2021/07/09

Shionogi Announces in Vitro and Real-World Data Presented at Eccmid 2021 Demonstrating Activity of Fetroja® (Cefiderocol) Against Critical Priority Gram-Negative Bacterial Pathogens

In vitro activity of FETROJA has been demonstrated against the most difficult-to-treat Gram-negative bacteria, including carbapenem-resistant isolates of Pseudomonas aeruginosa, Acinetobacter baumannii-calcoaceticus complex, Stenotrophomonas maltophilia, and Enterobacterales collected from across Europe and the U.S. For the resistant phenotypes, FETROJA was the most active agent tested1,2,3,4
Encouraging real-world data for FETROJA are emerging, both from use on compassionate grounds and also from the Early Access Program, in which over a third of patients receiving FETROJA for a Gram-negative bacterial infection were co-infected with COVID-195,6
Data have also shown that multi-drug resistant Gram-negative bacteria are prevalent across several countries in Europe, of which a notable proportion are carbapenem-resistant Gram-negative isolates like P. aeruginosa, associated with high mortality and high unmet medical need7,8,9

OSAKA, Japan and FLORHAM PARK, N.J., JULY 8, 2021 – Shionogi & Co., Ltd. (Head Office: Osaka, Japan; President & CEO: Isao Teshirogi, Ph.D.) (hereafter “Shionogi”) today announces key data for FETROJA® (cefiderocol), a novel siderophore cephalosporin, presented at the virtual European Congress of Clinical Microbiology and Infectious Diseases (ECCMID), July 9-12, 2021.

 

FETROJA has extensive in vitro activity against some of the most difficult to treat carbapenem-resistant Gram-negative bacteria

The susceptibility profiles of FETROJA and comparators were evaluated against a European and U.S. collection of Gram-negative bacteria as part of the SENTRY Antimicrobial Surveillance Program. In these studies, the in vitro activity of FETROJA was evaluated against non-fermenters such as P. aeruginosa, A. baumannii-calcoaceticus complex, and S. maltophilia, as well as Enterobacterales isolates, including carbapenem-resistant strains. FETROJA also demonstrated broad activity against the isolates resistant to recently approved beta-lactam / beta-lactamase inhibitor combinations. For the resistant phenotypes, FETROJA was the most active agent tested. In vitro activity does not necessarily correlate with clinical efficacy.1,2,3,4

 

“These data from the SENTRY studies are very encouraging as they show that cefiderocol is broadly active against Enterobacterales and non-fermenters like Pseudomonas, Acinetobacter and Stenotrophomonas, including carbapenem-resistant strains, performing better than all other comparators tested. Infections caused by multi-drug resistant Pseudomonas are inherently difficult to treat as many antibiotics are not effective against this critical pathogen,” commented Dr. Dee Shortridge, Senior Director for Antimicrobial Development at JMI Laboratories. “Increasing resistance in Gram-negative bacteria is a real issue, especially where it compromises carbapenems.”

Real-world data for early use of FETROJA are presented, including in those co-infected with COVID-19

An overview of susceptibility and clinical outcomes for isolates from 141 patients who received FETROJA in a global compassionate use program reported that clinical response was positive overall in patients receiving FETROJA to treat Gram-negative infections caused by pathogens resistant to all alternative antibiotics, or where unacceptable toxicity of alternative antibiotics had been documented. The most frequent pathogens were P. aeruginosa (50%) and A. baumannii complex (24%).5

 

Initial data from the FETROJA Early Access Program for patients with no appropriate therapeutic alternative for resistant Gram-negative infections have also been presented. Of the 237 patients treated with FETROJA, 37.1% (n=88) were also co-infected with COVID-19. Carbapenem-resistant A. baumannii (n=96; 40.5%) and carbapenem-resistant P. aeruginosa (n=78; 32.9%) were the most common pathogens. The most common infections were pneumonia (n=106; 44.7%) and BSI/sepsis (n=93; 39.2%). The high level of requests for FETROJA between April 1 and December 31, 2020 demonstrate the continued high unmet need for new antimicrobials, especially for pathogens associated with high rates of resistance such as carbapenem-resistant A. baumannii and carbapenem-resistant P. aeruginosa.

 

“Shionogi is excited to share these real-world data at ECCMID, providing initial evidence that FETROJA is addressing the high unmet need for new antimicrobials effective against important resistant pathogens, such as carbapenem-resistant Acinetobacter or Pseudomonas,” commented Dr. Mark Hill, Global Head of Market Access, Shionogi. “Antimicrobial resistance is a major health burden responsible for approximately 700,000 deaths globally every year, and it is of critical importance that we continue to develop effective new treatments to tackle this growing threat.”

