Shionogi Release: Cefiderocol, A Novel Investigational Siderophore Cephalosporin, Demonstrated Potent Activity Against Multi-Drug Resistant Gram-Negative Pathogens

OSAKA, Japan and FLORHAM PARK, N.J., Oct. 26, 2016 /PRNewswire/ -- Shionogi & Co., Ltd. (hereafter "Shionogi") presented the results of the first global surveillance study for its in-development investigational siderophore cephalosporin, cefiderocol (S-649266), at IDWeek 2016 in New Orleans, Louisiana. Cefiderocol showed potent activity against Gram-negative pathogens, including carbapenem-resistant strains of Pseudomonas aeruginosa and Acinetobacter baumannii as well as carbapenem-resistant Enterobacteriaceae. The results were presented using in vitro data from 8765 test strains of P. aeruginosa, A. baumannii, and Enterobacteriaceae isolated in 2014/2015 from patients in North America and across Europe.¹

The study, conducted by International Health Management Associates, Inc, evaluated the in vitro activity of cefiderocol in comparison with various marketed Gram-negative treatments, including colistin and the newer agents ceftazidime/avibactam and ceftolozane/tazobactam. Key findings from the study included¹:

• Cefiderocol showed the lowest MIC₅₀ and MIC₉₀ values of all compounds tested.
• The growth of 99.6% of all isolates was inhibited at 4 µg/mL of cefiderocol (MIC of <4 µg/mL).
• Cefiderocol was active against many of the Gram-negative pathogens that were not susceptible to other antibiotics (1290 isolates [14.7% of total studied] were non-susceptible to meropenem). Cefiderocol had MIC₉₀ values of 1, 1, and 4 g/mL against meropenem non-susceptible isolates of A. baumannii, P. aeruginosa, and Enterobacteriaceae, respectively; whereas the MIC₉₀ values of both ceftazidime/avibactam and ceftolozane/tazobactam against these pathogens were  >32 g/mL .

Multi-drug resistant pathogensa growing worldwide threat

The threat to public health of these MDR bacteria strains has reached a crisis point, according to the President's Council of Advisors on Science and Technology.² The magnitude of this threat has also been confirmed by the United Nations. At the recent United Nations General Assembly high-level meeting on antimicrobial resistance, the Director-General told the member states that antimicrobial resistance is a "fundamental threat" to global health and safety.³

"There is an enormous need for new anti-infectives to battle the growing problem of drug-resistant bacteria, which has reached critical proportions," said Dr Tsutae Den Nagata, Chief Medical Officer at Shionogi. "The study results presented at ID Week demonstrate that cefiderocol is highly active against the most problematic and serious Gram-negative carbapenem-resistant pathogens."       

Cefiderocolan investigational antibiotic agent⁴

Cefiderocol is a siderophore cephalosporin with a unique mechanism for penetrating efficiently into Gram-negative pathogens. Cefiderocol binds to free iron and is actively transported into bacterial cells through the outer membrane. ⁵ This Trojan horse strategy allows cefiderocol to enter the space in-between the bacterial cell walls and disrupt cell wall synthesis. ⁶ In addition, cefiderocol is stable against nearly all beta-lactamases, including both the serine and metallo-carbapenemases. ⁷

About the regulatory pathway of cefiderocol^8,9

Cefiderocol has been designated by the U.S. Food and Drug Administration (FDA) as a Qualified Infectious Disease Product, which allows for priority review and provides eligibility for fast-track approval status. Registrational studies are ongoing in patients with complicated urinary tract infections and in patients with carbapenem-resistant pathogens at various infection sites. Information is available at www.clinicaltrials.gov under the identifiers NCT02321800 and NCT02714595, respectively.

About Shionogi

Shionogi & Co., Ltd. is a 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 well-being of the patients we serve." Shionogi's research and development currently targets two therapeutic areas: infectious diseases and pain/CNS disorders. For over 50 years, Shionogi has developed and commercialized innovative oral and parenteral anti-infectives. In addition, Shionogi is engaged in new research areas, such as obesity/geriatric metabolic disease and oncology/immunology. Contributing to the health and QOL of patients around the world through development in these therapeutic areas is Shionogi's primary goal. For more details, please visit www.shionogi.co.jp/en/. For more information on Shionogi Inc., the US-based subsidiary of Shionogi & Co., Ltd., headquartered in Florham Park, NJ, USA, please visit www.shionogi.com. For more information on Shionogi Ltd., the UK-based subsidiary of Shionogi & Co., Ltd., headquartered in London, England, 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, 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, Echols R,* et al. In vitro antibacterial activity of S-649266 against Gram-negative clinical strains collected in North America and Europe, 2015. Poster presented at: IDWeek 2016; October 26-30, 2016; New Orleans, LA. Poster 1828.

²    President's Council of Advisors on Science and Technology. National Action Plan for Combating Antibiotic-Resistant Bacteria. Published March 2015. https://www.whitehouse.gov/sites/default/files/docs/national_action_plan_for_combating_antibotic-resistant_bacteria.pdf. Accessed October 10, 2016.

³   World leaders commit to act on antimicrobial resistance. United Nations website. http://www.un.org/sustainabledevelopment/blog/2016/09/world-leaders-commit-to-act-on-antimicrobial-resistance. Accessed October 10, 2016.

⁴   Kohira N, West J, Ito A, et al. In vitro antimicrobial activity of a siderophore cephalosporin, S-649266, against Enterobacteriaceae clinical isolates, including carbapenem-resistant strains. Antimicrob Agents Chemother. 2015;60(2):729-734.

⁵    Ito A, Nishikawa T. Masumoto S, et al. Siderophore Cephalosporin Cefiderocol Utilizes Ferric Iron Transporter Systems for Antibacterial Activity against Pseudomonas aeruginosa. Antimicrobial agents and chemotherapy. 2016;60(12)

⁶    Tillotson S, Glenn. Trojan Horse AntibioticsA Novel Way to Circumvent Gram- Negative Bacterial Resistance? Infectious Diseases: Research and Treatment 2016:9 4552 doi:10.4137/IDRT.S31567.

⁷    Ito-Horiyama T, Ishii Y, Ito A, et al. Stability of Novel Siderophore Cephalosporin S-649266 against Clinically Relevant Carbaoenemases. Antimicrobial Agents and Chemotherapy. 2016;60(7):4384-4386.

⁸   A study of efficacy/safety of intravenous S-649266 versus imipenem/cilastatin in complicated urinary tract infections. ClinicalTrials.gov website. https://clinicaltrials.gov/ct2/show/NCT02321800?term=649266&rank=1.  Accessed October 10, 2016.

⁹    Study of S-649266 or best available therapy for the treatment of severe infections caused by carbapenem-resistant Gram-negative pathogens (CREDIBLE - CR). ClinicalTrials.gov website. https://clinicaltrials.gov/ct2/show/NCT02714595?term=649266&rank=2. Accessed October 10, 2016.

*Dr Echols is a paid consultant of Shionogi Inc.

© 2016 Shionogi and Co., Ltd. All Rights Reserved. USCEF-0006 10/16

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