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Antimicrobial resistance: Shionogi advocates policy change to address the public health threat

AUTHORS Gareth Morgan2, Yoshinori Yamano1, Keiko Tone3, Masahiro Kinoshita1, Takuko Sawada1, Tsutae Nagata1

ADDRESSES 1 Shionogi & Co., Ltd., 1-8, Doshomachi 3 chome, Chuo-ku, Osaka 541-0045, Japan 2 Shionogi Inc., 300 Campus Drive, Florham Park, NJ 07932 USA 3 Shionogi B.V., Kingsfordweg 151, 1043 GR Amsterdam, the Netherlands

ntimicrobial resistance surgeries to chemotherapy Shionogi was found to invest a “AMR IS A SLOW (AMR) has become and organ transplants. We are greater proportion of revenue TSUNAMI THAT Aa serious threat to slowly losing the race to stay in antimicrobial research and THREATENS the effective prevention and ahead of bacterial resistance development (R&D) than similar TO UNDO treatment of infections caused mechanisms and, without action, companies evaluated. A CENTURY by bacteria, viruses, fungi and we face a future in which lack of Highlights of Shionogi’s OF MEDICAL parasites. AMR is a global issue effective could make antibacterial research PROGRESS” with potentially devastating routine medical procedures achievements include: TEDROS consequences to those infected dangerous, make more complex • 1959: sulfamethoxazole, a ADHANOM with resistant pathogens and interventions and procedures sulfonamide antibacterial GHEBREYESUS high direct and indirect costs to impossible, and reduce our still in clinical use today and DIRECTOR-GENERAL, WHO society. The ongoing coronavirus ability to respond to outbreaks of listed on the WHO Model (COVID-19) pandemic has infectious diseases. Antibacterial Lists of Essential Medicines demonstrated how devastating resistance is a predictable and in combination with for COVID-19). Highlights of infectious diseases can be. preventable crisis – but only if we trimethoprim. Shionogi’s antiviral research Although AMR is a slower- act now. AMR, and in particular • 1982: moxalactam include: moving threat, it is no less antibacterial resistance, must (), the world’s first • 2013: dolutegravir, an dangerous than COVID-19: every be regarded as an urgent global, . integrase inhibitor for human year, drug-resistant microbes regional and national priority • 1988: , the world’s immunodeficiency virus are responsible for an estimated for governments and health second oxacephem antibiotic. (HIV). 700,000 deaths and future organisations. • 1992 and 1997: and • 2018: baloxavir marboxil, the projections for the impact of , new oral world’s first cap-dependent unresolved AMR are as high as 10 INFECTIOUS DISEASE antibiotics. endonuclease inhibitor for million deaths per year by 2050 INNOVATION • 2005: , a new influenza virus. (ref. 1). Shionogi is a global antibiotic. “AMR is a slow tsunami that pharmaceutical company • 2019: , the world’s Bacterial infections secondary threatens to undo a century of established more than 140 years first approved siderophore to viral infections such as medical progress,” says Tedros ago in Osaka, Japan. Shionogi antibiotic. influenza and SARS-CoV-2 can Adhanom Ghebreyesus, director- is committed to prioritising be extremely serious. Most of general at the World Health patients and the company Shionogi has also discovered the deaths in the 1918 influenza Organization (WHO). Antibiotic recognises the importance important antiviral products pandemic, as well as the 1957 resistance is perhaps the most of continued investment in and has therapeutic, vaccine and 1968 pandemics, likely important component of AMR infectious disease research. and diagnostic programmes to resulted directly from secondary because effective antibiotics In the Access to Medicine address severe acute respiratory bacterial pneumonia2. Bacterial underpin much of modern- Foundation’s 2020 Antimicrobial syndrome coronavirus 2 (SARS- infections secondary to SARS- day healthcare, from common Resistance Benchmark survey, CoV-2, the causative pathogen CoV-2 have also been reported,

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Figure 1. The structure of cefiderocol. PBP, -binding protein10.

