Company Report Cards

Access to Medicine Foundation Company Report Cards

The 2018 Antimicrobial Resistance Benchmark includes 30 company report cards, which each provide a contextu- alised analysis of one company’s performance in the 2018 Benchmark. This includes a summary of its performance (both overall and per Research Area). Each report card includes overviews of the company’s portfolio and pipeline, and identifies tailored opportunities for it to increase access to antimicrobial medicines, while ensuring their appropriate use. The report cards are divided into five areas:

Performance This section explains the relevance of the company for the Antimicrobial Resistance Benchmark and its overall performance. It covers: • Drivers behind its scores • Main areas where the company scores well or poorly compared to peers

Sales and Operations This section provides a general description of the company’s global operations, including recent changes in its business (e.g., acquisitions or divestments), focusing on its antimicrobial business.

For biopharmaceutical companies with no products on the market, this section is called 'Operations'.

Antimicrobial Portfolio This provides a description of the number and type of antimicrobial medicines the company markets as of September 2017 and the proportion included on the WHO EML (Section 6).

Opportunities This section outlines opportunities for the company to do more to ensure access to antimicrobials and ensure their appropriate use. The opportunities take into account company-specific characteristics as far as possible.

Performance by Research Area These three sections summarise company performance for each of the Research Areas, by indicator. The paragraphs describe the company’s performance and highlight (where available) relevant examples of its activities.

83 Antimicrobial Resistance Benchmark 2018 Achaogen, Inc.

Stock exchange: XNAS • Ticker: AKAO • HQ: South San Francisco, CA, USA • Employees: 106 • Signatory to Davos Decl.: Yes • Signatory to Industry Roadmap: No

Performance by Research Area How Achaogen was evaluated: applicable indicators

Indicator reference Due to the variation 1 2.1 2.2 2.3 3 4 between companies R&D R&D A ○ ● ● ○ ● ● in scope, not all indi- 1 2 3 cators are applica- M&P M&P B ○ ○ ○ ble to every company. 1 2 3 4 5 6 7 See Appendix for full AA&S AA&S C ○ ○ ○ ○ ○ ○ ○ overview. ● Remaining potential score ● Applicable indicator ○ Not applicable PERFORMANCE

Achaogen is a biopharmaceutical company, selected for four projects in its antimicrobial R&D pipeline, all targeting having a pipeline that targets priority pathogens. It was evalu- priority pathogens. The company engages in numerous pub- ated in the area of Research & Development only. lic-private partnerships and agreements with various organi- The company’s R&D investment in antibiotic drug devel- sations to develop its antibiotic candidates. Achaogen has one opment in 2016 amounts to USD 74 million, which is high R&D project in late-stage clinical development. It reported compared to other biopharmaceutical companies in the no information about whether this project is supported by Benchmark. Achaogen is a mid-performing company com- access or stewardship provisions. pared to the biopharmaceutical companies in scope. It has

OPERATIONS

Achaogen, founded in 2002, is a biopharma- acute pyelonephritis. The company has a col- and the Bill & Melinda Gates Foundation. It was ceutical company focusing on the develop- laboration with Thermo Fisher Scientific, Inc. to listed on the NASDAQ stock exchange in 2014, ment of antibiotics to treat multidrug-resistant develop and commercialise an assay to measure having raised approximately USD 72 million from gram-negative bacterial infections. The compa- plazomicin levels in the blood, in order to ensure shareholders such as Domain Partners, Venrock, ny’s most advanced drug candidate, plazomicin, safe and effective dosing during treatment. Wellcome Trust and ARCH Venture Partners, is currently awaiting FDA approval following the Achaogen has no products on the market. To among others. In 2016, it raised USD 25 million completion of two successful Phase III trials: one date, it has received financial support from vari- from a private placement (led by New Enterprise in bloodstream infections caused by carbapen- ous funders for the development of its pipeline, Associates). em-resistant Enterobacteriaceae (CRE) and the including BARDA, the US National Institute of other in complicated urinary tract infection and Allergy and Infectious Diseases (NIAID), CARB-X

ANTIMICROBIAL PORTFOLIO

Achaogen does not have any products on the market.

OPPORTUNITIES

Plan ahead for access and stewardship during R&D. Achaogen is developing one antibiotic candidate (plazomicin) in late-stage clinical development. Achaogen can ensure access and stewardship provisions are in place for plazomicin (e.g., through partnerships).

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PERFORMANCE BY RESEARCH AREA

A RESEARCH & DEVELOPMENT Indicators 1 2.1 2.2 2.3 3 4 Antimicrobial 4 projects scored on ○ ● ● ○ ● ● pipeline 4 target priority pathogens

A.2.1-2.2 Four R&D projects that target A.3 Three R&D projects being developed A.4 No information on access or stewardship priority pathogens. with public partners. provisions. Biopharmaceutical companies in scope were Achaogen is developing two R&D projects in its Achaogen reports no information on access or selected based on their pipelines that target pri- priority pathogen pipeline through public-private stewardship provisions for its antibiotic candi- ority bacteria. Achaogen invested USD 74 mil- partnership. It has funding agreements with four date in late-stage development. It has signed lion in antibiotic drug development in 2016. public partners for the development of three the Davos Declaration, which includes a gen- The company is developing four projects that R&D projects in its priority pathogen pipeline. It eral commitment to ensuring access to antimi- target gram-negative bacteria. Three of these has received financial support from BARDA for crobial medicines and vaccines, and to support projects involve the development of new drug the development of plazomicin (≤USD 123.8 mil- the appropriate and responsible use of these candidates, while the remaining R&D pro- lion). The company also has a contract for ≤USD products. ject is an adaptation. Plazomicin, currently 5 million with the NIAID and recently received a awaiting FDA approval, is Achaogen’s most CARB-X award to support its LpxC inhibitor pro- advanced candidate. Plazomicin is an amino- gramme for the treatment of bacterial infec- glycoside with activity against carbapenem-re- tions, currently in preclinical stage. Furthermore, sistant Enterobacteriaceae, but is vulnerable to in May 2017, the company announced it would cross-resistance with other aminoglycosides receive ≤USD 10.5 million in grant funding (along such as gentamicin and amikacin. The two other with a USD 10 million equity investment) from R&D projects are candidates in preclinical stage the Bill & Melinda Gates Foundation to further and both target multidrug-resistant gram-neg- its preclinical R&D research on antibody candi- ative bacteria: one investigates LpxC inhibitor dates against gram-negative bacteria, including compounds and the other monoclonal antibod- those that cause neonatal sepsis. Achaogen has ies. The company is also developing C-Scape, also received BARDA funding for the develop- a combination of a ß-lactam and ß-lacta- ment of C-Scape (≤USD 18 million). mase inhibitor, both already on the market and off-patent.

Pipeline targeting priority pathogens

Discovery Preclinical Phase I Phase II Phase III Approval

• LpxC inhibitor • C-Scape – ESBL • Plazomicin – compounds – – Adaptation CRE, ESBL – GNB (new FDC of aminoglyco- • Monoclonal an approved side – Awaiting antibody pro- ß-lactam and approval FDC = Fixed dose combination GNB = Gram-negative bacteria gramme – GNB ß-lactamase inhibitor)

MANUFACTURING & PRODUCTION

As a biopharmaceutical company with no products on the market, Achaogen was not eligible for this Research Area.

APPROPRIATE ACCESS & STEWARDSHIP

As a biopharmaceutical company with no products on the market, Achaogen was not eligible for this Research Area.

ANIMAL HEALTH & DIAGNOSTICS

Activities in this area are not scored by the Achaogen is developing a diagnostic assay for Benchmark. This information is provided given therapeutic drug management of plazomicin in a the importance of animal health and diagnostics partnership with Thermo Fisher Scientific. This on the topic of AMR. diagnostic platform monitors the levels of plazomicin in the blood in order to ensure safe and effective dosing during treatment.

85 Antimicrobial Resistance Benchmark 2018 Aspen Pharmacare Holdings Limited

Stock exchange: XJSE • Ticker: APN • HQ: Durban, South Africa • Employees: 10,204 • Signatory to Davos Decl.: No • Signatory to Industry Roadmap: No

Performance by Research Area How Aspen was evaluated: applicable indicators

Indicator reference Due to the variation 1 2.1 2.2 2.3 3 4 between companies R&D R&D A ○ ○ ○ ○ ○ ○ in scope, not all indi- 1 2 3 cators are applica- M&P . M&P B ● ● ● ble to every company. 1 2 3 4 5 6 7 See Appendix for full AA&S AA&S C ● ● ● ● ● ● ● overview. ● Remaining potential score ● Applicable indicator ○ Not applicable PERFORMANCE

Aspen is a prominent producer of antibiotics globally by sales no evidence, however, that these principles are applied to its volume. As a generic medicine manufacturer, Aspen was third-party suppliers of antibiotic APIs and drug products. evaluated in Manufacturing & Production and Appropriate It reports mechanisms for maintaining high quality of anti- Access & Stewardship only. It reported no information to biotic production at its own manufacturing sites. The com- the Benchmark, and publicly available information is limited. pany reports no information regarding an equitable pricing Although the company’s performance in the Benchmark is approach, or where it files products for registration. Aspen lower compared to most other generic medicine manufactur- does not report any involvement in stewardship activities that ers in scope, it reports a set of environmental risk-manage- promote appropriate antibiotic use. ment principles that include an auditing process. There was

SALES AND OPERATIONS RevenuesAspen by product§ RevenuesMade: by region§ Final: no

Aspen is a global supplier and manufacturer In 2016, Aspen acquired GSK’s portfolio of of generic pharmaceutical products and active anaesthetic products (five medicines), as well as . . pharmaceutical ingredients, as well as infant exclusive rights to commercialise AstraZeneca’s . . nutritionals and consumer health products. The anaesthetics portfolio (seven medicines) in 100 bn ZAR bn ZAR company has a substantial presence in low- and countries worldwide (including, e.g., China, but . middle-income countries in regions such as Latin excluding, e.g., the USA). In 2009, Aspen and

America, Russia, Eastern Europe, sub-Saharan GSK formed the "GSK Aspen Healthcare for ● Total revenue ● Developed Europe Africa (SSA) and South Asia, with 25 manufac- Africa" collaboration in SSA, which came to an ● Asia Pacic turing facilities worldwide. Throughout SSA, it end in January 2017, with GSK paying Aspen ● Sub-Saharan Africa ● Rest of World is a market leader in the antibiotics, respiratory, GBP 45 million. pain, cough and cold segments. Its primary therapeutic focus areas are thrombosis, anaesthetics, cytotoxics, and infant nutritionals.

ANTIMICROBIAL PORTFOLIO Antimicrobial portfolio breakdown

According to publicly available data, Aspen mar- and ciprofloxacin, in both the Access and Watch kets at least 16 antimicrobial medicines, ten of groups. The remainder (five) of the company’s which are listed on the WHO EML (Section 6). portfolio includes antifungals, antiprotozoals and Eleven of the company’s antimicrobials are anti- the anthelminthic albendazole. The company biotics, with seven on the WHO EML (Section 6), also markets an antiseptic face wash contain- including ceftazidime, in the EML’s Watch group, ing triclosan.

* Countries in scope are 106 low- and middle-income countries where access to medicine is likely limited. † EML Section 6: Anti-Infective Medicines § Net revenue; FYE 30 June 2017

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OPPORTUNITIES

Engage in antimicrobial stewardship. Aspen can egy to the sites of third parties that manufacture existing antimicrobials, and ensure that they are engage in stewardship activities, e.g., through antibiotic APIs and drug products on its behalf, priced affordably. Currently, the company does surveillance activities, educational activities for as well as to external waste-treatment sites. not disclose such information. healthcare professionals on AMR (while mitigat- Aspen currently discloses a general environmen- ing conflicts of interest), and engage in appropri- tal risk-management strategy that it applies to ate promotion practices. its own manufacturing sites.

Expand environmental risk-management strat- Ensure affordability and registration plans for egy. Aspen can ensure its antibiotic discharge new and existing antimicrobials. Aspen can limits are applied to its environmental risk-man- seek to improve access in low- and middle-in- agement strategy. It can also extend this strat- come countries through registration of new and

PERFORMANCE BY RESEARCH AREA

RESEARCH & DEVELOPMENT

As a generic medicine manufacturer, Aspen’s main focus is the manufacturing of generic products and as such was not in scope for this Research Area.

B MANUFACTURING & PRODUCTION Indicators 1 2 3 scored on ● ● ●

B.1 Environmental risk-management princi- B.2 Limited transparency regarding environ- B.3 Commits to following GMP. ples for own sites. mental risk management. Aspen reports that it has mechanisms for main- Aspen has set environmental risk-management Aspen publishes its environmental risk-manage- taining a high quality of antibiotic production — principles to minimise the impact of antibiotic ment principles in its annual report. It does not namely following GMP standards. This commit- manufacturing discharge. These apply to its own disclose audit results, or the discharge levels of ment applies to its own manufacturing sites, but manufacturing sites and include auditing. There antibiotics. The company also does not share the the company does not report any commitment is no evidence that they are applicable to third- identities of its third-party suppliers of antibiotic relating to how GMP standards apply to its third- party manufacturers of antibiotic APIs and drug APIs and drug products or external waste-treat- party suppliers of antibiotic drug products. products or to external waste-treatment plants. ment plants. The company reports no information about setting discharge limits.

C APPROPRIATE ACCESS & Indicators 1 2 3 4 5 6 7 STEWARDSHIP scored on ● ● ● ● ● ● ●

C.1 No information on filing for registration. C.3 No insight into steps addressing supply C.4-C.7 No apparent involvement in steward- Aspen reports no information on where it has chain efficiency. ship activities. filed its newest antibiotics for registration in Aspen does not disclose how it works with Aspen does not report any involvement in stew- countries in scope.* This information is not oth- stakeholders (e.g., governments, procurers) to ardship activities (from education to surveillance erwise publicly available. align supply and demand for antimicrobial med- to appropriate promotion practices) that pro- icines, specifically to prevent or minimise stock- mote appropriate antibiotic use. C.2 No disclosure on equitable pricing outs in countries in scope.* The company also approach. does not report on whether it has processes in Aspen does not disclose an equitable pricing place to respond to stock-outs in countries in approach for its highest-volume antibiotics and/ scope.* or antimicrobial medicines.

87 Antimicrobial Resistance Benchmark 2018 Aurobindo Pharma Limited

Stock exchange: XNSE • Ticker: AUROPHARMA • HQ: Hyderabad, India • Employees: 13,982 • Signatory to Davos Decl.: No • Signatory to Industry Roadmap: No**

Performance by Research Area How Aurobindo was evaluated: applicable indicators

Indicator reference Due to the variation 1 2.1 2.2 2.3 3 4 between companies R&D R&D A ○ ○ ○ ○ ○ ○ in scope, not all indi- 1 2 3 cators are applica- M&P M&P B ● ● ● ble to every company. 1 2 3 4 5 6 7 See Appendix for full AA&S AA&S C ● ● ● ● ● ● ● overview. ● Remaining potential score ● Applicable indicator ○ Not applicable PERFORMANCE

Aurobindo is a prominent producer of antibiotics glob- Stewardship. Aurobindo discloses a comprehensive environ- ally by sales volume. As a generic medicine manufacturer, mental risk-management strategy, which is applied to exter- Aurobindo was evaluated in Manufacturing & Production and nal waste-treatment plants. The company reports that it has Appropriate Access & Stewardship only. The company per- mechanisms in place for maintaining high quality of antibi- forms well when compared with the other generic medicine otic production. Aurobindo does not report any involvement manufacturers in scope. It performs well in Manufacturing in stewardship activities that promote appropriate antibiotic & Production, but falls behind in Appropriate Access & use. RevenuesAurobindo by product§ RevenuesMade: by region§ Final: no SALES AND OPERATIONS . Aurobindo is a manufacturer of active pharma- it sold 1.45 billion units (DDDs) of antimicro- . . ceutical ingredients (APIs) and oral and inject- bial medicines. Within its antimicrobial business, . . able generic formulations. Its portfolio covers the company is currently focussing on devel- bn INR bn INR seven major therapeutic areas, including antibi- oping its manufacturing capacity of penems . . otics, antiretrovirals (ARVs) and cardiovascular — broad-spectrum antibiotics used for multi- and central nervous systems. It has nine manu- drug-resistant infections. In 2017, Aurobindo ● Antimicrobials ● India facturing units for APIs and intermediate prod- entered a multilateral agreement to provide a ● Other revenue ● USA ucts and seven for formulations, as well as R&D new class of ARVs (developed within a licens- ● Europe ● Rest of World centres in India and the USA. Aurobindo markets ing agreement with Gilead Sciences Inc. and ViiV its products in more than 150 countries world- Healthcare) to low- and middle-income coun- wide, with a focus on the USA and Europe. It tries. In return for guaranteed minimum sales Antimicrobial portfolio breakdown sells antimicrobial medicines in at least 92 coun- volumes, Aurobindo will supply a generic FDC tries, at least 50 of which are low- and mid- of dolutegravir/lamivudine/tenofovir for a maxi- dle-income countries.* In the fiscal year 2016, mum price of about USD 75 per patient per year. ANTIMICROBIAL PORTFOLIO Aurobindo markets at least 40 antimicrobial ing five on the EML’s Watch group. The remain- medicines, 28 of which are listed on the WHO der (22) of the company’s portfolio comprises EML (Section 6). Eighteen of the company’s 20 antivirals (16 of which target HIV) and two antimicrobial medicines are antibiotics, with antifungals. ● Antibiotics on WHO EML† WHO EML Categories 12 listed on the WHO EML (Section 6), includ- ● Antibiotics not on ● Access group only WHO EML† ● Access & Watch groups ● Other antimicrobial ● Watch group only OPPORTUNITIES medicines ● Reserve group ● Not grouped

Engage in antimicrobial stewardship. Aurobindo does not disclose such information. Expand environmental risk-management strat- can engage in stewardship activities, e.g., egy. Aurobindo can set and apply discharge through surveillance activities, educational activ- Ensure transparency regarding environmental limits for antibiotic manufacturing. It currently ities for healthcare professionals on AMR (while risk. Aurobindo can share more information on has an environmental risk-management strategy mitigating conflict of interest), and engage in how it manages environmental risk (e.g., the that applies to its own manufacturing sites and appropriate promotion practices. company can publish the results of audits car- external waste-treatment sites. ried out on its environmental risk-manage- Ensure affordability and registration plans for ment strategy and the identities of exter- Increase engagement in R&D innovation. new and existing antimicrobials. Aurobindo can nal waste-treatment plants). After the period Aurobindo is currently engaged in developing seek to improve access in low- and middle-in- of analysis, the company disclosed the identi- a new fixed dose combination of antiretrovi- come countries through the registration of new ties of external waste-treatment plants to the ral medicines. It can continue to engage in incre- and existing antimicrobials, and ensure that they Benchmark. mental R&D, and ensure access and stewardship are priced affordably. Currently, the company provisions are in place for these projects. * Countries in scope are 106 low- and middle-income 88 countries where access to medicine is likely limited † EML Section 6: Anti-Infective Medicines § Revenue from operations; FYE 31 March 2017 ** Company states it has applied to be a signatory Access to Medicine Foundation

PERFORMANCE BY RESEARCH AREA

A RESEARCH & DEVELOPMENT

As a generic medicine manufacturer, Aurobindo One fixed dose combination for HIV/AIDS. the treatment of HIV/AIDS. In 2017, Aurobindo was not eligible for this Research Area. However, On reviewing publicly available information, the received FDA tentative approval for this FDC, the company is active in antimicrobial R&D. Benchmark found that Aurobindo has one pro- as it consists of patented antiretrovirals from ject in its antimicrobial R&D pipeline that tar- Gilead Sciences Inc., Bristol-Myers Squibb Co. gets HIV. This involves dolutegravir/lamivudine/ and ViiV Healthcare. tenofovir disoproxil fumarate, a new FDC for

Pipeline targeting priority pathogens

Discovery Preclinical Phase I Phase II Phase III Approval

• Dolutegravir/ lamivudine/ tenofovir disoproxil fumarate – HIV – Adapta- tion (new FDC) – FDA tentative approval 2017

FDC = Fixed dose combination

B MANUFACTURING & PRODUCTION Indicators 1 2 3 scored on ● ● ●

B.1 Environmental risk-management strat- mation about setting discharge limits. Aurobindo After the period of analysis the company dis- egy for own and external sites. states that it does not use third-party suppli- closed the identities of external waste-treat- Aurobindo has an environmental risk-manage- ers for the manufacturing of antibiotic drug ment plants to the Benchmark. ment strategy to minimise the impact of anti- products. biotic manufacturing discharge. The strategy B.3 Commits to following GMP. includes auditing and applies to its own sites and B.2 Limited transparency regarding environ- Aurobindo reports that it has mechanisms for external waste-treatment plants. For a subset of mental risk management. maintaining a high quality of antibiotic produc- sites, Aurobindo follows a Zero-Liquid Discharge Aurobindo publishes its environmental risk-man- tion — namely following GMP standards. process (ZLD, a water treatment process in agement strategy in its annual report. It does which all wastewater is cleaned and reused); for not disclose audit results, or the discharge levels others it deactivates antibiotics prior to external of antibiotics. The company does not share the waste treatment. The company reports no infor- identities of its external waste-treatment plants.

C APPROPRIATE ACCESS & Indicators 1 2 3 4 5 6 7 STEWARDSHIP scored on ● ● ● ● ● ● ●

C.1 No information on filing for registration. C.3 No insight into steps addressing supply C.4-C.7 No apparent involvement in steward- Aurobindo reports no information on where it chain efficiency. ship activities. has filed its newest antibiotics for registration in Aurobindo does not disclose how it works with Aurobindo does not report any involvement in countries in scope.* This information is not oth- stakeholders (e.g., governments, procurers) to stewardship activities (from education to surveil- erwise publicly available. align supply and demand for antimicrobial med- lance to appropriate promotion practices) that icines, specifically to prevent or minimise stock- promote appropriate antibiotic use. C.2 No disclosure on equitable pricing outs in countries in scope.* The company also approach. does not report on whether it has processes in Aurobindo does not disclose an equitable pric- place to respond to stock-outs in countries in ing approach for its highest-volume antibiot- scope.* ics and/or antimicrobial medicines. The company states that its approach to affordability is through tenders.

89 Antimicrobial Resistance Benchmark 2018

Cempra, Inc. Merged with Melinta Therapeutics, Inc. in 2017

Stock exchange: XNAS • Ticker: CEMP • HQ: Chapel Hill, NC, USA • Number of employees: 45 • Signatory to Davos Decl.: Yes • Signatory to Industry Roadmap: No

Performance by Research Area How Cempra was evaluated: applicable indicators

Cempra is a biopharmaceutical company that has recently ical-stage development. The company engages in public-pri- merged with Melinta, selected for having a pipeline that tar- vate partnerships and agreements with various organisa- gets priority pathogens. It was evaluated in the area of tions to develop its antibiotic candidates. Cempra reported no Research & Development only. Its R&D investment in anti- information on having any access or stewardship provisions in biotic drug development in 2016 amounted to USD 82 mil- place for its late-stage clinical R&D projects. lion. It is a mid-performing company compared to the biopharmaceutical companies in scope. Cempra’s pipeline consists of one novel drug candidate and one adaptation, both in clin-

OPERATIONS

Cempra, founded in 2006, was a biopharma- otic to enter clinical use. This led to solithromy- cystic fibrosis patients. The company was also ceutical company focussing on the develop- cin, currently in clinical stage of development, investigating compounds from its macrolide ment of differentiated anti-infectives for acute in both intravenous and oral formulations, for platform, which have the potential to treat bac- and community care settings. In 2017, the com- the treatment of community-acquired bacterial teria typically responsible for human skin and pany announced it would merge with Melinta pneumonia and gonorrhoea. lung infections, as well as respiratory disease in Therapeutics, Inc., a biopharmaceutical company Prior to merging with Melinta, Cempra had no animal health. also in scope of the Benchmark. The merger was products on the market. In 2013, it received five- Cempra was listed on the NASDAQ stock completed in November 2017. year funding from the Biomedical Advanced exchange in 2012, raising approximately Research and Development Authority (BARDA) USD 47.7 million. Prior to this, between Cempra was formed by in-licensing Optimer for approximately USD 60 million to develop 2006 and 2009, company investors included Pharmaceuticals’ macrolide programme, with solithromycin. The company was considering Intersouth Partners, Aisling Capital, Optimer the aim of developing a superior macrolide, with additional indications for this compound, for Pharmaceuticals and Quaker Bioventures, less toxic properties than the recently intro- example, for the treatment of malaria, tubercu- among others. duced telithromycin—the first ketolide antibi- losis, H. pylori gastritis and various infections in

ANTIMICROBIAL PORTFOLIO

Cempra does not have any products on the market.

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PERFORMANCE BY RESEARCH AREA

A RESEARCH & DEVELOPMENT Indicators 1 2.1 2.2 2.3 3 4 Antimicrobial 3 projects scored on ○ ● ● ○ ● ● pipeline 3 target priority pathogens

A.2.1-2.2 One new medicine and two The compound is in development exclusively for A.4 No information on access or stewardship adaptations in the pipeline. the US market and is currently in Phase III clini- provisions. Biopharmaceutical companies in scope were cal trials for acute bacterial skin and skin struc- Cempra reports no information on access or selected based on their pipelines that target pri- ture infections (ABSSSI) and prosthetic joint stewardship provisions for its two antibiotic can- ority bacteria. Cempra invested USD 82 million in infections. didates in late-stage development. It has signed antibiotic drug development in 2016. The com- the Davos Declaration, which includes a gen- pany has three projects in its antimicrobial R&D A.3 One R&D project being developed with eral commitment to ensuring access to antimi- pipeline, all targeting priority bacteria. Its anti- public partners. crobial medicines and vaccines, and to support biotic candidate, solithromycin, is a macrolide Cempra is developing one R&D project in its pri- the appropriate and responsible use of these developed for community-acquired bacterial ority pathogen pipeline through public-private products. pneumonia (CABP). The medicine was submit- partnership. It has received financial support ted to the FDA in 2016 for market approval, but from BARDA for the development of solithromy- was rejected due to inadequate characteristics cin. This began in 2013 and will last for five years. of liver toxicity, and detected deficiencies in the The BARDA grant provides Cempra with funding manufacturing facilities of the company’s man- for the clinical development of the compound ufacturing contractors (Wockhardt Limited and for the treatment of bacterial infections in pae- Hospira, Inc.). A similar EMA application has sub- diatric populations. The most recent funding sequently been withdrawn. Additionally, solithro- instalment (March 2016 to mid-2018) amounted mycin is in Phase III clinical development for the to USD 25.5 million, for the conclusion of Phase treatment of gonorrhoea. Cempra is also devel- II/III studies on intravenous, oral capsule and oral oping a new and proprietary regimen of fusidic suspension formulations for paediatric patients acid (Taksta™), an existing antibiotic with activity with community-acquired bacterial pneumonia against methicillin-resistant S. aureus (MRSA). (CABP).

Pipeline targeting priority pathogens

Discovery Preclinical Phase I Phase II Phase III Approval

• Fusidic acid – S. • Solithromy- aureus – Adap- cin – S. aureus, tation (new dos- S. pneumoniae, ing regimen and Hib – CABP geographic tar- – Awaiting get area (USA)) approval – ABSSSI, bone and joint infections • Solithromy- cin – N. gonorrhoeae – Adap- tation (additional indica- ABSSSI = Acute bacterial skin and skin structure infections tion) – Uncom- CABP = Community-acquired bacterial pneumonia plicated gono- coccal infections

B MANUFACTURING & PRODUCTION

As a biopharmaceutical company with no products on the market, Cempra was not eligible for this Research Area.

