— First Gram-Negative Antibiotic Approved in the U.S. to Treat HABP/VABP in Over 15 Years —

DUBLIN, Feb. 1, 2018 /PRNewswire/ — Allergan plc (NYSE: AGN), a leading global pharmaceutical company, today announced that the U.S. Food and Drug Administration (FDA) has approved Allergan's supplemental New Drug Application (sNDA) to expand the approved use of AVYCAZ^® (ceftazidime and avibactam) to include the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP) caused by the following susceptible Gram-negative microorganisms: Klebsiella pneumoniae, Enterobacter cloacae, Escherichia coli, Serratia marcescens, Proteus mirabilis, Pseudomonas aeruginosa, and Haemophilus influenzae in patients 18 years of age or older. This expanded use is based on positive results from a pivotal Phase 3 study evaluating the efficacy and safety of AVYCAZ for the treatment of adult patients with HABP/VABP. The sNDA received priority review from FDA based on the Qualified Infectious Disease Product (QIDP) designation for the HABP/VABP indication.

Certain types of Gram-negative bacteria have become increasingly resistant to available antibiotics, resulting in increased illness and death as well as contributing to escalating healthcare costs.¹ New strategies to fight these challenging infections have been long-awaited by the medical community.

"Healthcare providers in the U.S. have not had access to a new treatment option for patients with HABP/VABP due to Gram-negative bacteria in over 15 years," said David Nicholson, Ph.D., Chief Research and Development Officer, Allergan. "Gram-negative pathogens are some of the most pressing antibiotic resistance threats and cause more than 40,000 resistant infections in the U.S. annually. Today's action by the FDA is further evidence of Allergan's commitment to improving outcomes and meeting critical needs in patients with life-threatening infectious diseases."

This is the third therapeutic indication for AVYCAZ. AVYCAZ was first approved in February 2015 in the U.S. for the treatment of adult patients with complicated intra-abdominal infections (cIAI), in combination with metronidazole, and in 2017 for complicated urinary tract infections (cUTI), including pyelonephritis, caused by designated susceptible Gram-negative bacteria, including certain Enterobacteriaceae and Pseudomonas aeruginosa.

"Clinical efficacy along with patient safety are critical priorities to clinicians managing serious Gram-negative bacterial infections. We are thrilled to have a new option available to treat HABP/VABP, some of the most challenging Gram-negative infections in the hospital setting," said Jose Vazquez, M.D., FIDSA, Division Chief and Professor of Medicine Infectious Diseases, Medical College of Georgia/Augusta University, Augusta, GA.

Data Supporting the Approval
A total of 870 hospitalized adult patients with HABP or VABP were randomized and received trial medications in a pivotal Phase 3, multinational, double-blind trial (REPROVE) comparing AVYCAZ 2.5 g (ceftazidime 2 grams and avibactam 0.5 grams) intravenously every 8 hours to meropenem 1 gram intravenously every 8 hours, for 7 to 14 days of therapy. Study medication dosages were adjusted per renal function. The protocol allowed for administration of prior and concomitant systemic antibacterial therapy for patients with proven or suspected Gram-positive or drug resistant infections.

Clinical efficacy was evaluated in the intent-to treat (ITT) population, which included all randomized patients who received study drug. Overall, 379 (43.6%) patients were ventilated at enrollment, including 290 (33.3%) patients with VABP and 89 (10.2%) with ventilated-HABP. Bacteremia at baseline was present in 4.8% of patients.

The primary efficacy endpoint of the study was 28-day all-cause mortality (28 to 32 days after randomization) in the ITT population. The study successfully demonstrated that AVYCAZ was non-inferior to meropenem with respect to the primary endpoint based on a 10% non-inferiority margin; the 28-day all-cause mortality rate was 9.6% (42/436) in patients treated with AVYCAZ compared with 8.3% (36/434) in meropenem treated patients (treatment difference of 1.5%; 95% confidence interval [CI]: -2.4, 5.3).  

