PBPs

OSAKA, Japan & CHENNAI, India & GENEVA, Switzerland & BOSTON--(BUSINESS WIRE)-- A new agreement is poised to accelerate antibiotic access for tens of thousands of patients in regions with the highest rates of antimicrobial resistance (AMR). The Global Antibiotic Research & Development Partnership (GARDP) and India-based Orchid Pharma Ltd (Orchid) have signed a sublicense agreement to manufacture cefiderocol, an antibiotic to treat certain Gram-negative infections. This agreement is a critical step in an ambitious project by Shionogi & Co. Ltd. (Shionogi), GARDP, and the Clinton Health Access Initiative (CHAI) that aims to provide access to cefiderocol in a number of predominantly low- and middle- income countries, pending local authorization or national regulatory approval. Launched in June 2022, the project represents a new model for bridging global gaps in equitable access to important antibiotics. Even though populations in low- and middle-income countries face a high burden of death from drug-resistant bacterial infections, their access to antibiotics with activity against resistant bacteria is usually delayed by more than a decade. That situation may worsen given that the number of serious, potentially life-threatening, infections due to carbapenem-resistant bacteria has been growing across multiple regions, including South Asia and Latin America. By addressing barriers that have historically limited the availability of important antibiotics in low- and middle-income countries, this innovative project aims to accelerate appropriate access for an affordable, quality-assured antibiotic to treat drug-resistant Gram-negative infections. “Access is one of the least talked about issues in the global AMR crisis. This is not just a global market failure but also a public health failure,” said Manica Balasegaram, Executive Director of GARDP. “We can effectively offset the burden of antibiotic resistance by reducing the access gap between high- and lower-income countries so that the right antibiotics are affordable and available for appropriate use. We are proud to work with Orchid to help make this a reality for cefiderocol, and we hope that this project can help pave the way for access to additional antibiotics in the future.” The licensing agreement signed between Shionogi and GARDP in June 2022 enables GARDP to make cefiderocol available in 135 countries (~70% of countries worldwide, including those with the highest AMR burden), none of which currently has access. Cefiderocol was approved by the US Food and Drug Administration in 2019 and the European Medicines Agency in 2020, and it is on the World Health Organization (WHO) Model List of Essential Medicines (please refer to the detailed US indications and Selected Important Safety Information for cefiderocol found below). “We are proud to work with Shionogi, GARDP, and CHAI to provide a global solution to access an important antibiotic for areas of need,” said Manish Dhanuka, Managing Director of Orchid Pharma, one of the world’s leading manufacturers of cephalosporin antibiotics. “Our decades-long expertise in cephalosporins will be advantageous in manufacturing affordable and quality-assured cefiderocol. This will address the unmet needs of patients across low- and middle-income countries where antimicrobial resistance is spreading.” Orchid was selected following a rigorous vetting process led by CHAI with GARDP. The manufacturing sublicense agreement has important access, environmental, and stewardship provisions, including cost-plus pricing, with a commitment to lower the costs based on volumes to help keep the product affordable for patients and health systems in low-resource settings. The sublicense access plan, constituting a part of the sublicense agreement, also stipulates that Orchid will submit the product to the WHO medicines prequalification (PQ) programme. Products listed with WHO PQ are eligible for a collaborative procedure for accelerated registration that reduces the time for national regulatory approvals to 90 days in participating countries. In March 2023, WHO PQ invited manufacturers of cefiderocol to submit expressions of interest, marking the first instance that WHO PQ opened eligibility to products that treat bacterial infections other than tuberculosis. The signing of the manufacturing sublicense agreement builds on the license agreement between Shionogi and GARDP and on the collaboration agreement between Shionogi, GARDP, and CHAI, both of which were signed in June 2022. Based on these agreements, CHAI will facilitate the technology transfer process between Shionogi and Orchid, and Shionogi will convey essential information for the manufacture of cefiderocol to Orchid, thus accelerating Orchid’s ability to manufacture the product and reducing