AstraZeneca today announced positive results from the Phase III REPROVE trial for Zavicefta (ceftazidime-avibactam), a new combination antibiotic for the treatment of a broad range of serious Gram-negative bacterial infections in hospitalised patients. Zavicefta has been developed in response to the urgent need for new antibiotics to treat serious infections that are becoming increasingly resistant to current antibiotics commonly used for serious infections, such as carbapenems and polymixins, including colistin.
The REPROVE trial assessed the efficacy of Zavicefta (ceftazidime-avibactam) compared with meropenem in the treatment of adult patients with hospital-acquired pneumonia (HAP), including ventilator-associated pneumonia (VAP). Zavicefta met the primary objective of statistical non-inferiority compared to meropenem at the test of cure visit (day 21 from randomisation). All-cause mortality rate at day 28 from randomisation was also similar in the two groups. Safety observed in the trial was consistent with the known safety profiles of both antibiotics. Full results from REPROVE are expected to be presented at future scientific meetings.
Hans Sijbesma, Managing Director, AstraZeneca Antibiotics Business Unit, said: “The positive results from this important Phase III trial validate our science-led approach and confirm the effectiveness of Zavicefta in treating hospital-acquired pneumonia, providing patients and physicians with a much-needed new treatment option in the fight against antibiotic-resistant pathogens.”
On 24 June 2016, Zavicefta was approved by the European Commission for intravenous use in the treatment of adult patients suffering from HAP, including VAP, as well as: Complicated intra-abdominal infections (cIAI); complicated urinary tract infections (cUTI), including pyelonephritis; and the treatment of aerobic Gram-negative infections in adult patients who have limited treatment options.
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NOTES TO EDITORS
REPROVE is a Phase III, randomised, multi-centre, double-blind, double-dummy, parallel-group, comparative trial to determine the efficacy, safety and tolerability of ceftazidime-avibactam administered intravenously as a two-hour infusion (2000 mg / 500 mg, every 8 hours, compared to meropenem, administered intravenously as a 30 minute infusion (1000 mg every 8 hours). A total of 879 patients were randomised to the REPROVE trial from 23 countries.
The primary endpoint was assessed in the clinically modified intent-to-treat (cMITT) and clinically evaluable (CE) trial populations. The cMITT population consists of all patients dosed who met clinical disease criteria, had microbiologically confirmed Gram-negative respiratory pathogens (with or without concomitant Gram-positive pathogens) and in whom no specific, disease-causing (e.g. etiologic) pathogens were identified. Patients with infections caused by Gram-negative pathogens not expected to respond to either trial drug were excluded from the cMITT analysis. The CE population consists of patients who met the cMITT criteria and also had an evaluable assessment, no important protocol deviations that would affect efficacy, received adequate treatment and received no unacceptable prior/concomitant antibiotics.
The non-inferiority margin was 12.5%.
Zavicefta (ceftazidime-avibactam) is a combination antibiotic that has been developed to treat serious Gram-negative bacterial infections. It consists of a combination of avibactam and ceftazidime – a third generation antipseudomonal cephalosporin with a well-established efficacy and safety profile. Avibactam is a first-in-class broad-spectrum β-lactamase inhibitor, which protects ceftazidime against degradation by Class A, C and some D β-lactamases.
Zavicefta offers a differentiated profile versus existing treatment options in serious Gram-negative infections through its coverage of a broad range Enterobacteriaceae species, including those that produce ESBL and KPC, together with activity against difficult-to-treat P. aeruginosa.
Zavicefta has previously demonstrated non-inferiority to comparators in Phase III trials in hospitalised adult patients with cIAI (RECLAIM 1 and 2) and cUTI (RECAPTURE 1 and 2). In addition, Zavicefta demonstrated statistically significant superior efficacy compared to doripenem for the European Medicines Agency-specified primary endpoint in the RECAPTURE trials. In the REPRISE trial, which evaluated the efficacy and safety of Zavicefta in patients with cIAI or cUTI infections caused by ceftazidime-resistant Gram-negative pathogens, efficacy was similar to best available treatment, and substantially higher microbiological cure rates were observed in cUTI patients treated with Zavicefta.
Ceftazidime-avibactam is being jointly developed by AstraZeneca and Allergan. AstraZeneca holds the global rights to commercialise Zavicefta, with the exception of North America, where the rights are held by Allergan.
About Hospital-Acquired Pneumonia (HAP) including Ventilator-Associated Pneumonia (VAP)
Hospital-acquired pneumonia (HAP), also known as nosocomial pneumonia, refers to the development of lung infections after a patient has been hospitalised for a minimum of 48 hours. If, after 48 hours, the infection develops during the use of intubation and mechanical ventilation, the condition is then called ventilator-associated pneumonia (VAP).
VAP is generally a severe illness, with patients requiring treatment in the intensive care unit (ICU). Some non-intubated patients with HAP can have either mild or more severe pneumonia.
Nosocomial pneumonia and HAP have similar clinical characteristics and the terms are often used interchangeably.
AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialisation of prescription medicines, primarily for the treatment of diseases in three therapy areas – Respiratory and Autoimmunity, Cardiovascular and Metabolic Diseases, and Oncology. The company is also active in inflammation, infection and neuroscience through numerous collaborations. 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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