C APPROPRIATE ACCESS & STEWARDSHIP

As a biopharmaceutical company with no products on the market, Cempra was not eligible for this Research Area.

91 Antimicrobial Resistance Benchmark 2018 Cipla Limited

Stock exchange: XNSE • Ticker: CIPLA • HQ: Mumbai, India • Number of employees: 23,043 • Signatory to Davos Decl.: Yes • Signatory to Industry Roadmap: Yes

Performance by Research Area How Cipla was evaluated: applicable indicators

Cipla is a prominent producer of antibiotics globally by sales nisms in place for maintaining a high quality of antibiotic pro- volume. As a generic medicine manufacturer, Cipla was eval- duction at its own manufacturing sites. The company reports uated in Manufacturing & Production and Appropriate Access that it has not filed its five newest antibiotics for registration & Stewardship only. The company is among the top perform- in countries in scope.* It reports equitable pricing strategies ing generic medicine manufacturers. It performs strongly for its five highest-volume antimicrobial medicines. Cipla’s in Appropriate Access & Stewardship but falls behind in performance in stewardship is driven by its engagement in a Manufacturing & Production. Cipla has no environmental number of stewardship activities including AMR surveillance risk-management strategy; however, it reports having mecha- programmes.

SALES AND OPERATIONS RevenuesCipla by product§ RevenuesMade: by region§ Final: no

Cipla is an Indian-based generic medicine man- sis, hepatitis C and reproductive health. In 2016, ufacturer founded in 1935. Its pharmaceuti- Cipla completed the acquisition of US-based . . cals segment develops, manufactures and mar- Exelan Pharma and InvaGen Pharmaceuticals, . . . kets generic medicines, as well as active phar- which expanded the company’s portfolio in the mn INR mn INR maceutical ingredients (APIs). Cipla (including USA, along with its manufacturing and R&D . associates) is present in over 80 countries, has capabilities. In early 2017, it divested its animal

43 manufacturing facilities worldwide and mar- health business (operated by subsidiaries Cipla ● Total revenue ● India kets over 1,500 products across various thera- Agrimed SA and Cipla Vet SA, primarily in ● Rest of World peutic areas, with a major focus on respiratory sub-Saharan Africa (SSA)) to Ascendis Pharma. ● USA ● South Africa health, API development and Global Access. Its Cipla sells antimicrobial medicines in Australia, business areas are: respiratory health, APIs and India, South Africa and the USA, as well as in Cipla Global Access. Cipla Global Access is an low- and middle-income countries* such as Sri international tender-based institutional busi- Lanka, Nepal, Myanmar, and in some regions of ness that concentrates on five key therapy areas: the Middle East, Latin America and SSA. HIV/AIDS, malaria, multidrug-resistant tuberculo-

ANTIMICROBIAL PORTFOLIO Antimicrobial portfolio breakdown

Cipla markets at least 25** antimicrobial med- remainder of the company’s portfolio comprises icines, 23 of which are listed on the WHO EML 13 antivirals (indicated for HIV/AIDS, hepatitis B (Section 6). The remaining two medicines are or hepatitis C) and two antiprotozoals indicated the antivirals lamivudine and efavirenz/lamivu- for the treatment of malaria. dine/tenofovir (listed on the EML with different doses than those marketed by Cipla). All ten of the company’s antibiotics appear on the WHO EML (Section 6), including two antibiotics in the EML’s Reserve group (colistin and linezolid). The ● Antibiotics on WHO EML† WHO EML Categories ● Antibiotics not on ● Access group only WHO EML† ● Access & Watch groups * Countries in scope are 106 low- and middle-income ● Other antimicrobial ● Watch group only countries where access to medicine is likely limited medicines ● Reserve group ** Cipla provided only a sample of its global antimicro- ● Not grouped bial portfolio † EML Section 6: Anti-Infective Medicines § Revenue from operations; FYE 31 March 2017; regional breakdown by business unit provided by company

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OPPORTUNITIES

Develop an environmental risk-management cational activities for HCPs include conflict of Increase engagement in R&D innovation. Cipla strategy. Cipla has stated a commitment interest mitigations. Cipla has conducted sev- is currently engaged in adapting generic antimi- to develop and implement an environmen- eral AMR surveys, and can engage in the devel- crobial medicines. For example, the company is tal risk-management strategy. It can ensure its opment of long-term AMR surveillance pro- currently engaged in developing new formula- strategy includes discharge limits and auditing grammes. tions for HIV/AIDS and for malaria in collabora- processes, which apply to the company’s own tion, respectively, with the Drugs for Neglected manufacturing sites, to the sites of third-party Improve access through the registration of Diseases Initiative (DNDi) and the Medicines suppliers and to external waste-treatment sites. antibiotics in more countries. Cipla can file its for Malaria Venture (MMV). It can continue to new and existing antimicrobials for registration engage in incremental R&D, and ensure access Increase engagement in antimicrobial steward- in more low- and middle-income countries. Cipla and stewardship provisions are in place for these ship. Cipla can engage in appropriate promotion has reported that it has not filed its newest anti- projects. activities. It can ensure that current AMR edu- biotics for registration in countries in scope.*

PERFORMANCE BY RESEARCH AREA

A RESEARCH & DEVELOPMENT

As a generic medicine manufacturer, Cipla was developing taste-masked granules of an abaca- final stages in WHO prequalification. Cipla aims not eligible for this Research Area. However, the vir/lamivudine/lopinavir/ritonavir combination to make RAS available to rural areas in Africa company is active in antimicrobial R&D. for paediatric patients with HIV/AIDS in collabo- and to national community health programmes, ration with DNDi. This project is currently in pre- with the support of international donors that Three R&D projects, most being developed clinical stage. The company has developed its have already pledged to procure it. Cipla is also with public partners. Rectal Artesunate Suppositories (RAS) together the first generic medicine manufacturer to The company reports that it has three anti- with MMV. The Global Fund’s Expert Review develop a combination of isoniazid/pyridoxine microbial R&D projects, targeting HIV, P. falci- Panel (ERP) authorized procurement of RAS hydrochloride/sulfamethoxazole/trimethoprim, parum (malaria) and M. tuberculosis. Regarding for pre-referral management of severe malaria which received WHO prequalification in 2016 for R&D collaborations with public partners, Cipla is in 2016 and the medicine is moving through its preventing tuberculosis in HIV/AIDS patients.

Pipeline targeting priority pathogens

Discovery Preclinical Phase I Phase II Phase III Approval

• abacavir/lamivu- • Rectal Artesu- dine/lopinavir/ nate Supposi- ritonavir (LPV/r/ tories (RAS) – ABC/3TC) – HIV P. falciparum – Adaptation – Adaptation (4-in-1 taste- (new formu- masked gran- lation) – Pae- ules) – Paediat- diatrics – ERP rics reviewed 2016 • Isoniazid/pyridoxine hydrochloride/sulfamethoxazole/ trimethoprim – M. tuberculosis – Adapta- tion (new FDC) – Opportunis- tic infections in HIV-Infected patients – WHO prequalification 2016

93 Antimicrobial Resistance Benchmark 2018

B MANUFACTURING & PRODUCTION Indicators 1 2 3 scored on ● ● ●

B.1 Commits to developing environmental B.2 No transparency on environmental risk B.3 Commits to following GMP. risk-management strategy. management. Cipla reports that it has mechanisms for main- Cipla currently has no environmental risk-man- Cipla does not publish any element looked for taining a high quality of antibiotic production — agement strategy in place to minimise the by the Benchmark, namely: antibiotic discharge namely following GMP standards. This commit- impact of antibiotic manufacturing discharge. levels, audit results, and the identities of its ment applies to its own manufacturing sites but Notably, however, it has committed to develop- third-party suppliers of antibiotic APIs and drug the company does not report any commitment ing one in 2018 in an effort to be in line with the products, or of its external waste-treatment relating to how GMP standards apply to its third- commitments in the Industry Roadmap. plants. It has, however, committed to develop party suppliers of antibiotic drug products. an environmental risk-management strategy in 2018 in line with its commitments as a signatory to the Industry Roadmap.

C APPROPRIATE ACCESS & Indicators 1 2 3 4 5 6 7 STEWARDSHIP scored on ● ● ● ● ● ● ●

C.1 Newest antibiotics not filed for report on whether it has processes in place to medicine manufacturers that reports taking registration. respond to stock-outs in countries in scope.* action in this regard by reflecting AMR trends Cipla reports that it has not filed its five newest After the period of analysis, Cipla reported to in its marketing materials, including informa- antibiotics for registration in countries in scope.* the Benchmark that it does have a mechanism tion about resistance trends. However, the com- in place for responding to stock-outs: namely it pany’s appropriate promotion practices do not C.2 Inter-country equitable pricing for has a standard operating procedure in place that include the decoupling of its sales force’s incen- antimicrobials. results in a safety stock being held in India. tives from volume of antibiotic sales. Cipla discloses inter-country equitable pricing approaches, taking gross national income (GNI) C.4 Some involvement in AMR-related C.6 Provides information on treatment into account, for its five highest-volume anti- education. duration. microbial medicines. These pricing approaches Cipla is the only generic medicine manufac- The company adapts its packaging to facili- reportedly apply in all countries in scope* where turer that reports different approaches to edu- tate appropriate use of antibiotics by patients, Cipla markets these products. This covers Latin cate HCPs on AMR. These activities are focussed by providing information on treatment duration. America, sub-Saharan Africa and a subset of on raising awareness of the rational use of anti- This can help to improve patient adherence to other countries. biotics. The company provides limited informa- treatment. tion on conflict of interest (COI) mitigation and C.3 General commitment to ensuring supply content development. After the period of analy- C.7 Conducted several AMR surveys. chain efficiency. sis, Cipla stated that its speaker contracts do not Cipla has stated that it has conducted some Cipla has made a general commitment to obligate HCPs to purchase, use, recommend or AMR-related prevalence studies. The company improve supply chain efficiency. During the arrange for the use of company products. delivers the results of these studies via confer- period of analysis, the Benchmark identified no ences and peer-reviewed journals. information on how Cipla works with stakehold- C.5 Adopts some appropriate promotion ers (e.g., governments, procurers) to align supply practices. and demand for antimicrobial medicines, specif- The Benchmark measures how companies ically to prevent or minimise stock-outs in coun- address stewardship through appropriate pro- tries in scope. The company also did not then motion practices. Cipla is one of two generic

94 Access to Medicine Foundation

95 Antimicrobial Resistance Benchmark 2018 Dr. Reddy’s Laboratories Ltd. Signatory to Davos Decl.: No Stock exchanges: XNSE; XNYS • Tickers: DRREDDY; RDY • HQ: Hyderabad, India • Employees: 22,681 Signatory to Industry Roadmap: No

Performance by Research Area How Dr.Reddy’s was evaluated: applicable indicators

Dr. Reddy's is a prominent producer of antibiotics globally approach to equitable pricing, where it has filed antibiotics by sales volume. As a generic medicine manufacturer, Dr. for registration, its actions to ensure efficient supply and its Reddy's was evaluated in Manufacturing & Production and involvement in stewardship activities. However, Dr. Reddy’s Appropriate Access & Stewardship only. Its performance is has an environmental risk-management strategy that is based low compared to most other generic medicine manufacturers on a zero-liquid discharge (ZLD) process at all its manufactur- in scope. It reported no information to the Benchmark, and ing sites, including manufacturing sites for antibiotics. publicly available information is limited, specifically regarding its approach to manufacturing high quality antibiotics, its

Dr. Reddy’s Made: Final: no SALES AND OPERATIONS Revenues by product§ Revenues by regionII

Dr. Reddy’s is a generic medicine manufac- R&D facilities: six in India, two in the USA and . turer founded in 1984, with commercial pres- two in Europe. In 2015, Dr. Reddy’s acquired sev- . ence in 26 countries. Its core therapeutic areas eral established brands from UCB for the ter- . . . include oncology, gastroenterology, cardiovascu- ritories of India, Nepal, Sri Lanka and Maldives, bn INR bn INR . lar health, diabetes and anti-infectives. The com- covering dermatology, respiratory diseases, ear, pany’s Global Generics segment manufactures nose and throat disorders, and paediatrics. In ● Total revenue ● USA and markets prescription and over-the-counter 2016, it completed the acquisition of eight prod- ● Rest of World (OTC) medicines (generics and medicines man- ucts from Teva’s US portfolio. In 2017, it signed a ● India ufactured in its biologics unit). Its Proprietary global licensing pact with CHD Bioscience (USA), ● Russia Products segment develops and manufactures to develop and commercialise CHD’s Phase III differentiated formulations in dermatology and clinical candidate DFA-02 for USD 30 million. neurology. It has 25 manufacturing facilities: 18 DFA-02 is a gentamicin/vancomycin extend- in India (including seven for active pharmaceu- ed-release gel indicated for the prevention of tical ingredients), three in the USA, two in the surgical site infection following non-emergency, UK and one each in China and Mexico. It has ten elective colorectal surgery.

ANTIMICROBIAL PORTFOLIO Antimicrobial portfolio breakdown

According to publicly available data, Dr. Reddy’s group (linezolid). The remaining six medicines markets at least 22 antimicrobial medicines, are three antivirals and three antifungals. The seven or more of which are listed on the WHO company also markets an influenza vaccine in EML (Section 6). Sixteen of the company’s anti- Germany, via its subsidiary Betapharm. microbial medicines are antibiotics, with at least three listed on the WHO EML (Section 6), including one antibiotic in the EML’s Reserve

● Antibiotics on WHO EML† WHO EML Categories ● Antibiotics not on ● Access group only WHO EML†,‡ ● Access & Watch groups * Countries in scope are 106 low- and middle-income ● Other antimicrobial ● Watch group only countries where access to medicine is likely limited. medicines ● Reserve group † EML Section 6: Anti-Infective Medicines ● Not grouped ‡ Includes antibiotics whose formulation or dose could not be determined § Revenue from operations; FYE 31 March 2017 || Sales (inc. excise duty), license fees, and service income; excluding other operating income; FYE 31 March 2017

96 Access to Medicine Foundation

OPPORTUNITIES

Engage in antimicrobial stewardship. information on discharge limits for its own and and existing antimicrobials, and ensure that they Dr. Reddy’s can engage in stewardship activi- third-party manufacturers’ sites. The company are priced affordably. Currently, the company ties, e.g., through surveillance activities, educa- currently discloses its environmental risk-man- does not disclose such information. tional activities for healthcare professionals on agement activities in its corporate sustainabil- AMR (while mitigating conflict of interest), and ity report. Engage in R&D innovation. Dr. Reddy’s can engage in appropriate promotion practices. engage in incremental R&D innovation to Ensure affordability and registration plans for address resistance, improve adherence and the Improve transparency on environmental risk new and existing antimicrobials. Dr. Reddy’s can appropriate use of antimicrobial medicines. management. Dr. Reddy’s can share informa- seek to improve access in low- and middle-in- tion on how it manages environmental risk, e.g., come countries through the registration of new

PERFORMANCE BY RESEARCH AREA

A RESEARCH & DEVELOPMENT

As a generic medicine manufacturer, Dr. Reddy’s’ main focus is the manufacturing of generic products and, as such, was not in scope for this Research Area.

B MANUFACTURING & PRODUCTION Indicators 1 2 3 scored on ● ● ●

B.1 Follows Zero-Liquid Discharge at own B.2 No transparency on environmental risk B.3 No statement on how antibiotic quality is sites. management. maintained. Dr. Reddy’s environmental risk-management Dr. Reddy’s does not disclose its strategy to min- Dr. Reddy’s makes no statement regarding how approach is based on following a zero-liquid dis- imise the impact of manufacturing discharge it ensures high quality antibiotic production fol- charge (ZLD) process at all its manufacturing of antibiotics. It does not publish any element lowing international manufacturing standards sites, including manufacturing sites for antibi- looked for by the Benchmark, namely: antibiotic accepted by recognised national and interna- otics. Dr. Reddy’s reports no information about discharge levels, audit results, and the identities tional authorities (such as GMP). setting discharge limits or auditing this pro- of its third-party suppliers of antibiotic APIs and cess. It does not appear to have extended this drug products, or of its external waste-treat- approach to its third-party manufacturers of ment plants. antibiotic APIs and drug products, or to external waste-treatment plants.

C APPROPRIATE ACCESS & Indicators 1 2 3 4 5 6 7 STEWARDSHIP scored on ● ● ● ● ● ● ●

C.1 No information on filing for registration. C.3 No insight into steps addressing supply C.4-C.7 No apparent involvement in Dr. Reddy’s reports no information on where it chain efficiency. stewardship activities. has filed its newest antibiotics for registration in Dr. Reddy’s does not disclose how it works with Dr. Reddy’s does not report any involvement in countries in scope.* This information is not oth- stakeholders (e.g., governments, procurers) to stewardship activities (from education to sur- erwise publicly available. align supply and demand for antimicrobial med- veillance to appropriate promotion practices) icines, specifically to prevent or minimise stock- that promote appropriate antibiotic use. C.2 No disclosure on equitable pricing outs in countries in scope.* The company also approach. does not report on whether it has processes in Dr. Reddy’s does not disclose an equitable pric- place to respond to stock-outs in countries in ing approach for its highest-volume antibiotics scope.* and/or antimicrobial medicines.

97 Antimicrobial Resistance Benchmark 2018 Entasis Therapeutics Inc.

Stock exchange: Privately held • HQ: Waltham, MA, US • Number of employees: 30 • Signatory to Davos Decl.: Yes • Signatory to Industry Roadmap: No

Performance by Research Area How Entasis was evaluated: applicable indicators

Entasis is a biopharmaceutical company, selected for having antibiotic candidate. Entasis engages in numerous public-pri- a pipeline that targets priority pathogens. It was evaluated in vate partnerships and agreements with various organisations the area of Research & Development only. Entasis invested to develop its antibiotic candidates. Entasis has one R&D pro- USD 10-20 million in antibiotic drug development in 2016. The ject in late-stage clinical development, for which it has an company is the leader among other biopharmaceutical com- access provision and stewardship commitment in place. panies in scope. It has five projects in its antimicrobial R&D pipeline, all targeting priority pathogens, including one novel

OPERATIONS

Entasis is a privately held US-based biophar- ing, among others, N. gonorrhoeae, P. aerug- was extended in September 2017 by an addi- maceutical company established in 2015 with inosa and A. baumannii. The company’s most tional USD 31.9 million from Pivotal bioVenture start-up funding from AstraZeneca and full advanced drug candidate is zoliflodacin, indi- Partners, Sofinnova Ventures and TPG Biotech. rights to a subset of its small-molecule anti-in- cated for the treatment of uncomplicated gon- fectives pipeline. The company focuses on cre- orrhoea. Entasis has no products on the market. ating innovative medicines to treat diseases In 2016, the company raised USD 50 million in caused by drug-resistant gram-negative bac- a Series B financing round, which was led by teria. Its pipeline includes both clinical and pre- Clarus and included Frazier Healthcare Partners, clinical small-molecule antibacterials, target- Novo Holdings A/S and Eventide Fund. This

ANTIMICROBIAL PORTFOLIO

Entasis does not have any products on the market.

OPPORTUNITIES

Develop stewardship plan for zoliflodacin. Entasis has signed a licensing agreement to ensure access and the responsible use of its antibiotic candidate (zoliflodacin) in late-stage clinical development, that covers 168 countries. It can develop a plan for ensuring appropriate use of the product, on approval, in remaining territories.

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PERFORMANCE BY RESEARCH AREA

A RESEARCH & DEVELOPMENT Indicators 1 2.1 2.2 2.3 3 4 Antimicrobial 5 projects scored on ○ ● ● ○ ● ● pipeline 5 target priority pathogens

A.2.1–2.2 One novel antibiotic in the clinical combinations: with sulbactam and with imipe- territories. In March 2017, Entasis received fund- pipeline. nem. ETX0282 is a combination of cefpodoxime ing from CARB-X to develop ETX0282/cefpo- Biopharmaceutical companies in scope were with a broad-spectrum class A and C ß-lacta- doxime through Phase I clinical development. selected based on their pipelines that target pri- mase inhibitor. The company also received a second CARB-X ority bacteria. Entasis invested USD 10-20 mil- award in October 2017 to progress its discov- lion in antibiotic drug development in 2016. A.3 Three R&D projects being developed ery-stage penicillin-binding protein inhibitor pro- The company has five projects in its antimicro- with public partners, including one PDP. gramme from lead optimization through Phase I bial R&D pipeline targeting priority pathogens, Entasis is developing three R&D projects in its clinical trials. largely focusing on gram-negative bacteria. Its priority pathogen pipeline through public-pri- novel antibiotic candidate zoliflodacin is an inno- vate partnership. In July 2017, the company A.4 Access provision and stewardship com- vative bacterial topoisomerase II inhibitor with announced a collaboration with Global Antibiotic mitment in place for zoliflodacin. a new mode of action, for which no cross-re- Research & Development Partnership (GARDP) Entasis reports that it has an access provision in sistance has been described. Although zolif- for the clinical development of zoliflodacin place and stewardship commitment for its anti- lodacin has broad-spectrum activity, it is cur- after successfully finishing Phase II studies that biotic in late-stage development. The access rently in development for the treatment of gon- were funded and conducted by the US National provision for its investigational antibiotic (zoliflo- orrhoea only. Entasis is seeking to optimize Institute of Allergy and Infectious Diseases dacin) has been developed through its collabora- the medicine’s dosing regimen for this indica- (NIAID). Through this PDP, GARDP is responsible tion with GARDP. GARDP is responsible for pro- tion, as well as limit its widespread use for other for the clinical trials, including financing, man- viding access and promoting the responsible use indications to prevent emergence of resist- aging, and coordinating Phase III trials, pharma- of zoliflodacin in their respective territories (168 ance. Additionally, Entasis has particular exper- covigilance and drug registration in the coun- countries identified by GARDP where access to tise in the structure and function of bacterial tries where it has licensing rights. Entasis retains medicine is likely limited). Entasis is committed ß-lactamases, and is involved in the develop- commercial rights in the majority of mature mar- to developing stewardship programmes, as well ment of new and improved ß-lactamase inhib- kets, and grants GARDP an exclusive and royal- as affordable and equitable pricing, in order to itors in combination with existing ß-lactams. ty-free licence (for the treatment of gonorrhoea) ensure access in mature markets. ETX2514 is a broad-spectrum ß-lactamase inhib- with sublicensing rights for global manufactur- itor, which is being developed in two different ing and sale and distribution in 168 countries or

Pipeline targeting priority pathogens

Discovery Preclinical Phase I Phase II Phase III Approval

• Gram-negative discovery platform • ETX0282/cef- • ETX2514/sul- • Zoliflodacin – GNB podoxime – bactam – A. (ETX0914) – N. GNB – ß-lacta- baumannii – gonorrhoeae mase inhibitor & ß-lactamase – Topoisomer- existing cepha- inhibitor & exist- ase II inhibitor – losporin ing ß-lactam Novel • ETX2514/imipenem* – GNB – ß-lactamase inhibitor & existing ß-lactam

GNB = Gram-negative bacteria * This project is considered as an adaptation for scoring, as ETX2514 is considered as a new project in the ETX2514/sulbactam combination.

B MANUFACTURING & PRODUCTION

As a biopharmaceutical company with no products on the market, Entasis was not eligible for this Research Area.

C APPROPRIATE ACCESS & STEWARDSHIP

As a biopharmaceutical company with no products on the market, Entasis was not eligible for this Research Area.

99 Antimicrobial Resistance Benchmark 2018 Fresenius Kabi AG

Stock exchange: XFRA • Ticker: FRE • HQ: Bad Homburg, Germany • Employees: 34,917 • Signatory to Davos Decl.: via MFE • Signatory to Industry Roadmap: No

Performance by Research Area How Fresenius Kabi was evaluated: applicable indicators

Indicator reference Due to the variation 1 2.1 2.2 2.3 3 4 between companies R&D R&D A ○ ○ ○ ○ ○ ○ in scope, not all indi- 1 2 3 cators are applica- M&P M&P B ● ● ● ble to every company. 1 2 3 4 5 6 7 See Appendix for full AA&S AA&S C ● ● ● ● ● ○ ● overview. ● Remaining potential score ● Applicable indicator ○ Not applicable PERFORMANCE

Fresenius Kabi is a prominent producer of antibiotics glob- quality standards to their production facilities. Fresenius ally by sales volume. As a generic medicine manufacturer, Kabi reports information on where it files antibiotics for reg- Fresenius Kabi was evaluated in Manufacturing & Production istration; however, there is no information available regard- and Appropriate Access & Stewardship only. The company is ing the company's approach to equitable pricing for its high- among the top performing generic medicine manufacturers. It est-volume antimicrobial medicines. Regarding stewardship, discloses an environmental risk-management strategy for its the company reflects AMR trends in its marketing materials own sites. Fresenius Kabi reports mechanisms for maintain- through leaflets on AMR-related topics for its top marketed ing a high quality of antibiotic production and also requires products. its third-party suppliers of drug products to apply the same

SALES AND OPERATIONS RevenuesFresenius Kabiby product § RevenuesMade: by region§ Final: no

Fresenius Kabi is a wholly owned subsidiary injectable and specialty sterile and non-ster- of Fresenius SE & Co. KGaA, and specialises in ile pharmaceuticals. Also in 2017, the company . medicines and technologies for infusion, trans- completed the acquisition of Merck KGaA’s . . . fusion and clinical nutrition in the field of crit- biosimilars business, whose product pipeline . . . bn EUR bn EUR ical and chronic care. It has four business seg- focused on oncology and autoimmune diseases. . . ments: intravenous (IV) drugs; infusion ther- Fresenius Kabi markets its antimicrobial med- apy; clinical nutrition; and medical devices & icines in 34 countries globally, six of which are ● IV drugs ● North America transfusion technology. Its IV drugs segment low- or middle-income countries.* All of the ● Infusion therapy ● Europe includes anti-infectives. In 2017, Fresenius Kabi company’s antimicrobial medicines are infusion ● Clinical nutrition ● Asia Pacic ● Medical devices, ● LATAM, Africa announced that it would acquire Akorn Inc., a or powder-for-injection formulations. Transfusion technology US-based manufacturer and marketer of prescription and over-the-counter ophthalmic,

ANTIMICROBIAL PORTFOLIO Antimicrobial portfolio breakdown

Fresenius Kabi markets at least 35 antimicro- The remaining three medicines are an antifun- bial medicines, 21 of which are listed on the gal (fluconazole) and the antivirals aciclovir and WHO EML (Section 6). Thirty-two of the compa- ganciclovir, indicated for infections caused by ny’s antimicrobial medicines are antibiotics, with herpes virus and cytomegalovirus, respectively. 19 listed on the WHO EML (Section 6), including five in the EML’s Reserve group (aztreonam, cefepime, daptomycin, linezolid and tigecycline).

* Countries in scope are 106 low- and middle-income countries where access to medicine is likely limited † EML Section 6: Anti-Infective Medicines § Sales, FYE 31 December 2016

100 Access to Medicine Foundation

OPPORTUNITIES

Increase engagement in antimicrobial steward- The company can also seek to improve access mental risk-management strategy is extended ship. Fresenius Kabi adopts some appropriate in low- and middle-income countries by ensur- to the sites of third parties who manufacture promotion practices through leaflets on AMR- ing its new and existing antimicrobials are priced antibiotic APIs and drug products on its behalf. related topics for its top marketed products. It affordably. Fresenius Kabi currently has an environmental can engage in more stewardship activities, e.g., risk-management strategy, that includes audit- through surveillance activities, educational activ- Improve transparency regarding environmental ing processes, and is applied to its own manufac- ities for healthcare professionals on AMR (while risk. Fresenius Kabi can share more information turing sites. mitigating conflict of interest), and expand on on how it manages environmental risk, e.g., the appropriate promotion practices. company can publish the results of audits car- Engage in R&D innovation. Fresenius Kabi can ried out on its environmental risk-management engage further in incremental R&D innovation to Improve access to new and existing antimicro- strategy. Fresenius Kabi already discloses envi- address resistance and improve appropriate use bials. Fresenius Kabi can file its new and exist- ronmental risk principles. of antimicrobial medicines. The company already ing antimicrobials for registration in more coun- engages in incremental R&D directed at improv- tries. Fresenius Kabi has filed two of its newest Expand its environmental risk-management ing usability of its medicines by HCPs. antibiotics for registration in countries in scope.* strategy. Fresenius Kabi can ensure its environ-

PERFORMANCE BY RESEARCH AREA

A RESEARCH & DEVELOPMENT

As a generic medicine manufacturer, Fresenius generic products and, as such, was not in scope Kabi’s main focus is the manufacturing of for this Research Area.

