Shionogi & Co, Ltd

Evaluated: medicine & vaccine pipelines for priority* bacteria & fungi

A.1 Highest relative investment in R&D
Shionogi discloses to the Benchmark its R&D investments during 2019 and 2020 in antibacterial and antifungal medicines and/or vaccines for pathogens in scope. Shionogi reports that it invested USD 74.22 mn in R&D for antibacterial and antifungal medicines and vaccines in 2019 and 2020. Shionogi invests the highest proportion of its revenues in R&D in this area and the third highest absolute amount compared to the other companies who reported investments to the Benchmark. Shionogi has pledged USD 20 mn to the AMR Action Fund over the next ten years. 

A.2.1 Medium-sized diverse pipeline
The company reports 11 projects targeting pathogens in scope: ten medicines and one vaccine, nine targeting bacterial pathogens and two targeting fungal pathogens. Out of the 11 projects, five are in discovery stage, two are in preclinical development, one is in clinical development and three received marketing approval during the period of analysis.

A.2.2 No clinical-stage novel projects
Shionogi’s clinical-stage medicine pipeline consists of one innovative R&D medicine, cefiderocol, a siderophore cephalosporin antibacterial for the treatment of multi-drug resistant infections. Cefiderocol (Fetroja®/ Fetcroja®) obtained marketing approval for the treatment of complicated urinary tract infections (cUTIs), including pyelonephritis, from the FDA in November 2019, and for HABP/VABP in September 2020. In April 2020, it received approval from the EMA for the indication of gram-negative bacterial infections. Cefiderocol is in Phase II trials for the extension of its indication to treat children. Cefiderocol does not meet any of WHO’s innovativeness criteria.

A.2.3 Newly active in vaccine development
Shionogi reports one innovative vaccine project in its pipeline. It consists of a preclinical vaccine candidate against S. pneumoniae developed in collaboration with HanaVax Inc.

A.2.4 Investing in early stage programmes targeting critical and/or urgent priorities
Shionogi has eight projects targeting pathogens defined as ‘critical’ by WHO’s list of priority pathogens and/or characterised as ‘urgent’ threats by the US Centers for Disease Control and Prevention (CDC). Cefiderocol, which accounts for four of these projects, targets several MDR gram-negative pathogens such as A. baumanii and Carbapenem-resistant/ESBL-resistant Enterobacteriaceae. Shionogi is carrying out several discovery and preclinical programmes targeting P. aeruginosa and C. auris.

A.3 Plans to improve access and stewardship for cefiderocol
Shionogi has four projects in its late-stage pipeline, all related to different indications of the same compound, cefiderocol, first marketed in December 2019. 
Shionogi reports having an ongoing Global Compassionate Use programme for cefiderocol. It is discussing a potential technology transfer agreement with generic medicine manufacturers to extend access to cefiderocol to other territories. It is also building partnerships with not-for-profit organisations to build a system to support stewardship of cefiderocol. Shionogi reports plans to conduct surveillance of cefiderocol. Shionogi applied for the inclusion of cefiderocol in the WHO’s EML and suggested including it in the Reserve (AWARE) category.

Evaluated: antibacterials manufacturing (APIs and drug products)

B.1 Comprehensive environmental risk-management for own sites and suppliers; tracks compliance with limits at own sites and suppliers
Shionogi reports a comprehensive strategy to minimise the environmental impact of wastewaters and solid waste from antibacterial manufacturing at its sites, including audits every five years. It reports setting discharge limits in the receiving environment for all antibacterials manufactured at its site, based on PNECs to limit AMR, as recommended by the AMR Industry Alliance, or the EMA. It also reports quantifying discharge levels at its site using a mass balance approach, verified by chemical analysis if applicable. Its sole manufacturing site in scope is reported to be fully compliant with discharge limits.

Shionogi requires third-party suppliers of antibacterials to follow the same standards, including limits based on PNECs. It reports conducting on-site audits every five years. It requests and reviews the discharge levels of its suppliers. It also reports five out of nine supplier sites have quantified discharge levels and three, or 33%, of those are compliant with discharge limits.

Shionogi expects its only external private waste-treatment plant to comply with its general environmental standards. It audits this plant every year which includes the suitability of technologies used for processing waste and protocols for preventing contamination. All solid waste and wastewater sent to this plant is set to be incinerated.

B.2 Publicly discloses information on environmental risk management; aggregated audit results and compliance with limits
Shionogi leads in public disclosure of its environmental risk-management strategy. It publishes some information on audit results, based on its ERM strategy, and covers wastewater management, solid waste management and discharge limits. It is a member of the AMR Industry Alliance, which publishes a list of recommended antibacterial discharge targets. It publicly discloses that all 5 antibacterials manufactured at its own site are compliant with discharge limits. In addition, it is publicly disclosed that five out of nine supplier sites have quantified discharge levels and three, or 33%, of those, which supply flomoxef (Flumarin®), doripenem (Doribax®) and sulfamethoxazole/trimethoprim (Bakuta®), are compliant with discharge limits. It also publishes a table listing its antibacterials in scope, their connection to own sites and suppliers, and which are compliant with discharge limits. Further, it publishes where five of its suppliers in scope are located (Japan and India) and the respective products supplied by each. The name of its only external private waste-treatment plant in scope is also disclosed.

