The FINANCIAL — Allergan plc on January 30 announced the U.S. Food and Drug Administration (FDA) has approved the company’s supplemental New Drug Application (sNDA) to update the label for AVYCAZ (ceftazidime and avibactam) with clinical data from two Phase 3 trials supporting the indication to treat patients with complicated urinary tract infections (cUTI), including pyelonephritis, caused by designated susceptible Gram-negative microorganisms.
In Trial 1, known as RECAPTURE, AVYCAZ was non-inferior to doripenem with regard to both primary endpoints. In Trial 2, known as REPRISE, AVYCAZ demonstrated a higher combined clinical and microbiological cure rate vs. best available therapy (BAT), including meropenem, imipenem, doripenem, and colistin. Additionally, both trials included a subset of patients with infections caused by pathogens producing certain ESBL groups and AmpC beta-lactamases in which the clinical and microbiological cure rates were similar to the overall results, according to Allergan.
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 U.S. Centers for Disease Control and Prevention (CDC) to classify these pathogens as urgent and serious public health threats, as there are very limited treatment options.
“Gram-negative pathogens are among the most urgent antibiotic resistance threats and cause more than 40,000 resistant infections in the U.S. alone each year,” said David Nicholson, Ph.D., Chief R&D Officer, Allergan. “This new sNDA approval for AVYCAZ is based on a large clinical database, comprising data from more than 1,300 patients with cUTI across Phase 3 studies, including a number of patients with infections due to ceftazidime non-susceptible (CAZ-NS) pathogens. It provides physicians with further clinical evidence that will assist them in making informed treatment decisions for their patients with cUTI, including those with difficult to treat pathogens.”
“The successful cumulative Phase 3 cUTI studies further validate the initial FDA approval of AVYCAZ based on Phase 2 data. The inclusion of the REPRISE data in the label represents a significant advancement in the available data to support efficacy in cUTI patients infected with challenging pathogens, including certain ESBL and KPC-producing Enterobacteriaceae, reinforcing Allergan’s leadership in responding to some of the most challenging infections facing our society today.”
Trial 1: RECAPTURE
In this pivotal multicenter, double-blind, Phase 3 study of 1,020 adults hospitalized with cUTI, AVYCAZ was non-inferior to doripenem with regard to both primary endpoints (patient-reported symptomatic response at Day 5 and combined patient-reported symptomatic response and microbiological cure at the Test of Cure [TOC] visit) in the microbiologically modified intent-to-treat (mMITT) population. The symptomatic response rate at Day 5 in the AVYCAZ treated patients was 70.2% (276/393) compared to 66.2% (276/417) in doripenem treated patients, a treatment difference of 4.0% (95% confidence interval [CI]: -2.4, 10.4). The combined symptomatic and microbiological response rate at TOC in the AVYCAZ treated patients was 71.2% (280/393) compared to 64.5% (269/417) in doripenem treated patients, a treatment difference of 6.7% (95% CI: 0.3 to 13.1).
AVYCAZ was effective in treating a subset of 75 cUTI patients infected with CAZ-NS pathogens. Additionally, in a subset of patients (n= 86 in the AVYCAZ group) with infections caused by pathogens producing certain ESBL groups (e.g. TEM-1, SHV-12, CTX-M15 and OXA-48) and AmpC, the microbiological and clinical cure rates were similar to the overall trial results.
Trial 2: REPRISE
In the multicenter, open-label, Phase 3 study of 305 patients with cUTI caused by ceftazidime non-susceptible Gram-negative pathogens, the combined clinical and microbiological cure rate at Days 21 to 25 in the mMITT population was higher in AVYCAZ-treated patients than in patients on BAT. The combined cure rates were 70.1% (101/144) for patients treated with AVYCAZ and 54% (74/137) for BAT-treated patients, a treatment difference of 16.1% (CI 95%; 4.8 to 27.1).
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 microbiological cure rates in this subset were similar to the overall trial results.