Oral presentation and nine posters presented at ICAAC “Trojan Horse” design facilitates efficacy
WASHINGTON–(BUSINESS WIRE)– Findings reported at the 54th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) showed Shionogi’s novel parenteral siderophore cephalosporin, S-694266, to exhibit marked potency against Gram-negative bacteria listed by the Centers for Disease Control and Prevention (CDC) at the urgent or serious level including multidrug-resistant Pseudomonas (MDRP), MDR-Acinetobacter (MDRA) and carbapenem-resistant Enterobacteriaceae (CRE).1 Pathogen resistance to current antibiotics is increasing worldwide.2
In laboratory and predictive animal models, S-649266 had more robust antibacterial activity than established antibiotics such as ceftazidime and cefepime against a range of Gram-negative bacteria including multidrug-resistant strains such as MDRP, MDRA and CRE. These studies demonstrated that S-649266 has high stability to serine- and metallo-type carbapenemases including KPC, OXA, IMP, VIM and NDM.
Additionally, S-649266 showed potent efficacy against MDRP and MDRA in rat lung infection models recreating human exposure profiles in which 2 g of S-649266 was administered 3 times daily with 1 hour infusion. Clinically, S-649266 has demonstrated safety and tolerability in healthy volunteers in single and multiple dose studies.
“Multidrug-resistant rod shaped bacteria are the key threat in hospitals today and S-649266 is a promising antibiotic to treat these superbugs,” said Dr. Richard P. Wenzel, Professor of Medicine at Virginia Commonwealth University and former President of the International Society for Infectious Diseases.
“Trojan Horse” Mechanism
S-649266 is designed to exploit the way Gram-negative bacteria acquire iron which is necessary for growth and multiplication. As a siderophore, S-649266 binds to iron. Accordingly, when Gram-negative bacteria acquire iron bound to S-649266, they also absorb S-649266. In this way, S-649266 is actively transported through the outer membrane into the periplasmic space where it binds to penicillin-binding proteins (PBPs) and disrupts cell wall synthesis. This use of the iron uptake system may allow S-649266 to be an effective approach to treat Gram-negative bacterial infections that are not able to be treated by available antibiotics.
“What makes S-649266 so promising is its mode of action as a ‘Trojan Horse’ invited in by the unsuspecting enemy bacteria and then effectively defeating it,” said Dr. Tsutae Den Nagata, Chief Medical Officer, Shionogi. “S-649266 is the most advanced product in our anti-infective development portfolio. We have already gained important insight from meetings with key opinion leaders in the US, Europe and Japan and are looking forward to the next stage of its development.”
Phase II clinical development is underway; Phase III is expected to start during 2015. Shionogi is currently developing S-649266. GSK has an option to jointly develop this compound with Shionogi.
Drug Resistance: A Critical Public Health Concern
Antibiotic resistance is a serious and growing issue. According to a report by the World Health Organization, antibiotic resistance has emerged as one of the most critical public health concerns of the 21st century3, as an increasing range of bacterial pathogens no longer respond to treatment with available anti-infectives. In the US, CDC estimates more than two million are infected every year with antibiotic-resistant bacteria, resulting in at least 23,000 deaths.4 Therefore, the identification and development of new antibiotics, especially those with new modes of action, is imperative.
Shionogi Leadership in Anti-Infective Development
For over 50 years, Shionogi has developed and commercialized innovative oral and parenteral anti-infectives. Sulfamethoxazole was discovered by Shionogi and launched in 1959. In 1982, Shionogi launched in Japan its first cephalosporin Shiomarin (moxalactam), a third-generation cephalosporin for the treatment of respiratory tract infections, sepsis, urinary tract infections, abdominal/pelvic infections, genitourinary infections and purulent meningitis. Shionogi is also the originator of Doribax® (doripenem for injection), a carbapenem anti-bacterial for the treatment of complicated intra-abdominal infections and complicated urinary tract infections (US indications). Tivicay® (dolutegravir), an anti-HIV agent Shionogi discovered and co-developed with ViiV Healthcare, was approved for marketing by the Food and Drug Administration in 2013, and by the European Commission in 2014.
Shionogi & Co., Ltd. is a major research-driven pharmaceutical company dedicated to placing the highest value on patients. Shionogi’s research and development currently targets two therapeutic areas: infectious diseases, and pain/CNS disorders. In addition, Shionogi is engaged in new research areas such as obesity/geriatric metabolic disease and oncology/immunology. Contributing to the health 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. For more information on Shionogi Inc., the U.S.–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.
1. http://www.cdc.gov/drugresistance/threat-report-2013/pdf/ar-threats-2013-508.pdf. Accessed September 1, 2014
2. http://www.who.int/mediacentre/factsheets/fs194/en/. Accessed September 1, 2014
3. WHO’s first global report on antibiotic resistance reveals serious, worldwide threat to public health. Retrieved May 2, 2014
4. http://www.cdc.gov/drugresistance/threat-report-2013/pdf/ar-threats-2013-508.pdf, Executive Summary, Paragraph 3, Line 1, Accessed September 2, 2014