Shionogi Announces Publication of Two Studies in The Lancet Infectious Diseases Highlighting the Efficacy and Safety of FETROJA� for the Treatment of Infections Due to Aerobic Gram-negative Bacteria in Adults With Limited Treatment Options

• Shionogi announces publication of data from two of its clinical trials; APEKS-NP and CREDIBLE-CR in the journal The Lancet Infectious Diseases
• APEKS-NP demonstrated that FETROJA (cefiderocol) is an effective and well-tolerated treatment option for Gram-negative nosocomial pneumonia infections, including Pseudomonas aeruginosa, Acinetobacter baumannii and Enterobacterales, in critically ill patients including those who are at risk of multi-drug resistant (MDR) infection¹
• CREDIBLE-CR provides descriptive evidence that FETROJA is an option for the treatment of high-risk, critically ill patients with carbapenem-resistant (CR) Gram-negative infections, including P. aeruginosa, A. baumannii, Enterobacterales and metallo-beta-lactamase expressing organisms²
• These clinical data build on previous clinical data in cUTI and in vitro data highlighting FETROJA�s extensive coverage against all Gram-negative pathogens considered of critical priority by the WHO – carbapenem-resistant A. baumannii, P. aeruginosa and Enterobacterales^3,4
• Antimicrobial resistance (AMR) is a major health burden that urgently needs to be addressed. Globally, approximately 700,000 people die as a result of infections caused by resistant pathogens every year,⁵ so new and effective treatment options are urgently needed

OSAKA, Japan & AMSTERDAM & FLORHAM PARK, N.J.–(BUSINESS WIRE)–Shionogi & Co., Ltd. (Head Office: Osaka, Japan; President & CEO: Isao Teshirogi, Ph.D.) (hereafter “Shionogi”) today announces the back to back publication of two studies in The Lancet Infectious Diseases journal highlighting the efficacy and safety of FETROJA^® (cefiderocol) against some of the most difficult-to-treat Gram-negative bacterial infections, including nosocomial pneumonia (NP), bloodstream infections (BSI), sepsis, and complicated urinary tract infections (cUTI).^1,2

APEKS-NP was a Phase 3 clinical trial designed to compare the efficacy and safety of FETROJA versus high-dose, extended-infusion meropenem (2g, q8h, 3-hour infusion) in critically ill patients with hospital-acquired, ventilator-associated, or healthcare-associated pneumonia (HAP, VAP, and HCAP, respectively) caused by a broad range of Gram-negative bacteria, like Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacterales. The study successfully met the primary endpoint of non-inferiority in all-cause mortality (ACM) at Day 14 with 12.4% for the FETROJA arm (18/145) and 11.6% for the meropenem arm (17/146; adjusted treatment difference 0.8% [95% CI –6.6 to 8.2]) in the modified intention-to treat-population (mITT population). FETROJA was well tolerated, and its safety profile was consistent with that of other cephalosporins and/or carbapenems.¹

The CREDIBLE-CR trial was a small descriptive Phase 3 open-label, pathogen-focused trial designed to assess the efficacy and safety of FETROJA in a high-risk, severely ill patient population with a range of CR infections including NP, BSI, sepsis, and cUTI caused by CR pathogens, including non-fermenters and carbapenemase-producing pathogens. Best available therapy (BAT) was combination therapy in 71% (27/38) of cases with 28 different BAT regimens being used, whereas 83% (66/80) of FETROJA treatment was monotherapy. Two thirds (66% [25/38]) of the BAT regimens contained colistin.²

The results of the CREDIBLE-CR study provided descriptive evidence of the efficacy and safety of FETROJA in CR Gram-negative infections in a highly heterogeneous patient population frequently presenting with complex comorbidities. The clinical and microbiological outcomes were generally similar between FETROJA and BAT, except for metallo-beta-lactamases infections where FETROJA was substantially better (FETROJA: 75% and 44%; BAT: 29% and 14%, respectively). 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)]. There was an observed mortality difference between treatment arms in the subset of patients with Acinetobacter spp. infections, likely linked to imbalances in risk factors at baseline. There was no mortality difference observed in P. aeruginosa or Enterobacterales without Acinetobacter spp. co-infection. No deaths were attributed to FETROJA-related adverse events as examined by investigators assessing the mortality imbalance.²

“The patient population in the CREDIBLE-CR study represents a real clinical scenario with the highest unmet need and provides descriptive evidence that cefiderocol may be a treatment option for physicians treating such critically ill patients,” commented Professor Matteo Bassetti, Lead Author and Head of the Infectious Diseases Clinic, San Martino Hospital, Genoa, Italy.