although extensive prophylactic an asymmetric bilayer generation cephalosporin- to inactivate beta-lactam use of antibiotics has limited consisting of phospholipids resistant. (Enterobacteriaceae antibiotics. New antibiotics the incidence. Recent analysis and lipopolysaccharides. include: Klebsiella pneumonia, must overcome resistance of Shionogi’s Early Access The difference in membrane Escherichia coli, Enterobacter mechanisms using more efficient Program for cefiderocol in Europe structure between Gram-positive spp., Serratia spp., Proteus penetration through the outer suggests that between April and and Gram-negative bacteria and spp., Providencia spp., and membrane and improved July 2020, 35% of requests for the wide diversity of enzymes Morganella spp.) stability over the ever-increasing cefiderocol were from patients that bacteria produce to counter diversity of acquired or intrinsic with SARS-CoV-2, driven largely antibiotics determine whether a Bacteria listed as critical are enzyme-based mechanisms. from southern Europe during the specific antibiotic can effectively all Gram-negative. Carbapenem-resistant peak of the COVID-19 pandemic treat a specific bacterial strain. are a class of antibiotics and are infections are not only a cause of (data on file). Drug-resistant bacteria, the workhorses for treating the high patient mortality, they are sometimes described as most serious Gram-negative also expensive. Infection with PROBLEM PATHOGENS multidrug resistant (MDR) or infections in hospitals. Twenty A. baumannii is associated with Bacteria are classified into two as ‘superbugs’ or ‘nightmare’ years ago, carbapenems were prolonged hospital stays, often categories, Gram-positive and bacteria, are a growing issue almost always effective, but requiring patients to be admitted Gram-negative, based on a in all parts of the world. MDR resistance is becoming common; to the intensive care unit4. In the method of staining developed bacteria are resistant to multiple for example, in Korea the United States (US), treatment of a in 1882 by Hans Christian classes of antibiotics. The resistance rate of A. baumannii single patient with a carbapenem- Gram. Gram-positive bacteria, WHO has categorised the most to (a commonly used resistant Enterobacteriaceae such as Staphylococcus and problematic bacteria as critical, carbapenem) increased to 85% infection is estimated to Streptococcus species, have a high or medium priority. The in 2015 (ref. 3). cost between $22,000 and thick layer and pathogens labelled as critical are: Gram-negative bacteria $65,000 (ref. 5). Outbreaks of no outer membrane; in contrast, • Acinetobacter baumannii, have three major resistance carbapenem-resistant infections Gram-negative bacteria, such carbapenem-resistant. mechanisms to carbapenem at specific institutions can be as Klebsiella, Pseudomonas • , antibiotics: porin channel expensive. A carbapenem- and Acinetobacter species, carbapenem-resistant. mutations to prevent cell entry, resistant K. pneumonia outbreak have a thinner peptidoglycan • Enterobacteriaceae, efflux pumps to expel antibiotics affecting 40 patients across five layer and an outer membrane, carbapenem-resistant, 3rd and beta-lactamase enzymes hospitals in west London, United

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Figure 2. Cefiderocol can enter Gram-negative bacterial cells via their iron uptake mechanism. 1. Cefiderocol chelates extracellular iron. 2. The chelated complex is actively transported into the periplasm by outer-membrane receptors. 3. Once in the periplasm, cefiderocol dissociates from the iron ions. 4. In common with other beta-lactam antibiotics, cefiderocol enters the periplasm via diffusion through porins. 5. Once inside the periplasm, cefiderocol binds and inhibits penicillin-binding proteins.