B MANUFACTURING & PRODUCTION Indicators 1 2 3 scored on ● ● ●

B.1 Environmental risk-management B.2 Limited transparency regarding environ- B.3 Commits to following GMP, including at strategy for own sites. mental risk management. 3rd-party sites. Fresenius Kabi has a general environmen- Fresenius Kabi publishes its environmental Fresenius Kabi reports that it has mechanisms tal risk-management strategy to minimise the risk-management principles in its annual report. for maintaining a high quality of antibiotic pro- impact of antibiotic manufacturing discharge. It does not disclose audit results, or the dis- duction — namely following GMP standards. This This applies to its own manufacturing sites and charge levels of antibiotics. The company also commitment applies to its own manufactur- includes audits. There is no information suggest- does not share the identities of its third-party ing sites. Fresenius Kabi requires its third-party ing that the strategy is applicable to third-party suppliers of antibiotic APIs and drug products, or suppliers to apply the same quality standards to manufacturers of antibiotic APIs and drug prod- external waste-treatment plants. their production facilities. ucts or to external waste-treatment plants. The company reports no information about setting discharge limits.

C APPROPRIATE ACCESS & Indicators 1 2 3 4 5 6 7 STEWARDSHIP scored on ● ● ● ● ● ○ ●

C.1 Some newest antibiotics filed in some bial medicines, specifically to prevent or mini- products, leaflets aimed at informing HCPs on countries in scope. mise stock-outs in countries in scope.* The com- AMR-related topics. These leaflets include AMR- Fresenius Kabi reports information about pany also does not report on whether it has related information under the "Special Warnings where it has filed some of its newest antibiot- processes in place to respond to stock-outs in and Precautions for Use" section. There is no ics for registration in some countries in scope.* countries in scope.* information available on decoupling of the com- However, the Benchmark is not able to publish pany's sales force’s incentives from volume of further information, as all details were provided C.4 No information on AMR-related antibiotic sales. on the basis of confidentiality. education. There is no information available regarding C.6 No antibiotics dispensed directly to C.2 No information available on equitable Fresenius Kabi’s involvement in AMR-related patients. pricing approach. educational activities for HCPs. Fresenius Kabi is not eligible for this indicator as There is no information available regarding it does not have any antibiotics in its portfolio Fresenius Kabi’s approach to equitable pricing C. 5 Adopts some appropriate promotion that are directly dispensed to patients. All of its for its highest-volume antibiotics and/or antimi- practices. antibiotics are administered in the hospital. crobial medicines. The Benchmark measures how companies address stewardship through appropriate pro- C.7 No information regarding AMR C.3 No insight into steps addressing supply motion practices. Fresenius Kabi is one of two surveillance programmes. chain efficiency. generic medicine manufacturers that reports There is no information available regarding Fresenius Kabi does not disclose how it works taking action in this regard by reflecting AMR Fresenius Kabi’s efforts to engage in AMR sur- with stakeholders (e.g., governments, procur- trends in its marketing materials. For exam- veillance programmes. ers) to align supply and demand for antimicro- ple, the company created, for its top marketed

101 Antimicrobial Resistance Benchmark 2018 GlaxoSmithKline plc

Stock exchange: XLON • Ticker: GSK • HQ: Brentford, UK • Employees: 99,300 • Signatory to Davos Decl.: Yes • Signatory to Industry Roadmap: Yes

Performance by Research Area How GSK was evaluated: applicable indicators

Indicator reference Due to the variation 1 2.1 2.2 2.3 3 4 between companies R&D R&D A ● ● ● ● ● ● in scope, not all indi- 1 2 3 cators are applica- M&P M&P B ● ● ● ble to every company. 1 2 3 4 5 6 7 See Appendix for full AA&S AA&S C ● ● ● ● ● ● ● overview. ● Remaining potential score ● Applicable indicator ○ Not applicable PERFORMANCE

GSK performs well in all three Research Areas, and is one of external waste-treatment plants. GSK has filed its five newest the leaders when compared with other large research-based antibiotics for registration in many countries in scope.* It also pharmaceutical companies in scope. GSK has the largest anti- reports a comparatively broad inter- and intra-country equi- microbial R&D pipeline of all large research-based pharma- table pricing approach for antimicrobial medicines, as well ceutical companies in scope: 55‡ projects, of which 40‡ target as multiple steps to improve supply chain efficiency. In stew- priority pathogens, including several novel candidates and ardship, GSK reports that it engages in several AMR educa- 12 new vaccine candidates. It has access and/or stewardship tion programmes aimed at healthcare professionals, taking provisions in place for most late-stage candidates. GSK dis- action to mitigate conflict of interest in these programmes. It closes the most comprehensive environmental risk-manage- has ceased remunerating sales staff based on sales volume. It ment strategy of all companies evaluated, which includes dis- engages in AMR surveillance and collaborates and shares its charge limits and reportedly applies to all GSK’s third-party data with public health authorities. suppliers of antibiotic APIs and drug products, as well as to

SALES AND OPERATIONS RevenuesGSK by product§ RevenuesMade: by region§ Final: no

GSK is a large research-based pharmaceuti- AIDS medicines. Shionogi joined ViiV Healthcare cal company with three divisions: pharmaceuti- in 2012. Equity positions in ViiV Healthcare are . . . cals, vaccines and consumer healthcare. In 2016, GSK: 76.5%, Pfizer: 13.5% and Shionogi: 10%. In . . . . GSK sold the largest volume of antibiotics of all 2015, GSK completed the acquisition of Novartis’ bn GBP bn GBP companies in scope of the Benchmark. During vaccine business (excluding influenza vaccines) . . 2016, the company’s leading antibiotics were and in return divested its marketed oncology sold in 126 countries, 57 of which were low- and portfolio to Novartis. In the same year, GSK sold ● Vaccines ● USA middle-income countries*. In 2009, GSK and two of its meningococcal vaccines to Pfizer ● Antimicrobials ● Rest of World Pfizer established ViiV Healthcare, a joint ven- (Mencevax® and Nimenrix®). ● Other pharmaceuticals ● Europe ● Consumer healthcare ture solely focused on the development of HIV/

ANTIMICROBIAL PORTFOLIO Antimicrobial portfolio breakdown

GSK markets at least 30 antimicrobial medi- minthics, as well as 15 antivirals (12 of which cines, 14 of which are included in the WHO EML target HIV). The company also markets a chlor- (Section 6). The majority of the company’s anti- hexidine antiseptic gel for umbilical cord care in microbial medicines are established products. neonates and has a large and diverse vaccines Nine of its medicines are antibiotics, includ- portfolio, which includes the vaccines Hiberix®, ing the amoxicillin/clavulanic acid formulation targeting Haemophilus influenzae type B, and Augmentin™, a 35-year old top-selling antibiotic Synflorix®, targeting S. pneumoniae. (by volume). The remainder (21) of the company’s portfolio includes antiprotozoals and anthel- ● Antibiotics on WHO EML† WHO EML Categories ● Antibiotics not on ● Access group only WHO EML† ● Access & Watch groups * Countries in scope are 106 low- and middle-income ● Other antimicrobial ● Watch group only countries where access to medicine is likely limited. medicines ● Reserve group ** GSK is involved in the COMBACTE-CDI network, a ● Not grouped recently launched project within the IMI COMBACTE research consortium. † EML Section 6: Anti-Infective Medicines § Group turnover; FYE 31 December 2016

102 Access to Medicine Foundation

OPPORTUNITIES

Develop access plans for gepotidacin. GSK has ments regarding its environmental risk-manage- and take further language and literacy needs a stewardship plan in place for its antibiotic can- ment strategy, as well as its safety data sheets. It into consideration. didate (gepotidacin) in late-stage clinical devel- has also disclosed its PNECs to the Benchmark opment. GSK can ensure that access plans are under a non-disclosure agreement. Expand practices for aligning supply and also in place for this candidate. demand. GSK can work with relevant stakehold- Expand on stewardship activities. GSK has ers (e.g., suppliers, procurers and payers) to align Improve transparency regarding environmen- established its SOAR surveillance programme supply and demand for all antimicrobials, espe- tal risk management. GSK can build on its cur- for monitoring resistance trends in respiratory cially for its antibiotics, in countries in scope.* rent level of transparency, e.g., by adding its tract infections. It can expand this programme to GSK has a general mechanism in place for align- Predicted No Effect Concentrations (PNECs) for include other diseases and territories, and inte- ing demand and supply, as well as product-spe- resistance selection to its safety data sheets. It grate its activities within existing structures such cific mechanisms for five products including can also work with suppliers to publish PNECs as WHO’s GLASS programme. GSK has adapted albendazole (Zendel®). that apply to its third-party manufacturers of its brochures in South Africa to facilitate the antibiotic APIs and drug products. The com- appropriate use of antibiotics by patients. It can pany currently publishes several policy docu- expand this practice to more countries in scope*

PERFORMANCE BY RESEARCH AREA

A RESEARCH & DEVELOPMENT Indicators 1 2.1 2.2 2.3 3 4 Antimicrobial 55 projects scored on ● ● ● ● ● ● pipeline 40 target priority pathogens

A.1 Comparatively high antimicrobial R&D pipeline, 28‡ of which are in clinical stage devel- ing adaptations) are considered novel, making investments. opment. Forty‡ of the company’s projects target the company’s clinical pipeline the most innova- GSK reports investments in antimicrobial R&D priority pathogens. It has the largest pipeline of tive among large research-based pharmaceutical in 2016, which are high compared to other large the large research-based pharmaceutical com- companies included in the Benchmark. GSK has research-based pharmaceutical companies in the panies assessed by the Benchmark, and the 11 antimicrobial vaccines in clinical development Benchmark. However, the Benchmark is not able highest number of projects that focus on pri- (excluding adaptations), six of which are devel- to publish further information, as all details were ority pathogens (for both medicines and vac- oped against diseases caused by a priority path- provided on the basis of confidentiality. cines). In antimicrobial R&D, GSK’s major focus ogen, including HIV, Shigella spp. and non-typea- is on HIV and gram-negative bacteria and, to a ble H. influenzae (for which no vaccines currently A.2.1-2.3 Largest priority pathogens pipeline, smaller extent, M. tuberculosis and gram-positive exist). GSK is also investigating the development including six novel clinical candidates. bacteria. Six out of seven‡ of GSK’s investiga- of a meningococcal vaccine (Bexsero®) for pro- GSK has 55‡ antimicrobial R&D projects in its tional medicines in clinical development (exclud- tection against gonorrhoea.

Pipeline targeting priority pathogens

Discovery Preclinical Phase I Phase II Phase III Approval

• Active Transport project – GNB – • Confidential pro- • GSK3342830 • Gepotidacin – • Dolutegravir/ • Dolutegra- In partnership with Sanofi ject – GNB & GPB ‡ – Enterobac- N. gonorrhoea, lamivudine – vir/rilpivir- • FimH inhibitors – GNB ▶Salmonella iNTS teriaceae, P. GPB – Gonor- HIV – Adapta- ine (Juluca®) – • Antibiotics early discovery project – vaccine – non-ty- aeruginosa, A. rhoea, ABSSSI – tion (new FDC) HIV – Adapta- GNB phoidal Salmo- baumannii Novel • Cabotegra- tion (new FDC) • Phenotypic screening and tar- nella enterica • GSK3036656 – ▶S. pneumoniae vir/rilpivirine – In partnership get-based programme for NMT ▶Enteric fever M. tuberculosis next generation long-acting – with Johnson & and ProRS – P. falciparum bivalent conju- – Novel vaccine HIV – Adapta- Johnson – FDA ▶Malaria next generation vaccine – gate vaccine – • MI254 – HIV – ▶COPD vaccine tion (new for- approval 2017 P. falciparum Salmonella enter- Novel – Hib mulation) – In • Chlorhex- ica Typhi & ▶Shigella GMMA partnership idine (Umbi- Stage: not published Paratyphi A vaccine – S. son- with Johnson & pro) – antisep- ▶ C. difficile vaccine nei Johnson tic – GNB & GPB • M. tuberculosis ▶S. aureus vaccine ▶Shigella conju- • Fostemsavir – – Adaptation • M. tuberculosis • GSK3488917 – gates vaccine – HIV – Novel (new formula- • M. tuberculosis HIV S. flexneri • Cabotegra- tion for umbil- • M. tuberculosis • Confidential ▶M. tuberculosis vir long-acting ical cord infec- • HIV project – HIV vaccine (PrEP) – HIV – tion) – EMA • HIV • Confidential • GSK2838232 – Novel approval 2016 ▶ Gr. B Streptococcus hexavalent project – HIV HIV – Novel ▶N. gonorrhoea vaccine • pfATP4 inhibitors ▶HIV vaccine – In vaccine – Adap- – P. falciparum partnership with tation (addi- ▶Vaccine • Malaria drug Sanofi tional indication GNB = Gram-negative bacteria discovery of Bexsero®) GPB = Gram-positive bacteria FDC = Fixed dose combination programme – ‡ GSK3342830 has been terminated after the P. falciparum period of analysis.

103 Antimicrobial Resistance Benchmark 2018

A.3 Twenty-four R&D projects being devel- is partially funded by both BARDA and the US try to improve affordability. Furthermore, the oped with public partners, including Defense Threat Reduction Agency under “Other company has stewardship provisions in place for eight PDPs. Transaction Authority” (OTA) agreements, which seven out of eight of its medicines in late-stage GSK is developing 24 R&D projects in its pri- are cost-sharing reimbursement contracts. development. Stewardship for GSK’s HIV candi- ority pathogen pipeline through public-pri- dates will be managed by ViiV Healthcare, which vate partnership.** The company is involved in A.4 Access and/or stewardship provisions in sponsors HIV drug resistance surveillance stud- eight PDPs and one open research consortium, place for most late-stage candidates. ies that are executed via several independent the highest number reported among all compa- GSK reports that it has access and/or steward- consortia. Moreover, GSK has a company-wide nies assessed by the Benchmark. Of these nine ship provisions in place for most of its R&D can- commitment to decouple sales force incentives projects, seven are in preclinical stage and two didates targeting priority pathogens in late-stage from volume of sales, an important steward- are in clinical stage. For the development of its development. It has access provisions for 11 out ship incentive in combating AMR. Only one out Phase II HIV vaccine, GSK partners with the Pox- of its 15 antimicrobial candidates in late-stage of seven of its vaccine candidates has an access Protein Public Private Partnership (P5), a pro- development. GSK states that it will market provision, while three have an access commit- ject that includes the US National Institute of its HIV candidates via ViiV Healthcare, which ment. For example, the agreement with the non- Allergy and Infectious Diseases (NIAID), the Bill has a general access to medicine policy that profit biotechnology organisation Aeras, for the & Melinda Gates Foundation, the South African includes a commitment to voluntary licensing development of an anti-tuberculosis vaccine Medical Research Council, the HIV Vaccine Trials to allow supplies of generic versions of its prod- includes a global access commitment clause, and Network (HVTN), the US Military HIV Research ucts in least-developed, low- and lower-middle WHO prequalification is foreseen. For this indi- Program and Sanofi. The company also collab- income countries and all sub-Saharan African cator, countries in scope are 106 low- and mid- orates with Aeras, a non-profit biotechnology countries. In addition, the policy includes a flex- dle-income countries where access to medicine organisation, on the development of its tubercu- ible pricing procedure in middle-income coun- is likely limited. losis vaccine, currently in Phase II clinical devel- tries that factors in the gross domestic product opment. GSK’s antibiotic candidate gepotidacin (GDP) and impact of the epidemic in each coun-

B MANUFACTURING & PRODUCTION Indicators 1 2 3 scored on ● ● ●

B.1 Most comprehensive environmental B.2 Limited transparency regarding environ- B.3 Commits to following GMP, including at risk-management strategy. mental risk management. 3rd-party sites. GSK is the only company in the Benchmark to GSK publishes several of its environmental GSK reports that it has mechanisms for main- undertake every environmental risk-manage- risk-management policy documents on its web- taining a high quality of antibiotic production ment activity that the Benchmark examines. site. It does not disclose audit results, or the dis- — namely following GMP standards. This com- Namely, the company applies an environmen- charge levels of antibiotics. The company also mitment applies to its own manufacturing sites. tal risk-management strategy to minimise the does not share the identities of its third-party GSK requires its third-party suppliers to apply impact of antibiotic manufacturing discharge. suppliers of antibiotic APIs and drug products or the same quality standards to their production It includes auditing and limits on antibiotic dis- external waste-treatment plants. facilities. charge, for its own manufacturing sites, third- party manufacturers of antibiotic APIs and drug products, and external waste-treatment plants.

C APPROPRIATE ACCESS & Indicators 1 2 3 4 5 6 7 STEWARDSHIP scored on ● ● ● ● ● ● ●

C.1 Filed five newest antibiotics in countries highest-volume antimicrobial medicines. These C.4 Multiple activities in AMR-related educa- in scope. approaches cover >50% of countries in scope.* tional programmes. GSK leads in this area, as it reports that it has For albendazole (Zentel™), GSK has commit- GSK reports that it is involved in educational filed its five newest antibiotics for registra- ted to applying intra- and inter-country equitable programmes for healthcare professionals (HCPs) tion in up to 71 countries in scope.* Three of its pricing (including donations) in endemic coun- that include AMR stewardship and rational use most recently introduced antibiotics were filed tries in scope.* of antibiotics, with conflicts of interest (COI) for registration in more than half of the coun- mitigation measures in place. Programmes tries in scope.* Its amoxicillin/clavulanic acid C.3 Taking multiple steps to improve supply such as “Surveillance of Antibiotic Resistance” antibiotic (Augmentin™) was filed for registra- chain efficiency. (SOAR) deliver content through ‘active learn- tion in the highest number of countries in scope* GSK engages with WHO and various Ministries ing channels’ (e.g., conferences and courses) to a (71). Another two of its antibiotics were regis- of Health of countries in scope* to align broad spectrum of HCPs, such as doctors, phar- tered in nine and 31 countries in scope.* GSK’s supply and demand forecasting for albenda- macists, and microbiologists. A general COI mit- five newest antibiotics were introduced between zole (Zentel™), aiming to ensure a continuous igation policy applies to all of the company's 1981 and 2007. exchange of information on, e.g., outbreaks. For programmes. Under this policy, GSK no longer five of its nine highest-volume antimicrobials, pays HCPs to participate in its educational pro- C.2 Leader in inter- and intra-country GSK has mechanisms in place to respond effi- grammes, and uses an external body to select equitable pricing. ciently in the event of stock-outs in countries in HCPs for sponsorship to attend congresses. GSK discloses that it applies an equitable pric- scope.* These mechanisms include inter-market Most educational programmes are not product ing strategic framework to all products includ- (e.g., country-level) stock transfers, and for cef- specific. GSK’s commercial teams are, in some ing antimicrobials. In addition, it discloses prod- tazidime (Fortum®) the prioritisation of emerg- cases, not involved in developing materials. uct-specific inter- and intra-country equitable ing markets over established markets. pricing approaches for seven out of nine of its

104 Access to Medicine Foundation

C.5 Comprehensive involvement in appropri- C.6 Implements brochure and/or packaging C.7 International programme for AMR ate promotion practices. adaptations to facilitate appropriate use. surveillance. The Benchmark measures how companies GSK has adapted its brochures in South Africa GSK runs one international programme, focused address stewardship through appropriate pro- to facilitate appropriate use of antibiotics by on AMR trends for community-acquired respira- motion practices. GSK reports that it takes patients. The company is also developing a digi- tory tract infections. The company shares the action in this regard: it reflects AMR trends in its tal solution that provides product information to results with public health authorities, through marketing materials and has decoupled all sales patients, taking illiteracy into account. conferences and multiple peer-reviewed jour- force incentives from sales volumes for all its nals. Additionally, the company is collaborating products. This approach is unique in the industry. with other organisations (such as the Open Data The company now remunerates its sales force Institute and the Wellcome Trust) to explore the based on their technical knowledge, and the possibility of developing a single industry-spon- quality of service they deliver through in-clinic sored antibiotic surveillance database, with har- evaluation and monitoring. monised measurements and results.

ANIMAL HEALTH & DIAGNOSTICS

Activities in this area are not scored by the While GSK does not have its own diagnostics work that addresses the diagnostic challenges Benchmark. This information is provided given division, the company reports that it works with for the epidemiological and clinical studies of the importance of animal health and diagnostics third parties to complement AMR product devel- carbapenem-resistant bacteria. on the topic of AMR. opment with diagnostic tests whenever possible. Additionally, the company reports that it GSK does not market antibiotics for animal use. provides scientific advice and seed-funding for It has a public policy in place which, states that public-private partnerships and for awards for the company will not license its new antibiotics the development of point-of-care diagnostics to for agricultural use. be used in conjunction with antibiotics. GSK also supports COMBACTE-CARE, a European net-

105 Antimicrobial Resistance Benchmark 2018 Johnson & Johnson

Stock exchange: XNYS • Ticker: JNJ • HQ: New Brunswick, NJ, US • Employees: 127,100 • Signatory to Davos Decl.: Yes • Signatory to Industry Roadmap: Yes

Performance by Research Area How Johnson & Johnson was evaluated: applicable indicators

Indicator reference Due to the variation 1 2.1 2.2 2.3 3 4 between companies R&D R&D A ● ● ● ● ● ● in scope, not all indi- 1 2 3 cators are applica- M&P M&P B ● ● ● ble to every company. 1 2 3 4 5 6 7 See Appendix for full AA&S . AA&S C ● ● ● ● ● ● ● overview. ● Remaining potential score ● Applicable indicator ○ Not applicable PERFORMANCE

Johnson & Johnson is one of the leaders when compared environmental risk-management strategy, which includes with other large research-based pharmaceutical compa- discharge limits and reportedly applies to all Johnson & nies in scope, driven by strong performances in Research & Johnson’s third-party suppliers of antibiotic APIs and drug Development, Manufacturing & Production and Appropriate products. It has filed its three newest antibiotics for registra- Access & Stewardship, largely centred around tuberculo- tion in some countries in scope.* It also reports equitable pric- sis-related activities. The company has one of the largest anti- ing strategies for some antibiotics, as well as multiple steps microbial R&D pipelines of the large research-based phar- to improve supply chain efficiency. In stewardship, Johnson maceutical companies in scope: 48** projects, of which 15** & Johnson engages in several tuberculosis-related educa- target priority pathogens, including one novel antimalarial tional programmes aimed at healthcare professionals, taking candidate and at least three new vaccine candidates. It has action to mitigate conflict of interest in these programmes. It access and stewardship provisions in place for some late- engages in tuberculosis-related surveillance programmes, and stage candidates. The company discloses a comprehensive collaborates and shares its data with public health authorities.

SALES AND OPERATIONS RevenuesJohnson & by Johnson product § RevenuesMade: by region§ Final: no

Johnson & Johnson is a large research-based developed and produced by Janssen Vaccines & . . pharmaceutical company with operations in Prevention BV (part of Janssen Pharmaceutical . . three segments: consumer healthcare, pharma- Companies), which divested its oral typhoid and . . ceuticals and medical devices. Its pharmaceuti- oral cholera vaccines to PaxVax and Valneva in bn USD . bn USD cals segment focuses on therapeutic areas such 2014 and 2015 respectively. . . as cardiovascular health and metabolism, immunology, infectious diseases and vaccines, neuro- ● Vaccines ● USA science and oncology. The company sells anti- ● Antimicrobials ● Rest of world ● Other pharmaceuticals microbial medicines or vaccines in 108 countries ● Consumer healthcare globally, 38 of which are low- to middle-income ● Medical devices countries.* Johnson & Johnson’s vaccines are

ANTIMICROBIAL PORTFOLIO Antimicrobial portfolio breakdown

Johnson & Johnson markets at least 22 antimi- HIV, two are used in the treatment of hepatitis crobial medicines, seven of which are listed on C, five are antifungals and four are anthelminth- the WHO EML (Section 6). Five of the compa- ics or antiprotozoals. The company has two vac- ny’s antimicrobial medicines are antibiotics. This cines on the market: Quinvaxem®, indicated for includes levofloxacin (Elequine®, Levaquin®), protection against five major childhood infec- listed on the EML's Watch group, and bedaqui- tious diseases, and Hepavax-Gene®, a recom- line (Sirturo®), included in the EML's comple- binant vaccine against hepatitis B. Johnson & mentary list of reserve second-line drugs for Johnson reports that these are being phased the treatment of multidrug-resistant tuberculo- out, citing availability of other products. ● Antibiotics on WHO EML† WHO EML Categories sis. Out of the remaining 17 medicines, six target ● Antibiotics not on ● Access group only WHO EML† ● Access & Watch groups ● Other antimicrobial ● Watch group only medicines ● Reserve group * Countries in scope are 106 low- and middle-income ● Not grouped countries where access to medicine is likely limited † EML Section 6: Anti-Infective Medicines § FYE 1 January 2017

106 Access to Medicine Foundation

OPPORTUNITIES

Plan ahead for access and stewardship during tal risk, e.g., the company can publish informa- such programmes is made publicly available. The R&D. Johnson & Johnson has stated a com- tion regarding the levels of antibiotic discharge. company does not report stewardship activities mitment to ensure access and stewardship Currently Johnson & Johnson discloses several for other antibiotics and can consider such activ- plans are in place for all of its candidates in the policy documents regarding its environmental ities for these antibiotics as well. pipeline. It can ensure that this commitment risk-management strategy. is followed through with specific plans apply- Improve access through the registration of new ing to all of its candidates in late-stage clinical Expand on stewardship activities. Johnson & antibiotics. Johnson & Johnson can improve development. Johnson engages in the DREAM surveillance access in low- and middle-income countries* programme, covering first- and second-line by filing its antimicrobials, particularly bedaqui- Improve transparency regarding environmental anti-tuberculosis medicines. The company can line (Sirturo®) for registration in these countries. risk. Johnson & Johnson can share more consider to expand this to more countries, e.g., Johnson & Johnson has currently filed to regis- information on how it manages environmen- in sub-Saharan Africa, and ensure data from ter this product in 23 countries in scope.*

PERFORMANCE BY RESEARCH AREA

A RESEARCH & DEVELOPMENT Indicators 1 2.1 2.2 2.3 3 4 Antimicrobial 48 projects scored on ● ● ● ● ● ● pipeline 15 target priority pathogens

A.1 Comparatively high antimicrobial R&D consist of two medicines, three vaccines and types resistant to at least three antibiotics). No investments. five** adaptations to existing pharmaceuticals, vaccines currently exist for either pathogen. Johnson & Johnson reports investments in anti- including the adaptation of its anti-tuberculo- microbial R&D in 2016, which are high com- sis medicine bedaquiline (Sirturo®) for paediatric A.3 Three R&D projects being developed pared to other large research-based pharmaceu- use. One of the investigational medicines is the with public partners, including two PDPs. tical companies in the Benchmark. However, the antibiotic cadazolid, an oxazolidinone-quinolone Johnson & Johnson is developing three R&D Benchmark is not able to publish further infor- hybrid targeting C. difficile, which was adopted projects in its priority pathogen pipeline through mation, as all details were provided on the basis through the acquisition of Actelion in 2017 and public-private partnership. The company is of confidentiality. is now in Phase III of clinical development. The developing an HIV vaccine in clinical stage other is a novel antimalarial medicine, a dihy- through a consortium of partners, including, A.2.1-2.3 Fifteen R&D projects that target pri- drofolate reductase inhibitor, in Phase I clini- the National Institutes of Health (NIH), the Bill ority pathogens, including one novel clinical development. The company is collaborat- & Melinda Gates Foundation, the International cal antimalarial medicine. ing with ViiV Healthcare on the combination of AIDS Vaccine Initiative (IAVI), the United States Johnson & Johnson has 48** antimicrobial R&D its HIV/AIDS medicine rilpivirine (Edurant®) with Military HIV Research Program (MHRP) and the projects in its pipeline, 23** of which are in clin- ViiV Healthcare’s HIV/AIDS medicines: dolutegra- Beth Israel Deaconess Medical Center (BIDMC), ical-stage development. Fifteen** of the com- vir (Tivicay®)/rilpivirine (Edurant®) combination, among others. Additionally, the company is pany’s projects target priority pathogens. Ten as well as a cabotegravir/rilpivirine (Edurant®) developing an antimalarial medicine through of these are in clinical-stage development, long-acting nanosuspension for injection. The a PDP with the Medicines for Malaria Venture making it the second-largest clinical-stage pipe- company has two vaccines in clinical develop- (MMV). line that targets priority pathogens, among the ment targeting HIV, and a third vaccine targeting large research-based pharmaceutical companies multidrug-resistant extra-intestinal E. coli (spe- assessed by the Benchmark. These ten projects cifically, targeting the four most prevalent sero-

Pipeline targeting priority pathogens

Discovery Preclinical Phase I Phase II Phase III Approval

• P218 (DHFR ▶HIV preventive • Cabotegra- • Dolutegra- inhibitor) – P. vaccine vir/rilpivirine vir/rilpivir- Stage: not published falciparum – ▶ExPEC4v vac- long-acting – ine (Juluca®) – Novel cine – ETEC: HIV – Adapta- HIV – Adapta- • Five confidential projects ▶HIV therapeutic CRE, ESBL tion (new for- tion (new FDC) vaccine • Rilpivirine mulation) – In – In partnership long-acting partnership with with GSK – FDA nanosuspension ViiV Healthcare approval 2017 for injection** – • Cadazolid – C. • Darunavir/cobi- HIV – Adapta- difficile cistat/emtricit- tion (new for- abine/tenofo- mulation) vir alafenamide • Bedaquiline for (Symtuza®) – ▶Vaccine paediatrics – HIV – Adapta- ETEC = Extraintestinal Pathogenic E. coli M. tuberculo- tion (new FDC) FDC = Fixed dose combination sis – Adaptation – EMA approval GNB = Gram-negative bacteria GPB = Gram-positive bacteria (new formula- 2017 ** Rilpivirine long-acting nanosuspension has been terminated after the period of analysis tion)

107 Antimicrobial Resistance Benchmark 2018

A.4 Access and stewardship provisions in entails a managed access programme through Johnson & Johnson is responsible for delivery place for some late-stage candidates. the Global Drug Facility and its own subsidiaries, of the long-acting injectable cabotegravir/rilpi- Johnson & Johnson reports that it commits and medical education on the use of bedaquiline virine (Edurant®) regimen to developing coun- to having access and stewardship provisions (Sirturo®) to paediatric healthcare professionals. tries. Only one of the remaining four candidates in place for all its candidates in development In addition, Johnson & Johnson has access pro- in late-stage development (ExPEC4v vaccine) before regulatory approval. To the Benchmark, visions in place for three other R&D candidates has an access commitment in place. For this indi- the company reports that it will expand the targeting priority pathogens in late-stage devel- cator, countries in scope are 106 low- and mid- access and stewardship activities currently in opment, including its HIV vaccine candidate and dle-income countries where access to medicine place for bedaquiline (Sirturo®) to its paediat- the antiretroviral combinations, developed in is likely limited. ric formulation in Phase II development. This collaboration with ViiV Healthcare.

