Allergan plc, a leading global pharmaceutical company, announced that the US Food and Drug Administration (FDA) has approved Allergan's supplemental New Drug Application (sNDA) to expand the approved use of Avycaz (ceftazidime and avibactam) to include the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP) caused by the following susceptible Gram-negative microorganisms: Klebsiella pneumoniae, Enterobacter cloacae, Escherichia coli, Serratia marcescens, Proteus mirabilis, Pseudomonas aeruginosa, and Haemophilus influenzae in patients 18 years of age or older. This expanded use is based on positive results from a pivotal phase 3 study evaluating the efficacy and safety of Avycaz for the treatment of adult patients with HABP/VABP. The sNDA received priority review from FDA based on the Qualified Infectious Disease Product (QIDP) designation for the HABP/VABP indication.
Certain types of Gram-negative bacteria have become increasingly resistant to available antibiotics, resulting in increased illness and death as well as contributing to escalating healthcare costs. New strategies to fight these challenging infections have been long-awaited by the medical community.
"Healthcare providers in the US have not had access to a new treatment option for patients with HABP/VABP due to Gram-negative bacteria in over 15 years," said David Nicholson, Ph.D., Chief Research and Development Officer, Allergan. "Gram-negative pathogens are some of the most pressing antibiotic resistance threats and cause more than 40,000 resistant infections in the U.S. annually. Today's action by the FDA is further evidence of Allergan's commitment to improving outcomes and meeting critical needs in patients with life-threatening infectious diseases."
This is the third therapeutic indication for Avycaz. Avycaz was first approved in February 2015 in the US for the treatment of adult patients with complicated intra-abdominal infections (cIAI), in combination with metronidazole, and in 2017 for complicated urinary tract infections (cUTI), including pyelonephritis, caused by designated susceptible Gram-negative bacteria, including certain Enterobacteriaceae and Pseudomonas aeruginosa.
"Clinical efficacy along with patient safety are critical priorities to clinicians managing serious Gram-negative bacterial infections. We are thrilled to have a new option available to treat HABP/VABP, some of the most challenging Gram-negative infections in the hospital setting," said Jose Vazquez, M.D., FIDSA, Division Chief and Professor of Medicine Infectious Diseases, Medical College of Georgia/Augusta University, Augusta, GA.
A total of 870 hospitalized adult patients with HABP or VABP were randomized and received trial medications in a pivotal phase 3, multinational, double-blind trial (REPROVE) comparing Avycaz 2.5 g (ceftazidime 2 grams and avibactam 0.5 grams) intravenously every 8 hours to meropenem 1 gram intravenously every 8 hours, for 7 to 14 days of therapy. Study medication dosages were adjusted per renal function. The protocol allowed for administration of prior and concomitant systemic antibacterial therapy for patients with proven or suspected Gram-positive or drug resistant infections.
Clinical efficacy was evaluated in the intent-to treat (ITT) population, which included all randomized patients who received study drug. Overall, 379 (43.6%) patients were ventilated at enrollment, including 290 (33.3%) patients with VABP and 89 (10.2%) with ventilated-HABP. Bacteremia at baseline was present in 4.8% of patients.
The primary efficacy endpoint of the study was 28-day all-cause mortality (28 to 32 days after randomization) in the ITT population. The study successfully demonstrated that Avycaz was non-inferior to meropenem with respect to the primary endpoint based on a 10% non-inferiority margin; the 28-day all-cause mortality rate was 9.6% (42/436) in patients treated with Avycaz compared with 8.3% (36/434) in meropenem treated patients (treatment difference of 1.5%; 95% confidence interval [CI]: -2.4, 5.3).
At baseline, 108/382 (28.3%) of patients in the microbiological intent-to-treat (micro-ITT) population, which included all patients with positive culture results indicating the presence of at least one Gram-negative pathogen, had Gram-negative isolates that were not susceptible to ceftazidime, including 53 patients with K. pneumoniae and 28 patients with P. aeruginosa isolates. The 28-day all-cause mortality in patients with ceftazidime non-susceptible Gram-negative isolates was 8.2% in the Avycaz arm and 8.5% in the meropenem arm.
Avycaz demonstrated a safety profile consistent with that observed in prior clinical trials with Avycaz and with the established safety profile for ceftazidime alone. The most common adverse reactions (= 5%) in HABP/VABP patients were diarrhea and vomiting.
Hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP) are serious bacterial infections that occur in hospitalized patients, which are associated with critically ill and vulnerable populations. The Gram-negative bacteria that commonly cause HABP/VABP include the Enterobacteriaceae (including Klebsiella penumoniae, Escherichia coli, Enterobacter cloacae, Proteus mirabilis) and Pseudomonas aeruginosa.
The economic burden associated with HABP/VABP is significant. These infections are associated with increased healthcare costs, high morbidity and mortality, and lengthened hospital stays. HABP/VABP is currently the second most common type of nosocomial infection in the US, especially in the intensive care unit (ICU) of hospitals.
Avycaz is a fixed-dose combination antibacterial indicated for the treatment of HABP/VABP, cIAI (in combination with metronidazole), and cUTI caused by designated susceptible Gram-negative microorganisms in patients 18 years or older. Avycaz consists of a combination of avibactam and ceftazidime.
Avibactam is a first-in-class non-beta-lactam beta-lactamase inhibitor which protects ceftazidime against degradation by certain beta-lactamases. Avibactam does not decrease the activity of ceftazidime against ceftazidime-susceptible organisms. Ceftazadime is a third-generation cephalosporin with a well-established efficacy and safety profile.
Avycaz has demonstrated in vitro activity against Enterobacteriaceae in the presence of some beta-lactamases and extended-spectrum beta-lactamases (ESBLs) of the following groups: TEM, SHV, CTX-M, Klebsiella pneumoniae carbapenemase (KPCs), AmpC and certain oxacillinases (OXA). Avycaz also demonstrated in vitro activity against Pseudomonas aeruginosa in the presence of some AmpC beta-lactamases, and certain strains lacking outer membrane porin (OprD). Avycaz is not active against bacteria that produce metallo-beta lactamases and may not have activity against Gram-negative bacteria that overexpress efflux pumps or have porin mutations.
Ceftazidime and avibactam is being jointly developed with Pfizer. Allergan holds the rights to commercialize ceftazidime and avibactam in North America under the brand name Avycaz, while Pfizer holds the rights to commercialize the combination in the rest of the world under the brand name ZAVICEFTA®.