Pair of Lancet studies give final word on a promising Shionogi antibiotic that turned out to be 'as good' as the other 'suboptimal' options
Last October, the FDA OK’d a semi-controversial new antibiotic from Shionogi.
In one of two large studies for the drug, known chemically as cefiderocol and commercially as Fetroja, more patients died in the treatment arm than the control arm. But it had already cleared another randomized controlled trial and the agency determined the benefits at a time of growing drug resistance outweighed the risk.
Now, a year and an expanded approval later, Shionogi has published the full results from both of those studies in a single issue of The Lancet Infectious Disease. And while the papers don’t provide any radically new information, they give a final, tempered note on the benefits of a drug that was developed for its new and promising approach to resistant bacteria, but whose late-stage trials left as many questions and answers.
“The best interpretation of cefiderocol that can be gleaned from these studies is that it is as good as comparator agents that are frankly suboptimal,” University of Maryland School of Medicine professor Emily Heil and Johns Hopkins pediatrics professor Pranita Tamma wrote in a concurrent review.
The results “have admittedly tempered some of our initial enthusiasm for cefiderocol, and more data are needed to confidently define its role in the treatment of drug-resistant infections,” they added.
Heil and Tamma titled the review “Cefiderocol: the Trojan horse has arrived but will Troy fall?” Fetroja earned the Grecian moniker because it entered bacteria through the iron transport pathway they rely on to survive, offering a gateway through the cell wall that helps gram-negative bacteria avoid antibiotics and circumventing several of the key methods they use to evolve drug resistance. Unlike other experimental antibiotics, it also was active against a variety of bacteria as opposed to any single one.
Sure enough, in one of the Phase III studies, called APEKS-NP, Fetroja proved just as good at treating patients with hospital-acquired pneumonia as patients who received the antibiotic meropenem. The difference in deaths — from any cause — at 14 days was 0.8%, far more than close enough to meet the primary endpoint of non-inferiority. Heil and Tamma noted that 70% of patients were in severe condition, and they commended Shionogi for using meropenem, which they deemed a better comparator than what other companies had used.
In the second study, though, known as CREDIBLE-CR, patients with drug-resistant bacteria were randomly assigned to receive Fetroja or the best available therapy. Of these patients, 45% had hospital-acquired pneumonia and 31% had blood-stream infection.
The results met the primary endpoint, a physician-assessed metric known as “clinical cure,” for both types of infection.
Yet, on mortality, the data were far worse for pneumonia and blood-stream infection than for urinary tract infections. A quarter of pneumonia patients died by day 14 on the treatment, compared with 11% on the control arm. For bloodstream infections, those figures were 22% vs 11%. For complicated UTIs, though, the figures were reversed: 12% mortality in the treatment arm, 42% in the control arm.
Those high mortality rates were primarily driven by one strain of bacteria, called Acinetobacter baumannii. Shionogi attributed the mortality rates in those patients to pre-existing risk factors, echoing investigators who noted little difference in that bacteria in the APEKS study. The reviewers argued, though, that APEKS didn’t have enough A baumannii patients to draw a conclusion.
The mortality could mean Fetroja might just be a bad option for that bacteria, the reviewers wrote, but it could also mean that Fetroja just isn’t much better than the alternatives.
“It adds credence to the idea that cefiderocol is as good as, but no better than, other drugs for most carbapenem-resistant organisms,” they said.
Going forward, Heil and Tamma recommended Fetroja for complicated UTIs and as a “salvage option” for patients with most other gram-negative, drug-resistant infections. They added it was still unclear how effectively bacteria will learn to resist the new drug.
“Cefiderocol will be a valuable soldier in battles against gram-negative resistance,” they wrote, “but it probably will not win the war.”