New Phase 3 Data Added to Avycaz Label

Pivotal trials support efficacy of ceftazidime/avibactam in UTIs

The FDA has allowed the label for Avycaz (ceftazidime/avibactam, Allergan/Pfizer) to be updated with clinical data from two phase 3 trials supporting the medication’s indication to treat patients with complicated urinary tract infections (cUTIs), including pyelonephritis, caused by designated susceptible gram-negative microorganisms.

The prevalence of infections caused by resistant gram-negative bacteria, specifically extended-spectrum beta-lactamase (ESBL) and Klebsiella pneumoniae carbapenamase (KPC)-producing carbapenem-resistant Enterobacteriaceae (CRE), and resistant Pseudomonas aeruginosa have steadily increased in recent years; this has led the Centers for Disease Control and Prevention to classify these pathogens as urgent and serious public health threats, as there are few treatment options.

The pivotal multicenter, double-blind RECAPTIRE trial involved 1,020 adults hospitalized with cUTIs. There were two primary endpoints: the patient-reported symptomatic response at day 5 and the combined patient-reported symptomatic response and microbiologic cure at the test-of-cure (TOC) visit. With regard to these endpoints, Avycaz was noninferior to doripenem in the microbiologically modified intent-to-treat (mMITT) population.

The symptomatic response rate at day 5 in Avycaz-treated patients was 70.2% (276/393) compared with 66.2% (276/417) in doripenem-treated patients, for a treatment difference of 4.0%.The combined symptomatic and microbiologic response rate at TOC in the Avycaz-treated patients was 71.2% (280/393) compared with 64.5% (269/417) in the doripenem-treated patients, for a treatment difference of 6.7%.

Avycaz was effective in treating a subset of 75 cUTI patients infected with CAZ-NS pathogens. In addition, in a subset of 86 patients with infections caused by pathogens producing certain ESBL groups (e.g., TEM-1, SHV-12, CTX-M15, and OXA-48) and AmpC, the clinical and microbiologic cure rates with Avycaz were similar to the overall trial results.

The multicenter, open-label REPRISE trial involved 305 patients with cUTIs caused by ceftazidime nonsusceptible gram-negative pathogens. In this study, the combined clinical and microbiologic cure rate at days 21 to 25 in the mMITT population was higher among Avycaz-treated patients than among patients receiving best available therapy (BAT). The combined cure rates were 70.1% (101/144) for patients treated with Avycaz and 54.0% (74/137) for BAT-treated patients, for a treatment difference of 16.1%.

Avycaz was effective in treating a subset of cUTI patients with pathogens containing certain ESBL groups (including select KPCs and OXA-48) and AmpC beta-lactamases. Clinical and microbiologic cure rates in this subset were similar to the overall trial results.

Avycaz was first approved in the U.S. in February 2015 for the treatment of adults with complicated intra-abdominal infections (cIAIs), in combination with metronidazole, and cUTIs, including pyelonephritis, caused by designated susceptible pathogens, including certain Enterobacteriaceae and Pseudomonas aeruginosa. In June 2016, the Avycaz label was expanded with phase 3 cIAI clinical data that evaluated the safety and efficacy of ceftazidime/avibactam in combination with metronidazole in cIAI patients, including subsets of patients with infections caused by CAZ-NS pathogens and by pathogens producing certain ESBLs.

Ceftazidime/avibactam has demonstrated in vitro activity against Enterobacteriaceae in the presence of some beta-lactamases and ESBLs of the following groups: TEM, SHV, CTX-M, KPCs, AmpC, and certain oxacillinases. Ceftazidime/avibactam also demonstrated in vitro activity against P. aeruginosa in the presence of some AmpC beta-lactamases and certain strains lacking outer-membrane porin. Ceftazidime/avibactam 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.

Avycaz is being jointly developed by Allergan and 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.

Source: Allergan; January 30, 2017.