Shionogi�s Innovative Antibiotic, FETCROJA� (cefiderocol), Is Now Available in Norway

FOR NORWEGIAN MEDICAL AND PHARMA TRADE MEDIA AND PROFESSIONAL SOCIETIES ONLY

• Following local reimbursement by the Norwegian Medicines Agency (Legemiddelverket), FETCROJA^� (cefiderocol) is now available in Norway for the treatment of infections due to aerobic Gram-negative bacteria in adults with limited treatment options¹
• Cefiderocol provides coverage against all Gram-negative pathogens considered of critical priority by the WHO – carbapenem-resistant Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacterales^2,3
• Cefiderocol is the first siderophore cephalosporin that uses the bacteria’s own iron uptake system to gain entry into the cell, acting like a Trojan horse⁴
• Antimicrobial resistance (AMR) is major health burden which urgently needs to be addressed, with 2,000 cases of antibiotic-resistant infections found in Norway in 2020 alone⁵

OSAKA, Japan & AMSTERDAM–(BUSINESS WIRE)–Shionogi & Co., Ltd. and its European subsidiary, Shionogi B.V. (hereafter “Shionogi”), today announces that its innovative antibiotic, cefiderocol, is now available in Norway for the treatment of infections due to aerobic Gram-negative bacteria in adults (18 years or older) with limited treatment options.¹

Cefiderocol is available to purchase in Norway through two distributors: Alliance Healthcare and Norsk Medisinaldepot (further details below).

Since its European Commission approval in 2020, over 23,000 patients in total have now been treated with cefiderocol throughout Europe. Data from multinational surveillance studies for cefiderocol have demonstrated potent in vitro activity against a broad spectrum of aerobic Gram-negative pathogens including all three WHO critical priority pathogens: carbapenem-resistant Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacterales,^2,3 as well as Stenotrophomonas maltophilia.⁶ Cefiderocol has also demonstrated in vitro activity against certain bacteria that contain very problematic resistant enzymes such as ESBLs, AmpC, serine- and metallo-carbapenemases.^7,8

Data from three clinical studies: APEKS-cUTI, APEKS-NP, and CREDIBLE-CR support the indication of cefiderocol in adult patients with limited treatment options for the treatment of infections due to aerobic Gram-negative organisms.¹ One of the studies included patients with Gram-negative infections caused by multidrug-resistant pathogens including carbapenem-resistant bacteria from the WHO priority list.²

“Over the past years, we have seen an increase in antimicrobial resistance in Norway and worldwide. The approval of new and effective antibiotic treatment options such as cefiderocol is very welcome news for both healthcare professionals and patients as it gives us a potential tool to treat some of the most challenging, multidrug resistant infections” commented Dirk Linke, President of the Norwegian Microbiology Society. “It is critical that we prioritise research and development in this area, ensuring sustainable pipelines for antibiotics development, better diagnostics, and responsible use to tackle this growing threat.”

AMR is a major health burden which urgently needs to be addressed. Between 2016 and 2020, a significant increasing trend in the estimated number of antibiotic-resistant infections was observed in Norway, with 2,000 cases in 2020 alone.⁵ Infections caused by carbapenem-resistant Gram-negative bacteria are often associated with a high mortality rate,⁹ resulting in ~35,000 deaths per year in the EU.¹⁰ If no action is taken, antibiotic resistance is predicted to kill 10 million people every year globally by 2050, at a cumulative cost to global economic output of 100 trillion USD.¹¹

In 2015, a National Strategy against Antibiotic Resistance was agreed upon in Norway, setting ambitious targets to achieve by 2020.¹² However, due to the COVID-19 pandemic, this strategy period has been extended.¹³ The overarching goals include more appropriate use of antibiotics in humans and animals, substantial reduction in consumption, improved understanding of AMR and to act as a driving force in international, normative work to strengthen access, responsible use and development of new antibiotics, vaccines and better diagnostic tools.¹⁴ To tackle the antibiotic market failure in Norway, a partially delinked pull incentive model was designed in 2018, aimed to ensure correct use, conservation and stable supply of critically important antibiotics.¹⁴ While this model has great potential, it is yet to be implemented.

