Adults with complicated urinary tract infections (cUTIs) and limited or no alternative treatment options could soon receive Shionogi & Co. Ltd.'s cefiderocol following FDA approval for the antibacterial. The approved indication also included kidney infections caused by susceptible gram-negative microorganisms. The new therapy, to be marketed as Fetroja, is expected to be available in early 2020.

"Fetroja will fill a very important unmet medical need because of its unique method of penetrating the cell wall of gram-negative bacteria and its ability to overcome many of the resistance mechanisms that bacteria employ against antibiotics," said Isao Teshirogi, president and CEO of Osaka, Japan-based Shionogi. Company shares (Tokyo:4507) rose ¥90 (US83 cents) to close at ¥6,289 on Friday.

The injectable medicine's label may limit its use in certain contexts, with a warning reflecting concerns over increased mortality among critically ill cefiderocol-treated patients in the company's Credible-CR study, a hot topic in October's meeting of the FDA's Antimicrobial Drugs Advisory Committee. Despite their concerns, adcom members recommended approval for cefiderocol by a large margin in light of the grave need for therapies against multidrug-resistant (MDR) infections by gram-negative bugs. (See BioWorld, Oct. 16, 2019, and Oct. 17, 2019.)

"A key global challenge the FDA faces as a public health agency is addressing the threat of antimicrobial-resistant infections, like cUTIs," said John Farley, acting director of the Office of Infectious Diseases in the FDA's Center for Drug Evaluation and Research. "This approval represents another step forward in the FDA's overall efforts to ensure safe and effective antimicrobial drugs are available to patients for treating infections," he said.

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.

Fetroja's safety and effectiveness were primarily demonstrated in the pivotal APEKS-cUTI trial, a study of 448 patients with cUTIs. Of the patients administered Fetroja, 72.6% had resolution of symptoms and eradication of the bacteria about seven days after completing treatment, compared with 54.6% in patients who received an alternative antibiotic. The clinical response rates were similar between the two treatment groups.

The most common adverse reactions to Fetroja in trials have included diarrhea, constipation, nausea, vomiting, elevations in liver tests, rash, infusion site reactions, candidiasis, cough, headache and hypokalemia.

Fetroja's label is 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. But that's attributable chiefly to different mechanisms of action between the two products and the contexts in which each is most appropriately used.

An approachable market

James Hackworth, SVP of development strategy and commercialization, Shionogi

Though Shionogi has long invested in the broader infectious diseases field, much of that effort outside of Japan and other Asian markets has been pursued through partnerships. "We're not changing that strategy entirely, but we've decided in the United States and in Europe to begin commercializing drugs ourselves in areas where we see the biggest unmet need, medically, and areas we think are the right size for us, from an investment point of view," James Hackworth, Shionogi's senior vice president of development strategy and commercialization, told BioWorld. The hospital infectious disease market fits both of those criteria very well, he said. To make the leap, Shionogi is now in the process of hiring people to work in the field.

Pricing for Fetroja has yet to be revealed, but financially speaking, it will be a relatively small contributor to Shionogi's revenues vs. royalties from its Roche Holdings AG-partnered flu treatment, Xofluza (baloxavir marboxil), which is forecast to generate $257.7 million for the company this year. Other revenue-generators for the company include Cymbalta (duloxetine), which generated $221.8 million in 2018 sales and Intuniv (guanfacine hydrochloride), which generated $48.8 million in 2018 sales and almost as much in the first half of 2019.

"Having only the complicated urinary tract infection indication is somewhat limiting," Hackworth acknowledged, but "it's not where we plan to stay with the drug," he said.

Next year, Shionogi plans to use data from its phase III APEKS-NP trial to support pursuit of an expanded indication in nosocomial pneumonia, also known as hospital-acquired or ventilator-associated bacterial pneumonia. That's "a big area of need for the drug," Hackworth said. (See BioWorld, Oct. 9, 2019.)

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