Shionogi New Antibiotic for Urinary Infections Set for FDA Advisory Review

Cefiderocol, a new antibiotic, appeared effective and generally safe for treatment of complicated urinary tract infections (cUTI) including pyelonephritis in patients with limited treatment options, FDA staff indicated in briefing documents ahead of an advisory committee meeting scheduled for Wednesday.
However, questions remained about its use in critically ill patients with carbapenem-resistant infections, which the FDA’s Antimicrobial Drugs Advisory Committee will be addressing. In addition to the usual safety and efficacy questions, FDA staff has asked the committee to assess “the finding of increased mortality” in one of the studies “in the overall risk benefit considerations for cefiderocol.”
Cefiderocol is a siderophore cephalosporin, described as having activity against several Gram-negative bacteria, with a proposed dose of 2 g intravenously every 8 hours, with dose adjustments for altered renal function. In 2015, the drug was granted both fast track and Qualified Infectious Disease Product designation for cUTI, hospital-acquired bacterial pneumonia (HAP), ventilator-associated bacterial pneumonia (VAP), and bacteremia, or bloodstream infections, agency staff said.
Drug maker Shionogi submitted data from three trials — the non-inferiority trial comparing cefiderocol with imipenem-cilastatin (IMP) for treatment of cUTI, with a non-inferiority margin no larger than 15%. APEKS-NP, a phase III trial comparing cefiderocol to meropenem in patients with HAP or VAP. Data from this trial was presented at the 2019 IDWeek meeting, which found mortality rates with cefiderocol to be non-inferior to meropenem in patients with nosocomial pneumonia. FDA staff noted that this trial was completed while the product was under review, and only top-line results were included.
The manufacturer also presented data from the CREDIBLE-CR trial, comparing cefiderocol to the best available therapy for infections caused by carbapenem resistant organisms “at various anatomical sites.” Results from trial datasets were submitted, agency staff said, but not the final clinical study report.
FDA staff seemed mostly satisfied with results of the non-inferiority trial, which met its non-inferiority endpoint of 15% for clinical and microbiologic success rates at test of cure visit (72.6% for cefiderocol vs 54.6% for IMP). However, they noted that “clinical response rates were similar between the treatment groups and the difference in overall response was driven primarily by the microbiologic success component of the composite endpoint.”
The most common adverse events (AEs) included diarrhea, hypertension, constipation, rash, and infusion site reactions. Agency staff also noted cephalosporin-class AEs, including hypersensitivity reactions, Clostridioides difficile colitis, seizure, and hepatobiliary adverse events. They also said there was one death in the cefiderocol arm unrelated to the study drug.
But FDA staff seemed concerned with the increased mortality in the CREDIBLE-CR study, where patients with either HAP or VAP, cUTI, and body substance isolation/sepsis due to carbapenem-resistant organisms were randomized to cefiderocol or the best available therapy (about two-thirds of which were colistin-based regimens). Not only was all-cause mortality higher in the cefiderocol group at day 14 (18.8% vs 12.2%, respectively), but also at day 28 (24.8% vs 18.4%), with the greatest mortality difference disfavoring cefiderocol in the HAP or VAP groups.
“An independent adjudication committee determined that a greater percentage of patients in the cefiderocol group than in the [best available therapy] group had infection-related death with treatment failure (15.8% vs. 8.2%), but also noted an imbalance in death due to underlying co-morbidities (9.9% vs. 4.1%),” agency staff wrote.
In addition, treatment-emergent AEs leading to death in the cefiderocol group were generally infection-related, FDA staff noted, such as septic shock, pneumonia, sepsis, and bacteremia.
They speculated on the reasons for the difference in mortality rates, noting that deaths were more common in patients with infections by organisms such as Acinetobacter baumannii, Stenotrophomonas maltophilia, and Pseudomonas aeruginosa.
“Whether this difference in mortality is a chance finding or truly reflects a deficit in the activity of cefiderocol in critically ill patients is unclear,” FDA staff wrote.
https://www.medpagetoday.com/infectiousdisease/generalinfectiousdisease/82754