B MANUFACTURING & PRODUCTION Indicators 1 2 3 scored on ● ● ●

B.1 Comprehensive environmental risk-man- does not set discharge limits for these plants nor B.3 Commits to following GMP, including at agement strategy. audits implementation of the strategy. 3rd-party sites. Johnson & Johnson undertakes almost all envi- Johnson & Johnson reports that it has mech- ronmental risk-management activities that the B.2 Limited transparency regarding environ- anisms for maintaining a high quality of antibi- Benchmark examines. Namely, it applies an envi- mental risk management. otic production — namely following GMP stand- ronmental risk-management strategy to mini- Johnson & Johnson publishes elements of its ards. This commitment applies to its own manu- mise the impact of antibiotic manufacturing dis- environmental risk-management strategy on its facturing sites. Johnson & Johnson requires its charge. It includes auditing and limits on antibi- website. It does not disclose audit results, or the third-party suppliers of drug products to apply otic discharge, for its own manufacturing sites discharge levels of antibiotics. The company also the same quality standards to their production and those of third-party manufacturers of antibi- does not share the identities of its third-party facilities. otic APIs and drug products. Johnson & Johnson suppliers of antibiotic APIs and drug products or states that its strategy applies to external external waste-treatment plants. waste-treatment plants, yet it also reports that it

C APPROPRIATE ACCESS & Indicators 1 2 3 4 5 6 7 STEWARDSHIP scored on ● ● ● ● ● ● ●

C.1 Filed three newest antibiotics in some C.3 Taking multiple steps to improve supply address stewardship through appropriate pro- countries in scope. chain efficiency. motion practices. Johnson & Johnson’s new Johnson & Johnson reports that it has filed Johnson & Johnson engages with PAHO, the anti-tuberculosis drug, bedaquiline (Sirturo®), its three newest antibiotics for registration in Global Drug Facility, WHO and others to align is provided solely through national tuberculosis some countries in scope* (between 7–23 coun- supply and demand forecasting for three of its programmes and therefore does not require any tries). Two of these antibiotics are licensed from seven highest-volume antimicrobial medicines: marketing materials. The company reports that Daiichi Sankyo for sale in Latin America only. bedaquiline (Sirturo®), darunavir (Prezista®) it does not deploy any sales organisations for the Johnson & Johnson has filed these two antibi- and mebendazole (Vermox®). It also has mech- sale of Sirturo® in countries in scope.* otics (introduced in 1990 and 1996) for registra- anisms in place (i.e., it maintains safety stocks) tion in seven and ten of the countries in scope* to respond efficiently in the event of stock-outs C.6 Implements packaging adaptation for in Latin America. Johnson & Johnson’s bedaqui- in countries in scope.* These mechanisms cover bedaquiline to facilitate appropriate use. line (Sirturo®) is the only product introduced in bedaquiline (Sirturo®), darunavir (Prezista®) and The company collaborated with Stop TB the past five years (2012) that has been filed for simeprevir (Olysio®). Partnership to adapt bedaquiline (Sirturo®) registration in more than ten countries in scope*. packaging by creating a six-month presentation Indeed, it has been filed in 23 such countries. It is C.4 Multiple activities in tuberculosis-related and a blister preparation of the medicine. The also worth noting that through the Global Drug educational programmes. former aims to improve patient adherence to Facility, more than 70 countries have approved Johnson & Johnson has provided tuberculo- treatment in Directly Observed Treatment (DOT) importation of bedaquiline prior to regulatory sis-related stewardship information only. The programmes, while the latter aims to facilitate approval. company reports that it is involved in tubercu- usage in different environmental conditions. losis educational programmes for HCPs that C.2 Product-specific equitable pricing. include AMR stewardship and rational use of C.7 Engages with WHO reference lab- Johnson & Johnson discloses equitable pricing antibiotics, with conflicts of interest (COI) miti- oratories and national tuberculosis approaches for four of its seven highest-volume gation measures in place. The company collabo- programmes. antimicrobial medicines: bedaquiline (Sirturo®), rates with third parties such as the International Johnson & Johnson runs one multi-country sur- darunavir (Prezista®), mebendazole (Vermox®) Union against Tuberculosis and Lung Disease veillance programme, focused on tuberculo- and simeprevir (Olysio®). It applies inter-coun- and USAID on the appropriate use of anti-tu- sis resistant trends. It engages numerous labo- try equitable pricing to three of these (not berculosis drugs, pharmacovigilance and multi- ratories to support the surveillance of tubercu- mebendazole), and intra-country equitable pric- drug-resistant tuberculosis management. The losis resistance trends via the Drug Resistance ing to bedaquiline, mebendazole and simeprevir. company supports these initiatives with unre- Emergence Assessment in multidrug-resistant Its inter-country pricing policy for bedaquiline stricted educational grants, which ensures inde- tuberculosis programme (DREAM). Although reflects countries’ ability to pay (measured by pendent content development. results are to be published in peer-reviewed GNI per capita) and disease burden (of multid- journals, the company is also sharing data with rug-resistant tuberculosis). C.5 No active promotion of bedaquiline. national tuberculosis programmes. The Benchmark measures how companies

108 Access to Medicine Foundation

ANIMAL HEALTH & DIAGNOSTICS

Activities in this area are not scored by the infrastructure. In December 2015, Johnson & form. The technology is aimed to improve rou- Benchmark. This information is provided given Johnson and the Foundation of Innovative New tine viral load testing of HIV/AIDS patients on the importance of animal health and diagnostics Diagnostics (FIND) entered into a collaboration antiretroviral therapy. on the topic of AMR. for the discovery of point-of-care diagnostics for tuberculosis case detection, including multid- Johnson & Johnson reports that it is develop- rug-resistant strains. ing bedaquiline sensitivity diagnostic plates and The company has also formed a partnership panels that are to be deployed on the Becton with Cue Inc. to develop an HIV viral load test on Dickinson and Thermo Fisher Scientific Inc. lab Cue’s Lab-In-A-Box molecular diagnostic plat-

109 Antimicrobial Resistance Benchmark 2018 Lupin Limited Signatory to Davos Decl.: via MFE Stock exchange: XNSE • Ticker: LUPIN • HQ: Mumbai, India • Number of employees: 16,792 • Signatory to Industry Roadmap: No

Performance by Research Area How Lupin was evaluated: applicable indicators

Lupin is a prominent producer of antibiotics globally by sales reports that it has mechanisms in place for maintaining a high volume. As a generic medicine manufacturer, Lupin was eval- quality of antibiotic production and requires its third-party uated in Manufacturing & Production and Appropriate Access suppliers to apply the same quality standards to their pro- & Stewardship only. The company’s performance in the duction facilities. Lupin does not report any information on Benchmark is lower compared to most other generic med- its access strategies regarding antimicrobial medicines, or its icine manufacturers in scope. Lupin does not report having involvement in stewardship activities that promote appropri- an environmental risk-management strategy. The company ate antibiotic use.

SALES AND OPERATIONS RevenuesLupin by product§ RevenuesMade: by region§ Final: no

Lupin is an Indian-based generic medicine man- 18 manufacturing facilities across India, Japan, ufacturer founded in 1968. It produces active the USA, Mexico and Brazil (five for active phar- . pharmaceutical ingredients (APIs), as well as maceutical ingredient production). The com- . . . generic medicines. The company develops pany invests in R&D for biosimilars, mainly in bn INR bn INR advanced drug-delivery systems and has a highly immunology, endocrine health and oncology. It . differentiated pipeline. It has operations in more has nine R&D facilities, in India and elsewhere, than 100 countries, with key markets for finished including the USA, Japan and the Netherlands. ● Total revenue ● USA drug products in the USA, India, Japan, Europe, In 2016, Lupin acquired Gavis Pharmacauticals, ● India South Africa, Philippines and Australia. The com- whose portfolio includes cardiovascular, cen- ● Rest of World ● Japan pany focusses on cardiovascular health, diabe- tral nervous system (CNS) and anti-infective tes and anti-infectives, with a strong history in medicines, among others. Also in 2016, Lupin anti-tuberculosis medicines and cephalosporin reached an agreement with Shionogi to acquire antibiotics. Its anti-tuberculosis formulations are 21 branded products coming off-patent in Japan, sold globally. Within the company’s India busi- for approx. USD 150 million. These cover ther- ness (contributing approx. 22% to global reve- apeutic areas such as the CNS, oncology and nues), the anti-infectives and anti-tuberculosis anti-infectives. business segments made up 18% of revenues in 2016 (fiscal year). Lupin (and subsidiaries) have

ANTIMICROBIAL PORTFOLIO Antimicrobial portfolio breakdown

According to publicly available data, Lupin mar- ny’s portfolio comprises the antifungal voricona- kets at least 25 antimicrobial medicines, 18 of zole, listed on the WHO EML (Section 6) for which are listed on the WHO EML (Section 6). the treatment of aspergillosis, the antiproto- Nineteen of the company’s antimicrobial medi- zoal tinidazole and four medicines containing the cines are antibiotics, with 13 listed on the WHO antiretroviral lamivudine. EML (Section 6), including six in the EML’s Watch group. The remainder (six) of the compa-

● Antibiotics on WHO EML† WHO EML Categories ● Antibiotics not on ● Access group only WHO EML† ● Access & Watch groups ● Other antimicrobial ● Watch group only medicines ● Reserve group * Countries in scope are 106 low- and middle-income ● Not grouped countries where access to medicine is likely limited † EML Section 6: Anti-Infective Medicines § Revenue from operations; FYE 31 March 2017

110 Access to Medicine Foundation

OPPORTUNITIES

Engage in antimicrobial stewardship. Lupin can company can publish information regarding the existing antimicrobials, and ensure that they are engage in stewardship activities, e.g., through levels of antibiotic discharge. Currently the com- priced affordably. Currently, the company does surveillance activities, educational activities for pany does not demonstrate evidence of having not disclose such information. healthcare professionals on AMR (while mitigat- an environmental risk-management strategy in ing conflicts of interest), and engage in appropri- place. Engage in R&D innovation. Lupin can engage in ate promotion practices. incremental R&D innovation to address resist- Ensure affordability and registration plans for ance, improve adherence and the appropriate Ensure transparency regarding environmental new and existing antimicrobials. Lupin can seek use of antimicrobial medicines. risk management. Lupin can share information to improve access in low- and middle-income on how it manages environmental risk, e.g., the countries through the registration of new and

PERFORMANCE BY RESEARCH AREA

A RESEARCH & DEVELOPMENT

As a generic medicine manufacturer, Lupin’s main focus is the manufacturing of generic products and, as such, was not in scope for this Research Area.

B MANUFACTURING & PRODUCTION Indicators 1 2 3 scored on ● ● ●

B.1 Reports no environmental risk- B.2 No transparency on environmental risk B.3 Commits to following GMP, including at management strategy. management. 3rd-party sites. Lupin does not report having an environmental Lupin does not disclose its strategy to minimise Lupin reports that it has mechanisms for main- risk-management strategy in place to minimise the impact of manufacturing discharge of anti- taining a high quality of antibiotic production the environmental impact of manufacturing dis- biotics. It does not publish any element looked — namely following GMP standards. This com- charge of antibiotics. for by the Benchmark, namely: antibiotic dis- mitment applies to its own manufacturing sites. charge levels, audit results, and the identities of Lupin requires its third-party suppliers to apply its third-party suppliers of antibiotic APIs and the same quality standards to their production drug products, or of its external waste-treat- facilities. ment plants.

C APPROPRIATE ACCESS & Indicators 1 2 3 4 5 6 7 STEWARDSHIP scored on ● ● ● ● ● ● ●

C.1 No information on filing for registration. C.3 No insight into steps addressing supply C.4-C.7 No apparent involvement in steward- Lupin reports no information on where it has chain efficiency. ship activities. filed its newest antibiotics for registration in Lupin does not disclose how it works with stake- Lupin does not report any involvement in stew- countries in scope.* This information is not oth- holders (e.g., governments, procurers) to align ardship activities (from education to surveillance erwise publicly available. supply and demand for antimicrobial medicines, to appropriate promotion practices) that pro- specifically to prevent or minimise stock-outs in mote appropriate antibiotic use. C.2 No disclosure on equitable pricing countries in scope.* The company also does not approach. report on whether it has processes in place to Lupin does not disclose an equitable pricing respond to stock-outs in countries in scope.* approach for its highest-volume antibiotics and/ or antimicrobial medicines.

111 Antimicrobial Resistance Benchmark 2018 Macleods Pharmaceuticals Ltd.

Stock exchange: Privately held • Ticker: - • HQ: Mumbai, India • Employees: > 13,500 • Signatory to Davos Decl.: No • Signatory to Industry Roadmap: No

Performance by Research Area How Macleods was evaluated: applicable indicators

Macleods is a prominent producer of antibiotics glob- report its approach to assuring high quality antibiotic produc- ally by sales volume. As a generic medicine manufacturer, tion consistent with international standards. Macleods has Macleods was evaluated in Manufacturing & Production and provided information on where it has filed two of its newest Appropriate Access & Stewardship only. Although the com- antibiotics for registration, but does not disclose an equita- pany’s performance in the Benchmark is lower compared to ble pricing approach for its antibiotics and antimicrobial medi- most other generic medicine manufacturers in scope, it dis- cines, or actions to ensure efficient supply. The company does closes an environmental risk-management strategy for its not report any involvement in stewardship activities that pro- own sites, which includes an auditing process. It does not mote appropriate antibiotic use.

SALES AND OPERATIONS RevenuesMacleods by product§ Made: Final: no

Macleods is an Indian-based privately-held man- wide range of therapeutic indications, including ufacturer of generic medicines focussing on tuberculosis, malaria, bacterial infections, dia- essential pharmaceuticals. The company is pres- betes and respiratory and cardiovascular dis- . ent in more than 100 countries worldwide, eases. The company has an in-house bioequiva- mn USD including in Southeast Asia, Africa and North lence centre and an R&D centre, and it is active America. It has a total of 14 manufacturing facil- in the development of incremental innovations ities: one for active pharmaceutical ingredients for antimicrobial medicines. Its antimicrobial ● Total revenue (APIs) and 13 for drug products. Current drug medicines are sold in over 52 countries globally, formulations include tablets, hard and soft gel- 43 of which are low- or middle-income coun- atine capsules and dry powder injections. The tries.* According to publicly available data, reve- company is actively seeking to expand its man- nues for the fiscal year 2016 amounted to USD ufacturing capabilities to include, among other 782 million. things, metered dose inhalation products and liquid injectables. Macleods’ products cover a

ANTIMICROBIAL PORTFOLIO Antimicrobial portfolio breakdown

Macleods markets at least 83 antimicrobial med- portfolio comprises eight antimalarials (all listed icines, 51 of which are listed on the WHO EML on the WHO EML) and 21 antivirals (including 19 (Section 6). Fifty-four of the company’s antimi- indicated for HIV/AIDS). crobial medicines are antibiotics, with 29 listed on the WHO EML (Section 6), including three in the EML’s Reserve group (cefepime, colistin and linezolid). The remainder (29) of the company’s

* Countries in scope are 106 low- and middle-income countries where access to medicine is likely limited. † EML Section 6: Anti-Infective Medicines § Turnover 2016-2017

112 Access to Medicine Foundation

OPPORTUNITIES

Engage in antimicrobial stewardship. Macleods registration of new and existing antimicrobials. on its behalf, as well as to external waste-treat- can engage in stewardship activities, e.g., Macleods has filed two of its newest anti-tuber- ment sites. Macleods currently has a general through surveillance activities, educational activ- culosis medicines for registration in 30 countries environmental risk-management strategy that it ities for healthcare professionals on AMR (while in scope.* It can seek to improve access in low- applies to its own manufacturing sites. mitigating conflicts of interest), and engage in and middle-income countries through the regis- appropriate promotion practices. tration of more antimicrobials, and ensure that Increase engagement in R&D innovation. these are priced affordably. Macleods is currently engaged in adapting Ensure transparency regarding environmental generic antimicrobial medicines. For example, risk management. Macleods can share informa- Expand environmental risk-management strat- the company is developing paediatric formulation on how it manages environmental risk, e.g., egy. Macleods can ensure that antibiotic dis- tions containing lower doses of anti-tubercu- by disclosing its environmental risk-management charge limits are added to its environmental losis medicines (in collaboration with the TB strategy and the levels of antibiotic discharge. risk-management strategy. It can also extend Alliance). It can continue to engage in incremen- this strategy to the sites of third parties who tal R&D, and ensure access and stewardship pro- Improve access through the affordability and manufacture antibiotic APIs and drug products visions are in place for these projects.

PERFORMANCE BY RESEARCH AREA

A RESEARCH & DEVELOPMENT

As a generic medicine manufacturer, Macleods its antimicrobial R&D pipeline targeting priority has a general access to medicine policy that was not eligible for this Research Area. However, pathogens. This includes ten lower-dose formu- includes global adoption, availability and afforda- the company is active in antimicrobial R&D. lations of tuberculosis medicines for paediatric bility. Macleods is also developing a dolutegravir/ use and an additional indication for clofazimine, lamivudine/tenofovir fixed dose combination for Several R&D projects being developed with currently indicated for leprosy. The company col- the treatment of HIV/AIDS. public partners. laborates with TB Alliance and UNITAID on the Macleods reports that it has twelve projects in development of these formulations. TB Alliance

Pipeline targeting priority pathogens

Stage unknown Preclinical Phase I Phase II Phase III Approval

• Clofazimine – • Cycloserine – M. tuberculosis – Adap- M. tuberculo- tation (new formulation: capsules 125 sis – Adaptation mg) – Paediatrics – ERP reviewed (Additional indi- • Ethionamide – M. tuberculosis – cation) Adaptation (new formulation: dispers- • Ethambutol – ible tablets 125 mg) – Paediatrics – M. tuberculo- WHO prequalified 2017 sis – Adaptation • Levofloxacin – M. tuberculosis – (new formula- Adaptation (new formulation: dispers- tion: dispersible ible tablets 100 mg) – Paediatrics – tablets 100 mg) ERP reviewed – Paediatrics • Moxifloxacin – M. tuberculosis – • Linezolid – M. Adaptation (new formulation: dispers- tuberculosis ible tablets 100 mg) – Paediatrics – – Adaptation ERP reviewed (new formula- • Pyrazinamide – M. tuberculosis – tion: dispersible Adaptation (new formulation: dispers- tablets 150 mg) ible tablets 150 mg) – Paediatrics – – Paediatrics WHO prequalified 2016 • Isoniazid – M. • Rifampicin/isoniazid – M. tuberculo- tuberculosis sis – Adaptation (new formulation: – Adaptation dispersible tablets 75 mg + 50 mg) – (new formula- WHO prequalified 2017 tion: dispersible • Rifampicin/isoniazid/pyrazina- tablets 100 mg) mide – M. tuberculosis – Adaptation – Paediatrics (new formulation: dispersible tablets • Dolutegravir/ 75+50+150 mg) – WHO prequalified lamivudine/ten- 2017 ofovir disoproxil fumarate – HIV – Adaptation FDC = Fixed dose combination (new FDC) ERP = Expert Review Panel

113 Antimicrobial Resistance Benchmark 2018

B MANUFACTURING & PRODUCTION Indicators 1 2 3 scored on ● ● ●

B.1 Environmental risk-management B.2 No transparency on environmental risk B.3 No statement on how antibiotic quality is strategy for own sites. management. maintained. Macleods has an environmental risk-manage- Macleods does not disclose its strategy to min- Macleods makes no statement regarding how ment strategy to minimise the impact of anti- imise the impact of manufacturing discharge it ensures high quality antibiotic production fol- biotic manufacturing discharge. This applies to of antibiotics. It does not publish any element lowing international manufacturing standards its own manufacturing sites and includes audit- looked for by the Benchmark, namely: antibiotic accepted by recognised national and interna- ing. There is no evidence that the strategy is discharge levels, audit results, and the identities tional authorities (such as GMP). applicable to third-party manufacturers of anti- of its third-party suppliers of antibiotic APIs and biotic APIs and drug products or to external drug products, or of its external waste-treat- waste-treatment plants. The company reports ment plants. no information about setting discharge limits.

C APPROPRIATE ACCESS & Indicators 1 2 3 4 5 6 7 STEWARDSHIP scored on ● ● ● ● ● ● ●

C.1 Filed two newest antibiotics in some C.3 No insight into steps addressing supply C.4-C.7 No apparent involvement in steward- countries in scope. chain efficiency. ship activities. Macleods has provided filing information on two Macleods does not disclose how it works with Macleods does not report any involvement in of its newest antibiotics: isoniazid/rifampicin stakeholders (e.g., governments, procurers) to stewardship activities (from education to sur- and isoniazid/pyrazinamide/rifampicin. These align supply and demand for antimicrobial med- veillance to appropriate promotion practices) two products both target tuberculosis and have icines, specifically to prevent or minimise stock- that promote appropriate antibiotic use. now been filed for registration in 30 countries in outs in countries in scope.* The company also scope,* mainly in sub-Saharan Africa. does not report on whether it has processes in place to respond to stock-outs in countries in C.2 No disclosure on equitable pricing scope.* approach. Macleods does not disclose an equitable pricing approach for its highest-volume antibiotic and/ or antimicrobial medicines. The company states that its approach to affordability is through tenders.

114 Access to Medicine Foundation Melinta Therapeutics, Inc.

Stock exchange: XNAS • Ticker: MLNT • HQ: New Haven, CT, USA • Number of employees: 11-50 • Signatory to Davos Decl.: Yes • Signatory to Industry Roadmap: No

Performance by Research Area How Melinta was evaluated: applicable indicators

Melinta is a biopharmaceutical company, selected for having pany has five projects in its antimicrobial R&D pipeline, four a pipeline that targets priority pathogens. At the end of of which target priority pathogens. Melinta has one antibiotic 2017, Melinta merged with Cempra and, in January 2018, approved by the FDA for the treatment of acute bacterial skin acquired The Medicines Company's infectious disease busi- and skin structure infections (ABSSSI), and has licensed the ness. The company was evaluated in the area of Research & commercialisation and co-development rights of this product Development only. It is a mid-performing company compared to partners in various geographic areas. to the biopharmaceutical companies in scope. The com-

SALES AND OPERATIONS

Melinta is a US-based biopharmaceutical com- lish its preclinical research programme targeting Pharmaceuticals, Inc. and Malin Corporation pany focussing on the development of antibiot- the ‘ESKAPE’ pathogens: E. faecium, S. aureus, plc. At the end of 2017, Melinta merged with ics for infections caused by drug-resistant bac- K. pneumoniae, A. baumannii, P. aeruginosa, and Cempra and announced the acquisition of the teria. The company was founded in 2000 (as Enterobacteriaceae. The company’s only anti- infectious disease business of The Medicines Rib-X Pharmaceuticals), by Yale University fac- microbial medicine on the market, delafloxa- Company, both biopharmaceutical companies in ulty, including a co-winner of the 2009 Nobel cin (Baxdela™), was acquired from Wakunaga scope of the Benchmark. The latter acquisition Prize for Chemistry for studies on the function Pharmaceutical in 2006 and approved by the was completed in January 2018 and included of the ribosome, a cellular structure responsi- FDA for the treatment of ABSSSI in 2017. It is three antimicrobial medicines marketed by The ble for protein synthesis. Based on these studies, available in both intravenous and oral formula- Medicines Company: the recently launched mer- the company’s drug discovery platform allows tions. The latter is expected to offer advantages openem/vaborbactam (Vabomere™) and estab- for atomic-level analysis of interactions between in terms of administration and reduced hospi- lished products oritavancin (Orbactiv®) and min- drug candidates and their bacterial targets at tal admission rates. Recent funding rounds for ocycline (Minocin®). On merging with Cempra, the ribosome, thereby aiding the design of anti- the company have been led by Vatera Holdings Melinta became listed on the NASDAQ stock biotics capable of bypassing resistance mecha- LLC (e.g., USD 67 million in 2015), together exchange with ticker MLNT. nisms. Melinta has used this platform to estab- with Quadrant Capital Advisors, Inc., Arisaph

ANTIMICROBIAL PORTFOLIO

Melinta has one antibiotic on the market, dela- ture infections (ABSSSI) and is available in both floxacin (Baxdela™), currently not included in intravenous and oral formulations. The oral for- the WHO EML (Section 6). Delafloxacin was mulation is expected to offer advantages in approved by the US FDA in June 2017 for the terms of ease of administration and reduced treatment of acute bacterial skin and skin struc- hospital admission rates.

