Måndag, 27 april 2015
Encouraging new data of relevance to Global public health crisis, presented at 25th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID)
COPENHAGEN, Denmark – AstraZeneca today presented positive 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. New Phase III data was also presented for ZINFORO™ (ceftaroline fosamil), an antibiotic approved for the treatment of adult patients with complicated skin and soft tissue infections (cSSTI) or community-acquired pneumonia (CAP).
AstraZeneca held a symposium at the congress, which highlighted the need for new treatment strategies to address antibiotic resistant infections, which remains a rapidly accelerating global concern. Epidemiological data was presented at the symposium which demonstrated the high clinical burden associated with Gram-positive and Gram-negative infections, including those caused by multidrug-resistant (MDR) pathogens.
‘Multi-resistant bacteria are a growing problem worldwide. Globalisation, travel and migration mean that those which evolve in one place swiftly reach others, adding risk, cost and complexity to treatment,’ said Professor David Livermore, University of East Anglia, Norwich, UK and speaker at the symposium. ‘New antibiotics - along with better stewardship and infection control - are our best answers to this challenge. And, in this context, ceftaroline and ceftazidime-avibactam are both welcome developments.’
AstraZeneca’s presence at ECCMID builds upon its continued commitment to scientific advancement in the area of infection and to working together with the wider infection community in order to translate this science into solutions to address the challenges faced.
CAZ-AVI Phase III Study Results: Complicated Intra-Abdominal Infections
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.1 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).2
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.2
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.2
CAZ-AVI Phase III Study Results: Resistant Pathogens
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.3
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. 4
Ceftaroline fosamil Phase III Study Results
The Phase III COVERS trial evaluated the safety and efficacy of ceftaroline fosamil for cSSTI patients with evidence of systemic inflammatory response or underlying comorbidities, administered via a 600 mg IV infusion over 120 minutes every eight hours, rather than the currently approved 600 mg every 12 hours dosing regimen. The study included patients from Asia, Europe, North and South America who were randomised 2:1 to receive ceftaroline fosamil 600 mg every eight hours, or to vancomycin 15 mg/kg every 12 hours plus aztreonam 1 g every eight hours for five to 14 days.5
Results demonstrated that ceftaroline fosamil was effective and well-tolerated for these patients at the adjusted dose, demonstrating non-inferiority versus vancomycin plus aztreonam. Ceftaroline fosamil was well tolerated with 45.6% and 45.5% patients treated with ceftaroline fosamil and vancomycin plus aztreonam respectively, experiencing ≥1 adverse event. The qualitative safety profile of ceftaroline fosamil 600 mg every eight hours was similar to previous trials with the 12 hour dosing, with no new safety signals identified.6
John Rex, Senior VP and Head of Infection, Global Medicines Development, AstraZeneca, said ‘These positive results for both CAZ-AVI and ceftaroline fosamil are extremely encouraging, particularly at a time when resistance to existing treatments is rapidly on the rise. We are proud of our antibiotic portfolio, which is contributing towards reinvigorating the pipeline of new treatment options in areas of enormously high unmet need.”
NOTES TO EDITORS
About ceftaroline fosamil
Ceftaroline fosamil is an intravenous cephalosporin antibiotic intended for use as a monotherapy in the treatment of adult patients with complicated skin and soft tissue infections (cSSTI) or community-acquired pneumonia (CAP).7 Ceftaroline fosamil is bactericidal and works by binding to and inhibiting penicillin-binding proteins (PBPs). PBPs are involved in bacterial cell wall synthesis and repair and their inhibition leads to reduced bacterial cell replication and/or cell death.7-9
Ceftaroline fosamil was granted Marketing Authorisation by the European Commission (EC) for the treatment of adult patients with cSSTI or CAP on 28 August, 2012. Ceftaroline fosamil is marketed as TEFLARO™ in the U.S.
