CAZ-AVI PHASE III RESULTS

        Print
| Source: AstraZeneca PLC
ASTRAZENECA ANNOUNCES POSITIVE TOP-LINE RESULTS FROM THE PHASE III PROGRAMME OF
CAZ-AVI IN PATIENTS WITH COMPLICATED INTRA-ABDOMINAL INFECTIONS (cIAI)

CAZ-AVI treated patients with cIAI as effectively as meropenem

CAZ-AVI also treated cIAI patients infected with ceftazidime-resistant bacteria
as effectively as meropenem

AstraZeneca today 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.

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.

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
(2000mg / 500mg) plus metronidazole, compared to meropenem, administered
intravenously as a 30 minute infusion (1g), 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.

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.

"We are very encouraged by these results which highlight the potential for CAZ
-AVI to provide a much-needed new treatment option for serious and life
-threatening intra-abdominal infections, especially where antibiotic resistance
poses a threat to treatment," said Briggs Morrison, Executive Vice President,
Global Medicines Development & Chief Medical Officer, AstraZeneca.

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.

CAZ-AVI is being jointly developed with Forest Laboratories, a wholly-owned
subsidiary of Actavis.  AstraZeneca holds the global rights to commercialise CAZ
-AVI, with the exception of North America where the rights are held by Forest
Laboratories.

About RECLAIM

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 (2000mg / 500mg, every 8 hours), plus metronidazole, administered
intravenously as a 60 minute infusion (0.5g every 8 hours), compared to
meropenem, administered intravenously as a 30 minute infusion (1g 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.

About CAZ-AVI

CAZ-AVI (ceftazidime-avibactam) is an investigational antibiotic being developed
to treat serious Gram-negative bacterial infections. It consists of ceftazidime,
a third-generation, antipseudomonal cephalosporin, that is an established
treatment for serious Gram-negative bacterial infections, and avibactam, a next
generation, non-beta lactam beta-lactamase inhibitor.

The addition of avibactam to ceftazidime protects ceftazidime from breakdown by
serine-beta-lactamases. 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.

About cIAI

Most intra-abdominal infections (IAI) are a result of processes involving
inflammation and perforations of the gastrointestinal tract, such as
appendicitis, peptic ulcer disease, and diverticulitis (a common digestive
disease which involves the formation of pouches within the bowel wall).  IAI is
an important cause of morbidity and mortality and it is the second most commonly
identified cause of severe sepsis in the intensive care unit.

From a clinical perspective, IAI are classified in two major categories:
complicated and uncomplicated. Complicated intra-abdominal infections
(cIAI) extend beyond the source organ into the peritoneal space (the space
between the two membranes that separate the organs in the abdominal cavity from
the abdominal wall). They cause peritoneal inflammation, and are associated with
localised or diffuse peritonitis.

Antimicrobial therapy is an important part of the clinical management of IAI.
The threat of antimicrobial resistance, however, is one of the major challenges
associated with the antimicrobial management of cIAI.

About AstraZeneca

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.

CONTACTS

Media Enquiries

Esra Erkal-Paler                          +44 20 7604 8030 (UK/Global)

Vanessa Rhodes                         +44 20 7604 8037 (UK/Global)

Ayesha Bharmal                          +44 20 7604 8034 (UK/Global)

Jacob Lund                                  +46 8 553 260 20 (Sweden)

Michele Meixell                             + 1 302 885 6351 (US)

Investor Enquiries

Karl Hård                                    +44 20 7604 8123  mob: +44 7789
654364

Jens Lindberg                             +44 20 7604 8414    mob: +44 7557
319729

Anthony Brown                           +44 20 7604 8067    mob: +44 7585 404943

Eugenia Litz                                +44 20 7604 8233    mob: +44 7884
735627

19 August 2014

-ENDS-