costs that might otherwise be passed on to patients. “Our work goes beyond researching and developing innovative new medicines to address significant unmet medical needs. We are also focused on developing sustainable programmes, including the critically important agreements with GARDP and CHAI, that focus on significant public health priorities, including access to and appropriate use of antibiotics,” said Takuko Sawada, Director and Vice Chairperson of the Board, Shionogi & Co. Ltd. “We welcome Orchid to this programme and are confident that together we will continue to make strides toward increasing access to medications for people living in low- and middle-income countries.” “CHAI is deeply committed to access to appropriate diagnosis and treatment for bacterial infections in people living in low- and middle-income countries. We are excited to bring the tools of market shaping to AMR and to support our partners in delivering this unique project to improve patients' lives,” said Dr David Ripin, Executive Vice President, Infectious Diseases and Chief Science Officer, CHAI. In the spirit of transparency and knowledge sharing, and as a baseline for similar agreements in the future, the license agreement and manufacturing sublicense agreement have been published online. About GARDP The Global Antibiotic Research & Development Partnership (GARDP) is a Swiss not-for-profit organization developing new treatments for drug-resistant infections that pose the greatest threat to health. GARDP was created by the World Health Organization and the Drugs for Neglected Diseases initiative (DNDi) in 2016 and legally founded in 2018 to ensure that everyone who needs antibiotics receives effective and affordable treatment. GARDP is funded by the governments of Australia, Germany, Japan, Monaco, the Netherlands, the Public Health Agency of Canada, South Africa, Switzerland, the United Kingdom, the Canton of Geneva, as well as the European Union, Wellcome Trust and private foundations. GARDP is registered under the legal name GARDP Foundation. About Orchid Established in 1992, Orchid Pharma Ltd. (Orchid) is a vertically integrated pharmaceutical company spanning the entire value chain with established credentials in research, manufacturing, and marketing. Orchid is the only Indian pharmaceutical company ever to have invented a New Chemical Entity (NCE, also colloquially called New Drug) which has cleared global clinical phase III trials. The molecule has been submitted for New Drug Approval in the US and Europe. Orchid is a pioneer in the production of quality cephalosporins, especially the sterile products, for which it is one out of few USFDA-approved facilities in the world, and the only one from India. Besides this, Orchid’s facilities are approved worldwide, including approvals like EUGMP, PMDA-Japan, and ANVISA-Brazil. About Shionogi Shionogi & Co., Ltd. is a leading global research-driven pharmaceutical company based in Japan 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." The company has discovered and developed novel medicines for HIV, influenza and antimicrobial resistance and currently markets products in several therapeutic areas including anti-infectives with the first siderophore cephalosporin. We are working to solve healthcare social issues by identifying disease areas with great social needs as core areas for research and development, with a focus on infectious diseases. For more information on Shionogi & Co., Ltd., visit . About CHAI The Clinton Health Access Initiative, Inc. (CHAI) is a global health organization committed to saving lives and reducing the burden of disease in low- and middle-income countries, while strengthening the capabilities of governments and the private sector in those countries to create and sustain high-quality health systems that can succeed without our assistance. For more information, please visit: . Other collaborators GSK GSK collaborated with Shionogi to develop cefiderocol, and both companies are committed to support access to medicines for patients living in low- and middle-income countries (LMICs). To help make cefiderocol affordable and available to more people through the Shionogi collaboration with GARDP and CHAI, GSK will forego its royalties from sales in LMICs. Ping An Ping An Insurance (Group) Company of China, Ltd. is collaborating with Shionogi to develop cefiderocol in Asia through their joint venture companies, and both companies are committed to supporting access to medicines for patients living in low- and middle-income countries (LMICs). To help make cefiderocol affordable and available to more people in Asia, Ping An Insurance (Group) Company of China, Ltd. supports the Shionogi collaboration with GARDP and CHAI. About cefiderocol Cefiderocol for injection is the first