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OSAKA, Japan & FLORHAM PARK, N.J.

Shionogi & Co., Ltd. (hereafter “Shionogi”) today announced there will be one oral presentation and 17 poster presentations featuring two of the company’s investigational compounds at the American Society for Microbiology (ASM) Microbe meeting, being held June 20–24, 2019 in San Francisco. Sixteen poster presentations are on cefiderocol, a late-stage investigational, novel siderophore cephalosporin, and one is on COT-143, a humanized monoclonal antibody.

“Cefiderocol has a unique mechanism of cell entry and is able to overcome the three major mechanisms of carbapenem-resistance of Gram-negative pathogens. The totality of cefiderocol data to be presented at ASM Microbe adds to the growing body of evidence of its potential activity against some of the world’s deadliest pathogens and we look forward to sharing these findings with the scientific community,” said Dr. Tsutae Den Nagata, Chief Medical Officer, Shionogi.

In addition, Shionogi will also present a poster on COT-143, an investigational humanized monoclonal antibody demonstrating anti-virulence activity targeting the PcrV protein of Pseudomonas aeruginosa.

Presentations will include data on these Shionogi agents from company-sponsored or investigator-initiated investigational studies.

The details for the presentations are as follows:

Oral presentation about cefiderocol and COT-143
Date and time: June 21, 2:30 p.m.-2:41 p.m.
Session title and location: Session S107: Pharma Pipeline Update: Part 1
Shionogi Pipeline; AAR Track Hub (Booth 5053) – Learn – exhibit and poster hall
Presenter: Yoshinori Yamano

The following poster presentations will take place on the following date and time, and session title and location:

Cefiderocol
Date and time: June 22, 11 a.m.-12 p.m. and 4 p.m.-5 p.m.
Session title and location: Session P494 – HMB12 – Inflammation During infection; exhibit and poster hall

• Poster #HMB-373: Development of Murine Models of Iron Overload and Depletion for the Study of Siderophore Antibiotics
  Presenter: James M. Kidd

Date and time: June 22, 11 a.m.-12 p.m. and 4 p.m.-5 p.m.
Session title and location: P514 – AAR09 – Pharmacological Studies of Investigational Agents Phase 2/3: Late-Stage Beta-Lactam Antibiotics; exhibit and poster hall

• Poster #AAR-761: A Multi-Site Study Comparing a Commercially Prepared Dried MIC Susceptibility System to the CLSI/ISO Broth Microdilution Method for Cefiderocol Using Gram-Negative Non-Fastidious Organisms
  Presenter: Thomas C. Lewis

• Poster #AAR-762: Cefiderocol Activity Against North American Clinical Isolates SIDERO-WT-2014-2017
  Presenter: Tiffany MacKenzie

• Poster #AAR-763: In Vitro Activity of Cefiderocol, a Novel Siderophore Cephalosporin, Against Clinical Gram- Negative Pathogens Collected From Canadian Intensive Care Units
  Presenter: Alyssa R. Golden

• Poster #AAR-764: In Vitro Antibacterial Activity of Cefiderocol Against Carbapenem-Non-Susceptible Gram-Negative Bacteria From Hospitalized Patients in the United States: SIDERO-WT-2014-2017
  Presenter: Sean Nguyen

• Poster #AAR-765: Cefiderocol Susceptibility Against Globally Isolated Meropenem Non-Susceptible Gram-Negative Bacteria Containing Serine- and Metallo-Carbapenemase Genes: SIDERO-WT-2014 and 2015
  Presenter: Masakatsu Tsuji

• Poster #AAR-766: Comparative Activity of Cefiderocol Against Pseudomonas aeruginosa by Infection Source and Census Region in the United States: SIDERO-WT-2014-2017
  Presenter: Melinda Soriano

• Poster #AAR-767: In Vitro Antibacterial Activity of Cefiderocol Against Gram-negative Clinical Strains Collected in North America and Europe, SIDERO-WT-2016
  Presenter: Masakatsu Tsuji

• Poster # AAR-768: Activity of Cefiderocol (CFDC), Ceftazidime‐Avibactam (CZA), and Eravacycline (ERV) Against Carbapenem‐Resistant (CR) E. coli Isolates From the US: Clonal Background, Resistance Genes, and Co‐Resistance
  Presenter: Brian Johnson

• Poster #AAR-769: In Vitro Activity of Cefiderocol Against Carbapenem-Resistant Acinetobacter spp., Enterobacter spp., Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa
  Presenter: Jose R. Mediavilla
• Poster #AAR-770: Comparative Activity of Cefiderocol Against Acinetobacter baumannii by Infection Sites in the US SIDERO-WT-2014-2017
  Presenter: Sean Nguyen

• Poster #AAR-771: Comparative Activity of Cefiderocol Against Stenotrophomonas maltophilia by Infection Sites in the US SIDERO-WT-2014-2017
  Presenter: Benjamin Georgiades

• Poster #AAR-772: Changes of Responsible Iron-Transporters for the Activity of Cefiderocol Against Pseudomonas aeruginosa Depending on the Culture Conditions
  Presenter: Akinobu Ito

• Poster #AAR-773: Comparative Impact of Human‐Simulated Exposures of Cefiderocol and Ceftazidime on Stenotrophomonas maltophilia in a Neutropenic Murine Thigh Infection Model
  Presenter: Iris H. Chen

• Poster #AAR-774: Characterization of Isolates Showing High MICs to Cefiderocol From Global Surveillance Study SIDERO-WT-2014
  Presenter: Akinobu Ito