CAZ-AVI (ceftazidime-avibactam) is an investigational antibiotic being developed to treat serious Gram-negative bacterial infections. CAZ-AVI is 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 beta-lactamase inhibitor, which protects ceftazidime against degradation by Class A, C and some D, beta-lactamases.10
CAZ-AVI offers a differentiated profile versus existing treatment options in serious Gram-negative infections through its activity against a broad range of isolates of carbapenem-resistant Enterobacteriaceae and difficult to treat Pseudomonas aeruginosa combined with robust coverage of extended spectrum beta-lactamase-expressing pathogens.10
CAZ-AVI is being jointly developed by AstraZeneca and Actavis. AstraZeneca holds the global rights to commercialise the product, with the exception of North America where the rights are held by Actavis. In the U.S., CAZ-AVI is marketed under the brand name AVYCAZ™ (ceftazidime-avibactam) for injection.
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
Petra Eurenius, AstraZeneca Nordic-Baltic, mobile phone +46 709 186562
Alicia Dunn, AstraZeneca Global Media team, mob +1 202 304 7674
Thomas Kudsk Larsen +44 20 7604 8199 mob: +44 7818 524185
Karl Hård +44 20 7604 8123 mob: +44 7789 654364
Eugenia Litz +44 20 7604 8233 mob: +44 7884 735627
Craig Marks +44 20 7604 8591 mob: +44 7881 615764
Christer Gruvris +44 20 7604 8126 mob: +44 7827 836825
1. ClinicalTrials.gov. Compare ceftazidime-avibactam + metronidazole versus meropenem for hospitalized adults with complicated intra-abdominal infections. NCT01499290. Available at: https://clinicaltrials.gov/ct2/show/NCT01499290 Last accessed March 2015.
2. Mazuski JE, Gasnik L, Armstrong J, et al. Efficacy and safety of ceftazidime-avibactam plus metronidazole versus meropenem in the treatment of complicated intra-abdominal infection – results from a Phase III program. Abstract to be presented at 25th ECCMID, Copenhagen, April 2015.
3. ClinicalTrials.gov. Ceftazidime-avibactam for the treatment of infections due to ceftazidime resistant pathogens. NCT01644643. Available at: https://clinicaltrials.gov/ct2/show/NCT01644643 Last accessed April 2015.
4. Carmeli Y, Armstrong J, Laud P, et al. Efficacy and safety of ceftazidime-avibactam and best available therapy in the treatment of ceftazidime-resistant infections – results from a Phase III study. Abstract to be presented at 25th ECCMID, Copenhagen, April 2015.
5. ClinicalTrials.gov. Evaluation of ceftaroline fosamil versus vancomycin plus aztreonam in the treatment of patients with skin infections. NCT01499277. Available at: https://clinicaltrials.gov/ct2/show/NCT01499277 Last accessed March 2015.
6. Dryden M, Wilson D, Iaconis J, et al. A Phase III trial of ceftaroline fosamil 600 mg q8h versus vancomycin plus aztreonam in patients with cSSTI with systemic inflammatory response or underlying comorbidities. Abstract to be presented at 25th ECCMID, Copenhagen, April 2015.
7. ZINFOROTM (ceftaroline fosamil) European Summary of Product Characteristics November 2014. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002252/WC500132586.pdf Last accessed March 2015.
8. Laudano JB. Ceftaroline fosamil: a new broad-spectrum cephalosporin. J Antimicrob Chemother. 2011;66(Suppl 3):iii11-iii18.
9. Biek D, Critchley IA, Riccobene TA, Thye DA. Ceftaroline fosamil: a novel broad-spectrum cephalosporin with expanded anti-Gram-positive activity. J Antimicrob Chemother. 2010;65(Suppl 4):iv9-iv16.
10. Lagace-Wiens P, Walkty A, Karlowsky JA. Ceftazidime–avibactam: an evidence-based review of its pharmacology and potential use in the treatment of Gram-negative bacterial infections. Core Evidence. 2014;9:13-25.