OSAKA, Japan and FLORHAM PARK, N.J., June 1, 2020 – Shionogi & Co., Ltd. (hereafter “Shionogi”) today announced the U.S. Food and Drug Administration (FDA) has accepted the company’s supplemental New Drug Application (sNDA) for FETROJA® (cefiderocol) and granted Priority Review designation with a Prescription Drug User Fee Act (PDUFA) date of September 27, 2020. Shionogi submitted the sNDA for FETROJA for the treatment of adult patients with hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP) caused by susceptible Gram-negative pathogens. HABP and VABP are also sometimes referred to as nosocomial pneumonia (NP).
“We are committed to working with the FDA in order to bring FETROJA to more patients fighting these challenging and life-threatening Gram-negative infections as quickly as possible,” said Akira Kato, Ph.D., president and CEO at Shionogi Inc. “This submission represents our heritage in and commitment to developing antimicrobial therapies and filling unmet needs in the field of infectious disease.”
The sNDA is based on results from the Phase III APEKS-NP study, which showed FETROJA met the primary endpoint of non-inferiority compared to high-dose extended-infusion meropenem in all-cause mortality 14 days after initiation of study drug in the treatment of patients with HABP, VABP and healthcare-associated bacterial pneumonia (HCABP).
The FDA approved FETROJA in November 2019 for patients 18 years of age or older who have limited or no alternative treatment options, for the treatment of complicated urinary tract infections, including pyelonephritis, caused by Gram-negative pathogens. It is the first approved antibiotic that functions as a siderophore and has a novel mechanism for penetrating the outer cell membrane of Gram-negative pathogens including carbapenem-resistant strains. See the full indication below.
APEKS-NP (Acinetobacter baumannii, Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae and Stenotrophomonas maltophilia in Nosocomial Pneumonia) was a multinational, multicenter, double-blind, randomized, non-inferiority trial designed to evaluate the efficacy and safety of FETROJA for the treatment of nosocomial pneumonia including HABP, VABP, and HCABP caused by Gram-negative pathogens. Patients were randomized on a 1:1 basis to receive FETROJA administered by intravenous infusion of two grams over a three-hour period every eight hours or high-dose (two grams) extended-infusion (over three-hours) meropenem administered every eight hours, for seven to 14 days in the 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 FETROJA group. Safety was investigated up to 28 days after the end of treatment unless there was an ongoing serious adverse event(s).
The study, which was first presented in October 2019 at IDWeek, found that FETROJA:
- 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 FETROJA (18/145) and 11.6% for high-dose meropenem (17/146), respectively (difference: 0.8, 95% CI: –6.6; 8.2)
- Met key secondary endpoints of clinical and microbiological outcomes at test of cure (TOC) defined as seven days after treatment, and Day 28 ACM:
- Clinical outcome at TOC: 64.8% (94/145) FETROJA versus 66.7% (98/147) meropenem high dose (difference: –2.0, 95% CI: –12.5; 8.5)
- Microbiological eradication at TOC: 47.6% (59/124) FETROJA versus 48% (61/127) meropenem high dose (difference: –1.4, 95% CI: –13.5; 10.7)
- Day 28 ACM: 21.0% (30/143) FETROJA versus 20.5% (30/146) meropenem high dose (difference: 0.5, 95% CI: –8.7; 9.8)
- Demonstrated no unexpected safety signals; the incidence of treatment-emergent adverse events was similar between treatment arms:
- 87.8% (130/148) for FETROJA versus 86% (129/150) for meropenem high dose (difference: 1.8; 95% CI: –5.8 to 9.5)
About FETROJA® (cefiderocol) for injection
FETROJA® (cefiderocol) is a cephalosporin antibiotic with a novel mechanism for penetrating the outer cell membrane of Gram-negative pathogens by acting as a siderophore. In addition to entering cells by passive diffusion through porin channels, FETROJA 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. These mechanisms allow FETROJA to achieve high concentrations in the periplasmic space where it can bind to penicillin-binding proteins and inhibit cell wall synthesis in the bacterial cells. FETROJA has also demonstrated in vitro activity against certain bacteria that contain very problematic resistant enzymes such as ESBLs, AmpC, serine- and metallo-carbapenemases. Data from multinational surveillance studies for FETROJA demonstrated potent in vitro activity against a wide spectrum of Gram-negative pathogens including carbapenem-resistant A. baumannii, P. aeruginosa, Enterobacteriaceae, and S. maltophilia. The clinical significance of the in vitro data is unknown. FETROJA has poor in vitro activity against Gram-positive or anaerobic bacteria.