Cefiderocol is available to purchase in Norway through the following distributors using the contact details below:

Alliance Healthcare

E-mail: kundeservice@alliance-healthcare.no

Phone: +47 64 85 04 00

Norsk Medisinaldepot (NMD)

Email: kundeservice@nmd.no

Phone: +47 24 05 30 00

Resistant Gram-negative infections

The increasing resistance of many infections caused by Gram-negative bacteria to existing therapies, including carbapenem-resistant Enterobacterales and non-fermenting species such as P. aeruginosa, A. baumannii, and S. maltophilia, makes them difficult to treat and results in high mortality rates.^15,16 The World Health Organization have identified carbapenem-resistant strains of Enterobacterales, P. aeruginosa and A. baumannii as the top priority in the research and development of new antibiotics.² Cefiderocol is the first antibiotic to address all three major mechanisms of carbapenem-resistance and is an important treatment option to address this urgent unmet need.¹⁷

Cefiderocol

Cefiderocol is the first siderophore cephalosporin antibiotic with a unique mechanism of entry through the outer membrane of Gram-negative pathogens by using the bacteria’s own iron uptake system to gain cell entry, acting like a Trojan horse.⁴ In addition to entering cells by passive diffusion through porin channels,¹⁸ 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.¹⁹ These mechanisms allow cefiderocol to achieve higher concentrations in the periplasmic space where it can bind to penicillin-binding proteins and inhibit cell wall synthesis in the bacterial cells.⁴

Carbapenem resistance (CR) in Gram-negative bacteria is due to three main mechanisms:

• Beta-lactamases which cause enzymatic breakdown of beta-lactams
• Changes in porin channels (through mutations and decrease in number) through which beta-lactams and other antibiotics diffuse into cells,
• Overexpression of efflux pumps which occurs post-exposure and pumps antibiotics out of cells²⁰

As a result of its unique structure and mechanism of cell uptake, cefiderocol can overcome these three major mechanisms of CR.

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 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.²¹

About Shionogi

Shionogi & Co., Ltd. is a 142-year-old global, research driven pharmaceutical company headquartered in Osaka, Japan, that is 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, CNS disorders, cardiovascular diseases and gastroenterology. Shionogi’s research and development currently target two therapeutic areas: infectious diseases, and pain/CNS disorders.

For more information on Shionogi & Co., Ltd., please visit http://www.shionogi.co.jp/en/.

Shionogi B.V. is the European headquarters of Shionogi & Co., Ltd. For more information on Shionogi B.V., please visit www.shionogi.eu.

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.

FETCROJA SMPC: https://www.ema.europa.eu/en/documents/product-information/fetcroja-epar-product-information_en.pdf

Job bag number: NP-NO-FDC-0001

Preparation date: January 2023

References

¹ FETCROJA SMPC. Available at: https://www.ema.europa.eu/en/documents/product-information/fetcroja-epar-product-information_en.pdf Last accessed January 2023

² World Health Organization. WHO publishes list of bacteria for which new antibiotics are urgently needed. February 27, 2017. Retrieved from https://www.who.int/news/item/27-02-2017-who-publishes-list-of-bacteria-for-which-new-antibiotics-are-urgently-needed. Last accessed January 2023

³ World Health Organization. 2019 Antibacterial Agents in Clinical Development. 2019. Retrieved from https://apps.who.int/iris/bitstream/handle/10665/330420/9789240000193-eng.pdf Last accessed January 2023

⁴ Tillotson GS. Trojan Horse Antibiotics—A Novel Way to Circumvent Gram-Negative Bacterial Resistance? Infectious Diseases: Research and Treatment. 2016;9:45-52 doi:10.4137/IDRT.S3156

⁵ European Centre for Disease Prevention and Control (ECDC). Assessing the health burden of infections with antibiotic-resistant bacteria in the EU/EEA, 2016–2020. Annex 2: Individual country results. 2022. Retrieved from https://www.ecdc.europa.eu/sites/default/files/documents/Annex_2_burden_estimates_country_sheets.pdf. Accessed January 2023

⁶ M Hackel, M Tsuji, Y Yamano, 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 Sep; 61(9): e00093-17.

