Shionogi: cefiderocol met primary endpoint in phase III study in adults with nosocomial pneumonia

Shionogi has reported positive Results from Cefiderocol Phase III study in adults with nosocomial pneumonia caused by gram-negative pathogens, as cefiderocol met primary endpoint of non-inferiority in 14-day all-cause mortality compared to high-dose meropenem.

“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.”

AMSTERDAM, Netherlands–(BUSINESS WIRE)–Shionogi & Co., Ltd. (hereafter “Shionogi”) announces 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 (ACM) 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.¹

Results from APEKS-NP showed cefiderocol met the primary endpoint of non-inferiority to high-dose meropenem, infused over three hours. At Day 14, 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). In the microbiologically evaluable per protocol population, ACM was 12.4% for cefiderocol (13/105) and 13% (13/100) for high-dose meropenem (difference: -0.3, 95% CI: −9.4, 8.7).

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 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. Nagata.

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:

• TEAEs: 87.8% (130/148) cefiderocol versus 86.0% (129/150) meropenem high dose (difference: 1.8, 95% CI: –5.8; 9.5)
• Drug-related TEAEs: 9.5% (14/148) cefiderocol versus 11.3% (17/150) meropenem high dose (difference: –1.9, 95% CI: –8.8; 5.1)
• Treatment-emergent serious adverse events (SAEs): 36.5% (54/148) cefiderocol versus 30.0% (45/150) meropenem high dose (difference: 6.5, 95% CI: –4.2; 17.2)
• Drug-related SAEs: 2.0% (3/148) cefiderocol versus 3.3% (5/150) meropenem high dose (difference: –1.3, 95% CI: –5.0; 2.4)
• Discontinuation due to TEAEs: 8.1% (12/148) cefiderocol versus 9.3% (14/150) meropenem high dose (difference: –1.2, 95% CI: –7.6; 5.2)
• Discontinuation due to drug-related TEAEs: 1.4% (2/148) cefiderocol versus 1.3% (2/150) meropenem high dose (difference: 0.0, 95% CI: –2.6; 2.6)
• TEAEs leading to death: 26.4% (39/148) cefiderocol versus 23.3% (35/150) meropenem high dose (difference: 3.0, 95% CI: –6.8; 12.8)