B.3 System in place to maintain production quality for own and suppliers’ sites; no requests for official corrective action 
Shionogi reports that its own sites and suppliers have a system to maintain high-quality antibacterial production consistent with international GMP standards. This includes periodic risk-based audits and tracking of corrective and preventive actions. Shionogi also requires its suppliers to audit their own suppliers. The Benchmark found no requests for official corrective action from the FDA or EMA related to non-conformities with cGMP at Shionogi’s own sites or any subsidiaries that manufacture antibacterials.

Evaluated: access activities relating to antibacterial & antifungal medicines & vaccines in 102 access countries***

Shionogi is not eligible for indicators: C.1.3 and C.2.3. For more information, see Appendix VII in the 2021 AMR Benchmark report.

C.1.1 No filings for relevant on-patent medicines
Shionogi’s performance is low as it has not yet filed its relevant on-patent medicine in access countries. Its relevant on-patent medicine is the antibiotic cefiderocol (Fetroja®/Fetcroja®), used to treat infections caused by aerobic Gram-negative bacteria when there are few treatment options available. It was approved by the FDA in 2019 . Cefiderocol is newly included in the WHO 22nd EML (2021) as a ‘Reserve’ group antibiotic effective against multi-drug resistant bacteria.

C.1.2 Limited filings for relevant off-patent medicines
Shionogi’s performance is low. It filed its off-patent antibiotics flomoxef and cefcapene, used to treat several bacterial infections, in one access country (China).

C.2.1 No access strategy for relevant on-patent medicine
Shionogi’s performance is low as it does not report strategies to expand access to its relevant on-patent medicine in access countries during the period of analysis. However, in July 2021, Shionogi, GARDP and CHAI announced a MOU to accelerate access to cefiderocol in low- and middle-income countries. 

C.2.2 Expanding access to off-patent/generic medicines
Shionogi’s performance is low as it does not provide access to its two relevant off-patent/generic antibacterial medicines, flomoxef and cefcapene, in access countries. These two medicines did not meet all regulatory requirements because their respective clinical trials were conducted prior to the ICH guidelines. Shionogi does not actively promote these medicines. However, in July 2021, GARDP identified flomoxef as a potential treatment option for neonatal sepsis.

C.3 No supply in access countries
Shionogi’s performance is low as it does not yet make its relevant products available in access countries.

Evaluated: stewardship activities relating to antibacterial & antifungal medicines globally.

C.4 Comprehensive COI mitigation strategies in place for its educational programmes
Shionogi performs strongly in conflict of interest (COI) mitigation for the five AMR-related educational programmes for HCPs assessed by the Benchmark. To mitigate COI for one programme, it provides financial resources to an independent third party (Radio Nikkei) to develop the programme. The remaining four programmes have all three COI mitigation strategies looked for by the Benchmark: (1) content is developed independently from its marketing department; (2) a pledge not to provide financial or material incentives to participants; and (3) it does not use branded materials.

C.5 Fully decouples incentives for sales agents from sales volumes, and engages in marketing practices to address appropriate use
Shionogi performs strongly in sales practices. It reports that it fully decouples incentives for sales agents from sales volumes of its antibacterial and/or antifungal medicines.
Shionogi engages in marketing practices that aim to address the appropriate use of its antibacterial and/or antifungal medicines. Its marketing materials reflect emerging resistance trends and/or include treatment guidelines for healthcare professionals: for cefiderocol (Fetroja®/Fetcroja®), doripenem (Finibax®) and flomoxef (Flumarin®).

C.6 Makes one type of brochure and/or packaging adaptation to facilitate appropriate use by patients
Shionogi adapts brochures to facilitate the appropriate use of cefcapene pivoxil (Flomox®) by patients. Shionogi is middle-performing in this measure, taking account of paediatric use. It has created a brochure that is easy to understand using simple illustrations, which is tailored to the treatment of children to improve paediatric use.

C.7 Active in multiple AMR surveillance programmes; openly publishes aggregated results
Shionogi is active in multiple AMR surveillance programmes. It runs the multinational SIDERO-WT programme, which is focused on resistance against Gram-negative bacteria in 13 countries and has been running since 2014. Shionogi only shares the aggregated results through peer-reviewed open-access journal articles, however, within 2021, it is planning to share the raw data on the AMR Register, an open-access data platform. For the remaining programmes, the aggregated results are shared through peer-reviewed open-access journal articles, as well as on an open-access data platform for the SENTRY programme (a programme managed by JMI laboratories).