The US Food and Drug Administration's (FDA's) Antimicrobial Drugs Advisory Committee on Wednesday voted 14–2 to recommend approval of cefiderocol lyophilized powder for intravenous administration for the treatment of complicated urinary tract infections (cUTIs), including pyelonephritis caused by gram-negative bacteria in patients with few or no alternative treatment options.
"I think the data from the cUTI study were straightforward and demonstrated meaningful activity," committee chairperson Lindsey R. Baden, MD, director of clinical research, Division of Infectious Diseases, Brigham and Women's Hospital, and associate professor, Harvard Medical School, Boston, Massachusetts, said at the meeting.
The clinical meaning of the data is "more nuanced" and must be balanced against the mortality risk seen in one study, he said. He noted that cefiderocol should be reserved for organisms that are difficult to treat.
Cefiderocol is a structurally modified cephalosporin that enters bacterial cells utilizing a siderophore-based mechanism. The proposed dosing regimen for this indication is 2 g intravenously (IV) every 8 hours, with dose adjustments made for altered renal function. The infusion time for cefiderocol is 3 hours, and the proposed duration of treatment is 7 to 14 days.
The FDA designated cefiderocol as a qualified infectious disease product ― a designation it gives antibacterial or antifungal products used to treat serious or life-threatening infections or that address unmet medical needs.
Complicated UTI Study
The committee's vote follows consideration of data from three studies. The pivotal trial was the cUTI study ― a phase 2, multicenter, multinational, double-blind, randomized, active-controlled, parallel-group study that compared cefiderocol with imipenem-cilastatin (IMP) in "patients with cUTI with or without pyelonephritis or acute uncomplicated pyelonephritis," the company notes in a briefing document.
The primary endpoint was the composite of clinical and microbiological response at the test-of-cure assessment, conducted 7 days (±2 days) after the completion of antibiotic treatment.
The primary endpoint was met by 183 of 252 patients (72.6%) in the cefiderocol group and by 65 of 119 of those (54.6%) in the IMP group (difference, 18.6%; 95% confidence interval [CI], 8.2% – 28.9%).
"Because the lower bound of this confidence interval exceeded zero, cefiderocol met statistical criteria for superiority to IMP, even though this study was designed as a noninferiority trial," the FDA explains in its briefing document.
Among the safety database of 300 participants who were given the proposed dosage of cefiderocol 2 g every 8 hours for 7 to 14 days, the most frequent adverse events were gastrointestinal (diarrhea, constipation, nausea, vomiting), hypertension, rash, and infusion site reactions.
Cephalosporin-class adverse events were seen in participants who received cefiderocol and included hypersensitivity reactions, Clostridium difficile colitis, seizure, and hepatobiliary adverse events. One death occurred in the cefiderocol group and was deemed unrelated to the study drug; no deaths occurred in the IMP group.
The CREDIBLE-CR study was a descriptive study that compared cefiderocol with best available therapy (BAT) in patients with infections caused by carbapenem-resistant organisms. The study randomly assigned patients who had contracted hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia (HABP/VABP), cUTI, and bloodstream infections (BSIs)/sepsis caused by carbapenem-resistant organisms to receive cefiderocol or BAT. Two thirds of BATs (66%) were colistin-based regimens.
All-cause mortality was higher in the group that received cefiderocol compared with the BAT group at day 14 (18.8% vs 12.2%) and at day 28 (24.8% vs 18.4%).
The greatest mortality difference occurred in the HABP/VABP/healthcare-associated bacterial pneumonia subgroup, followed by the BSI/sepsis subgroup.
According to an independent adjudication committee, a higher percentage of patients in the cefiderocol group experienced infection-related death with treatment failure compared with those in the BAT group (15.8% vs 8.2%); however, there was also an imbalance in mortality resulting from underlying comorbidities (9.9% vs 4.1%).
In pharmacokinetic analysis, cefiderocol exposure was not associated with mortality. The most common treatment-emergent adverse events (TEAEs) that resulted in death in those who received cefiderocol were primarily related to infection and included septic shock, pneumonia, sepsis, and bacteremia. Mortality was more common in those with infections caused 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," the FDA explains in its briefing document.
Thirty patients (29.7%) who received cefiderocol and seven (14.3%) who received BAT experienced hepatic TEAEs.
The panel widely agreed that product labeling needs to clearly identify safety issues, including the increased mortality risk seen in the CREDIBLE-CR study.
The APEKS-NP study was a randomized, prospective, double-blind, active-controlled noninferiority trial that compared cefiderocol with meropenem for the treatment of patients with HABP/VABP.
"This trial also completed enrollment during the NDA [new drug application] review and only top-line mortality results have been submitted to the Agency," according to the FDA's briefing document.
In the intent-to-treat population, the reported mortality rates at day 14 were 12.8% for those treated with cefiderocol and 11.4% for those treated with meropenem (treatment difference, 1.4%; 95% CI, -6.0% to 8.7%). At day 28, reported mortality rates were 21.2% in the cefiderocol group and 20.1% in the meropenem group (treatment difference, 1.1%; 95% confidence interval, -8.0% to 10.3%). The FDA has not reviewed or verified these data.
"I thought the cUTI study was well-designed, and I did not think those data should be negated by the [CREDIBLE-CR] study, given its design and given the unmet need for treating these infections; I was also reassured by the [APEKS-NP] data," voting committee member Nina M. Clark, MD, professor of medicine and interim codirector, Infectious Disease and Immunology Research Institute, Stritch School of Medicine and Loyola University Medical Center, in Maywood, Illinois, said at the meeting.
Clark said she agrees with other committee members about the need for additional data on other serious infections; that the labeling should be consistent with the cUTI study population; and that the FDA should recommend the monitoring of liver function.
Medscape Medical News © 2019
Cite this: FDA Panel Recommends Cefiderocol for Complicated UTI - Medscape - Oct 17, 2019.