Date and time: June 22, 11 a.m.-12 p.m. and 4 p.m.-5 p.m.
Session title and location: P507 – Antimicrobial Agents: Mechanisms of Action and Mechanisms of Resistance in Gram-negative ESKAPE Pathogens

• Poster #AAR-622: Characterization of a Pan-Resistant Pseudomonas aeruginosa Containing bla_NDM-1 and bla_IMP-1
  Presenter: David R. Lonsway

COT-143
Date and time: June 23, 11 a.m.-1 p.m.
Session title and location: P586 – AAR06 – Novel Approaches: Therapies, Diagnostics and Drug Discovery: Biologics; exhibit and poster hall

• Poster #AAR-670: COT-143, a Novel Monoclonal Antibody Against the PcrV Protein: In Vivo Bactericidal Efficacy Against Pseudomonas aeruginosa and Staphylococcus aureus Co-infection in Mice Lung Infection Models
  Presenter: Hideki Maki

About Cefiderocol–An Investigational Antibiotic Agent

Cefiderocol is a siderophore cephalosporin with a novel mechanism for penetrating the outer cell membrane of Gram-negative pathogens including multidrug-resistant strains. It has a unique ability to overcome all three major mechanisms of carbapenem resistance. 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.¹ In addition, cefiderocol can also enter cells by passive diffusion through porin channels and is stable against all known classes of beta-lactamases, including both the metallo- and serine-beta-lactamases.² These mechanisms allow cefiderocol to achieve higher concentrations in the periplasmic space where it can bind to receptors and inhibit cell wall synthesis in the bacterial cells.³ Data from multinational surveillance studies for cefiderocol demonstrated potent in vitro activity against a wide spectrum of Gram-negative pathogens including carbapenem-resistant Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacteriaceae, and Stenotrophomonas maltophilia.⁴ Cefiderocol has poor in vitro activity against Gram-positive or anaerobic bacteria. The clinical significance of in vitro data is unknown.

Two ongoing Phase III studies–in patients with HAP/VAP/HCAP† (APEKS-NP‡) and with carbapenem-resistant pathogens at various infection sites (CREDIBLE-CR) have recently completed enrollment. Information is available at www.clinicaltrials.gov under the identifiers NCT03032380 and NCT02714595, respectively. The company submitted a New Drug Application to the U.S. Food and Drug Administration in December 2018 and a marketing authorization application to the European Medicines Agency in March 2019.⁵

About Gram-negative Infections

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, A. baumannii, and S. maltophilia, means there is a critical need for new, effective therapies.^{4, 6-9} There are an increasing number of Gram-negative pathogens resistant to multiple antibiotics, making them difficult to treat and resulting in high mortality rates.¹⁰ In the U.S., at least two million people are infected with antibiotic-resistant bacteria, and at least 23,000 people die as a result each year.¹¹ The World Health Organization and the Centers for Disease Control and Prevention have identified carbapenem-resistant strains of Enterobacteriaceae, P. aeruginosa, and A.baumannii as the top priority in the research and development of new antibiotics.^6,11

About COT-143–An Investigational Compound

COT-143 is a humanized monoclonal antibody that binds to the PcrV protein of P. aeruginosa. The PcrV protein is an essential component of the type III secretion system responsible for releasing harmful toxins and is related to the pathogenicity of P. aeruginosa. By using a variety of nonclinical in vitro and in vivo models, COT-143 has demonstrated the potential to reduce tissue and cellular damage by the toxins released by this system, leading to the treatment of infection caused by P. aeruginosa.

It is estimated that 51,000 healthcare-associated P. aeruginosa infections occur in the U.S. each year and the rates of antibiotic resistance are increasing worldwide.^12-13 As resistance rises, there are limited options to treat or prevent P. aeruginosa infections. COT-143 is in early-stage development.

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 https://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.

†Hospital-Acquired Pneumonia/Ventilator-Acquired Pneumonia/Healthcare-Associated Pneumonia.
‡Nosocomial Pneumonia.

References

1. Ito A, Nishikawa T, Matsumoto 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.

2. Ito-Horiyama T, Ishii Y, Ito A, et al. Stability of Novel Siderophore Cephalosporin S-649266 against Clinically Relevant Carbapenemases. Antimicrob Agents Chemother. 2016;60(7):4384−4386.

3. 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.S31567

4. 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;61(9):e00093−17. doi.org/10.1128/AAC.00093-17.

5. 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.

6. 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/.

7. 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.

8. Livermore DM. Current epidemiology and growing resistance of gram-negative pathogens. Korean J Intern Med 2012; 27:128−42.

9. Brooke JS. Stenotrophomonas maltophilia: an emerging global opportunistic pathogen. Clin Microbiol Rev 2012; 25:2−41.

10. 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.

11. Centers for Disease Control and Prevention (CDC). Antibiotic Resistance Threats in the United States 2013. Retrieved from https://www.cdc.gov/drugresistance/pdf/ar-threats-2013-508.pdf.

12. Centers for Disease Control and Prevention (CDC) Pseudomonas aeruginosa in Healthcare Settings. Retrieved from https://www.cdc.gov/hai/organisms/pseudomonas.html.

13. Hirsch EB, Tam VH. Impact of multidrug-resistant Pseudomonas aeruginosa infection on patient outcomes. Expert Rev Pharmacoecon Outcomes Res 2010; 10(4):441−451. doi:10.1586/erp.10.49.

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