assist them in making informed treatment decisions for their patients with cUTI, including those with difficult to treat pathogens."

"The successful cumulative Phase 3 cUTI studies further validate the initial FDA approval of AVYCAZ based on Phase 2 data. The inclusion of the REPRISE data in the label represents a significant advancement in the available data to support efficacy in cUTI patients infected with challenging pathogens, including certain ESBL and KPC-producing Enterobacteriaceae, reinforcing Allergan's leadership in responding to some of the most challenging infections facing our society today."

Trial 1: RECAPTURE
In this pivotal multicenter, double-blind, Phase 3 study of 1,020 adults hospitalized with cUTI, AVYCAZ was non-inferior to doripenem with regard to both primary endpoints (patient-reported symptomatic response at Day 5 and combined patient-reported symptomatic response and microbiological cure at the Test of Cure [TOC] visit) in the microbiologically modified intent-to-treat (mMITT) population.  The symptomatic response rate at Day 5 in the AVYCAZ treated patients was 70.2% (276/393) compared to 66.2% (276/417) in doripenem treated patients, a treatment difference of 4.0% (95% confidence interval [CI]: -2.4, 10.4). The combined symptomatic and microbiological response rate at TOC in the AVYCAZ treated patients was 71.2% (280/393) compared to 64.5% (269/417) in doripenem treated patients, a treatment difference of 6.7% (95% CI: 0.3 to 13.1).

AVYCAZ was effective in treating a subset of 75 cUTI patients infected with CAZ-NS pathogens. Additionally, in a subset of patients (n= 86 in the AVYCAZ group) with infections caused by pathogens producing certain ESBL groups (e.g. TEM-1, SHV-12, CTX-M15 and OXA-48) and AmpC, the microbiological and clinical cure rates were similar to the overall trial results.

Trial 2: REPRISE
In the multicenter, open-label, Phase 3 study of 305 patients with cUTI caused by ceftazidime non-susceptible Gram-negative pathogens, the combined clinical and microbiological cure rate at Days 21 to 25 in the mMITT population was higher in AVYCAZ-treated patients than in patients on BAT. The combined cure rates were 70.1% (101/144) for patients treated with AVYCAZ and 54% (74/137) for BAT-treated patients, a treatment difference of 16.1% (CI 95%; 4.8 to 27.1).

AVYCAZ was effective in treating a subset of cUTI patients with pathogens containing certain ESBL groups (including select KPCs and OXA-48) and AmpC beta-lactamases. Clinical and microbiological cure rates in this subset were similar to the overall trial results.

About AVYCAZ^®

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 pathogens, including certain Enterobacteriaceae and Pseudomonas aeruginosa. In June 2016, the FDA approved the addition of Phase 3 cIAI clinical data to the label that evaluated the safety and efficacy of AVYCAZ, in combination with metronidazole in cIAI patients, including subsets of patients with infections caused by CAZ-NS pathogens and pathogens producing certain ESBLs.

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.

Ceftazidime and avibactam is being jointly developed with Pfizer. Allergan holds the rights to commercialize ceftazidime and avibactam in North America under the brand name AVYCAZ, while Pfizer 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 Gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Citrobacter freundii complex, Proteus mirabilis, 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 to treat only indicated 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. The decreased clinical response was not observed for patients with moderate renal impairment at baseline (CrCl of 30 to less than or equal to 50 mL/min) in the Phase 3 cUTI trials. 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 (NCSE), 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 patients (≥5% when used with metronidazole) were diarrhea (8%), nausea (7%), and vomiting (5%). The most common adverse reactions in cUTI patients (3%) were diarrhea and nausea.

Please see full Prescribing Information for AVYCAZ at www.avycaz.com.

About Gram-Negative Infections
According to the Centers for Disease Control and Prevention (CDC), rates for certain Gram-negative bacteria have increased significantly across the country. 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.

About Allergan plc
Allergan plc (NYSE: AGN), headquartered in Dublin, Ireland, is a bold, global pharmaceutical company and a leader in a new industry model – Growth Pharma. Allergan is focused on developing, manufacturing and commercializing branded pharmaceuticals, devices 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 70+ 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 every day.

For more information, visit Allergan's website at www.Allergan.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 September 30, 2016 (certain of 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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