FDA Accepts sNDA Filing for Pneumonia Drug

The US Food and Drug Administration (FDA) accepted a supplemental New Drug Application (sNDA) for ceftazidime and avibactam (AVYCAZ) for priority review, announced Allergan.

The sNDA filing seeks to expand current indications for AVYCAZ to include hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia (HABP/VABP) in adult patients on behalf of positive phase 3 clinical trial results evaluating AVYCAZ for the treatment of HABP/VABP. HABP/VABP is currently the second most common type of nosocomial infection in the US, and is associated with high mortality and morbidity.

"Hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia are among the most serious Gram-negative infections, and are increasingly caused by difficult to treat pathogens, leading to high morbidity and mortality, especially in the ICU and hospital, and increased economic burden," David Nicholson, PhD, Chief Research and Development Officer, Allergan, told MD Magazine. "Due to the urgent need, the FDA has granted AVYCAZ priority review for the HABP/VABP indication, and if approved, it would be the first new treatment for HABP/VABP caused by certain Gram-negative pathogens in 20 years."

The FDA granted priority review status based on previous Qualified Infectious Disease Product (QIDP) designation. Action on the filing is expected to occur in the first quarter of 2018.

The sNDA application seeks to add a new indication in the label based on favorable results from a pivotal phase 3 trial evaluating the efficacy and safety of AVYCAZ for the treatment of adult patients with HABP/VABP.

The double-blind REPROVE study demonstrated the non-inferiority of AVYCAZ to meropenem in the treatment of nosocomial pneumonia including VABP in hospitalized adults with regard to the 28-day all-cause mortality in the intent-to-treat population, the primary endpoint. The 2 intra-venous treatment arms included 2,000 mg of ceftazidime plus 500 mg of avibactam, or 1,000 mg of meropenem.

Primary outcome measures included the number of patients with clinical cure at test of cure visit in the clinically modified intent-to-treat analysis set, and the number of patients with clinical cure at test-of-cure visit in the clinically evaluable at test-of-cure analysis set.

AVYCAZ was also non-inferior to meropenem in the secondary endpoint, clinical cure at the test of cure visit in the intent-to-treat population.

In a subset of patients infected with Gram-negative pathogens producing certain ESBL group and AmpC beta-lactamases, the clinical and microbiological cure rates were similar to overall results.

In the study, the overall safety profile observed was consistent with current product labeling.

AVYCAZ was first approved in the US in February 2015 for treatment of adult patients with complicated intra-abdominal infections (cIAI) in combination with metronidazole, as well as complicated urinary tract infections (cUTI), including pyelonephritis, caused by designated susceptible bacteria like certain Enterobacteriaceae and Pseudomonas aeruginosa — pending the sNDA approval. Pending the approval, this will be the AVYCAZ’s third indication.

AVYCAZ demonstrated in vitro activity against Enterobacteriaceae in the presence of some beta-lactamases and ESBLS of TEM, SHV, CTX-M, Klebsiella pneumoniae carbapenemase (KPCs), AmpC and certain oxacillinases (OXA). There was also in vitro activity demonstrated against Pseudomonas aeruginosa in the presence of some AmpC beta-lactamases, and certain strains lacking outer membrane porin (OprD).

The antibiotic is developed to treat certain serious Gram-negative bacterial infections. It consists of ceftazidime, a third-generation cephalosporin treatment for serious Gram-negative bacterial infections and avibactam, a non-lactam lactamase inhibitor. The addition of avibactam to ceftazidime protects ceftazidime from a breakdown by certain lactamases.

The trial, “A Study Comparing Ceftazidime-Avibactam Versus Meropenem in Hospitalized Adults With Nosocomial Pneumonia” was made available in the US National Library of Medicine.

A press release was also made available.