and only siderophore cephalosporin antibiotic for the treatment of serious Gram-negative infections. It has a novel mechanism for penetrating the outer cell membrane of Gram-negative pathogens by acting as a siderophore. In addition to entering cells by passive diffusion through porin channels, 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. These mechanisms allow cefiderocol to achieve high concentrations in the periplasmic space where it can bind to penicillin-binding proteins and inhibit cell wall synthesis in the bacterial cells. Cefiderocol has also demonstrated in vitro activity against certain bacteria that contain problematic resistant enzymes such ESBLs, AmpC, and serine- and metallo-carbapenemases. Data from multinational surveillance studies for cefiderocol demonstrated potent in vitro activity against a wide spectrum of Gram-negative pathogens including carbapenem-resistant A. baumannii complex, P. aeruginosa, Enterobacterales, and S. maltophilia. The clinical significance of the in vitro data is unknown. Cefiderocol has no clinically relevant in vitro activity against most Gram-positive bacteria and anaerobic bacteria. US INDICATIONS Fetroja® (cefiderocol) is indicated in patients 18 years of age or older for the treatment of complicated urinary tract infections (cUTIs), including pyelonephritis caused by the following susceptible Gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, and Enterobacter cloacae complex. Fetroja is indicated in patients 18 years of age or older for the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia, caused by the following susceptible Gram-negative microorganisms: Acinetobacter baumannii complex, Escherichia coli, Enterobacter cloacae complex, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Serratia marcescens. USAGE To reduce the development of drug-resistant bacteria and maintain the effectiveness of Fetroja and other antibacterial drugs, Fetroja should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. SELECTED IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS Fetroja is contraindicated in patients with a known history of severe hypersensitivity to cefiderocol or other beta-lactam antibacterial drugs, or any other component of Fetroja. WARNINGS AND PRECAUTIONS Increase in All-Cause Mortality in Patients with Carbapenem-Resistant Gram-Negative Bacterial Infections An increase in all-cause mortality was observed in patients treated with Fetroja as compared to best available therapy (BAT) in a multinational, randomized, open-label trial in critically ill patients with carbapenem-resistant Gram-negative bacterial infections (NCT02714595). Patients with nosocomial pneumonia, bloodstream infections, sepsis, or cUTI were included in the trial. BAT regimens varied according to local practices and consisted of 1 to 3 antibacterial drugs with activity against Gram-negative bacteria. Most of the BAT regimens contained colistin. The increase in all-cause mortality occurred in patients treated for nosocomial pneumonia, bloodstream infections, or sepsis. The 28-Day all-cause mortality was higher in patients treated with Fetroja than in patients treated with BAT [25/101 (24.8%) vs 9/49 (18.4%), treatment difference 6.4%, 95% CI (-8.6, 19.2)]. All-cause mortality remained higher in patients treated with Fetroja than in patients treated with BAT through Day 49 [34/101 (33.7%) vs 10/49 (20.4%), treatment difference 13.3%, 95% CI (-2.5, 26.9)]. Generally, deaths were in patients with infections caused by Gram-negative organisms, including non-fermenters such as Acinetobacter baumannii complex, Stenotrophomonas maltophilia, and Pseudomonas aeruginosa, and were the result of worsening or complications of infection, or underlying comorbidities. The cause of the increase in mortality has not been established. Closely monitor the clinical response to therapy in patients with cUTI and HABP/VABP. Click here for Full U.S. Prescribing Information for Fetroja® (cefiderocol). View source version on businesswire.com: Contacts Media GARDP: Aleida Auld, aauld@gardp.org, +41 22 555 19 24 Orchid Pharma: Ms. Marina Peter, +91 78386 47648 Shionogi: ShionogiCommunications@shionogi.com (US); pressoffice@shionogi.eu (EU); CHAI: Corina Milic, cmilic@clintonhealthaccess.org, +14163716313 Source: Shionogi USA View this news release online at:

