• Potent in vitro activity of cefiderocol has been demonstrated
  against the most difficult-to-treat Gram-negative bacteria, including
  multidrug-resistant strains, collected from across Europe
• Cefiderocol has shown broad activity against a global collection of
  Gram-negative bacteria even in the presence of serine- and
  metallo-carbapenemase-encoding genes, which can contribute to
  carbapenem resistance
• According to WHO, development of new antibiotics against
  carbapenem-resistant strains of Pseudomonas aeruginosa,
  Acinetobacter baumannii, and Enterobacteriaceae is a
  critical priority¹

OSAKA, Japan & AMSTERDAM–(BUSINESS WIRE)–Shionogi & Co., Ltd. (Head Office: Osaka, Japan; President & CEO: Isao
Teshirogi, Ph.D.) and Shionogi B.V. the European subsidiary of Shionogi
& Co., Ltd respectively, (hereafter “Shionogi”) today announces key data
for cefiderocol, a late-stage investigational, novel siderophore
cephalosporin, presented at the European Congress of Clinical
Microbiology and Infectious Diseases (ECCMID), in Amsterdam,
Netherlands, April 13-16, 2019. The data in these presentations suggest
cefiderocol shows a high potential for treating infections caused by the
most difficult to treat Gram-negative (GN) bacteria collected from
across Europe, including multidrug-resistant strains.^2,3

The in vitro activity of cefiderocol was evaluated against GN
bacteria collected from across Europe and the activity was compared with
comparator agents in a multi-national surveillance study,²
which demonstrated not only the potent activity of cefiderocol against
carbapenem-resistant isolates of Enterobacteriaceae, but also
against the more difficult-to-treat carbapenem-resistant
non-fermentative bacteria, A. baumannii and P. aeruginosa. In
this study, 99.2% of GN isolates had minimum inhibitory concentrations
(MIC) of ≤4 mg/L.^a

In separate studies, the susceptibility profile of cefiderocol was
evaluated against a global collection of only carbapenem-resistant GN
bacteria.^3,4 In these studies, the in vitro activity
against the European isolates and the presence of carbapenemase genes
were evaluated. Cefiderocol showed antibacterial activity against 95.5%
of carbapenem-resistant GN isolates at ≤4 mg/L. The study also evaluated
regional differences in carbapenemase gene distribution. Significant
differences were seen in carbapenemase gene profile across bacterial
species between regions and especially between EU countries; yet
cefiderocol showed the potential to be effective against Enterobacteriaceae,
A. baumannii, and P. aeruginosa regardless of the presence of
serine- and metallo-carbapenemase-encoding genes.

Similar results were seen at a national level in a study conducted in
the UK, with cefiderocol demonstrating activity at low concentrations
against multi-drug-resistant carbapenemase-producing P. aeruginosa
and A. baumannii.⁵ The relevance of in vitro to
clinical efficacy has yet to be determined.

“Increasing resistance in Gram-negative bacteria complicates
treatment, especially where it compromises carbapenems, which are the
‘go-to’ antibiotics for difficult infections. The enzymes responsible
for this resistance – carbapenemases – are diverse. Different types
predominate in different countries and species, adding to the
challenge,” said Professor David Livermore, Professor of Medical
Microbiology, University of East Anglia.

“In the lab, cefiderocol stays active against Enterobacteriaceae with
any of the common carbapenemases. What’s more it’s also active against
Pseudomonas and Acinetobacter with carbapenemases. Pseudomonas is
inherently difficult as most antibiotics are not effective against this
critical pathogen, and Acinetobacter has unique carbapenemases that
evade all the inhibitors available so far. We found cefiderocol to be
almost universally active,”

Professor Livermore continued, “Overall, it’s this breadth of
cefiderocol’s potential coverage against carbapenemase producers that’s
so interesting. The UK doesn’t have the high prevalence of
carbapenemases producers that you see in Italy, Greece, Brazil and –
above all – India, but we do have diversity …. and that makes a single,
widely active, agent attractive.”

John Keller, Senior Vice President Global Business Division and Head of
European and US Operations Shionogi commented, “Shionogi is excited
to share these important data at ECCMID, which suggests the potential
activity of cefiderocol against some of the most challenging pathogens
identified by the World Health Organization. Antimicrobial resistance is
a major health burden and we are committed to developing effective
treatments to address this growing threat.”

Notably, in addition to these results, data from several external
susceptibility studies will also be presented at ECCMID, showing
activity of cefiderocol against multidrug-resistant Gram-negative
pathogens from Italy, Spain, Germany and the UK.

