Date: 2015-04-27
Type of information: Presentation of results at a congress
phase: 3
Announcement: presentation of results at 25th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID)
Company: AstraZeneca (UK) Forest Laboratories (USA - NJ), an Actavis' subsidiary (Ireland)
Product: ceftazidime/avibactam (CAZ-AVI)
Action
mechanism: antibiotic/cephalosporine/beta-lactamase inhibitor. 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 resistant to antibiotics and pose an increasing threat to public health. The addition of avibactam protects ceftazidime from being broken down by beta-lactamases that are produced by resistant bacteria. CAZ-AVI is being jointly developed with Forest Laboratories, a wholly-owned subsidiary of Actavis, now Allergan.
Disease: Gram-negative bacterial infections including Complicated Intra-Abdominal Infections (cIAI) and Complicated Urinary Tract Infections
Therapeutic area: Infectious diseases
Country:
Trial
details: The planned phase III development programme is designed to demonstrate that CAZ-AVI is an effective and well tolerated treatment for use in patients with complicated IAI / or complicated UTI Gram negative infections including those where pathogens resistant to commonly used antibiotics (such as extended-spectrum beta-lactamases producing Enterobacteriaceae with resistance to penicillins and third generation cephalosporins) are known or suspected. RECLAIM-1 and RECLAIM-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 administered intravenously as a two hour infusion (2000 mg / 500 mg, every 8 hours), plus metronidazole, administered intravenously as a 60 minute infusion (0.5 g every 8 hours), compared to meropenem, administered intravenously as a 30 minute infusion (1 g every 8 hours). A total of 1,066 patients have been randomised to the RECLAIM-1 and RECLAIM-2 trials from 30 countries. For the EMA, the co-primary analysis was conducted at the Test of Cure (TOC) in the Modified-Intent-to-Treat (MITT) and Clinically Evaluable (CE) patient populations. The non-inferiority margin was 12.5%; and the lower and upper bounds of the 95% confidence interval were -6.9% and 2.10% respectively for the MITT population and -4.61% and 2.89% for the CE population. For the FDA, the primary analysis was conducted at the TOC in the Microbiological Modified Intent-to-Treat (mMITT) population and the non-inferiority margin was 10%. The lower and upper bounds of the 95% confidence interval were -8.64% and 1.58% respectively. The MITT population included all enrolled patients who received at least one dose of the study drug; the CE population are the patients who completed their course of treatment without deviation from the study protocol; and the mMITT population are those patients from the MITT group who were identified as carrying a pathogen at the start of treatment.
This study programme will include five phase III trials designed to demonstrate that CAZ-AVI is an effective and well tolerated treatment for patients with cIAI and cUTI including those patients with infections that may be resistant to currently available antibiotics.
This study programme builds on results from two separate CAZ-AVI phase II trials:
• The cIAI Phase II trial showed that the efficacy of CAZ-AVI given with metronidazole in adult patients was similar to meropenem, an established treatment given to patients with Complicated Intra-Abdominal Infections
• The cUTI Phase II trial showed that the efficacy of CAZ-AVI in adult patients was similar to imipenem cilastatin, an established treatment given to patients with Complicated Urinary Tract Infections
• The data from both trials showed that CAZ-AVI in general was well tolerated.