A retrospective chart review interim analysis demonstrated that cefiderocol achieved clinical cure in 65% and 60% of patients with Pseudomonas aeruginosa and Acinetobacter baumannii respectively, the majority of whom were severely ill with comorbidities. OSAKA, Japan--(BUSINESS WIRE)-- Shionogi & Co., Ltd. (Head Office: Osaka, Japan; Chief Executive Officer: Isao Teshirogi, Ph.D.; hereafter "Shionogi") announces key data for Fetcroja® (cefiderocol), an innovative siderophore cephalosporin, to be presented at the 33rd European Congress of Clinical Microbiology & Infectious Diseases (ECCMID), April 15-18, 2023, including new real-world evidence demonstrating its efficacy against some of the most difficult-to-treat Gram-negative bacterial infections. In Europe, cefiderocol is commercially available under the brand name Fetcroja® for the treatment of infections due to aerobic Gram-negative organisms in adults with limited treatment options.1 In the US, cefiderocol is available under the brand name Fetroja® and is indicated in patients 18 years of age or older for the treatment of hospital-acquired bacterial pneumonia, ventilator-associated bacterial pneumonia (HABP/VABP) and complicated urinary tract infections (cUTIs) caused by certain susceptible Gram-negative microorganisms.2 Interim results are emerging from PROVE (Retrospective Cefiderocol Chart Review), an ongoing international, retrospective study of the real-world use of cefiderocol for Gram-negative infections across EU and US sites.3,4 The study includes 194 patients with Pseudomonas aeruginosa infections treated with cefiderocol (123 from the US and 71 from the EU). These were generally seriously ill patients, many requiring mechanical ventilation and/or vasopressor support. The interim results show that cefiderocol achieved clinical cure in 65% of these patients, and 81% of patients were alive within 30 days of starting cefiderocol treatment. The patients principally had respiratory tract and bloodstream infections. Cefiderocol was initiated for a documented pathogen in the majority of cases (77%), and as monotherapy in 57% of patients. Also in the study were 98 patients with Acinetobacter baumannii infections (71 from US and 27 from the EU). The patients had respiratory infection and bacteraemia as the most common infections. High levels of organ support were required in these patients, with 45% receiving mechanical ventilation and 30% requiring vasopressor support. Cefiderocol achieved clinical cure in 60% of patients, and 76% of patients were alive within 30-days of starting treatment. Cefiderocol was targeted as first treatment or as salvage therapy in 93% of patients, and as monotherapy in 41% of patients. “These interim results from PROVE build on a growing body of real-world evidence across Europe and the US demonstrating the efficacy of cefiderocol in treating patients with life-threatening infections, such as Acinetobacter baumannii and Pseudomonas aeruginosa, the majority of whom are very sick with multiple comorbidities,” commented Prof. Dr. Dominic Wichmann, Consultant in department of Intensive Care Medicine, University of Hamburg-Eppendorf. “These are pathogens that fall into the World Health Organization’s critical priority list, for which effective treatments are urgently needed.” Antimicrobial resistance (AMR) Antimicrobial resistance (AMR) is a major health burden which urgently needs to be addressed. Globally, in 2019, there were 1.27 million deaths attributable to bacterial AMR.5 Infections caused by carbapenem-resistant Gram-negative bacteria are often associated with a high mortality rate.6 If no action is taken, antimicrobial resistance is predicted to kill 10 million people every year by 2050, at a cumulative cost to global economic output of 100 trillion USD.7 About FETCROJA® (Cefiderocol) Cefiderocol is a siderophore cephalosporin antibiotic with an innovative mechanism for penetrating the outer cell membrane of Gram-negative pathogens by acting as a siderophore. In addition to entering cells by passive diffusion through porin channels, 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.8 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.9 Cefiderocol has also demonstrated in vitro activity against certain bacteria that contain very problematic resistant enzymes such as ESBLs, AmpC, serine- and metallo-carbapenemases.10,11 Data from multinational surveillance studies for cefiderocol demonstrated potent in vitro activity against a wide spectrum of Gram-negative pathogens including carbapenem-resistant A. baumannii, P. aeruginosa, Enterobacterales, and S. maltophilia.12 The clinical significance of the in vitro data is unknown. Cefiderocol has no clinically relevant activity against Gram-positive or anaerobic bacteria. FETCROJA® (Cefiderocol) INDICATION In Europe, cefiderocol is commercially available under the brand name Fetcroja® for the treatment of infections due to aerobic Gram-negative organisms in adults with limited treatment options. FETROJA® (Cefiderocol) US INDICATIONS Fetroja® (cefiderocol) is indicated in patients 18 years of age or older for the treatment of complicated urinary tract infections (cUTIs), including pyelonephritis caused by the following susceptible Gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, and Enterobacter cloacae complex. Fetroja is indicated in patients 18 years of age or older for the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia, caused by the following susceptible Gram-negative microorganisms: Acinetobacter baumannii complex, Escherichia coli, Enterobacter cloacae complex, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Serratia marcescens. USAGE To reduce the development of drug-resistant bacteria and maintain the effectiveness of Fetroja and other antibacterial drugs, Fetroja should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS Fetroja is contraindicated in patients with a known history of severe hypersensitivity to cefiderocol or other beta-lactam antibacterial drugs, or any other component of Fetroja. WARNINGS AND PRECAUTIONS Increase in All-Cause Mortality in Patients with Carbapenem-Resistant Gram-Negative Bacterial Infections An increase in all-cause mortality was observed in patients treated with Fetroja as compared to best available therapy (BAT) in a multinational, randomized, open-label trial in critically ill patients with carbapenem-resistant Gram-negative bacterial infections (NCT02714595). Patients with nosocomial pneumonia, bloodstream infections, sepsis, or cUTI were included in the trial. BAT regimens varied according to local practices and consisted of 1 to 3 antibacterial drugs with activity against Gram-negative bacteria. Most of the BAT regimens contained colistin. The increase in all-cause mortality occurred in patients treated for nosocomial pneumonia, bloodstream infections, or sepsis. The 28-Day all-cause mortality was higher in patients treated with Fetroja than in patients treated with BAT [25/101 (24.8%) vs 9/49 (18.4%), treatment difference 6.4%, 95% CI (-8.6, 19.2)]. All-cause mortality remained higher in patients treated with Fetroja than in patients treated with BAT through Day 49 [34/101 (33.7%) vs 10/49 (20.4%), treatment difference 13.3%, 95% CI (-2.5, 26.9)]. Generally, deaths were in patients with infections caused by Gram-negative organisms, including non-fermenters such as Acinetobacter baumannii complex, Stenotrophomonas maltophilia, and Pseudomonas aeruginosa, and were the result of worsening or complications of infection, or underlying comorbidities. The cause of the increase in mortality has not been established. Closely monitor the clinical response to therapy in patients with cUTI and HABP/VABP. Hypersensitivity Reactions Serious and occasionally fatal hypersensitivity (anaphylactic) reactions and serious skin reactions have been reported in patients receiving beta-lactam antibacterial drugs. Hypersensitivity was observed in Fetroja-treated patients in clinical trials. These reactions are more likely to occur in individuals with a history of beta-lactam hypersensitivity and/or a history of sensitivity to multiple allergens. There have been reports of individuals with a history of penicillin hypersensitivity who have experienced severe reactions when treated with cephalosporins. Before therapy with Fetroja is instituted, inquire about previous hypersensitivity reactions to cephalosporins, penicillins, or other beta-lactam antibacterial drugs. Discontinue Fetroja if an allergic reaction occurs. Clostridioides difficile-associated Diarrhea (CDAD) Clostridioides difficile-associated diarrhea (CDAD) has been reported for nearly all systemic antibacterial agents, including Fetroja. CDAD may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of C. difficile. Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial agents. If CDAD is suspected or confirmed, antibacterial drugs not directed against C. difficile may need to be discontinued. Manage fluid and electrolyte levels as appropriate, supplement protein intake, monitor antibacterial treatment of C. difficile, and institute surgical evaluation as clinically indicated. Seizures and Other Central Nervous System (CNS) Adverse Reactions Cephalosporins, including Fetroja, have been implicated in triggering seizures. Nonconvulsive status epilepticus (NCSE), encephalopathy, coma, asterixis, neuromuscular excitability, and myoclonia have been reported with cephalosporins particularly in patients with a history of epilepsy and/or when recommended dosages of cephalosporins were exceeded due to renal impairment. Adjust Fetroja dosing based on creatinine clearance. Anticonvulsant therapy should be continued in patients with known seizure disorders. If CNS adverse reactions including seizures occur, patients should undergo a neurological evaluation to determine whether Fetroja should be discontinued. Development of Drug-Resistant Bacteria Prescribing Fetroja in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. ADVERSE REACTIONS The most common adverse reactions