Positive Phase III results demonstrate efficacy of AVYCAZ in complicated urinary tract infections

Allergan plc. has 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.

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.

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.