Latest
news: * On April 27, 2015, AstraZeneca presented Phase III data demonstrating the efficacy and safety of ceftazidime-avibactam (CAZ-AVI), an investigational antibiotic being developed to treat serious Gram-negative bacterial infections including complicated intra-abdominal infections at 25th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID). Full Phase III results for the global RECLAIM-1 and RECLAIM-2 studies were presented at ECCMID. Both studies evaluated the safety and efficacy of CAZ-AVI, administered intravenously (IV) as a two hour infusion (2000 mg / 500 mg) every eight hours plus metronidazole 500 mg IV as a one hour infusion every eight hours, compared to meropenem, administered intravenously as a 30 minute infusion (1 g) every eight hours, in hospitalised adult patients with presumed or definite diagnosis of complicated intra-abdominal infections. Data from the RECLAIM-1 and RECLAIM-2 studies were analysed as a single-pooled dataset with the agreement of the FDA and the EMA. Results showed CAZ-AVI met the objective of statistical non-inferiority compared to meropenem. The number of patients randomised to CAZ-AVI plus metronidazole was 532, with 534 randomised to meropenem. The primary endpoint was a clinical cure rate 28 to 35 days after randomisation (the Test of Cure visit). Findings also showed CAZ-AVI treated cIAI patients infected with ceftazidime-resistant bacteria as effectively as meropenem. The adverse event rate for CAZ-AVI in combination with metronidazole was similar to meropenem (45.9% vs 42.9% with serious adverse event rates of 7.9% and 7.6% respectively). The most commonly reported adverse events for CAZ-AVI in combination with metronidazole were diarrhoea, nausea, vomiting and fever, which were not unexpected based on the known safety profiles of ceftazidime and metronidazole. Full Phase III results from the global REPRISE study were also presented at ECCMID. This study evaluated the safety and efficacy of CAZ-AVI, administered intravenously as a two hour infusion (2000 mg / 500 mg) in patients with complicated intra-abdominal or complicated urinary tract ceftazidime-resistant gram-negative infection. Patients with complicated intra-abdominal infection also received metronidazole. CAZ-AVI was compared to best available therapy. Results showed that efficacy for CAZ-AVI and Best Available Treatment was similar as reflected by the primary endpoint of clinical response at Test of Cure (TOC) visit. CAZ-AVI showed that in patients with complicated urinary tract infection (cUTI), microbiological cure rates at TOC (and beyond) were substantially higher in patients treated with CAZ-AVI. * On August 19, 2014, AstraZeneca announced positive top-line results from RECLAIM-1 and RECLAIM-2, the pivotal Phase III studies investigating the potential of the antibiotic ceftazidime-avibactam (CAZ-AVI) as a treatment for hospitalised adult patients with complicated intra-abdominal infections. The global RECLAIM-1 and RECLAIM-2 Phase III studies both evaluated the safety and efficacy of CAZ-AVI, administered intravenously as a two hour infusion (2000 mg / 500 mg) plus metronidazole, compared to meropenem, administered intravenously as a 30 minute infusion (1 g), in hospitalised adult patients with complicated intra-abdominal infections. Data from the RECLAIM-1 and RECLAIM-2 studies were analysed as a single-pooled dataset with the agreement of the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). In the RECLAIM-1 and RECLAIM-2 Phase III studies, CAZ-AVI met the objective of statistical non-inferiority compared to meropenem. The primary endpoint was a clinical cure rate 28 to 35 days after randomisation (the Test of Cure visit). CAZ-AVI also treated cIAI patients infected with ceftazidime-resistant bacteria as effectively as meropenem. * On October 18, 2011, AstraZeneca and Forest Laboratories have announced that ceftazidime/avibactam (CAZ-AVI) will enter phase III trials to investigate efficacy in treating hospitalised patients with serious Gram-negative bacterial infections including Complicated Intra-Abdominal Infections (cIAI) and Complicated Urinary Tract Infections (cUTI). CAZ-AVI combines a broad-spectrum cephalosporin (ceftazidime) and a novel beta-lactamase inhibitor (avibactam, formerly NXL104) to overcome antibiotic-resistance and treat the increasing number of infections resistant to existing therapies. This study programme is designed to support global regulatory filings planned for 2014. As part of the collaboration, development costs of the treatment will be shared between AstraZeneca and Forest. Forest will have the rights to commercialise CAZ-AVI in North America while AstraZeneca will have rights to commercialise CAZ-AVI in the rest of the world. In December 2009, AstraZeneca entered into an agreement to acquire Novexel, a private infection research company in France while simultaneously announcing an agreement to collaborate with Forest Laboratories on the future co-development and commercialisation of two late-stage antibiotic development programmes: ceftazidime/avibactam and ceftaroline fosamil/avibactam. These antibiotic combinations utilise Novexel’s novel investigational beta-lactamase inhibitor avibactam to overcome antibiotic-resistance and treat the increasing number of infections resistant to existing therapies. Development costs for CAZ-AVI will be shared between AstraZeneca and Forest.
The adverse event rate for CAZ-AVI in combination with metronidazole was similar to meropenem. The most commonly reported adverse events for CAZ-AVI in combination with metronidazole were diarrhoea, nausea, vomiting and fever, which were not unexpected based on the known safety profiles of ceftazidime and metronidazole.
Studies are also underway for CAZ-AVI in complicated urinary tract infections (cUTI), nosocomial pneumonia and for the treatment of cIAI and cUTI patients with ceftazidime-resistant infections.
The RECLAIM-1 and RECLAIM-2 Phase III studies could form the basis of regulatory submissions seeking approval for a broader range of indications, in line with new EMA guidelines on the evaluation of medicines to treat bacterial infections. EU filing is anticipated in the first quarter of 2015, pending a full analysis of the data from the studies. The results will also be submitted to a scientific meeting in the first half of 2015.AstraZeneca holds the global rights to commercialise CAZ-AVI, with the exception of North America where the rights are held by Forest Laboratories.