⁷ K Kazmierczak et al. In vitro activity of cefiderocol, a siderophore cephalosporin, against a recent collection of clinically relevant carbapenem-non-susceptible Gram-negative bacilli, including serine carbapenemase- and metallo-?-lactamase-producing isolates (SIDERO-WT-2014 Study). Int J Antimicrob Agents. 2019 Feb;53(2):177-184

⁸ A Ito et al. In Vitro Antibacterial Properties of Cefiderocol, a Novel Siderophore Cephalosporin, against Gram-Negative Bacteria. Antimicrobial Agents and Chemotherapy, 2018, 62(1):e01454-17.

⁹ Perez F, et al. ‘Carbapenem-Resistant Enterobacteriaceae: A Menace to our Most Vulnerable Patients’. Cleve Clin J Med. Apr 2013; 80(4): 225–33

¹⁰ European Centre for Disease Prevention and Control (ECDC). 35,000 annual deaths from antimicrobial resistance in the EU/EEA. Available at: https://www.ecdc.europa.eu/en/news-events/eaad-2022-launch#:~:text=More%20than%2035%20000%20people,a%20new%20report%20released%20today. Accessed January 2023

¹¹ O’Neill J. ‘Tackling Drug-Resistant Infections Globally: Final Report and Recommendations’. The Review on Antimicrobial Resistance. May 2016. https://amr-review.org/sites/default/files/160518_Final%20paper_with%20cover.pdf Last accessed December 2022

¹² Norwegian Ministries. National Strategy against Antibiotic Resistance 2015 – 2020. 2015. Retrieved from https://www.regjeringen.no/contentassets/5eaf66ac392143b3b2054aed90b85210/antibiotic-resistance-engelsk-lavopploslig-versjon-for-nett-10-09-15.pdf. Accessed January 2023

¹³ NORM, NORM-VET. Usage of Antimicrobial Agents and Occurrence of Antimicrobial Resistance in Norway. 2021. Retrieved from https://www.fhi.no/contentassets/c183b18ccc4a4005a6b9cfae28c97351/norm-norm-vet-2021.pdf. Accessed January 2023

¹⁴ Ardal, C. et al. Designing a Delinked Incentive for Critical Antibiotics: Lessons from Norway. The Journal of Law, Medicine & Ethics, 2018; 46(1): 43–49.

¹⁵ 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.

¹⁶ Brooke JS. Stenotrophomonas maltophilia: an Emerging Global Opportunistic Pathogen.Clin Microbiol Rev. 2012;25(1):2-41.

¹⁷ Antimicrobial Drugs Advisory Committee Cefiderocol Briefing Document. https://www.fda.gov/media/131705/download Last accessed December 2022

¹⁸ Fetcroja EMA Assessment Report. https://www.ema.europa.eu/en/documents/assessment-report/fetcroja-epar-public-assessment-report_en.pdf. Last accessed January 2023

¹⁹ Ito A, Nishikawa T., Masumoto S, et al. Siderophore Cephalosporin Cefiderocol Utilizes Ferric Iron Transporter Systems for Antibacterial Activity against Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2016;60(12):7396-7401

²⁰ Carbapenem Resistance: Mechanisms and Drivers of Global Menace. https://www.intechopen.com/online-first/carbapenem-resistance-mechanisms-and-drivers-of-global-menace Last accessed January 2023

²¹ Antimicrobial Resistance Benchmark 2021.

https://accesstomedicinefoundation.org/media/uploads/downloads/61ee760d03810_Antimicrobial%20Resistance%20Benchmark%20report%202021.pdf Last accessed January 2023

Contacts

For further information, contact:
Shionogi EU contact
Russell Stapley

russell.stapley@shionogi.eu

Havas SO Media contact
Nicola Lilley
Client Services Director
+44 07983 128 712

nicola.lilley@havasso.com

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