occurring in (≥2%) of patients receiving Fetroja compared to imipenem/cilastatin in the cUTI trial were: diarrhea (4% vs 6%), infusion site reactions (4% vs 5%), constipation (3% vs 4%), rash (3% vs <1%), candidiasis (2% vs 3%), cough (2% vs <1%), elevations in liver tests (2% vs <1%), headache (2% vs 5%), hypokalemia (2% vs 3%), nausea (2% vs 4%), and vomiting (2% vs 1%). The most common adverse reactions occurring in (≥4%) of patients receiving Fetroja compared to meropenem in the HABP/VABP trial were: elevations in liver tests (16% vs 16%), hypokalemia (11% vs 15%), diarrhea (9% vs 9%), hypomagnesemia (5% vs <1%), and atrial fibrillation (5% vs 3%). Click here for Full U.S. Prescribing Information for Fetroja® (cefiderocol). 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.13 For more information, please refer to: About Shionogi Shionogi & Co., Ltd. is a 145-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 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, 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. References 1 FETCROJA SMPC. Available at: Last accessed March 2023 2 Fetroja FDA prescribing information. Available at: Last accessed March 2023 3 Larcher R, et al. Real-world use of cefiderocol in the EU and US for Pseudomonas aeruginosa: interim data from the PROVE study. ECCMID abstract P2274 4 Timsit JF, et al. Real-world use of cefiderocol in the EU and US for Acinetobacter baumannii: interim data from the PROVE study. ECCMID abstract P2272 5 Antimicrobial Resistance Collaborators. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Lancet 2022; 399: 629–55 6 Perez F, et al. ‘Carbapenem-Resistant Enterobacteriaceae: A Menace to our Most Vulnerable Patients’. Cleve Clin J Med. Apr 2013; 80(4): 225–33 7 O’Neill. The Review on antimicrobial resistance. 2016. Available at: Last accessed March 2023 8 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 9 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 10 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-β-lactamase-producing isolates (SIDERO-WT-2014 Study). ). International Journal of Antimicrobial Agents, 2019; 53(2) 177-184 11 A Ito et al. In Vitro Antibacterial Properties of Cefiderocol, a Novel Siderophore Cephalosporin, against Gram-Negative Bacteria. Antimicrobial Agents and Chemotherapy, 2018, 62:e01454-17. 12 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. Antimicrobial Agents Chemotherapy. 2017;61(9) 13 Antimicrobial Resistance Benchmark 2021. Last accessed March 2023

OSAKA, Japan--( BUSINESS WIRE )--Shionogi & Co., Ltd. (Head Office: Osaka, Japan; Chief Executive Officer: Isao Teshirogi, Ph.D.; hereafter "Shionogi") announces key data for Fetcroja ® (cefiderocol), an innovative siderophore cephalosporin, to be presented at the 33 rd European Congress of Clinical Microbiology & Infectious Diseases (ECCMID), April 15-18, 2023, including new real-world evidence demonstrating its efficacy against some of the most difficult-to-treat Gram-negative bacterial infections. In Europe, cefiderocol is commercially available under the brand name Fetcroja ® for the treatment of infections due to aerobic Gram-negative organisms in adults with limited treatment options. 1 In the US, cefiderocol is available under the brand name Fetroja ® and is indicated in patients 18 years of age or older for the treatment of hospital-acquired bacterial pneumonia, ventilator-associated bacterial pneumonia (HABP/VABP) and complicated urinary tract infections (cUTIs) caused by certain susceptible Gram-negative microorganisms. 2 Interim results are emerging from PROVE (Retros p ective Cefide ro col Chart Re v i e w), an ongoing international, retrospective study of the real-world use of cefiderocol for Gram-negative infections across EU and US sites. 3,4 The study includes 194 patients with Pseudomonas aeruginosa infections treated with cefiderocol (123 from the US and 71 from the EU). These were generally seriously ill patients, many requiring mechanical ventilation and/or vasopressor support. The interim results show that cefiderocol achieved clinical cure in 65% of these patients, and 81% of patients were alive within 30 days of starting cefiderocol treatment. The patients principally had respiratory tract and bloodstream infections. Cefiderocol was initiated for a documented pathogen in the majority of cases (77%) and as monotherapy in 57% of patients. Also in the study were 98 patients with Acinetobacter baumannii infections (71 from US and 27 from the EU). The patients had respiratory infection and bacteraemia as the most common infections. High levels of organ support were required in these patients, with 45% receiving mechanical ventilation and 30% requiring vasopressor support. Cefiderocol achieved clinical cure in 60% of patients, and 76% of