Data from Pharmawand - Curated by EPG Health - Date added 06 October 2019

Shionogi & Co., Ltd. announced results from APEKS-NP, an international, double-blind, randomized Phase III clinical trial evaluating the efficacy and safety of the investigational antibiotic cefiderocol in patients with nosocomial pneumonia (NP) . Results from the study showed that cefiderocol met the primary endpoint of non-inferiority compared to high-dose meropenem in all-cause mortality at 14 days after initiation of study drug. Cefiderocol is a siderophore cephalosporin with a novel mechanism for penetrating the outer cell membrane of Gram-negative pathogens including multidrug-resistant strains. The APEKS-NP clinical study findings were presented as a late-breaking oral presentation at IDWeek 2019 on Thursday, October 3 at 2:15 p.m. EDT in Washington, D.C.

“Data from APEKS-NP provide meaningful evidence that cefiderocol has the potential to be an effective treatment option for severely ill hospitalized patients with pneumonia. In this trial, nearly 60 percent of patients were ventilated and approximately 33 percent experienced treatment failure of prior therapy,” said Dr. Tsutae “Den” Nagata, Chief Medical Officer, Shionogi. “Recently, several new antibiotics have been introduced to address some carbapenem-resistant infections, but they do not address all resistant Gram-negative pathogens. Clinicians are in urgent need of novel therapeutic approaches to overcome the multiple resistance mechanisms that make these strains so difficult to treat.”

Results from APEKS-NP showed cefiderocol met the primary endpoint of non-inferiority to high-dose meropenem, infused over three hours. At Day 14, all-cause mortality (ACM) 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% CI: –6.6;8.2).Cefiderocol also met key secondary endpoints of clinical and microbiological outcomes at test of cure (TOC), and Day 28 ACM: Clinical outcome at TOC: 64.8% cefiderocol versus 66.7% meropenem high dose (difference: –2.0, 95% CI: –12.5; 8.5) Microbiological eradication at TOC: 47.6% cefiderocol versus 48% meropenem high dose (difference: –1.4, 95% CI: –13.5; 10.7). Day 28 ACM: 21.0% cefiderocol versus 20.5% meropenem high dose (difference: 0.5, 95% CI: –8.7; 9.8)

“Carbapenem resistance is a growing problem in the U.S. and around the world, with increasing infections due to strains that are resistant to most or all currently available antibiotics. Patients with serious infections caused by resistant Gram-negative pathogens are facing a most serious challenge with high morbidity and mortality rates. These Phase III APEKS-NP data, combined with data from our Phase II APEKS-cUTI trial in complicated urinary tract infection, underscore the potential of cefiderocol to help solve an unmet medical need for patients battling life-threatening infections caused by deadly, hard-to-treat Gram-negative pathogens,” added Dr. Tsutae “Den” Nagata, Chief Medical Officer, Shionogi.

Additional study results showed clinical cure rates were similar between treatment arms in the modified intent-to-treat population for major target pathogens at TOC: Klebsiella pneumoniae: 64.6% (31/48) cefiderocol versus 65.9% (29/44) meropenem high dose (difference: –1.3, 95% CI: –20.8; 18.1). Escherichia coli: 63.2% cefiderocol (12/19) versus 59.1% (13/22) meropenem high dose (difference: 4.1, 95% CI: –25.8; 33.9). Pseudomonas aeruginosa: 66.7%(16/24) cefiderocol versus 70.8% meropenem high dose (17/24) (difference: –4.2, 95% CI: –30.4; 22.0). Acinetobacter baumannii: 52.2% (12/23) cefiderocol versus 58.3% (14/24) meropenem high dose (difference: –6.2, 95% CI: –34.5; 22.2).

No unexpected safety signals were observed in the study; the incidence of treatment-emergent adverse events (TEAEs) were similar between treatment arms.

About APEKS-NP -APEKS-NP ( Acinetobacter baumannii, Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae and Stenotrophomonas maltophilia in Nosocomial Pneumonia) was an international multicenter, double-blind, randomized, non-inferiority trial designed to evaluate cefiderocol for the treatment of nosocomial pneumonia including HAP, VAP, and HCAP caused by Gram-negative pathogens. Patients were randomized on a 1:1 basis to receive cefiderocol administered by intravenous infusion of two grams over a three-hour period every eight hours or high-dose meropenem administered by intravenous infusion of two grams over a three-hour period every eight hours, for seven to 14 days in hospital. Linezolid was additionally administered for at least five days in both arms to provide coverage for methicillin-resistant Staphylococcus aureus (MRSA) and for Gram-positive bacteria, in the cefiderocol group. Safety was investigated up to 28 days after the end of treatment unless there was an ongoing serious adverse event(s).

About Cefiderocol–An Investigational Antibiotic Agent :Cefiderocol is a siderophore cephalosporin with a novel mechanism for penetrating the outer cell membrane of Gram-negative pathogens including multidrug-resistant strains. It has a unique ability to overcome all three major mechanisms of carbapenem resistance (porin channel alterations, beta-lactamase inactivation, and efflux pump overproduction). Cefiderocol binds to ferric iron and is actively transported into bacterial cells through the outer membrane via the bacterial iron transporters, which function to incorporate this essential nutrient for bacteria.1 In addition, cefiderocol can also enter cells by passive diffusion through porin channels and is stable against all known classes of beta-lactamases, including both the metallo- and serine-beta-lactamases. These mechanisms allow cefiderocol to achieve higher concentrations in the periplasmic space where it can bind to receptors and inhibit cell wall synthesis in the bacterial cells.3 Data from multinational surveillance studies for cefiderocol demonstrated potent in vitro activity against a wide spectrum of Gram-negative pathogens including carbapenem-resistant Acinetobacter baumannii (A. baumannii), Pseudomonas aeruginosa (P. aeruginosa), Enterobacteriaceae, and Stenotrophomonas maltophilia (S. maltophilia).4 Cefiderocol has poor in vitro activity against Gram-positive or anaerobic bacteria. The clinical significance of in vitro data is unknown.

Shionogi submitted a New Drug Application to the FDA. Cefiderocol was designated as a Qualified Infectious Disease Product (QIDP) by the FDA with the assigned action date of November 14, 2019 under the Prescription Drug User-Fee Act (PDUFA). Additionally, Shionogi also submitted a marketing authorization application of cefiderocol to the European Medicines Agency and it was accepted in March 2019.

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