At baseline, 108/382 (28.3%) of patients in the microbiological intent-to-treat (micro-ITT) population, which included all patients with positive culture results indicating the presence of at least one Gram-negative pathogen, had Gram-negative isolates that were not susceptible to ceftazidime, including 53 patients with K. pneumoniae and 28 patients with P. aeruginosa isolates. The 28-day all-cause mortality in patients with ceftazidime non-susceptible Gram-negative isolates was 8.2% in the AVYCAZ arm and 8.5% in the meropenem arm.

AVYCAZ demonstrated a safety profile consistent with that observed in prior clinical trials with AVYCAZ and with the established safety profile for ceftazidime alone. The most common adverse reactions (≥ 5%) in HABP/VABP patients were diarrhea and vomiting.  

Hospital-Acquired Bacterial Pneumonia/Ventilator-Associated Bacterial Pneumonia (HABP/VABP)
Hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP) are serious bacterial infections that occur in hospitalized patients, which are associated with critically ill and vulnerable populations. The Gram-negative bacteria that commonly cause HABP/VABP include the Enterobacteriaceae (including Klebsiella penumoniae, Escherichia coli, Enterobacter cloacae, Proteus mirabilis) and Pseudomonas aeruginosa.

The economic burden associated with HABP/VABP is significant. These infections are associated with increased healthcare costs, high morbidity and mortality, and lengthened hospital stays. HABP/VABP is currently the second most common type of nosocomial infection in the U.S., especially in the intensive care unit (ICU) of hospitals.²

About AVYCAZ
AVYCAZ is a fixed-dose combination antibacterial indicated for the treatment of HABP/VABP, cIAI (in combination with metronidazole), and cUTI caused by designated susceptible Gram-negative microorganisms in patients 18 years or older. AVYCAZ consists of a combination of avibactam and ceftazidime.

Avibactam is a first-in-class non-beta-lactam beta-lactamase inhibitor which protects ceftazidime against degradation by certain beta-lactamases. Avibactam does not decrease the activity of ceftazidime against ceftazidime-susceptible organisms. Ceftazadime is a third-generation cephalosporin with a well-established efficacy and safety profile.

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 pneumoniaecarbapenemase (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

Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia (HABP/VABP)
AVYCAZ (ceftazidime and avibactam) is indicated for the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP) caused by the following susceptible Gram-negative microorganisms: Klebsiella pneumoniae, Enterobacter cloacae, Escherichia coli, Serratia marcescens, Proteus mirabilis, Pseudomonas aeruginosa, and Haemophilus influenzae in patients 18 years or older.

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 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. 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. Clinical cure rate 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 rate 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. The decreased clinical response was not observed for patients with moderate renal impairment at baseline (CrCl 30 to less than or equal to 50 mL/min) in the Phase 3 cUTI trials or the Phase 3 HABP/VABP trial. 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 CrCl.
  
  
• 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. The most common adverse reactions in HABP/VABP patients (≥ 5%) were diarrhea (15%) and vomiting (6%).

Please also see the full Prescribing Information at www.AVYCAZ.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 on existing trends and information as of the date of this release. 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; the impact of uncertainty around timing of generic entry related to key products, including RESTASIS^®, on our financial results; uncertainty associated with financial projections, projected cost reductions, projected synergies, restructurings, increased costs, and adverse tax consequences; 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, 2016 and Allergan's Quarterly Report on Form 10-Q for the period ended September 30, 2017. Except as expressly required by law, Allergan disclaims any intent or obligation to update these forward-looking statements.

1 Examples of Antimicrobial (Drug) Resistance/Gram-Negative Bacteria, National Institute of Allergy and Infectious Diseases, https://www.niaid.nih.gov/research/gram-negative-bacteria 

2 Analytical Framework for Examining the Value of Antibacterial Products, U.S. Dept. of Health and Human Services, https://aspe.hhs.gov/system/files/pdf/76891/rpt_antibacterials.pdf

SOURCE Allergan plc

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