patients were alive within 30-days of starting treatment. Cefiderocol was targeted as first treatment or as salvage therapy in 93% of patients, and as monotherapy in 41% of patients. “These interim results from PROVE build on a growing body of real-world evidence across Europe and the US demonstrating the efficacy of cefiderocol in treating patients with life-threatening infections, such as Acinetobacter baumannii and Pseudomonas aeruginosa, the majority of whom are very sick with multiple comorbidities , ” commented Prof. Dr. Dominic Wichmann, Consultant in department of Intensive Care Medicine, University of Hamburg-Eppendorf. “These are pathogens that fall into the World Health Organization’s critical priority list, for which effective treatments are urgently needed.” Antimicrobial resistance (AMR) Antimicrobial resistance (AMR) is a major health burden which urgently needs to be addressed. Globally, in 2019, there were 1.27 million deaths attributable to bacterial AMR. 5 Infections caused by carbapenem-resistant Gram-negative bacteria are often associated with a high mortality rate. 6 If no action is taken, antimicrobial resistance is predicted to kill 10 million people every year by 2050, at a cumulative cost to global economic output of 100 trillion USD. 7 About FETCROJA ® (Cefiderocol) Cefiderocol is a siderophore cephalosporin antibiotic with an innovative mechanism for penetrating the outer cell membrane of Gram-negative pathogens by acting as a siderophore. In addition to entering cells by passive diffusion through porin channels, 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. 8 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. 9 Cefiderocol has also demonstrated in vitro activity against certain bacteria that contain very problematic resistant enzymes such as ESBLs, AmpC, serine- and metallo-carbapenemases. 10,11 Data from multinational surveillance studies for cefiderocol demonstrated potent in vitro activity against a wide spectrum of Gram-negative pathogens including carbapenem-resistant A. baumannii, P. aeruginosa , Enterobacterales, and S. maltophilia . 12 The clinical significance of the in vitro data is unknown. Cefiderocol has no clinically relevant activity against Gram-positive or anaerobic bacteria. FETCROJA ® (Cefiderocol) INDICATION In Europe, cefiderocol is commercially available under the brand name Fetcroja ® for the treatment of infections due to aerobic Gram-negative organisms in adults with limited treatment options. 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. 13 For more information, please refer to: https://www.shionogi.com/global/en/sustainability/amr.html About Shionogi Shionogi & Co., Ltd. is a 145-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 https://www.shionogi.com/global/en/ 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, 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. © 2022 Shionogi Europe. All Rights Reserved. References 1 FETCROJA SMPC. Available at: https://www.ema.europa.eu/en/documents/product-information/fetcroja-epar-product-information_en.pdf Last accessed April 2023 2 Fetroja FDA prescribing information. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/209445s002lbl.pdf Last accessed April 2023 3 Larcher R, et al. Real-world use of cefiderocol in the EU and US for Pseudomonas aeruginosa: interim data from the PROVE study. ECCMID abstract P2274 4 Timsit JF, et al. Real-world use of cefiderocol in the EU and US for Acinetobacter baumannii : interim data from the PROVE study. ECCMID abstract P2272 5 Antimicrobial Resistance Collaborators. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Lancet 2022; 399: 629–55 6 Perez F, et al. ‘Carbapenem-Resistant Enterobacteriaceae: A Menace to our Most Vulnerable Patients’. Cleve Clin J Med. Apr 2013; 80(4): 225–33 7 O’Neill. The Review on antimicrobial resistance. 2016. Available at: https://amrreview.org/sites/default/files/160518_Final%20paper_with%20cover.pdf Last accessed March 2023 8 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 9 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 10 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-β-lactamase-producing isolates (SIDERO-WT-2014 Study). ). International Journal of Antimicrobial Agents , 2019; 53(2) 177-184 11 A Ito et al. In Vitro Antibacterial Properties of Cefiderocol, a Novel Siderophore Cephalosporin, against Gram-Negative Bacteria. Antimicrobial Agents and Chemotherapy, 2018, 62:e01454-17. 12 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. Antimicrobial Agents Chemotherapy . 2017;61(9) 13 Antimicrobial Resistance Benchmark 2021. https://accesstomedicinefoundation.org/medialibrary/resources/61ee760d03810_Antimicrobial%20Resistance%20Benchmark%20report%202021.pdf Last accessed April 2023 NP-EU-FDC-0414 April 2023