AstraZeneca, a global, innovation-driven biopharmaceutical business, 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 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.
CAZ-AVI is an antibiotic being developed to treat serious gram-negative bacterial infections which are becoming increasingly resistant to antibiotics and pose a threat to public health. 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-ß lactam ß-lactamase inhibitor. The addition of avibactam to ceftazidime protects ceftazidime from breakdown by ß-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.
In the US, CAZ-AVI (Avycaz) 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 per cent 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 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 per cent. 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 per cent confidence interval for the difference (CAZ-AVI – doripenem) in the percentage of patients for (1) were -2.39 per cent and 10.42 per cent respectively and for (2) were 0.30 per cent and 13.12 per cent 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 per cent. The lower and upper bounds of the 95 per cent confidence interval for the difference (CAZ-AVI – doripenem) in the percentage of patients with a favourable microbiological response were 0.3 per cent and 12.4 per cent respectively. This result shows statistical superiority of CAZ-AVI with the lower limit of the 2-sided 95 per cent 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.