OSAKA, Japan & FLORHAM PARK, N.J.--(BUSINESS WIRE)-- Shionogi & Co., Ltd. (hereafter “Shionogi”) today announced FETROJA^® (cefiderocol) is now available in the U.S. for patients 18 years of age or older who have limited or no alternative treatment options, for the treatment of complicated urinary tract infections (cUTIs), including pyelonephritis, caused by the following susceptible Gram-negative microorganisms: Escherichia coli (E. coli), Klebsiella pneumoniae (K. pneumoniae), Proteus mirabilis (P. mirabilis), Pseudomonas aeruginosa (P. aeruginosa), and Enterobacter cloacae (E. cloacae) complex. FETROJA, which was approved by the U.S. Food and Drug Administration on November 14, 2019, is the first approved antibiotic that functions as a siderophore and has the ability to overcome many of the resistance mechanisms that Gram-negative bacteria employ against antibiotics. Under FETROJA’s Qualified Infectious Disease Product (QIDP) status, approval of the cUTI indication was based on limited clinical safety and efficacy data.

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FETROJA® is now available in the U.S. for patients 18 years of age or older who have limited or no alternative treatment options, for the treatment of complicated urinary tract infections. (Photo: Shionogi Inc.)

“The infectious disease community faces a serious challenge in combating cUTIs caused by Gram-negative pathogens, leading to high mortality rates. This illustrates a dire need for a treatment option able to overcome many mechanisms of resistance in Gram-negative bacteria,” said Akira Kato, Ph.D., president and CEO at Shionogi Inc.

The increasing resistance of many infections caused by Gram-negative bacteria to existing therapies, including carbapenem-resistant Enterobacteriaceae and non-fermenting species such as P. aeruginosa, Acinetobacter baumannii (A. baumannii), and Stenotrophomonas maltophilia (S. maltophilia), poses a serious health challenge.^1-5 There is an increasing number of Gram-negative pathogens resistant to multiple antibiotics, making them difficult to treat and resulting in high mortality rates.⁶ In the United States, more than 2.8 million antibiotic-resistant infections occur each year, and more than 35,000 people die as a result.⁷ If no action is taken, antibiotic resistance is predicted to kill 10 million people every year by 2050 at a cumulative cost to global economic output of 100 trillion USD.⁸ The World Health Organization (WHO) and the Centers for Disease Control and Prevention have identified carbapenem-resistant strains of Enterobacteriaceae, P. aeruginosa, and A. baumannii as the top priorities in the research and development of new antibiotics.^2,7

“We are proud to make FETROJA available for patients and their infectious disease care teams. Currently, FETROJA is the only available antibiotic which provides in vitro coverage against all Gram-negative pathogens considered top priority by the WHO,” said Nate McCutcheon, Chief Commercial Officer, Shionogi Inc. “At Shionogi, we are currently expanding our organization to better assist hospitals and infectious disease specialists to support this community in dire need.”

Please visit www.fetroja.com for more information.

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.⁹ These mechanisms allow cefiderocol 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.⁹ FETROJA has also demonstrated in vitro activity against certain bacteria that contain very problematic resistant enzymes such as ESBLs, AmpC, serine- and metallo-carbapenemases.⁹ 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.¹ The clinical significance of the in vitro data is unknown. FETROJA has poor in vitro activity against Gram-positive or anaerobic bacteria.

Shionogi also submitted a marketing authorization application for cefiderocol to the European Medicines Agency and it was accepted in March 2019.¹⁰

Important Safety Information

Contraindications

FETROJA^® (cefiderocol) is contraindicated in patients with a known history of severe hypersensitivity to cefiderocol or other beta-lactam antibacterial drugs, or any other component of FETROJA.

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.

Hypersensitivity Reactions

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions and serious skin reactions have been reported in patients receiving beta-lactam antibacterial drugs. Hypersensitivity was observed in FETROJA clinical trials. These reactions are more likely to occur in individuals with a history of beta-lactam hypersensitivity and/or a history of sensitivity to multiple allergens. There have been reports of individuals with a history of penicillin hypersensitivity who have experienced severe reactions when treated with cephalosporins. Before therapy with FETROJA is instituted, inquire about previous hypersensitivity reactions to cephalosporins, penicillins or other beta-lactam antibacterial drugs. Discontinue FETROJA if an allergic reaction occurs.

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

Cephalosporins, including FETROJA, have been implicated in triggering seizures. Nonconvulsive status epilepticus (NCSE), encephalopathy, coma, asterixis, neuromuscular excitability, and myoclonia have been reported with cephalosporins particularly in patients with a history of epilepsy and/or when recommended dosages of cephalosporins were exceeded due to renal impairment. Adjust FETROJA dosing based on creatinine clearance. Anticonvulsant therapy should be continued in patients with known seizure disorders. If CNS adverse reactions including seizures occur, patients should undergo a neurological evaluation to determine whether FETROJA should be discontinued.

Development of Drug-Resistant Bacteria

Prescribing FETROJA in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and may increase the risk for development of drug-resistant bacteria.