Kingdom (UK), between 2014 and and transport iron across the carbapenem antibiotics with dissociates and the cefiderocol 2015 resulted in costs totalling cell membrane. Cefiderocol broader antibacterial spectrums, molecule binds to penicillin €1.1 million6. Unless addressed works by mimicking naturally including both Gram-positive binding proteins (PBPs), thereby now, increases in antibacterial occurring siderophore molecules and Gram negative bacteria. disrupting synthesis and resistance will further strain and chelating with iron. The Work on siderophore-conjugated killing the bacteria (Fig. 2). already stretched healthcare chelated complex is actively antibiotics resumed in the In view of the growing budgets and ultimately affect transported across the outer early 2000s, when reports challenges of antimicrobial patient care. membrane of the bacterial of carbapenem resistance resistance and cefiderocol’s novel cell into the periplasmic emerged and the need for new mechanism of cell entry, Shionogi CEFIDEROCOL – space through specialised antibiotics became clear. Further has made cefiderocol available A ‘TROJAN HORSE’ iron transporter channels. research by Shionogi led to the to patients with the most urgent Shionogi has developed Cefiderocol’s ‘Trojan horse’ identification of cefiderocol10. need prior to commercial launch cefiderocol, an antibiotic recently method of cell entry enables Cefiderocol was designed through expanded access approved by both the US Food more efficient penetration by with a cephalosporin nucleus programmes (commonly referred and Drug Administration7 overcoming certain intrinsic or and a catechol side chain to as compassionate use or and the European Medicines acquired antibiotic resistance to mimic siderophores and special access programmes, for Agency8 that targets Gram- mechanisms9. thereby facilitate cell entry. The patients with life-threatening negative bacteria including Research into synthetic addition of side chains to the infections who have no other those identified by the WHO beta-lactams conjugated with cephalosporin nucleus enhances treatment options). As of July as critical priority pathogens. siderophores was started in the its potency and stability against 2020, more than 200 patients Cefiderocol is the first of a novel 1980s (ref. 9), but early attempts beta-lactamase enzymes from more than 10 countries have class of siderophore-conjugated to develop antibiotics of this (Fig. 1). The catechol side chain been provided with cefiderocol. cephalosporin antibiotics. Iron type were unsuccessful. In the enables the formation of a is an essential micronutrient early 1990s, Shionogi identified chelating complex with ferric POLICY CHANGE IS CRITICAL required by bacteria to grow. two siderophore iron, enabling the antibiotic/ In 2015, the WHO issued a Siderophores are natural with potent antibacterial iron complex to cross the outer document titled ‘Global action iron-chelating compounds activity against Gram-negative membrane through active iron plan on antimicrobial resistance’, secreted by bacteria and other pathogens but chose to transporters. Once inside the stating that “Without harmonized microorganisms to acquire focus on the development of periplasmic space, the iron and immediate global action, the

