FDA Grants Cefiderocol Priority Review for New Indication

The US Food and Drug Administration’s (FDA) November 2019 approval of cefiderocol for the treatment of complicated urinary tract infections (cUTI) was one of the most notable infectious disease pipeline developments of the year.

Cefiderocol functions as a siderophore and has a novel mechanism of action which penetrates the outer cell membrane of Gram-negative pathogens.

Today, Shionogi announced that the FDA accepted a supplemental new drug application concerning use of cefiderocol in patients with hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP). The FDA granted the drug priority review with a Prescription Drug User Fee Act (PDUFA) date of September 27, 2020.

The supplemental new drug application is based on results from the Phase III APEKS-NP study, in which cefiderocol met the primary endpoint of non-inferiority relative to high-dose extended-infusion meropenem in all-cause mortality in the treatment of patients with HABP, VABP and healthcare-associated bacterial pneumonia.

According to Shionogi’s press release, the antibiotic “demonstrated no unexpected safety signals; the incidence of treatment-emergent adverse events was similar between treatment arms.”

“We are committed to working with the FDA in order to bring FETROJA (cefiderocol) to more patients fighting these challenging and life-threatening Gram-negative infections as quickly as possible,” said Akira Kato, PhD, president and CEO of Shionogi. “This submission represents our heritage in and commitment to developing antimicrobial therapies and filling unmet needs in the field of infectious disease.”

APEKS-NP, which stands for Acinetobacter baumannii, Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae and Stenotrophomonas maltophilia in Nosocomial Pneumonia, was designed to evaluate the efficacy and safety of cefiderocol for nosocomial pneumonia.

Patients were randomized 1:1. Those enrolled received cefiderocol administered by intravenous infusion of 2 grams over a 3-hour period every 8 hours or high-dose (2 grams) extended-infusion, or meropenem administered every 8 hours, for 7 to 14 days inpatient.

Investigators also administered linezolid for at least 5 days in both treatment groups to cover Gram-positive bacteria and methicillin-resistant Staphylococcus aureus.

Cefiderocol met the primary endpoint of non-inferiority to high-dose meropenem. At Day 14, all-cause mortality in the modified intent-to-treat population was 12.4% for cefiderocol (18/145) and 11.6% for high-dose meropenem (17/146), respectively (difference: 0.8, 95% confidence interval —6.6; 8.2)

The drug also met key secondary endpoints of clinical and microbiological outcomes at test of cure defined as seven days after treatment.

At the time of cefiderocol’s previous approval, the cephalosporin antibiotic was not approved for use in this indication based on concerns over a higher all-cause mortality rate in the cefiderocol group of the CREDIBLE-CR study. Whether the difference in mortality was a chance finding or represents a deficit in the activity of cefiderocol in critically ill patients was an open question after the trial.

Mortality at Day 14 of CREDIBLE-CR was 18.8% versus 12.2% for cefiderocol and a best available therapy group respectively. However, while no specific reason for the imbalance in mortality could be identified, it appeared that a portion of the deaths were related to progression of infection and lack of clinical response rather than an adverse effect of the medication.

Cefiderocol binds to ferric iron in order to be actively transported through a bacterial cell’s outer membrane, taking advantage of cellular mechanisms which typically collect ferric iron for nutrition. This novel mechanism of action enables high drug concentrations in the periplasmic space where cefiderocol can inhibit cell wall synthesis in the bacterial cells.

“FETROJA (cefiderocol) has also demonstrated in vitro activity against certain bacteria that contain very problematic resistant enzymes such as ESBLs, AmpC, serine- and metallo-carbapenemases,” authors of the press release added.

Due to the increase in all-cause mortality observed in patients treated with cefiderocol in CREDIBLE-CR, clinicians are advised to reserve cefiderocol for use as a last resort in patients who have limited or no alternative treatment options. Close monitoring is also advised.

Before treatment with cefiderocol is initiated, clinicians should ask about previous hypersensitivity reactions to cephalosporins, penicillin, or other beta-lactam antimicrobials.

Like most systemic antibacterial agents, Clostridioides difficile-associated diarrhea has been reported among patients treated with cefiderocol. Resulting illness may range from mild diarrhea to fatal colitis.

Common adverse reactions, defined as occurring in more than 2% of patients receiving cefiderocol, compared to imipenem/cilastatin in clinical trials were: diarrhea (4% vs 6%), infusion site reactions (4% vs 5%), constipation (3% vs 4%), rash (3% vs <1%), candidiasis (2% vs 3%), cough (2% vs <1%), elevations in liver tests (2% vs <1%), headache (2% vs 5%), hypokalemia (2% vs 3%), nausea (2% vs 4%), and vomiting (2% vs 1%).

As with all antimicrobial agents, appropriate prescribing is also necessary to slow the development of resistance. While there are potentially risks associated with cefiderocol, careful prescription may be able to shed further light on what real-world niche the drug occupies.