Epidemiology studies highlight the prevalence of carbapenem-resistant Gram-negative isolates which are associated with high mortality and unmet need

A retrospective chart review carried out at sites across the UK, France and Spain–the CARBAR study–identified that over 8% of Gram-negative isolates were carbapenem-resistant. Pneumonia was the most prevalent infection caused by carbapenem-resistant Gram-negative isolates (40.7%). The most frequent pathogen identified in these patients was carbapenem-resistant P. aeruginosa (37%) followed by Enterobacterales (36%). 59% of patients required mechanical ventilation and the mortality rate was 44% across all pathogens, indicating a high unmet need, significant healthcare utilization and limited treatment options in this patient population.7,8,9

Antimicrobial resistance (AMR)

Antimicrobial resistance (AMR) is a major health burden that urgently needs to be addressed. Globally, approximately 700,000 people die as a result of infections caused by resistant pathogens every year.10 Infections caused by carbapenem-resistant Gram-negative bacteria are often associated with a high mortality rate.11 If no action is taken, antimicrobial resistance is predicted to kill 10 million people every year by 2050, at a cumulative cost to global economic output of 100 trillion USD.10

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, Enterobacterales, 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.

US INDICATIONS

Fetroja® (cefiderocol) is indicated in patients 18 years of age or older for the treatment of complicated urinary tract infections (cUTIs), including pyelonephritis caused by the following susceptible Gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, and Enterobacter cloacae complex.

Fetroja is indicated in patients 18 years of age or older for the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia, caused by the following susceptible Gram-negative microorganisms: Acinetobacter baumannii complex, Escherichia coli, Enterobacter cloacae complex, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Serratia marcescens.

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.

SELECT IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

Fetroja 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 non-fermenters such as Acinetobacter baumannii complex, 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.

Closely monitor the clinical response to therapy in patients with cUTI and HABP/VABP.

For Full US 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 60 years. Shionogi is proud to be one of the few large pharmaceutical companies that continue 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.12

 

For more information please refer to: https://www.shionogi.com/global/en/sustainability/amr.html

About Shionogi

Shionogi & Co., Ltd. is a major Japanese 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.”

 

Shionogi Inc., the U.S. subsidiary, currently holds the rights to products in several therapeutic areas with a specific commercialization focus on anti-infectives within the hospital. With the recent successful launch of FETROJA® (cefiderocol), Shionogi Inc. is positioned for growth by expanding its portfolio through business development efforts aligned with infectious disease/hospital promotion and our pipeline. Shionogi Inc. is based in N.J.

 

For more information on Shionogi Inc., please visit www.shionogi.com. For more information on Shionogi & Co., Ltd., visit https://www.shionogi.com/global/en/.

Forward-Looking Statement

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, lack of availability 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.

For further information, contact:

Shionogi & Co., Ltd.
https://www.shionogi.com/global/en/contact.html

Shionogi Media Contact
Lindsay Bohlander, Senior Director, Corporate Development & Communications Shionogi
+1 973-307-3718
Lindsay.bohlander@shionogi.com

References

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    ECCMID 2021. Shortridge D, et al. Activity of Cefiderocol and Comparators against European Isolates of Pseudomonas aeruginosa, Acinetobacter baumannii-calcoaceticus species complex, and Stenotrophomonas maltophilia, including Carbapenem- Resistant Isolates. Presentation #01563
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    ECCMID 2021. Shortridge D, et al. Activity of Cefiderocol and Comparators against European Enterobacterales including Carbapenem-Resistant Isolates. Poster #01563
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    ECCMID 2021. Shortridge D, et al. Activity of Cefiderocol and Comparators against European Enterobacterales including Carbapenem-Resistant Isolates. Poster #01563
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    ECCMID 2021. Shortridge D, et al. Activity of Cefiderocol and Comparators against US Enterobacterales including Carbapenem-Resistant Isolates. Poster #01591
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    ECCMID 2021. Longshaw C, et al. Overview of susceptibility and clinical outcomes for isolates from cefiderocol global compassionate use programme. Poster #04725
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    ECCMID 2021. Karas A, et al. Insights from the Cefiderocol Early Access Programme for patients with Gram negative infection and limited treatment options in Europe. Poster #01877
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    ECCMID 2021. Goldenberg S, et al. The CARBAR part 1 study: a pooled analysis of the epidemiology data for UK, France and Spain: Bacterial susceptibility & resistance. Poster #3175
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    ECCMID 2021. Goldenberg S, et al. Patients with confirmed or suspected carbapenem non-susceptible Gram-negative infections from the CARBAR part 2 study: Bacterial susceptibility & resistance. Poster #396
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    ECCMID 2021. Goldenberg S, et al. The burden of nosocomial pneumonia infections involving carbapenem non-susceptible bacteria in Europe: the pooled results of the CARBAR study. Poster #3447
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    O’Neill. The Review on antimicrobial resistance. 2016. Available at: https://amr review.org/sites/default/files/160518_Final%20paper_with%20cover.pdf Last accessed June 2021
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    Perez F, et al. ‘Carbapenem-Resistant Enterobacteriaceae: A Menace to our Most Vulnerable Patients’. Cleve Clin J Med. Apr 2013; 80(4): 225–33
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    Antimicrobial Resistance Benchmark 2020. https://accesstomedicinefoundation.org/media/uploads/downloads/5e270aa36821a_Antimicrobial_Resistance_Benchmark_2020 pdf Last accessed July 2021