OPPORTUNITIES

Develop access and stewardship plans for prod- Melinta has signed licensing agreements to help now has a total of three antibiotic candidates in ucts on the market. Regarding products on ensure access to a range of countries in scope.* late-stage clinical development. The company the market, e.g., meropenem/vaborbactam Melinta can develop a strategy for ensuring can ensure access and stewardship provisions (Vabomere™), part of The Medicines Company's appropriate use of the product in all countries. are in place for these candidates, for example, acquisition, Melinta can plan for access and through partnerships. stewardship provisions, e.g., through part- Plan ahead for access and stewardship during nerships. Regarding delafloxacin (Baxdela™), R&D. Melinta merged with Cempra in 2017 and

* Countries in scope are 106 low- and middle-income countries where access to medicine is likely limited. 115 Antimicrobial Resistance Benchmark 2018

PERFORMANCE BY RESEARCH AREA

A RESEARCH & DEVELOPMENT Indicators 1 2.1 2.2 2.3 3 4 Antimicrobial 5 projects scored on ○ ● ● ○ ● ● pipeline 4 target priority pathogens

A.2.1-2.2 Four R&D projects that target a A.3 No public-private partnerships reported. ment with Eurofarma Laboratórios, one of the priority pathogen. Melinta conducts R&D in-house and with pri- largest pharmaceutical companies in Brazil, for Biopharmaceutical companies in scope were vate-sector partners. It does not participate in the development and commercialisation of the selected based on their pipelines that target public-private partnerships, or in partnerships medicine in Brazil and other Latin American priority bacteria. Melinta has five projects in with non-profit organisations, for antimicro- countries where Eurofarma operates. For this its antimicrobial R&D pipeline, four of which bial R&D. indicator, countries in scope are 106 low- and target priority bacteria. Its antibiotic, delaflox- middle-income countries where access to medi- acin (Baxdela™), is a fluoroquinolone targeting A.4 Access provision in place, but no infor- cine is likely limited. Regarding stewardship pro- both gram-negative and gram-positive bacteria mation regarding stewardship. visions, Melinta signed the Davos Declaration, (including methicillin-resistant S. aureus), many Melinta reports that it has an access provision which includes a general commitment to support of which are resistant to other quinolones. The in place for its recently approved antibiotic, but the appropriate and responsible use of antimi- compound was approved by the FDA in 2017 for reports no information on stewardship provi- crobial medicines and vaccines. the treatment of ABSSSI, in both oral and intra- sions. In 2017, Melinta licensed the commer- venous formulations. It is currently in Phase III cialisation and co-development rights of dela- clinical trials for community-acquired bacterial floxacin (Baxdela™) to the Menarini Group in pneumonia. Additionally, Melinta has two preclin- 68 countries in Europe, Asia-Pacific, and the ical R&D projects for the development of new Commonwealth of Independent States (CIS). drug classes (such as pyrrolocytosines) through Additionally, Melinta and Malin Corporation plc its ESKAPE pathogen programme, and one mac- entered into an agreement for the commer- rolide discovery programme. cialisation and distribution of the drug in certain countries in the Middle East and Africa. The company has also entered into a similar agree-

Pipeline targeting priority pathogens

Discovery Preclinical Phase I Phase II Phase III Approval

• ESKAPE patho- • Delafloxa- • Delafloxacin gen programme cin (Baxdela™) (Baxdela™) – – GNB & GPB – – Adaptation ESBL, P. aerugi- pyrrolocytosines (new indication) nosa, S. aureus, • Macrolide pro- – CABP S. pneumoniae gramme – GNB – ABSSSI – FDA approval 2017

ABSSSI = Acute bacterial skin and skin structure infections CABP = Community-acquired bacterial pneumonia GNB = Gram-negative bacteria GPB = Gram-positive bacteria

B MANUFACTURING & PRODUCTION

Melinta is a biopharmaceutical company that did not meet the criteria for evaluation in this Research Area. It does, however, have products on the market.

C APPROPRIATE ACCESS & STEWARDSHIP

Melinta is a biopharmaceutical company that did not meet the criteria for evaluation in this Research Area. It does, however, have products on the market.

116 Access to Medicine Foundation Merck & Co., Inc.

Stock exchange: XNYS • Ticker: MRK • HQ: Kenilworth, NJ, US • Employees: 68,000 • Signatory to Davos Decl.: Yes • Signatory to Industry Roadmap: Yes

Performance by Research Area How Merck & Co., Inc. was evaluated: applicable indicators

Merck & Co., Inc. is active in many important areas related to APIs and drug products. The company reports no information AMR, reflected in its good performance in certain areas of about setting discharge limits. Regarding access, Merck & Co., the Benchmark. Due to a lack of publicly available information Inc. has not publicly disclosed where it has filed its newest and engagement with the Benchmark, it performs less well antibiotics for registration. It has, however, publicly commit- in areas evaluating depth of engagement in AMR. The com- ted to engaging in equitable pricing for some antimicrobials. pany has a relatively small antimicrobial R&D pipeline: 16 pro- Regarding stewardship, the company reports that it engages jects of which nine target priority pathogens, including two in several AMR educational activities aimed at healthcare pro- new vaccine candidates. The company discloses an environ- fessionals. It has also established a long-running AMR surveil- mental risk-management strategy that reportedly also applies lance programme. to all Merck & Co., Inc.’s third-party suppliers of antibiotic

SALES AND OPERATIONS RevenuesMerck & Co., by Inc.product § RevenuesMade: by region§ Final: no

Merck & Co., Inc. (known as MSD outside of the specialising in the development and supply of . . . US and Canada) is a large research-based phar- antibiotics to treat infections arising in acute .II . maceutical company with three business seg- care settings, frequently caused by drug-resist- . . ments: pharmaceuticals, vaccines and animal ant bacteria. At the end of 2016, Merck & Co., bn USD bn USD health. The company sells its products in more Inc. and Sanofi Pasteur ended their vaccines . than 140 countries worldwide. Its core thera- joint venture in Europe (Sanofi Pasteur MSD, peutic areas include infectious diseases and vac- established 1994) to independently manage ● Vaccines & ● USA antimicrobials ● Europe, Middle East, Africa cines. In 2015, Merck & Co., Inc. acquired Cubist their product portfolios. ● Other human ● Asia Paci c, Japan Pharmaceuticals for USD 9.5 billion, a company pharmaceuticals ● Rest of World ● Other revenue (inc. Animal Health)

ANTIMICROBIAL PORTFOLIO Antimicrobial portfolio breakdown

According to publicly available data, Merck & The company also markets an antibody, bezlo- Co., Inc. markets at least 19 antimicrobial medi- toxumab (Zinplava®), indicated, in conjunction cines, nine of which are listed on the WHO EML with antibacterial therapy, to reduce recurrence (Section 6). Nine of the company’s antimicrobials of of C. difficile infections. The company’s vac- are antibiotics, with four listed on the WHO EML cines portfolio includes both traditional child- (Section 6), including two in the EML’s Reserve hood immunisations (such as a measles, mumps group: daptomycin (Cubicin®) and ceftolozane/ and rubella combination vaccine) and newer tazobactam (Zerbaxa®). Out of the remain- additions, such as Gardasil®/ Gardasil®9 for use ● Antibiotics on WHO EML† WHO EML Categories ing ten medicines, seven are antivirals used for against certain strains of human papillomavirus ● Antibiotics not on ● Access group only ® treating HIV/AIDS or hepatitis C, two are antifun- (HPV), and RotaTeq for use against rotavirus. WHO EML† ● Access & Watch groups gals, and one is an anthelminthic. ● Other antimicrobial ● Watch group only medicines ● Reserve group ● Not grouped

* Countries in scope are 106 low- and middle-income countries where access to medicine is likely limited † EML Section 6: Anti-Infective Medicines § FYE 31 December 2016 || For 16 top-selling products

117 Antimicrobial Resistance Benchmark 2018

OPPORTUNITIES

Plan ahead for access and stewardship during its own and third-party manufacturing sites. Expand on stewardship activities. Merck & Co., R&D. Merck & Co., Inc. discloses no information Inc. engages in educational activities for health- regarding access and stewardship provisions for Improve access through the registration and care professionals on AMR globally. It also devel- its candidates. Merck & Co., Inc. can develop and affordability of new and existing antimicrobi- oped the SMART surveillance programme, which implement access and stewardship plans for all als. Merck & Co., Inc. discloses information on has been measuring resistance trends globally its candidates in late-stage clinical development. its registration approach for six antimicrobials, since 2002. The company can collaborate with including antimicrobial medicines and vaccines. public health authorities, and can ensure that Expand environmental risk-management strat- It can seek opportunities to ensure greater the data is made publicly available via an open egy. Merck & Co., Inc. can ensure that it sets and access in more low- and middle-income coun- database. Merck & Co., Inc. can also engage in applies discharge limits for antibiotic manufac- tries through the registration of new and exist- improving appropriate promotion practices. turing. The company publishes its environmental ing antimicrobials, and ensure that these are risk-management policies that it applies to both priced affordably.

PERFORMANCE BY RESEARCH AREA

A RESEARCH & DEVELOPMENT Indicators 1 2.1 2.2 2.3 3 4 Antimicrobial 16 projects scored on ● ● ● ● ● ● pipeline 9 target priority pathogens

A.1 No information on antimicrobial R&D the adaptation of the existing medicines ceftolo- the company collaborates with the University investments. zane/tazobactam (Zerbaxa™) and tedizolid of Granada and the regional government of Merck & Co., Inc. reports no information on its (Sivextro®) for Hospital-Acquired and Ventilator- Andalusia, Spain, in a research alliance called antimicrobial R&D investments. Associated Bacterial Pneumonia (HABP/VABP). Medina Discovery, which focuses on the screen- Its clinical-stage projects consist of a next-gen- ing and validation of drug targets for infectious A.2.1-2.3 Nine candidates targeting priority eration HIV/AIDS medicine, a ß-lactamase inhib- diseases. Merck & Co., Inc. also collaborates with pathogens. itor targeting gram-negative bacteria, and a vac- Rutgers University, USA, for the discovery of Merck & Co., Inc. does not publicly report infor- cine against S. pneumoniae. novel antimicrobial medicines, with funding from mation on candidates in Phase I development. the National Institutes of Health (NIH). According to publicly available information, the A.3 Some preclinical R&D projects being company has 16 antimicrobial R&D projects in its developed with public partners. A.4 Access and stewardship commitment in pipeline, including ten projects in clinical-stage Merck & Co., Inc. is developing three preclini- place. development. Nine of the company’s projects cal R&D projects in its priority pathogen pipe- Merck & Co., Inc. has a Global AMR Action Plan target priority pathogens. Although its priority line through public-private partnerships (includ- which describes the company’s commitment pathogen pipeline is relatively small compared ing non-profit organisations). It is developing to support access and stewardship for its novel to other large research-based pharmaceutical a vaccine for shigellosis through its joint ven- antimicrobials portfolio. It has signed the Davos companies assessed by the Benchmark, eight ture with the Wellcome Trust called Hilleman Declaration, which includes a general commit- of the nine projects that target priority patho- Laboratories. Hilleman Laboratories focuses on ment to ensuring access to antimicrobial medi- gens are focused on multidrug-resistant bacteria developing affordable vaccines and addressing cines and vaccines, and to support the appropri- (the remaining project targets HIV). This includes R&D gaps for low-resource settings. In addition, ate and responsible use of these products.

Pipeline targeting priority pathogens

Discovery Preclinical Phase I Phase II Phase III Approval

• Discovery programmes through ▶ Shigella vaccine ▶ S. pneumoniae • Cilastatin/imi- Medina Discovery – GNB, P. falci- conjugate vac- penem/relebac- parum, M. tuberculosis cine V114 tam (MK7655A) • Partnership with Orchid Pharma, – P. aeruginosa, India – Bacteria & fungi CRE – cIAI, cUTI, • Partnership with Rutgers University – HABP/VABP Bacteria • Ceftolozane/ tazobactam (Zerbaxa™) – GNB – Adapta- tion (Additional indication) – HABP/VABP • Tedizolid phos- phate (Sivex- tro®) – GPB ▶ Vaccine cIAI = Complicated intra-abdominal infections – Adaptation cUTI = Complicated urinary tract infections (Additional indi- FDC = Fixed dose combination cation) – HABP/ GNB = Gram-negative bacteria VABP GPB = Gram-positive bacteria HABP/VABP = Hospital-acquired/Ventilator-associated bacterial • Doravirine pneumonia (MK1439) – HIV

118 Access to Medicine Foundation

B MANUFACTURING & PRODUCTION Indicators 1 2 3 scored on ● ● ●

B.1 Environmental risk management at own B.2 Limited transparency regarding environ- B.3 Commits to following GMP, including at and external sites. mental risk management. 3rd-party sites. Merck & Co., Inc. has an environmental risk-man- Merck & Co., Inc. publishes elements of its envi- Merck & Co., Inc. reports that it has mechanisms agement strategy to minimise the impact of ronmental risk-management strategy on its for maintaining a high quality of antibiotic pro- antibiotic manufacturing discharge. The strategy website. It does not disclose audit results, or the duction — namely following GMP standards. This applies to its own manufacturing sites and to discharge levels of antibiotics. The company also commitment applies to its own manufacturing third-party manufacturers of antibiotic APIs and does not share the identities of its third-party sites. Merck & Co., Inc. requires its third-party drug products. The company commits to audit- suppliers of antibiotic APIs and drug products or suppliers of drug products to apply the same ing the implementation of this strategy at both external waste-treatment plants. quality standards to their production facilities. types of site. There is no evidence of the strategy being applicable to external waste-treatment plants. The company reports no information about setting discharge limits.

C APPROPRIATE ACCESS & Indicators 1 2 3 4 5 6 7 STEWARDSHIP scored on ● ● ● ● ● ● ●

C.1 Some newest antibiotics filed in some tries in scope. tices in its marketing materials or decoupling its countries in scope. sales force’s incentives from volume of antibi- Merck & Co., Inc. has filed some of its newest C.4 Multiple activities in AMR-related educa- otic sales. antibiotics, cilastatin/imipenem (Primaxin®) and tional programmes. ertapenem (Invanz®), for registration in some Merck & Co., Inc. is involved in educational pro- C.7 International programme for AMR countries in scope.* However, further details are grammes for HCPs that include AMR steward- surveillance. not publicly available. ship and rational use of antibiotics, with con- Merck & Co., Inc. runs a global surveillance pro- flicts of interest (COI) mitigation measures in gramme focused on AMR trends, namely the C.2 Makes general commitment to equitable place. Programmes include its recently launched “Study for Monitoring Antimicrobial Resistance pricing. knowledge platform that provides direct links Trends” (SMART), which has a global scope Merck & Co., Inc. discloses a general (not prod- to high-quality information and educational and has been measuring resistance trends in uct-specific) inter- and intra-country equitable resources on AMR. The company also reports intra-abdominal samples since 2002. The data pricing approach covering countries in scope.* working with relevant stakeholders (e.g., CDC has been published in several peer- reviewed and a Colombian public health institute) to publications over the years. The company also C.3 Some insight into approach to supply develop stewardship guidelines and programme publicly commits to providing updated data by chain efficiency. metrics and support antimicrobial stewardship country and region. The company also engages Merck & Co., Inc. does not disclose how it works programmes in hospitals. in two other AMR-related surveillance pro- with stakeholders (e.g., governments, procur- grammes, the Program to Assess Ceftolozane- ers) to align supply and demand for its high- C.5-C.6 No information regarding brochure Tazobactam Susceptibility (PACTS) and est-volume antimicrobial medicines, specifi- and/or packaging adaptations, or Surveillance of Tedizolid Activity and Resistance cally to prevent or minimise stock-outs in coun- appropriate promotion practices. (STAR). tries in scope.* It does, however, publish a set Merck & Co., Inc. does not report any language, of Supply Chain Standards, including the capac- cultural or literacy adaptations made to its bro- ity to respond to changing demand. The com- chures or packaging that would promote appro- pany also does not report on whether it has pro- priate use. Furthermore, the company does cesses in place to respond to stock-outs in coun- not report any appropriate promotion prac-

ANIMAL HEALTH & DIAGNOSTICS

Activities in this area are not scored by the develop alternatives to antibiotics for animal and feed companies with guidelines on resist- Benchmark. This information is provided given use and to facilitate the appropriate use of anti- ance management, appropriate dosage, and the importance of animal health and diagnostics biotics in animals. Merck & Co., Inc. runs a sur- length of usage to support the appropriate use on the topic of AMR. veillance programme that monitors the emer- of antibiotics. gence of bacterial resistance to Merck & Co., Inc. Merck & Co., Inc. is the only company in scope Animal Health antibiotics. Additionally, the com- that is involved in antibiotics for use in animal pany reports that it provides veterinarians, com- health. The company conducts research to mercial production operations, farmers, ranchers

119 Antimicrobial Resistance Benchmark 2018 MGB Biopharma

Stock exchange: Privately held • Ticker: - • HQ: Bellshill, Scotland, UK • Employees: 2-10 • Signatory to Davos Decl.: Yes • Signatory to Industry Roadmap: No

Performance by Research Area How MGB Biopharma was evaluated: applicable indicators

Indicator reference Due to the variation 1 2.1 2.2 2.3 3 4 between companies R&D R&D A ○ ● ● ○ ● ○ in scope, not all indi- 1 2 3 cators are applica- M&P M&P B ○ ○ ○ ble to every company. 1 2 3 4 5 6 7 See Appendix for full AA&S AA&S C ○ ○ ○ ○ ○ ○ ○ overview. ● Remaining potential score ● Applicable indicator ○ Not applicable PERFORMANCE

MGB Biopharma is a biopharmaceutical company, selected in its antimicrobial R&D pipeline, all targeting priority patho- for having a pipeline that targets priority pathogens. It was gens, including one novel antibiotic candidate. The company evaluated in the area of Research & Development only. The engages in numerous public-private partnerships and agree- company performs well compared to other biopharmaceu- ments with various organisations to develop its antibiotic tical companies in scope. MGB Biopharma has four projects candidates.

OPERATIONS

MGB Biopharma, founded in 2010, is a biop- didate, MGB-BP-3, is active against gram-posi- of the company in the development of its MGB harmaceutical company focussing on a new tive bacteria and has recently completed a Phase pipeline. MGB Biopharma has no products on the class of anti-infectives, the DNA Minor Groove I clinical safety study in the oral treatment of C. market. In 2017, the company closed a USD 1 mil- Binders (MGBs), which interact with microbial difficile infection. The compound is an analogue lion financing round to fund the development cell DNA and interfere with its replication. MGBs of the naturally occurring antibiotic (and anti- and production of MGB-BP-3 for a Phase II clin- were originally developed at the University of viral) distamycin. MGB Biopharma has plans to ical study in C. difficile infection. The financing Strathclyde in Glasgow, which licensed the tech- extend the therapeutic indications of this com- round was led by Archangel Investors Limited nology to MGB Biopharma, granting the compound and is currently developing MGBs that are and included contributions from TRI Capital Ltd, pany exclusive global rights in all fields except active against viruses, fungi and parasites. The Barwell plc and Scottish Investment Bank. cancer. The company’s most advanced drug can- University of Strathclyde remains a close partner

ANTIMICROBIAL PORTFOLIO

MGB Biopharma does not have any products on the market.

OPPORTUNITIES

Plan ahead for access and stewardship during R&D. MGB Biopharma has one antibiotic candidate (MGB-BP-3) in clinical development, currently in Phase I. MGB Biopharma is encouraged to implement access and stewardship plans for this candidate as it moves into Phase II clinical development.

120 Access to Medicine Foundation

PERFORMANCE BY RESEARCH AREA

A RESEARCH & DEVELOPMENT Indicators 1 2.1 2.2 2.3 3 4 Antimicrobial 4 projects scored on ○ ● ● ○ ● ○ pipeline 4 target priority pathogens

A.2.1-2.2 One novel antibiotic in the clinical also active against other gram-positive bacteria, A.4 No R&D candidates in late-stage pipeline. such as methicillin-resistant S. aureus (MRSA), development. Biopharmaceutical companies in scope were vancomycin-resistant Enterococcus (VRE) and MGB Biopharma is not eligible for this indicator selected based on their pipelines that target pri- Streptococci. The company is also developing as it does not have any R&D candidates in late- ority bacteria. MGB Biopharma has four pro- intravenous and topical formulations of the com- stage development. jects in its antimicrobial R&D pipeline, all target- pound in preclinical stages, and has discovery ing priority pathogens. MGB Biopharma is cur- platforms for gram-negative bacteria and fungi. rently developing its MGB-BP-3 antibiotic for the treatment of C. difficile infections. MGB-BP-3’s A.3 All R&D projects being developed with antimicrobial activity is based on a new mode of public partner. action, namely its activity as a DNA Minor Groove MGB Biopharma is developing all three R&D pro- Binder (MGB). Despite being in development for jects in its priority pathogen pipeline in collabo- treatment of C. difficile infections, MGB-BP-3 is ration with the University of Strathclyde.

Pipeline targeting priority pathogens

Discovery Preclinical Phase I Phase II Phase III Approval

• Gram-negative platform – GNB • MGB-BP-3 – S. • MGB-BP-3 – C. • Antifungal platform – Candida aureus, S. pneu- difficile – DNA moniae – Adap- Minor Groove tation (addi- Binder – Novel tional indication) – GPB infections

GNB = Gram-negative bacteria GPB = Gram-positive bacteria

B MANUFACTURING & PRODUCTION

As a biopharmaceutical company with no products on the market, MGB Biopharma was not eligible for this Research Area.

C APPROPRIATE ACCESS & STEWARDSHIP

As a biopharmaceutical company with no products on the market, MGB Biopharma was not eligible for this Research Area.

121 Antimicrobial Resistance Benchmark 2018 Motif Bio plc

Stock exchanges: XLON; XNAS • Ticker: MTFB • HQ: London, United Kingdom • Employees: 7 • Signatory to Davos Decl.: Yes • Signatory to Industry Roadmap: No Performance by Research Area How Motif Bio was evaluated: applicable indicators

Motif Bio is a biopharmaceutical company, selected for having During the period of analysis, the company did not engage a pipeline that targets priority pathogens. It was evaluated in in public-private partnerships but conducted R&D in-house the area of Research & Development only. Motif Bio invested and/or with private-sector partners to develop its candidate USD 35 million in antibiotic drug development in 2016. Its per- compounds. Motif Bio has one R&D project in late-stage clin- formance in the Benchmark is low compared with other bio- ical development, and reports that it has both an access and pharmaceutical companies in scope. It has two projects in its stewardship commitment in place for this candidate. antimicrobial R&D pipeline, both targeting priority pathogens.

OPERATIONS

Motif Bio is a biopharmaceutical company in 2015 following the merger of the two compa- ronments in Europe regarding R&D, approval which specialises in developing novel antibiot- nies. In 2017, it was granted ‘orphan drug’ status and market viability of products combating anti- ics against infections caused by multidrug-re- by the FDA (for developing a drug or biologi- microbial resistance. Motif Bio has no products sistant bacteria. The company’s most advanced cal product to treat a rare disease or condition) on the market. In 2016, the company raised USD antibiotic drug candidate, iclaprim, is active for treating S. aureus lung infections in patients 25 million from UK and US investors though a against gram-positive bacteria. It is currently with cystic fibrosis. The company aims to collab- NASDAQ IPO. being developed for the treatment of acute orate with universities and other pharmaceuti- bacterial skin and skin structure infections and cal companies to expand its pipeline of antibi- hospital-acquired pneumonia, including infec- otics against gram-positive and gram-negative tions caused by methicillin-resistant S. aureus bacteria. Motif Bio is a member of the BEAM alli- (MRSA) and multidrug-resistant S. pneumoniae. ance, a group of biopharmaceutical companies The compound was acquired from Nuprim Inc. addressing the regulatory and commercial envi-

ANTIMICROBIAL PORTFOLIO

Motif Bio does not have any products on the market.

OPPORTUNITIES

Plan ahead for access and stewardship during R&D. Motif Bio has stated a commitment to ensure access and stewardship provisions are in place for its antibiotic candidate (iclaprim) in late-stage clinical development. It can ensure that these provisions are applied and implemented accordingly.

122 Access to Medicine Foundation

PERFORMANCE BY RESEARCH AREA

A RESEARCH & DEVELOPMENT Indicators 1 2.1 2.2 2.3 3 4 Antimicrobial 2 projects scored on ○ ● ● ○ ● ● pipeline 2 target priority pathogens

A.2.1-2.2 Two candidates targeting priority lin-resistant S. aureus (MRSA). Iclaprim is cur- strains of Burkholderia, Stenotrophomonas and pathogens. rently in Phase III clinical development and is Achromobacter, in partnership with the Cystic Biopharmaceutical companies in scope were being developed for acute bacterial skin and skin Fibrosis Foundation. selected based on their pipelines that target pri- structure infections (ABSSSI) and hospital-ac- ority bacteria. Motif Bio invested USD 35 mil- quired bacterial pneumonia (HABP). Motif Bio is A.4 Access and stewardship commitments lion in antibiotic drug development in 2016. The also developing another antibiotic in the preclini- for iclaprim. company has two projects in its antimicrobial cal stage, targeting MRSA. Motif Bio reports that it has both an access and R&D pipeline targeting priority pathogens, both a stewardship commitment in place for its anti- in development for the treatment of gram-pos- A.3 No public-private partnerships reported biotic candidate in late-stage development. The itive bacterial infections. The company’s most during the period of analysis. company commits to filing iclaprim for registra- advanced antibiotic candidate is iclaprim, an anti- Motif Bio conducts R&D in-house and/or with tion based on public health needs and disease biotic designed to be effective against bacteria private-sector partners. During the period of prevalence. It also commits to ensuring access to that are resistant to other antibiotics, including analysis, it did not participate in public-private its product in low- and middle-income countries, trimethoprim, a commonly used antibiotic with partnerships, or in partnerships with non-profit with pricing strategies that take affordability into the same mechanism of action. Iclaprim is an organisations, for antimicrobial R&D. After the account. For this indicator, countries in scope antibiotic of the dihydrofolate reductase (DHFR) period of analysis, the company announced in are 106 low- and middle-income countries where inhibitor class that is active against methicil- vitro testing of iclaprim’s activity against various access to medicine is likely limited.

Pipeline targeting priority pathogens

Discovery Preclinical Phase I Phase II Phase III Approval

• MTF101 – GPB • Iclaprim – S. aureus, S. pneumoniae – Dihy- drofolate reductase inhibitor – ABSSSI, HABP/ VABP*

ABSSSI = Acute bacterial skin and skin structure infections GPB = Gram-positive bacteria HABP/VABP = Hospital-acquired/Ventilator-associated bacterial pneumonia * After the period of analysis, Motif Bio stated that Phase III trials for iclaprim in patients with HABP/VABP have started

B MANUFACTURING & PRODUCTION

As a biopharmaceutical company with no products on the market, Motif Bio was not eligible for this Research Area.

C APPROPRIATE ACCESS & STEWARDSHIP

As a biopharmaceutical company with no products on the market, Motif Bio was not eligible for this Research Area.