About Cefiderocol – An Investigational Antibiotic Agent

Cefiderocol is a parenteral siderophore cephalosporin with a novel
mechanism for penetrating the outer cell membrane of Gram-negative
pathogens including multidrug-resistant strains. 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.⁶ 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-β-lactamases.⁷
These mechanisms allows cefiderocol to achieve higher concentrations in
the periplasmic space where it can bind to receptors and inhibit cell
wall synthesis in the bacterial cells.⁸ Data from global
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.⁹ Cefiderocol has poor in vitro activity
against Gram-positive or anaerobic bacteria.

Two Phase III studies are ongoing in patients with HAP/VAP/HCAP†
(APEKS-NP‡) and with carbapenem-resistant pathogens at various infection
sites (CREDIBLE-CR). Information is available at www.clinicaltrials.gov under
the identifiers NCT02714595 and NCT03032380, respectively.

Cefiderocol is not currently commercially available.

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.^9,10,11,12 There are an
increasing number of Gram-negative pathogens resistant to multiple
antibiotics, making them difficult to treat and resulting in high
mortality rates.¹³ In the U.S., at least 2 million people are
infected with antibiotic-resistant bacteria, and at least 23,000 people
die as a result each year.¹⁴ In the EU, about 25 000 patients
die from an infection with the selected multidrug-resistant bacteria.¹⁵
The World Health Organization have identified carbapenem-resistant
strains of Enterobacteriaceae, P. aeruginosa and A.
baumannii as the top priority in the research and development of new
antibiotics.¹

About Shionogi

Shionogi & Co., Ltd. (“Shionogi”) 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, 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, please visit http://www.shionogi.co.jp/en/.
Shionogi B.V. is the European subsidiary of Shionogi & Co., Ltd. based
in Amsterdam, Netherlands. For more information on Shionogi B.V., please
visit http://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.

^a The approved CLSI breakpoint for cefiderocol is defined as
4 mg/L

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

‡ Nosocomial Pneumonia.

© 2019 Shionogi Limited. London, WC2B 6UF. All Rights Reserved.

References

¹ World Health Organization. Global priority list of
antibiotic-resistant bacteria to guide research, discovery and
development of new antibiotics. Available at: https://www.who.int/medicines/publications/WHO-PPL-Short_Summary_25Feb-ET_NM_WHO.pdf
Last accessed February 2019

² ECCMID 2019. Tsuji M, et al. Cefiderocol in vitro Activity
Against Gram-negative Clinical Isolates Collected in Europe: Results
from 3 SIDERO-WT surveillance studies during 2014-2016

³ ECCMID 2019. Tsuji M, et al. Cefiderocol in vitro Activity
Against Gram-negative Clinical Isolates Collected in Europe: Results
from SIDERO-CR 2014/16

⁴ ECCMID 2019. Tsuji M, et al. Cefiderocol Susceptibility
Profiling Against a Global Collection of Gram-negative bacteria
containing Serine- and Metallo-carbapenemase genes

⁵ ECCMID 2019. Mushtaq S, Saduki Z, Vickers A, Livermore D.
In vitro activity of cefiderocol against multidrug-resistant Pseudomonas
aeruginosa and Acinetobacter baumannii from the UK

⁶ 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.

⁷ 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

⁸ 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.

⁹ M Hackel, M Tsuji, Y Yamano, et al. n 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.
Antimicrobial Agents Chemotherapy. 2017;61(9), posted online.

¹⁰ 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.

¹¹ Livermore DM. Current epidemiology and growing resistance
of gram-negative pathogens. Korean J Intern Med 2012; 27:128−42.

¹² Brooke JS. Stenotrophomonas maltophilia: an emerging
global opportunistic pathogen. Clin Microbiol Rev 2012; 25:2−41.

¹³ 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.

¹⁴ 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

¹⁵ European Centre for Disease Prevention and Control (ECDC).
Technical Report: the bacterial challenge: time to react. 2009.
Retrieved from https://ecdc.europa.eu/sites/portal/files/media/en/publications/Publications/0909_TER_The_Bacterial_Challenge_Time_to_React.pdf

Contacts

For further information, contact:
Shionogi & Co., Ltd.
Corporate
Communications
Telephone: +81-6-6209-7885
Fax:
+81-6-6229-9596

Shionogi Europe Media Contact
Russell Stapley
European
Marketing Director
+44 (0) 7741 626375
russell.stapley@shionogi.eu

Havas So Media Contact
Jessica Stuart
Account Manager
+44
(0) 2037 933768
jessica.stuart@havasso.com