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world is heading towards a post- costs to bring one new have made commitments to with commercialised antibiotics antibiotic era where common product to approval exceed appropriately control their have had to file for bankruptcy infections could once again kill”. US$1 billion11. manufacturing processes, and or seek acquisition, negatively Shionogi supports the call to 4. Ensure appropriate use of others should follow. impacting market diversification action and advocates six policy antibiotics through regulation and career opportunities for pillars (Fig. 3) to address the of animal use, stewardship A BROKEN MARKET skilled researchers. In April AMR crisis: and timely surveillance of Developing antibiotics is a long, 2019, Achaogen filed for resistance epidemiology. New complex and risky process, with bankruptcy after launching 1. Create a predictable and diagnostics and enhanced many failures along the way. plazomicin, and all assets sustainable market for AMR surveillance are needed to Appropriate use initiatives, were sold; in December 2019, products through economic guide appropriate use and including stewardship by Melinta Therapeutics filed for incentives, such as payments better understand where health-care practitioners, aim bankruptcy; and in July 2020, that are not associated resistant pathogens are to slow the rate of resistance Tetraphase Pharmaceuticals with (are delinked from) an issue. development by restricting was acquired by La Jolla the volume of product sold 5. Make effective medicines the use of new antibiotics and Pharmaceutical Company. (known as pull incentives), available for patients in need targeting their use to instances Simply put, the market for and establish new, antibiotic- directly or through alliance in which treatment options are antibiotics that address AMR specific, value assessments partners. In parts of the limited. Although appropriate is broken. for reimbursement. world, basic medical care and use of antibiotics is essential, Shionogi strongly supports 2. Harmonise global regulations common antibiotics are not the consequence is a low level the introduction of new for development and approval readily available. Improving of use for new agents, which in incentives, funding, and of new antibiotics. Despite access to the healthcare turn limits revenue to support value assessment models for progress, regulatory agencies infrastructure that many continued commercialisation reimbursement to restore a around the world still have people take for granted and a healthy pipeline of new viable commercial market different requirements for should be a high priority. antibiotics. The uncertainty and maintain innovation in development programmes 6. Reduce environmental impact around market size, combined this critical field. Shionogi and approve new agents with from the manufacture of with the increasingly challenging advocates for incentives for different product labelling. antibiotics. New standards task of discovering and R&D (push incentives) and 3. Establish clinical trial have been developed to developing novel antibiotics, has incentives for commercialisation networks to help execute measure and control of the led many large manufacturers (pull incentives), as well as clinical studies more discharge of antibiotics to exit or scale back their other value assessment and efficiently. Operationalising into the environment antibiotics development reimbursement reforms to clinical studies for new during manufacturing. programmes12 and to focus their stimulate the market for novel antibacterial products is Biopharmaceutical activities on more predictable antibacterial agents. Shionogi is difficult and extremely companies belonging to areas. Of equal concern, a excited to see visible progress expensive. Development the AMR Industry Alliance number of smaller companies with respect to push incentives,

Figure 3. Six policy pillars required to address antimicrobial resistance.