123 Antimicrobial Resistance Benchmark 2018 Mylan NV Signatory to Davos Decl.: Yes Stock exchange: XNAS • Ticker: MYL • HQ: Canonsburg, PA, US • Number of employees: > 35,000 Signatory to Industry Roadmap: No

Performance by Research Area How Mylan was evaluated: applicable indicators

Mylan is one of the largest producers of antibiotics globally by the same quality standards to their production facilities. The sales volume. As a generic medicine manufacturer, Mylan was company reports no information on where it files products evaluated in Manufacturing & Production and Appropriate for registration; however, it discloses a general intra-coun- Access & Stewardship only. It has the highest performance try equitable pricing approach. The company also engages in among generic medicine manufacturers in scope. The com- stakeholder engagement to ensure efficient supply. Regarding pany discloses an environmental risk-management strategy stewardship, Mylan adapts its packaging with symbols and that is applied to its own manufacturing sites. Mylan reports pictograms illustrating the necessary antibiotic dosage sched- mechanisms for maintaining a high quality of antibiotic pro- ule for patients. duction and also requires its third-party suppliers to apply

SALES AND OPERATIONS RevenuesMylan by product§ RevenuesMade: by regionII Final: no

Mylan, founded in 1961, is a US-based global pro- (UNAIDS), the Clinton Health Access Initiative vider of generic and specialty pharmaceuticals. and the Bill & Melinda Gates Foundation (BMGF), . The company produces and markets innova- among others. Under the agreement, the com- . . . tive and generic medicines, active pharmaceuti- pany will supply a generic fixed dose combina- bn USD bn USD cal ingredients and consumer healthcare prod- tion of dolutegravir/lamivudine/tenofovir diso- ucts in approximately 165 countries and territo- proxil fumarate (developed as part of a licens- ries worldwide. The company's key therapeutic ing agreement with Gilead Sciences Inc. and ● Total revenue ● North America areas include cardiovascular, CNS and anaes- ViiV Healthcare) for a maximum price of about ● Europe thesia, infectious disease, immunology, res- USD 75 per patient per year. In return, the BMGF ● Rest of World piratory and allergy, dermatology and oncol- will guarantee minimum sales volumes of the ogy. In 2017, Mylan announced a multilateral drug. Since 2015, Mylan has made several large agreement to provide a new class of antiretro- acquisitions, including those of Meda, Abbott's virals (ARVs) to low- and middle-income coun- non-US developed markets specialty and tries. This agreement includes the South African branded generics business and the non-sterile, government, the Kenyan government, the topicals-focused specialty and generics business Joint United Nations Programme on HIV/AIDS of Renaissance Acquisition Holdings.

ANTIMICROBIAL PORTFOLIO Antimicrobial portfolio breakdown

Mylan markets at least 49 antimicrobial medi- The remainder (28) of the company’s portfo- cines, 38 of which are listed on the WHO EML lio comprises two antifungals and 26 antivirals, (Section 6). Twenty-one of the company’s anti- including 22 indicated for HIV/AIDS, the largest microbial medicines are antibiotics, with 19 listed anti-HIV portfolio in the Benchmark. on the WHO EML (Section 6), including one on the EML’s Reserve group (linezolid).

● Antibiotics on WHO EML† WHO EML Categories * Countries in scope are 106 low- and middle-income ● Antibiotics not on ● Access group only countries where access to medicine is likely limited WHO EML† ● Access & Watch groups † EML Section 6: Anti-Infective Medicines ● Other antimicrobial ● Watch group only § Net sales and other revenues from third-parties; FYE 31 medicines ● Reserve group December 2016 ● Not grouped || Third-party net sales; FYE 31 December 2016

124 Access to Medicine Foundation

OPPORTUNITIES

Expand engagement in antimicrobial steward- Expand environmental risk-management strat- cally for its antiretrovirals. It can seek to improve ship. Mylan adapts its packaging with symbols egy. Mylan can ensure antibiotic discharge limits access in low- and middle-income countries and pictograms illustrating the necessary dosage are added to its environmental risk-manage- through registration of new and existing anti- schedule for patients. It can expand this prac- ment strategy. It can also extend this strategy microbials, and ensure that more products are tice to more countries in scope* and take further to the sites of third parties who manufacture priced affordably. language and literacy needs into consideration. antibiotic APIs on its behalf, as well as to exter- Mylan can engage in more stewardship activi- nal waste-treatment sites. Mylan has a general Increase engagement in R&D innovation. Mylan ties, e.g., through surveillance activities, educa- environmental risk-management strategy that it is currently engaged in developing new fixed tional activities for healthcare professionals on applies to its own manufacturing sites. dose combinations of antiretroviral medicines. It AMR (while mitigating conflict of interest), and can continue to engage in incremental R&D, and engage in appropriate promotion practices. Ensure affordability and registration plans for ensure access and stewardship provisions are in new and existing antimicrobials. Mylan dis- place for these projects. closed its approach to equitable pricing specifi-

PERFORMANCE BY RESEARCH AREA

A RESEARCH & DEVELOPMENT

As a generic medicine manufacturer, Mylan was the Fixed Dose Combination (FDC) efavirenz/ antiretrovirals from Gilead Sciences Inc., Bristol- not eligible for this research area. However, the lamivudine/tenofovir disoproxil fumarate, which Myers Squibb Co. and ViiV Healthcare. Mylan company is active in antimicrobial R&D. has been shown to be non-inferior while con- commits to pricing these generics affordably. In taining a reduced drug dose, and can be sold at particular, Mylan has announced a new agree- Two new fixed dose combinations for HIV/AIDS. a lower price. The other project involves dolute- ment with UNAIDS and other partners to make Mylan reports that it has two projects in its anti- gravir/lamivudine/tenofovir disoproxil fumarate, the dolutegravir/lamivudine/tenofovir disoproxil microbial R&D pipeline targeting a priority path- a new FDC for the treatment of HIV/AIDS. In fumarate combination available to public sector ogen, namely HIV. One project involves a dose 2017, Mylan received FDA tentative approval for purchasers in low- and middle-income countries reduction to efavirenz (600 mg to 400 mg), in both of these FDCs, as they consist of patented at around USD 75 per person, per year.

Pipeline targeting priority pathogens

Discovery Preclinical Phase I Phase II Phase III Approval

• Efavirenz/lamivudine/tenofovir disoproxil fumarate – HIV – Adaptation (new FDC with reduced dose: 400 mg efavirenz instead of 600 mg in the existing FDC) – FDA tentative approval 2017* • Dolutegravir/ lamivudine/ tenofovir disoproxil fumarate – HIV – Adapta- tion (new FDC) – FDA tentative approval 2017

125 Antimicrobial Resistance Benchmark 2018

B MANUFACTURING & PRODUCTION Indicators 1 2 3 scored on ● ● ●

B.1 Environmental risk-management B.2 Limited transparency regarding environ- B.3 Commits to following GMP, including at strategy for own sites. mental risk management. 3rd-party sites. Mylan has an environmental risk-management Mylan reports some of its environmen- Mylan reports that it has mechanisms for main- strategy that includes minimising the impact of tal risk-management initiatives in its Global taining a high quality of pharmaceutical pro- antibiotic manufacturing discharge. The strat- Sustainability Report, published on its website. It duction that includes antibiotic production — egy applies to its own sites and includes audit- does not disclose audit results, or the discharge namely following GMP standards. This commit- ing. At a number of sites in India, Mylan fol- levels of antibiotics. The company also does not ment applies to its own manufacturing sites. lows a Zero-Liquid Discharge process (ZLD, a share the identities of its third-party suppliers of Mylan requires its third-party suppliers to apply water treatment process in which all wastewa- antibiotic APIs and drug products, or of external the same quality standards to their production ter is cleaned and reused). The company's envi- waste-treatment plants. facilities. ronmental risk-management strategy has not been extended to Mylan's third-party manufacturers of antibiotic APIs and drug products, or to external waste-treatment plants. The company reports no information about setting discharge limits.

C APPROPRIATE ACCESS & Indicators 1 2 3 4 5 6 7 STEWARDSHIP scored on ● ● ● ● ● ● ●

C.1 No information on filing for registration. C.3 Taking multiple steps to improve supply C.4-C.7 Some involvement in AMR steward- Mylan reports no information on where it has chain efficiency. ship activities. filed its newest antibiotics for registration in Mylan engages with the Global Fund, PEPFAR Mylan adapts its packaging with symbols and countries in scope.* This information is not oth- and the South African government to align pictograms illustrating the necessary dosage erwise publicly available. supply and demand forecasting for five of its schedule for patients. This can help to improve highest-volume antimicrobials. These are all HIV/ patient adherence to treatment. However, it C.2 Intra-country equitable pricing for AIDS medicines. The company also has response does not report of any activities in HCP educa- antimicrobials. mechanisms in place for its HIV/AIDS medicines tion, appropriate promotion practices, or surveil- Mylan discloses a general (not product-spe- in order to respond efficiently in the event of lance programmes. cific) intra-country equitable pricing approach. stock-outs in countries in scope.* These mecha- It reports that this applies to at least its 5 high- nisms are designed to enable Mylan to anticipate est-volume antimicrobial medicines (all HIV/AIDS and respond to competing suppliers’ stock-outs. medicines) in countries in scope.* Under this general approach, the lowest prices are reserved for Global Fund, PAHO and PEPFAR.

126 Access to Medicine Foundation Nabriva Therapeutics plc

Stock exchange: XNAS • Ticker: NBRV • HQ: Dublin, Ireland • Number of employees: 66 • Signatory to Davos Decl.: Yes • Signatory to Industry Roadmap: No

Performance by Research Area How Nabriva was evaluated: applicable indicators

Nabriva is a biopharmaceutical company, selected for having does not provide evidence of engaging in public-private part- a pipeline that targets priority pathogens. It was evaluated nerships and agreements to develop and commercialise its in the area of Research & Development only. Nabriva has candidate compounds. Nabriva has no access or steward- invested USD 48 million in antibiotic drug development in ship provisions in place for its late-stage clinical antimicrobial 2016. The company performs well compared to other biop- candidates. harmaceutical companies in scope. Nabriva’s R&D pipeline consists of five projects, all of which target priority pathogens, including one novel antibiotic candidate. The company

OPERATIONS

Nabriva is a biopharmaceutical company The company then became public in 2015. In addressing the regulatory and commercial envi- engaged in research and development of novel 2017, it relocated its corporate headquarters to ronments in Europe regarding R&D, approval and antibiotics to treat bacterial infections, with Ireland. Nabriva is currently developing lefam- market viability of products combating antimi- a focus on the pleuromutilin class of antibiot- ulin, a semi-synthetic compound that inhib- crobial resistance. Nabriva has no products on ics. Pleuromutilins were discovered in the 1950s its the synthesis of bacterial protein. Lefamulin the market. In 2016, the company had USD 6.5 and have since been used systemically in ani- has recently completed a Phase III trial eval- million worth of revenues from research premi- mals and topically in humans. In 2006, Nabriva uating its safety and efficacy in patients with ums and grants. was incorporated as a spin-off from the Sandoz CABP. Nabriva is a member of the BEAM alli- GmbH Antibiotics Research Institute in Austria. ance, a group of biopharmaceutical companies

ANTIMICROBIAL PORTFOLIO

Nabriva does not have any products on the market.

OPPORTUNITIES

Plan ahead for access and stewardship during R&D. Nabriva is developing one antibiotic candidate (lefamulin) in late-stage clinical development. Nabriva can ensure access and stewardship provisions are in place for lefamulin, e.g., through partnerships.

127 Antimicrobial Resistance Benchmark 2018

PERFORMANCE BY RESEARCH AREA

A RESEARCH & DEVELOPMENT Indicators 1 2.1 2.2 2.3 3 4 Antimicrobial 5 projects scored on ○ ● ● ○ ● ● pipeline 5 target priority pathogens

A.2.1-2.2 Pipeline focused on pleuromutilin and for paediatric use. Lefamulin is seen by A.4 No information on access or stewardship antibiotics. WHO as a new innovative antibiotic, as this is the provisions. Biopharmaceutical companies in scope were first pleuromutilin for systemic use in humans. Nabriva reports no information on access or selected based on their pipelines that target pri- Additionally, Nabriva is developing a pleuromuti- stewardship provisions for its antibiotic candi- ority bacteria. Nabriva invested USD 48 mil- lin in topical form (BC7013) for the treatment of date in late-stage development. It has signed lion in antibiotic drug development in 2016. The uncomplicated skin and skin structure infections the Davos Declaration, which includes a gen- company has five projects in its antimicrobial (uSSSI). The company also owns a pleuromutilin eral commitment to ensuring access to antimi- R&D pipeline, all targeting priority pathogens, discovery platform. crobial medicines and vaccines, and to support including one topical formulation. Currently, the appropriate and responsible use of these Nabriva has one systemic pleuromutilin antibi- A.3 No public-private partnerships reported. products. otic (lefamulin) in Phase III clinical trials to eval- Nabriva conducts R&D in-house and/or with pri- uate the safety and efficacy of intravenous to vate-sector partners. It does not participate in oral lefamulin in patients with CABP. Nabriva public-private partnerships, or in partnerships intends to develop lefamulin for additional indi- with non-profit organisations, for antimicro- cations, including for the treatment of acute bac- bial R&D. terial skin and skin structure infections (ABSSSI)

Pipeline targeting priority pathogens

Discovery Preclinical Phase I Phase II Phase III Approval

• Pleuromutilin molecule platform – • Lefamulin (IV/ • BC7013 – S. • Lefamulin (IV/ • Lefamulin (IV/ GNB & GPB oral) – Adapta- aureus, VRE, oral) – Adapta- oral) – Hib, S. tion (new for- CRE, ESBL, P. tion (additional aureus, S. pneu- mulation) – Pae- aeruginosa – indication) – moniae, VRE – diatrics Pleuromutilin ABSSSI Pleuromutilin – topical formula- CABP – Novel tion

ABSSSI = Acute bacterial skin and skin structure infections CABP = Community-acquired bacterial pneumonia GNP= Gram-negative bacteria GPB = Gram-positive bacteria

B MANUFACTURING & PRODUCTION

As a biopharmaceutical company with no products on the market, Nabriva was not eligible for this Research Area.

C APPROPRIATE ACCESS & STEWARDSHIP

As a biopharmaceutical company with no products on the market, Nabriva was not eligible for this Research Area.

128 Access to Medicine Foundation Novartis AG

Stock exchange: XSWX • Ticker: NOVN • HQ: Basel, Switzerland • Employees: 118,393 • Signatory to Davos Decl.: Yes • Signatory to Industry Roadmap: Yes

Performance by Research Area How Novartis was evaluated: applicable indicators

Indicator reference Due to the variation 1 2.1 2.2 2.3 3 4 between companies R&D R&D A ● ● ● ○ ● ● in scope, not all indi- 1 2 3 cators are applica- M&P M&P B ● ● ● ble to every company. 1 2 3 4 5 6 7 See Appendix for full AA&S . AA&S C ● ● ● ● ● ● ● overview. ● Remaining potential score ● Applicable indicator ○ Not applicable PERFORMANCE

Novartis is among the top performing large research-based its newest antibiotics in some countries in scope* and com- pharmaceutical companies, following close behind the lead- mits to engaging in inter-country equitable pricing for its ers. This is driven by strong performance in Manufacturing & antimicrobials. The company reports that it widely applies Production and Appropriate Access & Stewardship. Its per- intra-country equitable pricing for one product. It also reports formance in Research & Development is on par with the aver- engaging with local healthcare facilities to align supply and age for this group of companies. The company has an antimi- demand. Regarding stewardship, Novartis engages in numer- crobial R&D pipeline of 32** projects, of which 16 target a pri- ous AMR educational activities aimed at healthcare profes- ority pathogen, including two novel antimalarial candidates. sionals, taking steps to mitigate conflict of interest, and is cur- It has an access commitment in place for four of its R&D can- rently adjusting incentives for its sales teams to increase the didates. The company discloses a comprehensive environ- weight of fixed pay in overall compensation and to reduce the mental risk-management strategy, which includes discharge variable component. In contrast to other large research-based limits and reportedly applies to all Novartis’ third-party sup- pharmaceutical companies in scope, Novartis does not report pliers of antibiotic APIs and drug products. Novartis has filed engaging in antibiotic-specific AMR surveillance programmes.

SALES AND OPERATIONS RevenuesNovartis by product§ RevenuesMade: by region§ Final: no

.II Novartis is a large research-based pharmaceu- Sandoz also sells other drug products, pharma- . . tical company with three divisions: Innovative ceutical intermediates and active pharmaceutical . . . Medicines, Alcon (eye-care products) and ingredients (APIs). It sold and/or donated 2,425 . . Sandoz (generic medicines). The Innovative million doses of antimicrobial medicines during bn USD bn USD Medicines division has two business units: phar- the fiscal year 2016. In 2015, Novartis divested . maceuticals (primary care and specialty medi- its vaccine business (excluding influenza vac- . cines) and oncology. The bulk of antimicrobial cines) to GSK in an asset swap that included the ● Antimicrobials ● USA ● Other generics ● Europe medicines in the company's portfolio are mar- acquisition of GSK’s marketed oncology portfo- ● Other branded ● Asia, Africa, Australasia keted by Sandoz. Sandoz markets antimicrobi- lio. The influenza vaccines unit ceased operation medicines ● Rest of World als in about 140 countries globally, of which 71 in 2014 and was finally acquired by CSL Limited ● Alcon or more are low- or middle-income countries.* in 2015 (including its development pipeline).

ANTIMICROBIAL PORTFOLIO Antimicrobial portfolio breakdown

Novartis markets at least 67 antimicrobial med- by its generics division Sandoz. Of 41 antibiotics icines, the second largest reported antimicro- on the market, 36 are listed on the WHO EML bial portfolio among the large research-based (Section 6), including three antibiotics in the pharmaceutical companies assessed by the EML’s Reserve group (cefepime, daptomycin and Benchmark. Sixty of these 67 medicines are linezolid). The remainder (26) of the company’s listed on the WHO EML (Section 6). The bulk of portfolio includes antivirals, antifungals, anti- the company’s antimicrobial medicines are clas- protozoals and anthelminthics, the majority of sical fermentation-derived antibiotics (penicil- which are listed on the WHO EML (Section 6). ● Antibiotics on WHO EML† WHO EML Categories lins, cephalosporins and macrolides), marketed ● Antibiotics not on ● Access group only WHO EML† ● Access & Watch groups ● Other antimicrobial ● Watch group only * Countries in scope are 106 low- and middle-income medicines ● Reserve group countries where access to medicine is likely limited. ● Not grouped † EML Section 6: Anti-Infective Medicines § Net sales; FYE 31 December 2016 || Approximately

129 Antimicrobial Resistance Benchmark 2018

OPPORTUNITIES

Plan ahead for access and stewardship during of antibiotic discharge. Currently, Novartis dis- Engage in more stewardship activities. Novartis R&D. Novartis has a general registration proce- closes several elements of its environmental engages in several stewardship activities. The dure in place for candidates that reach Phase III risk-management strategy. company can engage in antibiotic resistance sur- clinical development, and has specifically stated veillance programmes, collaborate with public a commitment to apply this to its late-stage can- Expand environmental risk-management strat- health authorities and ensure that data is made didates. Novartis can ensure that this proce- egy. Novartis can apply its antibiotic discharge publicly available through open databases. dure is applied, while also implementing further limits to third parties who manufacture antibi- access and stewardship plans for all its candi- otic APIs on its behalf. Novartis has set discharge Expand its SMS for Life programme to more dates in late-stage clinical development. limits for its own manufacturing sites and exter- countries. Novartis can expand its SMS for Life nal waste-treatment plants as part of its envi- (2.0) programme, a public-private partnership Improve transparency regarding environmental ronmental risk-management strategy. between Novartis and local public health facil- risk management. Novartis can share more ities to track medicines stock levels, to more information on how it manages environmen- countries in scope.* The programme is already tal risk, e.g., the company can disclose the levels operating in six African countries.

PERFORMANCE BY RESEARCH AREA

A RESEARCH & DEVELOPMENT Indicators 1 2.1 2.2 2.3 3 4 Antimicrobial 32 projects scored on ● ● ● ○ ● ● pipeline 16 target priority pathogens

A. 1 Average antimicrobial R&D investments. antimalarial medicines (both imidazolopipera- A.4 Access commitment in place, but no Novartis reports investments in antimicrobial zines); LFF571 (an antibiotic targeting C. difficile information regarding stewardship. R&D in 2016, which are average compared to in Phase II development); and LYS228 (an antibi- Novartis reports that it has an access commit- other large research-based pharmaceutical com- otic with activity against carbapenem-resistant ment in place for its four R&D candidates tar- panies in the Benchmark, however the exact Enterobacteriaceae spp. (CRE), currently start- geting priority pathogens in late-stage develop- amount is confidential. These investments cover ing Phase II clinical trials). Additionally, Novartis ment, but reports no information on steward- antimicrobial medicines only, as Novartis is not is awaiting approval for the inclusion of tuber- ship provisions. In the 2016 Access to Medicine involved in vaccine development. culosis as an additional indication for its leprosy Index, Novartis was a leader in registering prod- medicine, clofazimine (Lamprene®). ucts in countries in scope.* The company com- A.2.1-2.2 Pipeline focused on gram-negative mits to applying the same strategy to its late- bacteria and malaria. A.3 Six R&D projects being developed with stage investigational candidates. For exam- Novartis has 32** antimicrobial R&D projects in public partners, including two PDPs. ple, the PDP funding agreements for its anti- its pipeline, seven of which are in clinical stage Novartis is developing six R&D projects in its malarial candidates include clauses to ensure development. Sixteen of the company’s projects priority pathogen pipeline through public-pri- broad access. Regarding stewardship provisions, target priority pathogens. It has an average-sized vate partnership (including non-profit organisa- Novartis signed the Davos Declaration, which pipeline compared to other large research- tions). Two antimalarial candidates, cipargamin includes a general commitment to support the based pharmaceutical companies assessed and KAF156/lumefantrine, are being developed appropriate and responsible use of antimicro- by the Benchmark. The company has a strong through PDPs with the Medicines for Malaria bial medicines and vaccines. After the period of focus on malaria and bacteria, mostly gram-neg- Venture (MMV). Development of KAF156/lume- analysis, Novartis stated its practice of initiat- ative. It has nine drug candidates in preclini- fantrine is co-funded by the Bill & Melinda Gates ing global surveillance for potential resistance to cal development (eight of which target bacte- Foundation and development of cipargamin is its novel antimicrobial agents a minimum of four ria), and four drug candidates in clinical develop- co-funded by the Wellcome Trust. The other years prior to expected launch (in line with FDA ment. Novartis’ clinical pipeline consists of four four projects are in preclinical stage and involve recommendations). investigational medicines including: two novel public research institutes.

Pipeline targeting priority pathogens

Discovery Preclinical Phase I Phase II Phase III Approval

• Inhibitors/modulators of bacterial • JA-43-AO00 – • LYS228 ‡ – GNB • LFF571 – C. dif- • Clofazimine outer membrane biogenesis – GNB GNB & GPB ficile, S. aureus, (LAM320) – • Bacterial cell wall inhibitors – GNB • EE-67-VB84 – P. VRE M. tuberculo- • Inhibitors/modulators of bacterial aeruginosa • KAF156/lume- sis – Adaptation cell envelope biogenesis and func- • FB-11-AR48 – fantrine – P. fal- (additional indi- tion – GNB GNB & GPB ciparum – Novel cation) – Await- • Phenotypic screening of natural • Cipargamin • Cipargamin ing approval products – GNB (KAE609) – (KAE609) – P. • Discovery of new combinations of P. falciparum falciparum – existing and new chemical entities – Adaptation Novel – GNB (new formula- • Uncomplicated malaria – P. falci- tion: intrave- parum nous) • Confidential GNB = Gram-negative bacteria project – GNB GPB = Gram-positive bacteria ** After the period of analysis, Novartis submitted an – Adaptation ‡ This candidate moved to Phase II clinical adaptive project of tobramycin for the treatment of development after the period of analysis. (new formula- bronchiectasis-related Pseudomonas, including the tion) assessment of resistance. 130 Access to Medicine Foundation

B MANUFACTURING & PRODUCTION Indicators 1 2 3 scored on ● ● ●

B.1 Comprehensive environmental risk-man- B.2 Limited transparency regarding environ- B.3 Commits to following GMP, including at agement strategy. mental risk management. 3rd-party sites. Novartis undertakes almost all environmental Novartis publishes elements of its environmen- Novartis reports that it has mechanisms for risk-management activities that the Benchmark tal risk-management strategy on its website. It maintaining a high quality of antibiotic produc- examines. Namely, it applies an environmen- does not disclose audit results, or the discharge tion — namely following GMP standards. This tal risk-management strategy to minimise the levels of antibiotics. The company also does not commitment applies to its own manufactur- impact of antibiotic manufacturing discharge. share the identities of its third-party suppliers ing sites. Novartis requires its third-party suppli- This includes auditing at its own manufacturing of antibiotic APIs and drug products or external ers of drug products to apply the same quality sites and those of third-party manufacturers of waste-treatment plants. standards to their production facilities. antibiotic APIs and drug products. Novartis sets limits on antibiotic discharge for its own manufacturing sites and external waste-treatment plants, yet not to third-party manufacturers of antibiotic APIs and drug products.

C APPROPRIATE ACCESS & Indicators 1 2 3 4 5 6 7 STEWARDSHIP scored on ● ● ● ● ● ● ●

C.1 Filed newest antibiotics in some coun- Nigeria and Tanzania. Alignment of supply and example, the company has started to increase tries in scope. demand for these products is managed through the weight of fixed pay in overall compensation Novartis reports information about where it has SMS For Life, a public-private partnership and to reduce the variable component. filed five of its newest antibiotics for registra- between Novartis and local healthcare facilities tion in some countries in scope* (between one set up to track stock levels. Initially established C.6 Implements brochure and/or packaging and eight countries). These products were intro- for mobile phones, the programme was updated adaptations to facilitate appropriate use. duced between 2011 and 2017. in Nigeria in 2016 to include a tablet- and smart- Novartis has adapted several brochures (to phone-based version of its stock-level tracking include demographic and literacy considera- C.2 Inter- and intra-country equitable platform. tions) to facilitate appropriate use of antibiotics pricing. by patients. For example, paediatric brochures Novartis discloses a general (not product-spe- C.4 Multiple activities in AMR-related educa- have been incorporated to illustrate the appro- cific) commitment to applying inter-coun- tional programmes. priate dosage of amoxicillin, and the packaging try equitable pricing to its highest-volume Novartis reports that it is involved in educational for its penicillin G antibiotic in Africa has been antimicrobials including antibiotics. It applies programmes for HCPs that include AMR stew- adapted for patients who may be illiterate. intra-country equitable pricing approaches for ardship and rational use of antibiotics, with con- artemether/lumefantrine (Coartem®) in the flicts of interest (COI) mitigation measures in C.7 No apparent involvement in surveillance majority of countries in scope.* This approach place. Programmes include topics on diagnosis, programmes. was first developed and implemented in part- treatment and management of multidrug-resist- Novartis reports no involvement in antibi- nership with WHO in 2001. Novartis has inde- ant bacterial infections. The company provides otic resistance-specific programmes aimed at pendently extended this approach beyond its ini- a protocol to mitigate COI. All educational activ- increasing global surveillance capabilities. tial ten-year term. ities reported were developed in collaboration with third parties. C.3 Local engagement to align supply and demand. C.5 Comprehensive involvement in appropri- Novartis engages with primary and local health- ate promotion practices. care facilities to align supply and demand fore- The Benchmark measures how companies casting for two of its highest-volume antimi- address stewardship through appropriate pro- crobial medicines: artemether/lumefantrine motion. Novartis reports that it takes action in (Coartem®) and efavirenz. This applies in the this regard: it reflects AMR trends in its market- following countries in scope*: Cameroon, the ing materials and is currently adjusting incen- Democratic Republic of Congo, Ghana, Kenya, tives for its sales teams around the world. For

131 Antimicrobial Resistance Benchmark 2018 Pfizer Inc.

Stock exchange: XNYS • Ticker: PFE • HQ: New York, NY, US • Employees: 96,500 • Signatory to Davos Decl.: Yes • Signatory to Industry Roadmap: Yes

Performance by Research Area How Pfizer was evaluated: applicable indicators

Pfizer** is among the top performing large research-based Pfizer discloses a comprehensive environmental risk-man- pharmaceutical companies, following close behind the lead- agement strategy, which includes discharge limits and report- ers. It performs well in Manufacturing & Production and edly applies to all Pfizer’s third-party suppliers of antibiotic Appropriate Access & Stewardship, achieving an average per- APIs and drug products. Pfizer has filed four of its five newest formance in Research & Development. The company does not antibiotics in countries in scope.* It also reports having mech- report its antimicrobial R&D investments and its R&D pipe- anisms in place for responding efficiently to stock-outs in line is comparatively small compared to other large research- countries in scope.* Regarding stewardship, Pfizer is engaged based pharmaceutical companies assessed by the Benchmark: in a number of AMR educational and training activities for seven antimicrobial projects. Notably, six of these target pri- healthcare professionals, taking steps to mitigate conflicts of ority pathogens, including four vaccines. It has access pro- interest, as well as engaging in established AMR surveillance visions in place for its vaccines in late-stage development. programmes that have an emphasis on data-sharing.