Adverse Reactions

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.

Indications and Usage

Indication

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.

Usage

To reduce the development of drug-resistant bacteria and maintain the effectiveness of FETROJA and other antibacterial drugs, FETROJA should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria.

For full Prescribing Information, please visit Shionogi.com.

Shionogi’s Commitment to Fighting Antimicrobial Resistance

Shionogi has a strong heritage in the field of anti-infectives and has been developing antimicrobial therapies for more than 50 years. Shionogi is proud to be one of the few large pharmaceutical companies that continues to focus on research and development in anti-infectives. The company invests the highest proportion of its pharmaceutical revenues in relevant anti-infectives R&D compared to other large pharmaceutical companies.¹¹

About Shionogi

Shionogi & Co., Ltd. is a Japanese major research-driven pharmaceutical company dedicated to bringing benefits to patients based on its corporate philosophy of “supplying the best possible medicine to protect the health and wellbeing of the patients we serve.” The company currently markets products in several therapeutic areas including anti-infectives, pain, cardiovascular diseases, and gastroenterology. Our pipeline is focused on infectious disease, pain, CNS, and oncology. For more information on Shionogi & Co., Ltd., visit www.shionogi.co.jp/en. Shionogi Inc. is the U.S. subsidiary of Shionogi & Co., Ltd. based in N.J. For more information on Shionogi Inc., please visit www.shionogi.com.

Forward-Looking Statements

This announcement contains forward-looking statements. These statements are based on expectations in light of the information currently available, assumptions that are subject to risks and uncertainties which could cause actual results to differ materially from these statements. Risks and uncertainties include general domestic and international economic conditions such as general industry and market conditions, and changes of interest rate and currency exchange rate. These risks and uncertainties particularly apply with respect to product-related forward-looking statements. Product risks and uncertainties include, but are not limited to, completion and discontinuation of clinical trials; obtaining regulatory approvals; claims and concerns about product safety and efficacy; technological advances; adverse outcome of important litigation; domestic and foreign healthcare reforms and changes of laws and regulations. Also, for existing products, there are manufacturing and marketing risks, which include, but are not limited to, inability to build production capacity to meet demand, unavailability of raw materials, and entry of competitive products. The company disclaims any intention or obligation to update or revise any forward-looking statements whether as a result of new information, future events, or otherwise.

References

1. Hackel M, Tsuji M, Yamano Y, et al. In Vitro Activity of the Siderophore Cephalosporin, Cefiderocol, Against a Recent Collection of Clinically Relevant Gram-Negative Bacilli from North America and Europe, Including Carbapenem Non-Susceptible Isolates: The SIDERO-WT-2014 Study. Antimicrob Agents Chemother. 2017;61(9):e00093−17. doi.org/10.1128/AAC.00093-17.
2. World Health Organization. Global priority list of antibiotic-resistant bacteria to guide research, discovery, and development of new antibiotics. February 27, 2017. Retrieved from https://www.who.int/medicines/publications/global-priority-list-antibiotic-resistant-bacteria/en/.
3. Diene SM, Rolain JM. Carbapenemase genes and genetic platforms in gram-negative bacilli: Enterobacteriaceae, Pseudomonas and Acinetobacter species. Clin Microbiol Infect 2014; 20:831−38.
4. Livermore DM. Current epidemiology and growing resistance of gram-negative pathogens. Korean J Intern Med 2012; 27:128−42.
5. Brooke JS. Stenotrophomonas maltophilia: an emerging global opportunistic pathogen. Clin Microbiol Rev 2012; 25:2−41.
6. Tangden T, Giske CG. Global dissemination of extensively drug-resistant carbapenemase-producing Enterobacteriaceae: clinical perspectives on detection, treatment and infection control. J Intern Med 2015; 277:501−12.T.
7. Centers for Disease Control and Prevention (CDC). Antibiotic Resistance Threats in the United States 2019, Atlanta, GA: U.S. Department of Health and Human Services, CDC; 2019. Retrieved fromhttps://www.cdc.gov/drugresistance/pdf/threats-report/2019-ar-threats-report-508.pdf.
8. O’Neill J. ‘Tackling Drug-Resistant Infections Globally: Final Report and Recommendations’. Review on Antimicrobial Resistance. May 2016. Retrieved from https://amr-review.org/sites/default/files/160518_Final%20paper_with%20cover.pdf.
9. FETROJA^® (cefiderocol) prescribing information. Florham Park, N.J. Shionogi Inc.: November 2019.
10. Shionogi & Co, Ltd. Shionogi announces submission of cefiderocol marketing authorisation application. April 1, 2019. Retrieved from http://www.shionogi.co.jp/en/company/news/2019/pmrltj000000418y-att/e_190401_2.pdf.
11. Antimicrobial Resistance Benchmark 2020. Retrieved from https://accesstomedicinefoundation.org/media/uploads/downloads/5e270aa36821a_Antimicrobial_Resistance_Benchmark_2020.pdf.

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