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such as the US Department of INDUSTRY IS ALIGNED. antibiotics to market this decade. there is an urgent need for Health and Human Services’ WHAT IS NEXT? Although this action buys time, new treatments, and we know Biomedical Advanced Research The biopharmaceutical industry it does not solve the issue that how to develop agents to treat and Development Authority has made significant progress the antibiotics market is broken them. Shionogi recognises (BARDA) Broad Spectrum aligning on the need to address and requires urgent action by that establishing mechanisms Antimicrobials Program, the AMR and committing to governments around the world. to incentivise development global non-profit partnership tangible action. However, AMR Two countries have taken a and commercialisation of Combating Antibiotic-Resistant is a complex issue requiring leadership role in addressing new antibiotics, such as pull Bacteria Biopharmaceutical collaboration across multiple the need for action. The UK has incentives and novel value Accelerator (CARB-X), and a sectors and stakeholders. announced a pilot programme assessments or reimbursement programme launched by the We note progress with new for delinked purchase of two systems, will take time, Innovative Medicines Initiative initiatives by organisations antibiotics. NHS England will stakeholder engagement and called New Drugs for Bad Bugs. such the WHO, the Food and pay a company a fixed fee for political goodwill at national and Since its inception in 2013, Agriculture Organization of the an antibiotic that targets AMR global levels. To help prevent Shionogi has participated in United Nations, and the World and in return will receive the another infectious disease the Global Health Innovative Organisation for Animal Health antibiotic whenever needed at crisis we must take action to Technology Fund, Japan’s first to lead and coordinate the global no additional cost. If the pilot address AMR. At Shionogi we public–private partnership fund One Health response to AMR is successful, rollout of these are proud of our commitment to created to advance the research in cooperation with the United purchasing arrangements addressing infectious diseases and development of innovative Nations and other agencies. is expected across the UK’s and will take a leadership role to medicines for the treatment In 2016, Shionogi and more National Health Service. ensure that new antibiotics are of infectious diseases in the than 100 life-sciences companies Sweden is implementing a available to benefit individual developing world. and associations signed a pilot programme designed to patients and society as a whole. Although push funding is declaration on AMR at the guarantee access to medically REFERENCES important, pull incentives are World Economic Forum calling important antibiotics, 1. Tackling Drug-Resistant crucial to ensure that new for collective action to create providing an annual payment Infections Globally: Final Report antibiotics are made available a sustainable and predictable to a company for access to an and Recommendations (Review on Antimicrobial Resistance, 2016). to consumers. To date, there market for antibiotics, antibiotic in addition to the 2. Morens, D. M., Taubenberger, J. K. & has been a lot of discussion but vaccines and diagnostics, usual reimbursement. Shionogi Fauci, A. S. J. Infect. Dis. 198, 962–970 little tangible action in terms while emphasising the need applauds the UK and Sweden for (2008). 3. Kim, Y. A. & Park, Y. S. Korean J. Intern. of pull incentives. Shionogi for conservation of new and piloting new AMR policies. Med. 33, 247–255 (2018). recognises that pull incentives existing treatments. Together In addition to pull incentives, 4. Eberle, B.M. et al. Crit. Care Med. 38, have to fit country and regional with 12 other leading companies, novel approaches are needed 2133–2138 (2010). 5. Bartsch, S. M. et al. Clin. Microbiol. situations and supports Shionogi went further, signing an to the assessment processes Infect. 23, 48.e9–48.e16 (2017). selection and implementation Industry Roadmap that includes that many countries use 6. Otter, J. A. et al. Clin. Microbiol. Infect. from a suite of pull incentives, action plans for antibiotic to determine the value of 23,188–196 (2017). 7. FETROJA® full prescribing such as partially delinked or research and appropriate use, antibiotics. Health technology information. https://www. fully delinked market-entry access and manufacturing. assessments evaluate benefits accessdata.fda.gov/drugsatfda_docs/ rewards, subscription payment The companies involved versus costs of new medicines, label/2019/209445s000lbl.pdf. schemes, and government subsequently formed the AMR 8. FETCROJA® product information. but they tend to exclude https://www.ema.europa.eu/ purchases, in addition to Industry Alliance, a private sector population-level benefits, en/medicines/human/EPAR/ innovative, antibacterial- coalition that unites biotechs, such as reduced transmission, fetcroja#product-information-section. specific, value based pricing diagnostic manufacturers, reduction in resistance rates and 9. Tonziello, G., Caraffa, E., Pinchera, B., Granata, G. & Petrosillo, N. Infect. Dis. and reimbursement initiatives, generic drug manufacturers, enablement of other medical Rep. 11, 8208 (2019). such as diagnosis-related and leading research-based procedures. The COVID-19 10. Sato, T. & Yamawaki, K. Clin. Infect. group-linked reimbursement pharmaceutical companies. pandemic has demonstrated the Dis. 69, S538–S543 (2019). 11. Wouters, O. J., McKee, M. & Luyten, reform. Shionogi appreciates In July 2020, Shionogi threat of societal transmission J. JAMA. 323, 844–853 (2020). the ongoing discussion of pull partnered with more than 20 of infectious diseases and 12. Boucher, H.W. et al. Clin Infect Dis. incentives by governments biopharmaceutical companies hopefully it will spur change Online ahead of print at https://doi. org/10.1093/cid/ciaa092. and other organisations and to launch an initiative known towards a harmonised, strongly advocates moving as the AMR Action Fund to dedicated, value assessment for quickly from discussion to help small biotechnology antibiotics across countries. ACKNOWEDGEMENTS implementation. Shionogi also companies bridge the financial The authors would like to thank supports the implementation gap that will continue to exist OUR CALL TO ACTION colleagues from Shionogi for their of measures that address until implementation of new SARS-CoV-2 was largely help in the development of this manufacturing issues as part market-based policy reforms that unknown until early 2020, white paper, in particular Hiroyuki of the overall development and support antibiotics. Industry has but AMR is a threat we know Yoshida, Yusuke Ariyoshi, commercialisation need. stepped up, committing nearly and understand. We know the Andrew Koren, James Bond, Lisa US$1 billion to bring two to four priority pathogens for which Butkowski and Kelli Smith.

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