SALES AND OPERATIONS RevenuesP zer by product§ RevenuesMade: by region§ Final: no

Pfizer is a large research-based pharmaceuti- and biosimilars. In 2016, the company acquired cal company with two business segments: Pfizer AstraZeneca’s small-molecule anti-infectives . . . . Essential Health and Pfizer Innovative Health, business and late-stage pipeline, including com- . . . which includes vaccines. Pfizer sells antimicro- mercialisation rights to avibactam/ceftazi- bn USD bn USD bial medicines in at least 122 countries globally, dime (Zavicefta™).** In 2017, Pfizer and Basilea . . of which 53 or more are low- to middle-income Pharmaceutica Ltd. entered into an agreement countries.* In 2016, the company sold more than whereby Pfizer was granted exclusive rights to ● Vaccines ● USA 160 million doses of vaccines, including 61 mil- develop and commercialise the antifungal isavu- ● Antimicrobials ● Developed Rest of World lion doses of Prevnar 13® in partnership with conazole (Cresemba®) in several European ● Other pharmaceuticals ● Developed Europe ● Emerging markets Gavi, the Vaccines Alliance. In 2009, GSK and countries, China and 16 Asian-Pacific countries Pfizer established ViiV Healthcare (GSK: 76.5%, (exc. Japan).** Pfizer purchased two meningo- Pfizer: 13.5% and Shionogi: 10%), a joint ven- coccal vaccines, Mencevax® and Nimenrix®, from ture solely focused on the development of HIV/ GSK in 2015. It had previously purchased from AIDS medicines. In 2015, Pfizer completed the Baxter, in 2014, the vaccines NeisVac-C® and acquisition of Hospira — a provider of generic FSME-IMMUN®/TicoVac®, indicated for meningi- injectable medicines (including antimicrobials) tis and tick-borne encephalitis, respectively.

ANTIMICROBIAL PORTFOLIO Antimicrobial portfolio breakdown

Pfizer markets at least 114 antimicrobial med- 6), including seven in the EML’s Reserve group. icines, the largest reported antimicrobial port- The remainder (31) of the company’s portfo- folio among the large research-based pharma- lio includes antifungals (systemic and topical), ceutical companies assessed by the Benchmark. antiprotozoals and anthelminthics, as well as Sixty of these 114 medicines are listed on the eight antivirals. Pfizer also markets two antisep- WHO EML (Section 6). Eighty-three of the com- tic irrigation solutions and six vaccines, including pany’s antimicrobial medicines are antibiot- Prevnar 13® for pneumococcal pneumonia, and ics, with 45 listed on the WHO EML (Section four meningococcal vaccines. ● Antibiotics on WHO EML† WHO EML Categories ● Antibiotics not on ● Access group only ** Assets, specifically marketed products, acquired from * Countries in scope are 106 low- and middle-income WHO EML† ● Access & Watch groups AstraZeneca in 2016, and Basilea in 2017, remain subject countries where access to medicine is likely limited. ● Other antimicrobial ● Watch group only to integration into the Pfizer portfolio (including MAA † EML Section 6: Anti-Infective Medicines medicines ● Reserve group § transfer process in several markets). These assets have FYE 31 December 2016 ● Not grouped therefore been excluded from this analysis.

132 Access to Medicine Foundation

OPPORTUNITIES

Plan ahead for access and stewardship during charge, and publish the identities of third parties Ensure access to more antimicrobials. Pfizer is R&D. Pfizer has registration and affordability who manufacture antibiotic APIs and drug prod- currently committed to engaging in inter-coun- plans in place for all of its vaccine candidates. It ucts on its behalf. Currently, Pfizer discloses sev- try equitable pricing for its antimicrobial med- also has stewardship plans in place for its anti- eral policy documents on its environmental risk icines. Pfizer can expand its affordability strat- biotic candidate (avibactam/aztreonam) in the management. egy by engaging in intra-country equitable pric- form of AMR surveillance programmes and edu- ing for its antimicrobial medicines, and improv- cational activities for HCPs. Pfizer can ensure Expand environmental risk-management strat- ing access to recently acquired assets from that access plans are also in place for avibactam/ egy. Pfizer has set discharge limits for its own AstraZeneca and Basilea such as avibactam/ aztreonam. manufacturing sites and third parties who manu- ceftazidime (Zavicefta®) and isavuconazole facture antibiotic APIs and drug products as part (Cresemba®). Improve transparency regarding environmental of its environmental risk-management strategy. risk. Pfizer can share more information on how It can ensure these antibiotic discharge limits are it manages environmental risk, e.g., the com- applied to external waste-treatment sites. pany can disclose the levels of antibiotic dis-

PERFORMANCE BY RESEARCH AREA

A RESEARCH & DEVELOPMENT Indicators 1 2.1 2.2 2.3 3 4 Antimicrobial 7 projects scored on ● ● ● ● ● ● pipeline 6 target priority pathogens

A.1 No information on antimicrobial R&D clinical development targeting S. aureus, C. dif- A.4 Access provisions in place for its investments. ficile and group B Streptococcus (for which no vaccines in late-stage development. Pfizer reports no information on its antimicrobial vaccines currently exist) and a 20-valent pneu- Pfizer reports that it has access provisions in R&D investments. mococcal vaccine. place for both of its vaccines in late-stage development. It reports that it has a stewardship pro- A.2.1-2.3 Six R&D projects focussed on prior- A.3 Two R&D projects being developed with vision in place for its antibiotic candidate in late- ity pathogens. public partners. stage development, and commits to plan access Pfizer has seven antimicrobial R&D projects in its Pfizer is developing two R&D projects in its pri- plans during R&D but does not provide informa- pipeline, six of which are in clinical stage devel- ority pathogen pipeline through public-pri- tion on details of such action plans. For its two opment. Six of the company’s projects target private partnerships (including non-profit organ- vaccines in Phase II and III clinical stage, it will ority pathogens. Although Pfizer has a smaller isations).*** After acquiring avibactam from apply an equitable pricing policy that is based on pipeline compared to leaders in this area, all of AstraZeneca in 2016, Pfizer continued the devel- countries’ ability to pay, while covering research its projects focus on multidrug-resistant bac- opment of avibactam/aztreonam in collabora- and development costs. It is unknown if this terial infections. Pfizer has one project in pre- tion with Allergan, currently in Phase II clinical policy applies to its avibactam/aztreonam com- clinical development that focusses on new fixed development, through the COMBACTE-CARE bination. Furthermore, Pfizer plans to continue dose combinations (FDCs) of existing ß-lactam programme (IMI’s New Drugs 4 Bad Bugs con- its AMR surveillance programmes, as well as and ß-lactamase inhibitors. Pfizer is involved in sortium). The project also includes funding from launch educational initiatives regarding the risks the clinical development of new vaccines and BARDA. In 2016, Pfizer received funding from of AMR and how vaccines could play a role in new FDCs of existing antibiotics. This includes the Bill and Melinda Gates Foundation to con- addressing this public health threat. For this indi- the development of a new combination of the duct a Phase I/II clinical trial to evaluate the cator, countries in scope are 106 low- and mid- existing ß-lactam aztreonam and the ß-lacta- investigational group B Streptococcus (GBS) vac- dle-income countries where access to medicine mase inhibitor avibactam, a project that was cine in South Africa. Moreover, Pfizer is part of is likely limited. obtained with the acquisition of AstraZeneca’s a public-private consultation group led by WHO antibiotics division, in collaboration with on group B Streptococcus vaccine development, Allergan. Pfizer has no new chemical entities in which aims to develop standardised antibody its pipeline. Nevertheless, it has four vaccines in assays to identify correlates of protection.

Pipeline targeting priority pathogens

Discovery Preclinical Phase I Phase II Phase III Approval

• Discovery of ▶Pneumococ- ▶S. aureus 4-anti- ▶C. diffi- FDCs with exist- cal conju- gen vaccine cile vaccine ing small mol- gate 20-valent (PF06290510) (PF06425090) ecules – GNB vaccine – Adaptation (PF06482077) • Avibactam/ (new FDC) – S. pneumo- aztreonam ▶Vaccine niae (PF06947387) cIAI = Complicated intra-abdominal infection FDC = Fixed dose combination – MBL – cIAI, GNB = Gram-negative bacteria ▶Group B Strep- HABP/VABP GPB = Gram-positive bacteria tococcus – Adaptation HABP/VABP = Hospital-acquired/Ventilator- *** Pfizer is involved in the COMBACTE- 6‑valent con- (new FDC) – In associated bacterial pneumonia CDI network, a recently launched pro- MBL = metallo-ß-lactamase jugate vaccine partnership with ject within the IMI COMBACTE research ‡ This candidate moved to Phase III clinical devel- (PF06760805) Allergan plc‡ consortium. opment after the period of analysis.

133 Antimicrobial Resistance Benchmark 2018

B MANUFACTURING & PRODUCTION Indicators 1 2 3 scored on ● ● ●

B.1 Comprehensive environmental risk- B.2 Limited transparency regarding environ- B.3 Commits to following GMP, including at management strategy. mental risk management. 3rd-party sites. Pfizer undertakes many of the environmental Pfizer publishes elements of its environmen- Pfizer reports that it has mechanisms for main- risk-management activities that the Benchmark tal risk-management strategy on its website. It taining a high quality of antibiotic production examines. Namely, it applies an environmen- does not disclose audit results, or the discharge — namely following GMP standards. This com- tal risk-management strategy to minimise the levels of antibiotics. The company also does not mitment applies to its own manufacturing sites. impact of antibiotic manufacturing discharge. share the identities of its third-party suppliers Pfizer requires its third-party suppliers of drug It includes auditing and limits on antibiotic dis- of antibiotic APIs and drug products or external products to apply the same quality standards to charge, at its own manufacturing sites and those waste-treatment plants. their production facilities. of third-party manufacturers of antibiotic APIs and drug products. Pfizer's manufacturing sites include primary waste treatment. Secondary waste treatment occurs on- and off-site. The environmental risk-management strategy does not apply to off-site waste-treatment plants.

C APPROPRIATE ACCESS & Indicators 1 2 3 4 5 6 7 STEWARDSHIP scored on ● ● ● ● ● ● ●

C.1 Filed four of five newest antibiotics in procurers) to align supply and demand for anti- force from sales volume. In addition to provid- countries in scope. microbial medicines, specifically to prevent or ing AMR-related trends in its marketing mate- Pfizer reports that it has filed four of its five minimise stock-outs in countries in scope.* It has rials, Pfizer’s materials are reviewed by medi- newest antibiotics, introduced in 1991-2005, launched a website on supply status of injecta- cal experts to ensure they are aligned with anti- for registration in countries in scope* (between bles, including antimicrobial medicines such as biotic stewardship principles. Moreover, sales 30-63 countries). The fifth antibiotic, introduced piperacillin/tazobactam (Zosyn®). force training includes topics such as challenges in 1999, has not been filed for registration in in AMR and stewardship. any country in scope.* Pfizer did not report filing C.4 Multiple activities in AMR-related educa- information about newer antibiotics acquired tional programmes. C.6 Provides information on treatment recently (i.e., from AstraZeneca in 2016 and from Pfizer reports that it is involved in educational duration. Basilea in 2017), as these products are still being programmes for HCPs that include AMR stew- Pfizer adapts its packaging to facilitate appropri- integrated into the Pfizer portfolio (e.g., ongoing ardship and rational use of antibiotics, with con- ate use by providing information on treatment MAA transfer processes in several markets). flict of interest (COI) mitigation measures in duration. This can help to ensure that patients place. Programmes such as “Sharing Hospital complete the treatment course. C.2 Makes general commitment to equitable Anti-infectives Perspectives and Experience” pricing. (SHAPE) and the “Infectious Disease Education C.7 Open source surveillance programme. Pfizer discloses a general (not product-specific) and Learning” (IDEAL) support the implemen- Pfizer reports that is involved in several sur- commitment to applying inter- and intra-country tation of local antimicrobial stewardship pro- veillance programmes, focused on AMR trends. equitable pricing to antimicrobials in countries grammes. Its COI mitigation strategy consists Pfizer’s ATLAS programme stands out among in scope.* Pfizer is also committed to long-term of external content development and SOPs to all AMR surveillance programmes identified by public-private donation programmes for azithro- review content and potential COIs. The company the Benchmark, as it is completely accessible to mycin (Zithromax®) and fluconazole (Diflucan®). participates in various interactive courses and the public. The company is highly active in sur- massive open online courses (MOOCs) in col- veillance activities globally, some of which have C.3 Mechanisms in place to respond to laboration with third parties, aiming at chang- been running for over 14 years. Pfizer reports stock-outs. ing the behaviour of HCPs in stewardship and that it collaborates with public health agencies Pfizer reports that it has mechanisms in place resistance. for its surveillance programme in Latin America. for responding efficiently to stock-outs of all of its antimicrobial medicines and vaccines in C.5 Comprehensive involvement in appropri- countries in scope.* These are based on a set of ate promotion practices. demand and supply principles, such as ensuring The Benchmark measures how companies supplies are distributed equitably between coun- address stewardship through appropriate pro- tries, sharing information on shortages with pur- motion. Pfizer reports that it takes action in this chasers, and assigning additional resources in regard: it reflects AMR trends in its marketing the event of delays. Pfizer does not disclose how materials and is currently working on a pilot pro- it works with stakeholders (e.g., governments, ject to decouple the remuneration of its sales

ANIMAL HEALTH & DIAGNOSTICS

Activities in this area are not scored by the Pfizer does not market antimicrobials for use in ies of carbapenem-resistant bacteria. The com- Benchmark. This information is provided given animals. pany has also entered into collaborations with the importance of animal health and diagnostics diagnostic manufacturers to support commer- on the topic of AMR. Pfizer supports COMBACTE-CARE, a European cial availability of susceptibility tests for its new network that addresses the diagnostic chal- antibiotics. lenges for the epidemiological and clinical stud-

134 Access to Medicine Foundation Polyphor Ltd.

Stock exchange: Privately held • Ticker: - • HQ: Allschwil, Switzerland • Employees: approx. 100 • Signatory to Davos Decl.: Yes • Signatory to Industry Roadmap: No

Performance by Research Area How Polyphor was evaluated: applicable indicators

Polyphor is a biopharmaceutical company, selected for having Polyphor engages in public-private partnerships to develop its a pipeline that targets priority pathogens. It was evaluated in candidate compounds. The company has one R&D project in the area of Research & Development only. It invested more late-stage clinical development, but reports no information on than USD 5 million in antibiotic drug development in 2016. access or stewardship provisions for this candidate. The company performs well when compared with other biopharmaceutical companies in scope. It has three projects in its antimicrobial R&D pipeline, all targeting priority pathogens.

OPERATIONS

Polyphor, founded in 1996, is a privately-held ard-of-care treatment. Polyphor also develops platform, frequently used in research collabora- Swiss-based biopharmaceutical company, focus- an inhaled formulation of murepavadin for cystic tions with other pharmaceutical companies. sing on the development of macrocycle drugs fibrosis as part of a consortium, funded by the Polyphor is a member of the BEAM alliance, a that address antibiotic resistance and severe Innovative Medicines Initiative (IMI), a public-pri- group of biopharmaceutical companies address- pulmonary diseases. Polyphor discovered a new vate partnership of EFPIA and the EU. ing the regulatory and commercial environments class of antibiotics effective against gram-neg- While murepavadin is selective for P. aeruginosa, in Europe regarding R&D, approval and market ative bacteria, the Outer Membrane Protein the next generation of OMPTAs are broad-spec- viability of products combating antimicrobial Targeting Antibiotics (OMPTA). The most trum antibiotics, which target most important resistance. advanced drug candidate is murepavadin, indi- gram-negative pathogens, including extensively Polyphor has no products on the market. In 2017, cated for the treatment of infections caused by drug-resistant (XDR) and multidrug-resistant the company announced that it had successfully P. aeruginosa. Murepavadin recently entered (MDR) strains. In early 2017, Polyphor received a completed a CHF 40 million private financing Phase III clinical studies, after showing encour- CHF 2.3 million award from the Wellcome Trust round, 98% of which came from existing inves- aging results in a Phase II study in patients to advance the development of its broad-spec- tors, with substantial contributions from Varuma with ventilator-associated bacterial pneumo- trum, gram-negative preclinical candidates. The AG and Ingro Finanz AG. nia (VABP), when co-administered with stand- company has a proprietary macrocycle discovery

ANTIMICROBIAL PORTFOLIO

Polyphor does not have any products on the market.

OPPORTUNITIES

Plan ahead for access and stewardship during R&D. Polyphor is developing one antibiotic candidate (murepavadin) in late-stage clinical development. Polyphor can ensure access and stewardship provisions are in place for murepavadin, for example, through partnerships.

135 Antimicrobial Resistance Benchmark 2018

PERFORMANCE BY RESEARCH AREA

RESEARCH & DEVELOPMENT Indicators 1 2.1 2.2 2.3 3 4 Antimicrobial 3 projects scored on ○ ● ● ○ ● ● pipeline 3 target priority pathogens

A.2.1-2.2 Novel antibiotics that address teins. This makes Polyphor one of the few com- 2013, the company signed an exclusive world- cross-resistance. panies developing innovative antibiotics that wide licence agreement with Roche to develop Biopharmaceutical companies in scope were address cross-resistance. and commercialise murepavadin. In 2015, Roche selected based on their pipelines that target pri- decided to discontinue its involvement and ority bacteria. Polyphor invested more than USD A.3 At least one R&D project being devel- Polyphor continues the clinical development of 5 million in antibiotic drug development in 2016. oped with public partners.* the compound. The company has three projects in its antimicro- Polyphor is developing one R&D project in its bial R&D pipeline targeting priority pathogens, priority pathogen pipeline through a public-pri- A.4 No information on access or stewardship focussed on gram-negative bacteria. Polyphor’s vate partnership*: this is its preclinical OMPTA provisions novel antibiotic murepavadin (POL7080) tar- platform, developed in collaboration with the Polyphor reports no information on access or geting P. aeruginosa is entering Phase III clini- University of Zürich and with financial sup- stewardship provisions for its antibiotic candi- cal trials. Murepavadin is a synthetic macrocy- port from the Swiss government (amount date in late-stage development. It has signed clic protein that binds to a specific protein in not known). In 2017, the development of this the Davos Declaration, which includes a gen- the outer membrane of P. aeruginosa, interfer- broad-spectrum platform targeting gram-neg- eral commitment to ensuring access to antimi- ing with its proper functioning and ultimately ative pathogens also received funding from the crobial medicines and vaccines, and to support killing the pathogen. The company has more Wellcome Trust (CHF 2.3 million). Polyphor the appropriate and responsible use of these compounds in preclinical stage using the same is not developing its clinical stage candidate, products. molecular target class, outer membrane pro- murepavadin, via public-private partnership. In

Pipeline targeting priority pathogens

Discovery Preclinical Phase I Phase II Phase III Approval

• POL7080 • Murepavadin inhaled – P. (POL7080 IV) – aeruginosa P. aeruginosa – • Broad spectrum HABP/VABP – OMPTA com- Novel ‡ pounds – GNB (inc. MDR and XDR)

GNP = Gram-negative bacteria HABP/VABP = Hospital-acquired/Ventilator-associated bacterial pneumonia ‡ Phase III clinicaI trials are expected to commence in the first months of 2018.

B MANUFACTURING & PRODUCTION

As a biopharmaceutical company with no products on the market, Polyphor was not eligible for this Research Area.

C APPROPRIATE ACCESS & STEWARDSHIP

As a biopharmaceutical company with no products on the market, Polyphor was not eligible for this Research Area.

* After the Benchmark’s period of analysis, Polyphor entered into collaboration with the public-private partnership Innovative Medicines Initiative (IMI), as part of the iABC consortium, to co-fund and advance the development of its inhaled formulation of murepavadin.

136 Access to Medicine Foundation Roche Holding AG

Stock exchange: XSWX • Ticker: ROG • HQ: Basel, Switzerland • Employees: 94,052 • Signatory to Davos Decl.: Yes • Signatory to Industry Roadmap: Yes

Performance by Research Area How Roche was evaluated: applicable indicators

Indicator reference Due to the variation 1 2.1 2.2 2.3 3 4 between companies R&D R&D A ● ● ● ○ ● ○ in scope, not all indi- 1 2 3 cators are applica- M&P M&P B ● ● ● ble to every company. 1 2 3 4 5 6 7 See Appendix for full AA&S AA&S C ● ● ● ● ● ● ● overview. ● Remaining potential score ● Applicable indicator ○ Not applicable PERFORMANCE

Roche has relatively low sales of antibiotics compared to environmental risk-management strategy, which includes dis- the other large research-based pharmaceutical companies charge limits and reportedly applies to all Roche’s third-party in scope. The company is currently making efforts to re-en- suppliers of antibiotic APIs and drug products. Roche, cur- ter the antibiotics market and performs less well in the rently actively marketing antibiotics only in China, has filed Benchmark compared to other large research-based phar- two of its newest antibiotics in some countries in scope.* It maceutical companies. It performs well in Manufacturing makes no information available regarding equitable pricing & Production, but falls behind in the areas of Research & for antimicrobials. Roche reports engaging in some steward- Development and Appropriate Access & Stewardship. It has a ship activities, including ad hoc AMR educational activities for comparatively small antimicrobial R&D pipeline of eight pro- healthcare professionals. It provides funding to two surveil- jects, three of which target priority pathogens, including one lance programmes in China. novel biological antibiotic. Roche discloses a comprehensive

SALES AND OPERATIONS Revenues by product§ Revenues by regionII Roche Made: Final: no

Roche is a large research-based pharmaceuti- ment with Polyphor (ended in 2015), a company . . cal company with two divisions: pharmaceuti- also in scope of the Benchmark, and agreements . cals and diagnostics. Its pharmaceutical business with two different biotechnology companies, . includes therapeutic areas such as oncology, Discuva and Warp Drive Bio, for use of their bio- . . neuroscience, infectious diseases and immunol- informatics platforms to search for new classes bn CHF bn CHF . ogy. Although it is the third-largest company in of antibiotics. Roche also develops and com- . . scope of the Benchmark (based on total rev- mercialises a wide array of point-of-care diag- ● Antimicrobials ● North America enues), its antibiotic sales are low compared nostic tests for viruses (e.g. HIV, HBV and HCV) ● Other pharmaceuticals ● Europe, Middle East, Africa to several other large research-based pharma- and bacteria (e.g., M. tuberculosis, C. difficile and ● Diagnostics ● Asia Paci c and Japan ceutical companies in scope. The company had methicillin-resistant S. aureus). ● Other revenues ● Rest of World reduced its antimicrobial research at the turn of the century but has since sought to rebuild it by collaborating with smaller biopharmaceutical companies. Examples include a licensing agree-

ANTIMICROBIAL PORTFOLIO Antimicrobial portfolio breakdown

Roche markets at least 11 antimicrobial med- group, and ceftriaxone (Rocephin®), in both the icines, seven of which are listed on the WHO Access and Watch groups. The remaining nine EML (Section 6). Two of the company’s antimi- medicines are two antiprotozoals and seven crobial medicines are antibiotics, both listed on antivirals (including one PEGylated and one the WHO EML (Section 6): sulfamethoxazole/ non-PEGylated interferon for the treatment of trimethoprim (Bactrim®), in the EML’s Access viral hepatitis).

● Antibiotics on WHO EML† WHO EML Categories * Countries in scope are 106 low- and middle-income ● Antibiotics not on ● Access group only countries where access to medicine is likely limited WHO EML† ● Access & Watch groups † EML Section 6: Anti-Infective Medicines ● Other antimicrobial ● Watch group only § Revenues from external customers, inc. sales, royalties medicines ● Reserve group and other operating income; FYE 31 December 2016 ● Not grouped || Sales; FYE 31 December 2016

137 Antimicrobial Resistance Benchmark 2018

OPPORTUNITIES

Plan ahead for access and stewardship during Engage in antimicrobial stewardship. Roche on its behalf. Roche currently discloses several R&D. Roche has two candidates in clinical devel- currently supports some education and surveil- policies on environmental risk management. opment, both in Phase I. Roche is encouraged lance programmes. It can engage more actively to implement access and stewardship plans for in stewardship activities, e.g., through strength- Expand environmental risk-management strat- these candidates as they move into Phase II clin- ening its role in more surveillance activities, edu- egy. Roche has set discharge limits for its own ical development. cational activities for healthcare professionals on and third party manufacturing sites as part of its AMR (while mitigating conflicts of interest) and environmental risk-management strategy. Roche Ensure access by addressing affordability for engage in appropriate promotion practices. can ensure these discharge limits are applied to antimicrobial medicines. Roche has reported its external waste treatment plants. that it has low-priced generic antibiotics availa- Improve transparency regarding environmental ble on the market, and that the price of its orig- risk management. Roche can share more infor- inators has also decreased. Roche can improve mation on how it manages environmental risk, the affordability of its antimicrobial medicines e.g., disclose the levels of antibiotic discharge by developing an equitable pricing strategy that and publish the identities of third parties who takes socio-economic factors into account. manufacture antibiotic APIs and drug products

PERFORMANCE BY RESEARCH AREA

A RESEARCH & DEVELOPMENT Indicators 1 2.1 2.2 2.3 3 4 Antimicrobial 8 projects scored on ● ● ● ○ ● ○ pipeline 3 target priority pathogens

A. 1 No information on antimicrobial R&D Roche is developing a new ß-lactamase inhib- A.3 One R&D project being developed with investments. itor, nacubactam, which is currently in Phase I public partners. Roche reports no information on its antimicro- clinical development. Roche is engaged in a col- Roche is developing one R&D project in its pri- bial R&D investments. laborative antibiotics discovery project with ority pathogen pipeline through public-private drug discovery company Discuva. This collabo- partnership. The company received funding from A.2.1-2.2 One novel biological agent in the ration involves the use of Discuva’s proprietary BARDA (potentially up to USD 150 mn) to fur- clinical pipeline. SATIN technology platform, a novel technology ther develop its ß-lactamase inhibitor nacubac- Roche has eight** antimicrobial R&D projects in that identifies the molecular targets of chemi- tam and accelerate the development of tests for its pipeline, seven of which are in clinical stage cal compounds that affect bacterial growth and detecting specific viral and bacterial infections. development. Three of the company’s projects genes. The platform comprises several different Roche also conducts R&D with private-sector target priority pathogens, the lowest number varieties of transposons — genes that are spe- partners.‡ of projects targeting priority pathogens among cifically engineered for each target pathogen, large research-based pharmaceutical compa- coupled with high-throughput Next Generation A.4 No R&D candidate in late-stage nies. However, all three of these projects are Sequencing (NGS) technology, bioinformat- development. focussed on bacteria. Roche also focusses its ics and machine learning. This allows for ongo- Roche is not eligible for this indicator as it does R&D activities on influenza and hepatitis B. The ing genome-wide analysis of bacterial events not have any R&D candidates in late-stage company has at least one project in preclinical throughout the chemistry optimisation process. development. stage.*** Roche is developing an antibody-drug Roche does not have any drug candidates tar- conjugate, a novel antibody bound to a rifamy- geting a priority pathogen beyond Phase II of cin analogue, against S. aureus. It is a highly spe- clinical development. cific and innovative biological agent. Additionally,

Pipeline targeting priority pathogens

Discovery Preclinical Phase I Phase II Phase III Approval

• SATIN (Selective Antibiotic Target • Nacubactam IdentificatioN) – Bacteria – In part- (RG6080) – nership with Discuva Ltd CRE • S. aureus therapeutic antibody conjugate (RG7861) – Novel

** After the Benchmark’s period of analysis, Roche ‡ After the Benchmark’s period of analysis, Roche reported termination of one of these projects reported having 13 active research collaborations with (MHAA4549A). academic groups globally to support novel antibiotic dis- *** After the Benchmark’s period of analysis, Roche covery focussing on multidrug-resistant gram-nega- entered into collaboration with Warp Drive Bio around tive bacteria. the Genome Mining™ Platform, which provides access to over one hundred novel classes of natural antibiotics.

