Briefing documents released ahead of Wednesday's meeting of the FDA's Antimicrobial Drugs Advisory Committee, slated to review Shionogi & Co. Ltd.'s cefiderocol for treatment of complicated urinary tract infections (cUTIs), spotlighted a finding of increased mortality among critically ill cefiderocol-treated patients in the company's Credible-CR study. Unclear whether it was "a chance finding or truly reflects a deficit in the activity of cefiderocol," FDA reviewers asked committee members to discuss the point.

Still, committee members were asked to vote on just one question: whether safety and efficacy data are sufficient to support the approval. Expectations Shionogi will find support for cefiderocol in the adcom are high, especially in light of the growing need to treat multidrug-resistant infections with difficult-to-treat gram-negative bacteria.

Osaka, Japan-based Shionogi is seeking FDA approval for the treatment of cUTIs, including pyelonephritis due to gram-negative bacteria in patients with limited or no alternative treatment options. Such a label would be significantly narrower than that given to another recently approved antibacterial for cUTIs, Merck & Co. Inc.'s Recarbrio (imipenem, cilastatin and relebactam), which gained FDA approval in July to treat adults with cUTIs and complicated intra-abdominal infections.

Bacteria in the urinary tract are generally flushed out via urination. But infection linked to certain other conditions, such as a kidney stone, or a structural problem in the urinary tract, can necessitate treatment with antibiotics. Pyelonephritis, a subset of cUTI, is a type of kidney infection that can lead to serious health problems if not treated quickly.

The most common gram-negative bacterial pathogens behind cUTIs include Enterobacteriaceae, primarily Escherichia coli and Klebsiella pneumoniae, and non-fermenting pathogens, such as Pseudomonas aeruginosa, the FDA said. Cefiderocol has shown in vitro activity against all those and other gram-negative species identified by the World Health Organization as being the highest priority for finding new treatments.

Between 2000 and 2009, the frequency of hospitalizations in the U.S. for cUTI increased by about 50% for multidrug resistant (MDR) P. aeruginosa and by about 300% for extended-spectrum beta-lactamase (ESBL)-producing organisms, according to data cited by FDA reviewers.

Fighting resistance

Cefiderocol is the first antibiotic to overcome all three of the primary mechanisms of gram-negative bacterial resistance to beta-lactams, according to Shionogi.

Cefiderocol, which was granted both fast track and qualified infectious disease product status by the FDA, is a structurally modified cephalosporin antibacterial drug. It leverages a siderophore-based mechanism for bacterial cell entry. Proposed dosing for the treatment of cUTIs is 2 grams via I.V. every eight hours, with dosage adjustments for altered renal function. The infusion time is three hours and the proposed treatment duration is seven to 14 days.

During the candidate's development, the FDA agreed that an adequate and well-controlled trial in cUTI with a noninferiority margin no larger than 15% would support a limited use indication. In its pivotal study of the drug, APEKs-cUTI, Shionogi surpassed that goal, showing that cefiderocol met the primary efficacy endpoint of composite of clinical cure and microbiologic eradication at test of cure (TOC) in 72.6% of patients, which was superior to imipenem/cilastatin (IPM/CS) at 54.6%, a weighted difference of 18.58% (95% CI: 8.23, 28.92).

Among those who received cefiderocol during the study, 40% of patients experienced an adverse event vs. 50% of patients in the IPM/CS arm. Serious adverse events occurred in 4.7% of patients who received cefiderocol and 8.1% who received IPM/CS.

In summarizing the data, FDA reviewers said, "the trial supports the conclusion that cefiderocol is effective for the treatment of cUTI."

An imbalance to explore

But Shionogi also conducted another trial of cefiderocol called Credible-CR, which compared cefiderocol with the best available therapy (BAT) in infections caused by carbapenem-resistant pathogens across body sites, including cUTI. A descriptive study with no pre-specified hypothesis, it enrolled patients with hospital-acquired bacterial pneumonia (HABP), ventilator-associated bacterial pneumonia (VABP), cUTI, and bloodstream infections/sepsis due to carbapenem-resistant organisms.

Patients enrolled were randomized to receive cefiderocol or BAT, of which 66% were colistin-based regimens. All-cause mortality was higher in the cefiderocol group compared to the BAT group at day 14 (18.8% vs. 12.2%) and day 28 (24.8% vs. 18.4%), respectively.

"The greatest mortality difference disfavoring cefiderocol was noted in the HABP/VABP/healthcare-associated bacterial pneumonia subgroup, followed by the BSI/sepsis subgroup," FDA reviewers reported. The reason? According to an independent adjudication committee, a greater percentage of patients in the cefiderocol group than in the BAT group had infection-related death with treatment failure (15.8% vs. 8.2%). However, they also noted an imbalance in death due to underlying co-morbidities of 9.9% in the cefiderocol group vs. 4.1% in the BAT group. Furthermore, pharmacokinetic analysis did not show an association between cefiderocol exposure and mortality, the reviewers said.

Shionogi acknowledged "the serious nature of the outcome of all-cause mortality," in its documents for the adcom, but said it "found no conclusive reasons" for the mortality difference seen in Credible-CR. "Shionogi is of the opinion that the difference in mortality is best understood by examining the detailed patient level information which gives a clear picture of the clinical context that led to the outcome of death," it said.

Cefiderocol has an assigned PDUFA date of Nov. 14. In addition to its pursuit of U.S. approval, Shionogi is seeking European approval of cefiderocol with an MAA that has been granted accelerated assessment by the EMA's CHMP. It is also advancing efforts to provide data that could eventually underpin label expansions covering the treatment of HABP/VABP. (See BioWorld, Oct. 9, 2019.)

Should Shionogi secure approval to treat cUTIs, global revenue from cefiderocol is expected to be about $26 million, according to Cortellis, potentially rising to $141 million by 2024. Shares of Shionogi (TYO:4507) closed at ¥5,884 (US$54.30) on Oct. 11. The market was closed Monday in observance of Sports Day.

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