Actavis Announces Positive Topline Results From The Phase III Program Of Ceftazidime-Avibactam In Patients With Complicated Intra-Abdominal Infections(cIAI)

DUBLIN, Aug. 19, 2014 /PRNewswire/ -- Actavis plc (NYSE: ACT) today confirmed positive topline results from RECLAIM-1 and -2, pivotal Phase III studies evaluating the potential for the investigational antibiotic, ceftazidime-avibactam as a treatment for adult hospitalized patients with complicated intra-abdominal infections.

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Ceftazidime-avibactam consists of a cephalosporin (ceftazidime), an established treatment for serious bacterial infections, and a next generation non-beta lactam beta-lactamase inhibitor (avibactam).  The compound 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 ceftazidime-avibactam, 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 hospitalized adult patients with complicated intra-abdominal infections.  Data from the RECLAIM-1 and RECLAIM-2 studies were analyzed as a single-pooled dataset with the agreement of the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA).

In the RECLAIM-1 and RECLAIM-2 Phase III studies, ceftazidime-avibactam met the objective of statistical non-inferiority compared to meropenem.  The primary endpoint was a clinical cure rate 28 to 35 days after randomization (the Test of Cure visit).  Also, ceftazidime-avibactam was  effective in treating cIAI patients infected with ceftazidime-resistant bacteria.

The most commonly reported adverse events for ceftazidime-avibactam in combination with metronidazole were diarrhea, nausea, vomiting and fever.

"We are very pleased by these results, which support the potential of ceftazidime-avibactam as a new treatment option for patients with these serious and life-threatening intra-abdominal infections," said David Nicholson,PhD, Senior Vice President, Actavis Global Brands R&D.

"As a result of limited available options, infections due to antibiotic resistant Gram-negative bacteria are becoming  increasingly more difficult to treat.  New agents are needed and ceftazidime-avibactam could be a welcome addition for physicians who manage high-risk patients with these hard to treat infections," said Keith Kaye, MD, Professor of Medicine in the division of  infectious disease at Wayne State University Hospital in Detroit, Mich.

Ceftazidime-avibactam is being jointly developed with Astra Zeneca.  Forest Laboratories LLC., a subsidiary of Actavis plc, holds the rights to commercialize ceftazidime-avibactam in North America, while AstraZeneca holds the rights to commercialize ceftazdime-avibactam in the rest of the world.

NOTES TO EDITORS

About RECLAIM
RECLAIM-1 and -2 are Phase III, randomized, multi-center, double-blind, double-dummy, parallel-group, comparative studies to determine the efficacy, safety, and tolerability of ceftazidime/avibactam (2000 mg / 500 mg, q8h) plus metronidazole (0.5 g q8h) versus meropenem (1 g q8h) in the treatment of complicated intra-abdominal infections in hospitalized adults.¹ As agreed with both the US Food and Drug Administration (FDA) and the European Medicines Authority (EMA), data from the RECLAIM-1 and -2 studies have been analysed as single-pooled dataset. A total of 1,066 patients have been randomized to the RECLAIM-1 and -2 trials from 30 countries.

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. 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. 

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 CEFTAZIDIME-AVIBACTAM
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 and respected treatment for serious Gram-negative bacterial infections, and avibactam, a next generation, non-B lactam B-lactamase inhibitor.

The addition of avibactam to ceftazidime protects ceftazidime from breakdown by B-lactamases. ceftazidime-avibactam offers a differentiated profile versus existing treatment options in serious Gram-negative infections through its coverage of a broad range of species of carbapenem-resistant Enterobacteriaceae (CRE) together with difficult to treat Pseudomonas aeruginosa combined with robust coverage of extended spectrum B-lactamase (ESBL)-expressing pathogens.

About cIAIs
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. In fact, it is the second most commonly identified cause of severe sepsis in the intensive care unit (ICU).

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 localized or diffuse peritonitis.

Antimicrobial therapy is an important part of the clinical management of IAI, especially in critically ill patients requiring immediate empiric antibiotic therapy. The threat of antimicrobial resistance, however, is one of the major challenges associated with the antimicrobial management of cIAI.

About Actavis
Actavis plc (NYSE:ACT), headquartered in Dublin, Ireland, is a unique specialty pharmaceutical company focused on developing, manufacturing and commercializing high quality affordable generic and innovative branded pharmaceutical products for patients around the world.

Actavis markets a broad portfolio of branded and generic pharmaceuticals and develops innovative medicines for patients suffering from diseases principally in the central nervous system, gastroenterology, women's health, urology, cardiovascular, respiratory and anti-infective therapeutic categories. The Company is an industry leader in product research and development, with one of the broadest brand development pipelines in the pharmaceutical industry, and a leading position in the submission of generic product applications. Actavis has commercial operations in more than 60 countries and operates more than 30 manufacturing and distribution facilities around the world.

For more information, visit Actavis' website at www.actavis.com.

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Statements contained in this communication that refer to Actavis' estimated or anticipated future results, including estimated synergies, or other non-historical facts are forward-looking statements that reflect Actavis' current perspective of existing trends and information as of the date of this communication. Actual results may differ materially from Actavis' current expectations depending upon a number of factors affecting Actavis' business. These factors include, among others, the timing and success of product launches; the difficulty of predicting the timing or outcome of product development efforts and regulatory agency approvals or actions, if any; market acceptance of and continued demand for Actavis' products; difficulties or delays in manufacturing; and such other risks and uncertainties detailed in Actavis' periodic public filings with the Securities and Exchange Commission, including but not limited to Actavis plc's Annual Report on Form 10-K for the year ended December 31, 2013, Quarterly Report on Form 10-Q for the quarter ended June 30, 2014 and from time to time in Actavis' other investor communications. Except as expressly required by law, Actavis disclaims any intent or obligation to update or revise these forward-looking statements.

SOURCE Actavis plc