AstraZeneca : Positive Phase III results demonstrate efficacy of antibiotic medicine CAZ-AVI in complicated Urinary Tract Infections

AstraZeneca today announced positive topline results from RECAPTURE 1 and RECAPTURE 2, the pivotal Phase III studies evaluating the antibiotic, CAZ-AVI (ceftazidime-avibactam), as a treatment for adult hospitalised patients with complicated Urinary Tract Infections (cUTI), including pyelonephritis.

CAZ-AVI consists of a cephalosporin (ceftazidime), an established treatment for serious bacterial infections, and a next generation non-beta lactam beta-lactamase inhibitor (avibactam). CAZ-AVI is being developed to treat a broad range of Gram-negative bacterial infections which are becoming increasingly resistant to antibiotics and pose a threat to public health. The addition of avibactam protects ceftazidime from being broken down by beta-lactamases that are produced by these resistant bacteria.

In the US, where AstraZeneca's partner Allergan holds the commercialisation rights, CAZ-AVI (AVYCAZTM) was approved by the Food and Drug Administration (FDA) in February 2015 for cUTI and complicated intra-abdominal Infections (cIAI) for patients 18 years of age and older who currently have limited or no alternative treatment options, based on a previously submitted New Drug Application with Phase II data. In the EU, where AstraZeneca holds the commercialisation rights, the regulatory submission seeking approval for a broad 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 RECAPTURE 2 Phase III studies evaluated the safety and efficacy of CAZ-AVI, 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 hospitalised 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, CAZ-AVI met the objective of statistical non-inferiority compared to doripenem for both the EMA primary and FDA co-primary endpoints. Additionally, for the EMA primary endpoint, CAZ-AVI was statistically superior (at the 5% level) to doripenem.

CAZ-AVI was also effective in treating cUTI patients infected with ceftazidime-resistant bacteria.

The most commonly reported adverse events were headache, nausea, constipation and diarrhoea. 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 randomisation).

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."

"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.

The RECAPTURE data will be provided to the EMA as part of the regulatory review process for the on-going CAZ-AVI Marketing Authorisation Application.

RECAPTURE 1 and RECAPTURE 2 are Phase III, randomised, multi-centre, double-blind, double-dummy, parallel-group, comparative studies to determine the efficacy, safety, and tolerability of CAZ-AVI(2000 mg / 500 mg, q8h) versus doripenem (500mg, q8h) in the treatment of complicated urinary tract infections in hospitalised 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 randomised to the RECAPTURE1 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.

For the EMA, the primary analysis of Favourable microbiological response was conducted at the TOC in the mMITT population and the non-inferiority margin was 12.5%. The lower and upper bounds of the 95% confidence interval for the difference (CAZ-AVI - doripenem) in the percentage of patients with a favourable microbiological response were 0.3% and 12.4% respectively. This result shows statistical superiority of CAZ-AVI with the lower limit of the 2-sided 95% confidence interval for the treatment difference of 0.33 being above zero.

The mMITT population included all enrolled patients who met the cUTI diagnosis criteria and were identified as carrying an eligible baseline pathogen.

CAZ-AVI is an antibiotic being developed 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, a next generation, non-β lactam β-lactamase inhibitor.

The addition of avibactam to ceftazidime protects ceftazidime from breakdown by β-lactamases. CAZ-AVI offers a differentiated profile versus existing treatment options in serious Gram-negative infections through its coverage of a broad range of species of Enterobacteriaceae including those that produce ESBL and KPC together with activity against difficult to treat Pseudomonas aeruginosa.

CAZ-AVI is being jointly developed with Allergan. AstraZeneca holds the global rights to commercialise CAZ-AVI, with the exception of North America where the rights are held by 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 commercialising 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.

AstraZeneca is a global, innovation-driven biopharmaceutical business that focuses on the discovery, development and commercialisation 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

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Key: RIA - Respiratory, Inflammation and Autoimmunity, CVMD - Cardiovascular and Metabolic Disease, ING - Infection, Neuroscience and Gastrointestinal

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