Cefiderocol, under the brand name FETCROJA®, is approved by the European Commission for the treatment of infections due to aerobic Gram-negative bacteria in adults 18 years or older with limited treatment options.
Indications and Usage
Indication from USPI
FETROJA® (cefiderocol) is indicated in patients 18 years of age or older who have limited or no alternative treatment options for the treatment of complicated urinary tract infections (cUTI), including pyelonephritis caused by the following susceptible Gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, and Enterobacter cloacae complex.
Approval of this indication is based on limited clinical safety and efficacy data for FETROJA.
Important Safety Information
Warnings and Precautions
Increase in All-Cause Mortality in Patients with Carbapenem-Resistant Gram-Negative Bacterial Infections
An increase in all-cause mortality was observed in patients treated with FETROJA as compared to best available therapy (BAT) in a multinational, randomized, open-label trial in critically-ill patients with carbapenem-resistant Gram-negative bacterial infections (NCT02714595). Patients with nosocomial pneumonia, bloodstream infections, sepsis, or cUTI were included in the trial. BAT regimens varied according to local practices and consisted of 1 to 3 antibacterial drugs with activity against Gram-negative bacteria. Most of the BAT regimens contained colistin.
The increase in all-cause mortality occurred in patients treated for nosocomial pneumonia, bloodstream infections, or sepsis. The 28-Day all-cause mortality was higher in patients treated with FETROJA than in patients treated with BAT [25/101 (24.8%) vs. 9/49 (18.4%), treatment difference 6.4%, 95% CI (-8.6, 19.2)]. All-cause mortality remained higher in patients treated with FETROJA than in patients treated with BAT through Day 49 [34/101 (33.7%) vs. 10/49 (20.4%), treatment difference 13.3%, 95% CI (-2.5, 26.9)]. Generally, deaths were in patients with infections caused by Gram-negative organisms, including nonfermenters such as Acinetobacter baumannii, Stenotrophomonas maltophilia, and Pseudomonas aeruginosa, and were the result of worsening or complications of infection, or underlying comorbidities. The cause of the increase in mortality has not been established. The safety and efficacy of FETROJA have not been established for the treatment of nosocomial pneumonia, bloodstream infections or sepsis.
Reserve FETROJA for use in patients who have limited or no alternative treatment options for the treatment of cUTI. Closely monitor the clinical response to therapy in patients with cUTI.
Clostridioides difficile-associated Diarrhea (CDAD)
Clostridioides difficile-associated diarrhea (CDAD) has been reported for nearly all systemic antibacterial agents, including FETROJA. CDAD may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of C. difficile.
Careful medical history is necessary because CDAD has been reported to occur more than two months after the administration of antibacterial agents.
If CDAD is suspected or confirmed, antibacterial drugs not directed against C. difficile may need to be discontinued. Manage fluid and electrolyte levels as appropriate, supplement protein intake, monitor antibacterial treatment of C. difficile, and institute surgical evaluation as clinically indicated.
Seizures and Other Central Nervous System (CNS) Adverse Reactions
Development of Drug-Resistant Bacteria
The most common adverse reactions occurring in (>2%) of patients receiving FETROJA 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%).
Report side effects to the FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch. Report side effects to Shionogi Inc. at 1-800-849-9707.
For full Prescribing Information, please visit Shionogi.com.
Shionogi’s Commitment to Fighting Antimicrobial Resistance
For Further Information, Contact:
Corporate Communications Department
Shionogi & Co., Ltd.
Shionogi Inc. U.S. Media Contact
Lindsay BohlanderDirector, Advocacy & PR
- 1Access to Medicine Foundation. Antimicrobial Resistance Benchmark 2020. Retrieved from https://accesstomedicinefoundation.org/media/uploads/downloads/5e270aa36821a_Antimicrobial_Resistance_Benchmark_2020.pdf.