“From the results of APEKS-NP and CREDIBLE-CR studies supply further evidence to demonstrate the value of FETROJA as a potential treatment option for patients with multi-drug resistant Gram-negative infections,” said Takuko Sawada, Director and Executive Vice President, Senior Vice President of Integrated Disease Care Department of Shionogi.

FETROJA is the first treatment which provides coverage against all Gram-negative pathogens considered of critical priority by the WHO – carbapenem-resistant A. baumannii, P. aeruginosa, and Enterobacterales.^3,4

Antimicrobial resistance (AMR)

Antimicrobial resistance (AMR) is a major health burden which urgently needs to be addressed. Globally, approximately 700,000 people die as a result of infections caused by resistant pathogens every year. Infections caused by carbapenem-resistant Gram-negative bacteria are often associated with a high mortality rate.⁶ If no action is taken, antibiotic resistance is predicted to kill 10 million people every year by 2050, at a cumulative cost to global economic output of 100 trillion USD.⁵

About FETROJA^® (cefiderocol) for injection

FETROJA^® (cefiderocol) is a cephalosporin antibiotic with 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, FETROJA 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.⁷ These mechanisms allow FETROJA 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. ⁸ FETROJA has also demonstrated in vitro activity against certain bacteria that contain very problematic resistant enzymes such as ESBLs, AmpC, serine- and metallo-carbapenemases.^9,10 Data from multinational surveillance studies for FETROJA demonstrated potent in vitro activity against a wide spectrum of Gram-negative pathogens including carbapenem-resistant A. baumannii, P. aeruginosa, Enterobacterales, and S. maltophilia. ¹¹ The clinical significance of the in vitro data is unknown. FETROJA has poor in vitro activity against Gram-positive or anaerobic bacteria.

Cefiderocol, under the brand name FETCROJA^®, is approved by the European Commission for the treatment of infections due to aerobic Gram-negative bacteria in adults 18 years or older with limited treatment options.

Indications and Usage

Indications from USPI

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

FETROJAis 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%).

Report side effects to the FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch. Report side effects to Shionogi Inc. at 1-800-849-9707.

For full Prescribing Information, please visit Shionogi.com.

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.¹²

For more information please refer to: https://www.shionogi.com/global/en/sustainability/amr.html

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 https://www.shionogi.com/global/en/. Shionogi Inc. is the U.S. subsidiary of Shionogi & Co., Ltd. based in N.J. For more information on Shionogi Inc., please visit www.shionogi.com.

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 Wunderrink RG et al, Cefiderocol versus high-dose, extended-infusion meropenem for the treatment of Gram-negative nosocomial pneumonia (APEKS-NP): a Phase 3, randomised, double-blind, non-inferiority study, The Lancet Infectious Disease 2020. Available at: https://doi.org/10.1016/S1473-3099(20)30731-3. Last accessed October 2020

² Bassetti M, Efficacy and safety of cefiderocol for the treatment of serious infections caused by carbapenem-resistant Gram- negative bacteria (CREDIBLE-CR): results of a Phase 3 randomised, open-label, parallel-assigned, pathogen-focused study, The Lancet Infectious Disease 2020. Available at: https://doi.org/10.1016/S1473-3099(20)30796-9. Last accessed October 2020

³ 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/. Last accessed July 2020

⁴ World Health Organization. 2019 Antibacterial Agents in Clinical Development. 2019. Retrieved from https://apps.who.int/iris/bitstream/handle/10665/330420/9789240000193-eng.pdf Last accessed July 2020

⁵ O’Neill, J. et al. Review on antimicrobial resistance. Tackling drug-resistant infections globally: final report and recommendations. 2016 https://amr-review.org/sites/default/files/160518_Final%20paper_with%20cover.pdf Last accessed July 2020

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 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

⁸ 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

⁹ 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-?-lactamase-producing isolates (SIDERO-WT-2014 Study). ). International Journal of Antimicrobial Agents, 2019; 53(2) 177-184

¹⁰ 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.

¹¹ 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)

¹²Antimicrobial Resistance Benchmark 2020. https://accesstomedicinefoundation.org/media/uploads/downloads/5e270aa36821a_Antimicrobial_Resistance_Benchmark_2020 pdf Last accessed July 2020

Contacts

For further information, contact:
Shionogi & Co., Ltd.
Corporate Communications

Telephone: +81-6-6209-7885

Fax: +81-6-6229-9596

Shionogi Inc. U.S. Media Contact
Takashi Koide, Associate Director, Corporate Development & Communications

+1 973-524-5418

takashi.koide@shionogi.com