138 Access to Medicine Foundation

B MANUFACTURING & PRODUCTION Indicators 1 2 3 scored on ● ● ●

B.1 Comprehensive environmental risk-man- B.2 Limited transparency regarding environ- B.3 Commits to following GMP, including at agement strategy. mental risk management. 3rd-party sites. Roche undertakes almost all environmental Roche publishes elements of its environmen- Roche reports that it has mechanisms for main- risk-management activities that the Benchmark tal risk-management strategy on its website. It taining a high quality of antibiotic production examines. Namely, it applies an environmen- does not disclose audit results, or the discharge — namely following GMP standards. This com- tal risk-management strategy to minimise the levels of antibiotics. The company also does not mitment applies to its own manufacturing sites. impact of antibiotic manufacturing discharge. share the identities of its third-party suppliers Roche requires its third-party suppliers of drug It includes auditing and limits on antibiotic dis- of antibiotic APIs and drug products or external products to apply the same quality standards to charge, both for its own manufacturing sites and waste-treatment plants. their production facilities. those of third-party manufacturers of antibiotic APIs and drug products. Roche states that its strategy applies to external waste-treatment plants, yet it also reports that it does not set discharge limits for these plants nor audits implementation of the strategy.

C APPROPRIATE ACCESS & Indicators 1 2 3 4 5 6 7 STEWARDSHIP scored on ● ● ● ● ● ● ●

C.1 Filed two newest antibiotics in some in scope.* After the period of analysis, Roche quired infections. The company reports that it countries in scope. reported to the Benchmark that it does have a only actively markets and promotes this antibi- Roche has provided filing information on two of global expert group to allocate available supply otic in China. its newest antibiotics: ceftriaxone (Rocephin®) to prevent stock-outs from happening. was introduced in 1984 and has now been C.6 No information regarding brochure and/ filed for registration in 49 countries in scope.* C.4 Some involvement in AMR-related or packaging adaptations. Sulfamethoxazole/trimethoprim (Bactrim®) was education. Roche does not provide sufficient information introduced in 1969 and has now been filed for Roche has provided information for its China on linguistic, cultural or literacy adaptations registration in 34 countries in scope,* mainly in headquarters, the only country where it actively made to its brochures or packaging to facilitate Latin America and sub-Saharan Africa. markets antibiotics. The company reported that appropriate use of antibiotics by patients. its China headquarters provides on-demand C.2 No equitable pricing approach. educational materials for rational use of antibi- C.7 Supports academic surveillance pro- Roche does not disclose an equitable pricing otics for self-learning purposes, but stated that grammes financially. approach for its highest-volume antibiotics and/ due to limited resources, it does not initiate edu- Roche has only provided information for sur- or antimicrobial medicines. It does report that cational programmes independently. veillance activities taking place in China, the it views competition from generic medicines as only country where it actively markets antibiot- the main mechanism triggering price reductions. C.5 No involvement in appropriate promo- ics. The company supports two surveillance pro- tion practices. grammes focussed on AMR trends in China. It C.3 No insight into steps addressing supply The Benchmark measures how companies provides funding for these two programmes, chain efficiency. address stewardship through appropriate pro- which focus on community-acquired E. coli and Roche does not disclose how it works with motion. The company does not report taking pneumonia infections in secondary and ter- stakeholders (e.g., governments, procurers) to action in this regard either through reflect- tiary care hospitals in China. The sharing of the align supply and demand for antimicrobial med- ing AMR trends in its marketing materials or results from these studies is the sole respon- icines, specifically to prevent or minimise stock- decoupling its sales force’s incentives from sibility of the researchers; however, the lead- outs in countries in scope*. The company also volume of antibiotic sales. Roche has only pro- ing researchers have stated plans to publish the does not report on whether it has processes vided information for the antibiotic ceftriaxone results in peer-reviewed journals. in place to respond to stock-outs in countries (Rocephin®), which is used in community-ac-

ANIMAL HEALTH & DIAGNOSTICS

Activities in this area are not scored by the Additionally, since 2014, Roche has partnered Benchmark. This information is provided given with UNAIDS and the Clinton Health Access the importance of animal health and diagnostics Initiative (CHAI), among others, to help diagnose on the topic of AMR. and combat HIV infections in children and adults in 82 developing countries with a high burden Roche develops and commercialises a wide array of disease. of diagnostic tests for viruses (e.g., HIV, HBV and HCV) and bacteria (e.g., M. tuberculosis, C. difficile and methicillin-resistant S. aureus). For example, the cobas® Liat® system is an in vitro diagnostic platform where results can be made available in less than 30 minutes for viruses (e.g., influenza A/B) and bacteria (e.g., C. difficile).

139 Antimicrobial Resistance Benchmark 2018 Sanofi

Stock exchange: XPAR • Ticker: SAN • HQ: Paris, France • Employees: 106,859 • Signatory to Davos Decl.: Yes• Signatory to Industry Roadmap: Yes

Performance by Research Area How Sanofi was evaluated: applicable indicators

Sanofi is among the top performing large research-based reportedly applies to all the company’s third-party suppliers pharmaceutical companies in scope, following close behind of antibiotic APIs and drug products, as well as mechanisms the leaders. This is driven by strong performance in Research to assure quality of antibiotic manufacturing is maintained. & Development with average performance in Manufacturing Sanofi reports that it has filed its five newest antibiotics in & Production and Appropriate Access & Stewardship. The some countries in scope.* The company engages in equitable company’s R&D pipeline consists of 32‡ antimicrobial pro- pricing strategies on non-antibiotic antimicrobials only. Sanofi jects, of which 18‡ target priority pathogens, including one reports having mechanisms in place for responding efficiently novel antimalarial candidate and six new vaccine candidates. to stock-outs in countries in scope.* The company engages It has access provisions in place for three out of five of its in a number of AMR educational activities, as well as surveil- vaccines in late-stage development. Sanofi discloses a com- lance programmes. prehensive environmental risk-management strategy, which

SALES AND OPERATIONS RevenuesSano by product§ RevenuesMade: by region§ Final: no

Sanofi is a large research-based pharmaceutical Sanofi Pasteur. In 2016, the company sold more company organised into five business units: gen- than 1 billion doses of vaccines globally. At the . . . eral medicines and emerging markets; diabetes end of 2016, Sanofi Pasteur and Merck & Co., . . . and cardiovascular; consumer healthcare; spe- Inc. ended their vaccines joint venture in Europe bn EUR bn EUR cialty care; and vaccines. Its specialty care busi- (Sanofi Pasteur MSD, established 1994) to inde- . . ness unit develops treatments for rare diseases, pendently manage their product portfolios. At multiple sclerosis, oncology and immunology. the same time, the company completed the ● Vaccines ● USA The company sells antimicrobial medicines and acquisition of Boehringer Ingelheim’s consumer ● Pharmaceuticals ● Europe vaccines in 140 countries globally, including 72 healthcare business, in exchange for its animal ● Emerging Markets ● Rest of World low- and middle-income countries.* health business (Merial). Sanofi’s vaccine business is run via subsidiary

Antimicrobial portfolio breakdown ANTIMICROBIAL PORTFOLIO

Sanofi markets at least 31** antimicrobial med- cated for the treatment of malaria. Its vaccines icines, 18 of which are listed on the WHO EML portfolio is one of the largest of the companies (Section 6). Twenty-one of the company’s anti- assessed by the Benchmark and covers a wide microbial medicines are antibiotics, with 11 range of indications, including pneumococcal listed on the WHO EML (Section 6), includ- disease (Pneumo™ 23), meningococcal disease ing five in the EML’s Watch group. The remain- (e.g., Menomune®) and infections caused by der (ten) of the company’s portfolio consists of Haemophilus influenzae type B (ActHib®). antiprotozoal medicines, including seven indi- ● Antibiotics on WHO EML† WHO EML Categories ● Antibiotics not on ● Access group only WHO EML† ● Access & Watch groups ● Other antimicrobial ● Watch group only OPPORTUNITIES medicines ● Reserve group ● Not grouped

Plan ahead for access and stewardship during e.g., apply for WHO prequalification. Sanofi Increase engagement in stewardship activities. R&D. Sanofi discloses no information regarding can implement further access and stewardship Sanofi engages in some stewardship activities. access and stewardship provisions for its anti- plans for all its candidates in late-stage clinical Sanofi can take steps to ensure that its current microbial medicines in late-stage clinical devel- development. AMR educational activities for healthcare pro- opment. For its vaccine candidates, it plans to, fessionals include processes to mitigate conflicts * Countries in scope are 106 low- and middle-income countries where access to medicine is likely limited. 140 † EML Section 6: Anti-Infective Medicines § Net sales not inc. the held-for-exchange Animal Health segment; FYE 31 December 2016 ** Sanofi provided only a sample (approx. 50%) of its global antimicrobial portfolio. Access to Medicine Foundation

of interest. It can also expand its current surveil- microbial medicines. Sanofi can seek to improve facturers of antibiotic APIs and drug products. lance activities to more countries, collaborating access for more antimicrobial medicines (spe- Sanofi currently discloses several policies on with public health authorities and ensuring that cifically antibiotics) by expanding its affordabil- environmental risk management. the data is made publicly available via an open ity strategy to more products and more coun- database. Sanofi can also engage in appropriate tries in need. Expand environmental risk-management strat- promotion practices. egy. Sanofi has set discharge limits for its own Improve transparency regarding environmental manufacturing sites as part of its environmental Ensure access by addressing affordability for risk management. Sanofi can share more infor- risk-management strategy. It can ensure these antimicrobial medicines. Sanofi currently states mation on how it manages environmental risk, discharge limits are applied to third parties who a commitment to applying product-specific e.g., disclose the levels of antibiotic discharge, manufacture APIs on its behalf, as well as to inter-country equitable pricing to two of its anti- and publish the identity of third party manu- external waste-treatment sites.

PERFORMANCE BY RESEARCH AREA

A RESEARCH & DEVELOPMENT Indicators 1 2.1 2.2 2.3 3 4 Antimicrobial 32 projects scored on ● ● ● ● ● ● pipeline 18 target priority pathogens

A.1 Comparatively high vaccine R&D cene-containing compound active against both organisation, on the development of its tubercu- investments. chloroquine-susceptible and chloroquine-re- losis vaccine, currently in Phase II clinical devel- Sanofi reports that it invested more than USD sistant P. falciparum, while artefenomel dis- opment. The remaining three R&D projects (two 500 million in the development of vaccines in plays important chemical dissimilarities to other preclincial, one clinical) involve public research 2016, which is high compared to other large artemisinins, making it likely to remain effective institutes. research-based pharmaceutical companies in the against artemisinin-resistant strains. Six out of Benchmark. The company reports no informa- 12 of Sanofi’s innovative vaccines in development A.4 Access provisions in place for most tion on investments made for the development target priority pathogens. Four of these are clin- vaccines in late-stage development. of antimicrobial medicines. ical-stage projects, including an HIV vaccine can- Sanofi reports that it has access provisions in didate (for which no vaccines currently exist). place for three out of five of its vaccines in late- A.2.1-2.3 Eighteen R&D projects in priority stage development. It reports that it has an pathogen pipeline, with broad focus. A.3 Eleven R&D projects being developed access commitment in place for its antimalarial Sanofi has 32‡ antimicrobial R&D projects in with public partners, including seven candidate in late-stage development, but does its pipeline, 19‡ of which are in clinical stage PDPs. not report information on access provisions. development. Eighteen‡ of the company’s pro- Sanofi is developing 11 R&D projects in its pri- For its three vaccines in late-stage develop- jects target priority pathogens. Its pipeline size ority pathogen pipeline through public-pri- ment, Sanofi plans to file for WHO prequalifica- is above average when comparing it to other vate partnerships (including non-profit organ- tion and/or for the European Medicines Agency large research-based pharmaceutical companies isations).*** Eight of these R&D projects are in (EMA) article 58 (a scientific assessment of a assessed by the Benchmark. Its pipeline covers development through a PDP or open research medicine for use outside the EU). For the anti- a broad range of priority pathogens, includ- consortium. Seven projects are in development malarial candidate in late-stage development ing both gram-negative and gram-positive bac- through a PDP, five are in preclinical stage and (artefenomel/ferroquine), the company commits teria, HIV, P. falciparum (malaria) and M. tuber- two are in clinical stage. For the development of to ensuring sufficient supply, but does not pro- culosis. Looking only at R&D for multidrug-re- its Phase II HIV vaccine, Sanofi partners with the vide a clear strategy for achieving this goal. For sistant bacteria, the company has seven discov- Pox-Protein Public Private Partnership (P5), a this indicator, countries in scope are 106 low- ery-stage projects, one vaccine in preclinical project that includes the US National Institute of and middle-income countries where access to stage and three vaccines in clinical development, Allergy and Infectious Diseases (NIAID), the Bill medicine is likely limited. Regarding stewardship including one that targets M. tuberculosis. The & Melinda Gates Foundation, the South African provisions, Sanofi signed the Davos Declaration, company has one novel antimalarial medicine in Medical Research Council, the HIV Vaccine Trials which includes a general commitment to support clinical development (artefenomel/ferroquine), Network (HVTN), the US Military HIV Research the appropriate and responsible use of antimi- in collaboration with the Medicines for Malaria Program and GSK. The company also collab- crobial medicines and vaccines. Venture (MMV). Ferroquine is a promising ferro- orates with Aeras, a non-profit biotechnology

Pipeline targeting priority pathogens

Discovery Preclinical Phase I Phase II Phase III Approval

• Novel natural product discovery – ▶S. pneumoniae ▶S. pneumoniae ▶DTP-HepB-Po- ▶C. difficiletox - GNB vaccine paediatric vac- lio-Hib hexava- oid bivalent vac- • Influx enhancement – GNB – In part- • Malaria blood cine (PPrV) lent paediatric cine‡ nership with GSK stage inhibitor – vaccine (Shan6, ▶DTP-Polio-Hib • Phenotypic Screening – GNB P. falciparum PR5I) – Adap- paediatric pen- • Staphylococcus project – S. aureus tation tavalent vaccine • Tuberculosis growth inhibitors (mac- ▶M. tuberculosis (Pentaxim®) rolides) – M. tuberculosis bivalent vaccine – Adaptation • Tuberculosis growth inhibitors (H4:IC31®) (new target (Griselimycin) – M. tuberculosis ▶HIV Vaccine – In demographic: • Tuberculosis growth Inhibitors (Per- partnership with Japan) sisters) – M. tuberculosis GSK • Malaria project – P. falciparum • Artefenomel/ ▶Malaria vaccine – P. falciparum Ferroquine – P. falciparum – Novel ▶Vaccine 141 GNB = Gram-negative bacteria *** Sanofi is involved in the COMBACTE-CDI network, a ‡ C. difficile vaccine has been terminated recently launched project within the IMI COMBACTE after the period of analysis. research consortium. Antimicrobial Resistance Benchmark 2018

B MANUFACTURING & PRODUCTION Indicators 1 2 3 scored on ● ● ●

B.1 Comprehensive environmental risk- B.2 Limited transparency regarding environ- B.3 Commits to following GMP, including at management strategy. mental risk management. 3rd-party sites. Sanofi undertakes almost all of the environ- Sanofi publishes elements of its environmen- Sanofi reports that it has mechanisms for main- mental risk-management activities that the tal risk-management strategy on its website. It taining a high quality of antibiotic production Benchmark examines. Namely, it applies an envi- does not disclose audit results, or the discharge — namely following GMP standards. This com- ronmental risk-management strategy to mini- levels of antibiotics. The company also does not mitment applies to its own manufacturing sites. mise the impact of antibiotic manufacturing dis- share the identities of its third-party suppliers Sanofi requires its third-party suppliers of drug charge. It includes auditing for its own manufac- of antibiotic APIs and drug products or external products to apply the same quality standards to turing sites and those of third-party manufactur- waste-treatment plants. their production facilities. ers of antibiotic APIs and drug products, and for external waste-treatment plants. Sanofi has also set antibiotic discharge limits for its own manufacturing sites.

C APPROPRIATE ACCESS & Indicators 1 2 3 4 5 6 7 STEWARDSHIP scored on ● ● ● ● ● ● ●

C.1 Filed five newest antibiotics in some its antibiotics and non-antibiotic antimicrobial its non-product-specific materials. However, the countries in scope. medicines. The company demonstrates no evi- company’s appropriate promotion practices do Sanofi reports that it has filed its five newest dence of engaging with relevant stakeholders not include the decoupling of its sales force’s antibiotics, introduced between 1989 and 1997, (e.g., governments, procurers) to align the supply incentives from volume of antibiotic sales. for registration in some countries in scope* and demand for antimicrobial medicines. It does (between 20-45 countries). Two of these anti- report informing and following-up on stock-outs C.6 Provides information on treatment biotics are on the WHO EML (Section 6): cefix- with local or regional authorities. duration. ime (Oroken®), which is registered in 20 coun- Sanofi adapts its packaging to facilitate appro- tries mainly in sub-Saharan Africa; and levoflox- C.4 Some involvement in AMR-related priate use of antibiotics by patients, by providing acin (Tavanic®), which is registered in 45 coun- education. information on treatment duration. This can help tries across multiple regions. Sanofi reports that it is engaged in several edu- to improve patient adherence to treatment. cational activities, focusing on infectious disease C.2 Inter-country equitable pricing for management and appropriate use and prescrip- C.7 Public health partnership to monitor antimicrobials. tion of antibiotics, running e.g., in France, China, AMR trends in France. Sanofi discloses inter-country equitable pric- India and Vietnam. Content is delivered via web- Sanofi is engaged in one surveillance pro- ing approaches for two of its highest-volume sites, conferences and meetings to a wide range gramme. Sanofi partners with public health insti- antimicrobial medicines in some countries in of healthcare professionals, including medical tutions to monitor AMR trends in France, for scope.* The two approaches cover: (1) meglu- doctors, microbiologists and pharmacists. It is example. Sanofi cooperates with French national mine (Glucantime®) indicated for Leishmaniasis, not clear, however, how the company ensures institutes in the monitoring of antimicrobial mainly in Latin American countries; and (2) amo- content is developed independently or how it resistance trends. The company does not own diaquine/artesunate (ASAQ Winthrop®) indi- mitigates possible conflicts of interest. the data, and depends on its partners to publish cated for malaria, mainly in Africa. For amodi- results in journals or at congresses. aquine/artesunate, the pricing approach is being C.5 Adopts some appropriate promotion implemented in cooperation with partners such practices. as the Global Fund, WHO and MSF. The Benchmark measures how companies address stewardship through appropriate pro- C.3 Global mechanisms in place for respond- motion practices. Sanofi reports that it takes ing to stock-outs. action in this regard by reflecting AMR trends Sanofi reports that it has global mechanisms in in its marketing materials, including informa- place for responding efficiently to stock-outs of tion about resistance trends and guidelines in

142 Access to Medicine Foundation Shionogi & Co., Ltd.

Stock exchange: XTKS • Ticker: 4507 • HQ: Osaka, Japan • Number of employees: 5,896 • Signatory to Davos Decl.: Yes • Signatory to Industry Roadmap: Yes

Performance by Research Area How Shionogi was evaluated: applicable indicators

Indicator reference Due to the variation 1 2.1 2.2 2.3 3 4 between companies R&D R&D A ● ● ● ○ ● ● in scope, not all indi- 1 2 3 cators are applica- M&P M&P B ● ● ● ble to every company. 1 2 3 4 5 6 7 See Appendix for full AA&S AA&S C ● ○ ○ ● ● ● ● overview. ● Remaining potential score ● Applicable indicator ○ Not applicable PERFORMANCE

Shionogi is the smallest research-based pharmaceutical com- ers of antibiotic APIs and drug products. The company pro- pany in scope, with sales mostly in Japan. The company’s per- vides no evidence of activities related to facilitating access. formance is lower compared to large research-based phar- Shionogi's commitment to stewardship is driven by engage- maceutical companies in scope in Research & Development, ment in a number of stewardship educational activities, as Manufacturing & Production and Appropriate Access & well as surveillance programmes in partnership with academic Stewardship. The company's R&D pipeline consists of 25 anti- institutions in Japan. It does not remunerate sales staff based microbial projects, of which 15 target priority pathogens. on sales volume of antibiotics. Shionogi discloses an environmental risk-management strategy, which is not applied to the company's third-party suppli-

Shionogi Made: Final: no SALES AND OPERATIONS Revenues by product§ Revenues by regionII

Shionogi is a large research-based pharmaceu- eight antimicrobial medicines in Japan, Taiwan . . tical company headquartered in Japan. Its core and the US. During the fiscal year 2016, it sold therapeutic areas are infectious diseases and approximately 15 million doses of antimicrobial . . pain/central nervous system disorders, though medicines. In 2012, following a long-term col- bn JPY bn JPY . its portfolio also covers additional areas, such laboration on the development of several novel . as cardiovascular health and paediatrics. Within integrase inhibitors for the treatment of HIV/ ● Antimicrobials ● Japan the infectious diseases area, the company is AIDS, Shionogi joined ViiV Healthcare, a joint ● Other pharmaceuticals ● Europe especially focused on three areas of research: venture originally established by GSK and Pfizer, ● USA severe bacterial and fungal infections, HIV/AIDS solely focused on the development of HIV/AIDS ● Other and viral respiratory infections and emerging/ medicines. Equity positions in ViiV Healthcare re-emerging infections. The company markets are GSK: 76.5%, Pfizer: 13.5% and Shionogi: 10%.

ANTIMICROBIAL PORTFOLIO Antimicrobial portfolio breakdown

Shionogi markets eight antimicrobial medi- other antiretroviral agents, for the treatment of cines, two of which are listed on the WHO EML HIV/AIDS. Dolutegravir was developed in collab- (Section 6). Six of the company’s antimicrobial oration with ViiV Healthcare and is listed on the medicines are antibiotics, including the combina- WHO EML (Section 6). tion sulfamethoxazole/trimethoprim (Baktar®), listed on the EML’s Access group. The remaining two medicines are antivirals: one indicated for influenza A/B infections and the other, dolute- ● Antibiotics on WHO EML† WHO EML Categories ® gravir (Tivicay ), indicated, in combination with ● Antibiotics not on ● Access group only WHO EML† ● Access & Watch groups ● Other antimicrobial ● Watch group only medicines ● Reserve group ● Not grouped

* Countries in scope are 106 low- and middle-income countries where access to medicine is likely limited † EML Section 6: Anti-Infective Medicines § Net sales; FYE 31 March 2017 || Net sales; FYE 31 March 2016

143 Antimicrobial Resistance Benchmark 2018

OPPORTUNITIES

Improve access to antimicrobial medicines. Ensure transparency on its approach to envi- Continue developing early-stage projects. Shionogi can develop an access strategy for ronmental risk management. Shionogi has Shionogi has a large early-stage pipeline of R&D countries in scope,* that includes the filing stated a commitment to disclose its environ- projects targeting priority pathogens. It can of its newest antibiotics (including flomoxef mental risk-management strategy, the identi- ensure that these early-stage projects move (Flumarin®)), for registration. Currently, Shionogi ties of its third-party suppliers and its external along the pipeline into clinical development. has not filed its antibiotics for registration in waste-treatment sites. countries in scope.* Increase engagement in stewardship activities. Expand environmental risk-management strat- Shionogi has engaged with academic institutes Plan ahead for access and stewardship during egy. Shionogi can ensure its environmental for several short-term surveillance programmes. R&D. Shionogi is developing one antibiotic can- risk-management strategy is applied to third It can ensure the development of long-term didate (cefiderocol) in late-stage clinical devel- parties who manufacture antibiotic APIs on its AMR surveillance programmes, and ensure that opment. It is currently seeking partners to behalf, as well as to external waste-treatment data is made publically available through open plan for its commercialisation, through licens- sites. It currently has an environmental risk-man- databases and collaboration with public health ing. Shionogi can ensure that these partner- agement strategy that includes discharge limits, authorities. ship agreements include access and stewardship which are applied to its own manufacturing sites. provisions.

PERFORMANCE BY RESEARCH AREA

A RESEARCH & DEVELOPMENT Indicators 1 2.1 2.2 2.3 3 4 Antimicrobial 25 projects scored on ● ● ● ○ ● ● pipeline 15 target priority pathogens

A.1 Comparatively high antimicrobial R&D including bacteria, fungi, HIV and M. tuberculo- tion on access provisions. Shionogi commits to investments. sis. Cefiderocol, a new cephalosporin, is its most providing its investigational antibiotic (cefidero- Shionogi reports that it invested more than advanced compound which is currently in Phase col) only for indications for which limited or no USD 200 million in antimicrobial R&D in 2016, III clinical development. Shionogi is also develop- alternative treatment options are available and which is relatively high compared to other large ing an antibody against P. aeruginosa. where cefiderocol is likely to be an appropri- research-based pharmaceutical companies in ate treatment option. This would include infec- the Benchmark. The company’s antimicrobial A.3 Some preclinical R&D projects being tions caused by, e.g., carbapenem-resistant and/ R&D investments are almost as high as its rev- developed with public partners. or multidrug-resistant gram-negative pathogens. enues earned from antimicrobial medicines. Shionogi is developing four preclinical projects Shionogi plans to commercialise cefiderocol in These investments cover antimicrobial medi- in its priority pathogen pipeline through pub- the countries in which it has affiliate companies cines only, as Shionogi is not involved in vaccine lic-private partnerships. Three of these projects (the USA, China, Singapore, EU countries and development. involve collaboration with universities, which are Taiwan), and is currently in talks with partners focused on the discovery of novel medicines that to commercialise it outside of these countries. A.2.1-2.2 Fifteen R&D projects in priority target HIV and multidrug-resistant gram-posi- For this indicator, countries in scope are 106 low- pathogen pipeline, one in clinical stage. tive bacteria. The remaining project involves the and middle-income countries where access to Shionogi has 25 antimicrobial R&D projects in screening of Shionogi’s compound libraries for medicine is likely limited. There is no informa- its pipeline, two of which are in clinical stage candidates with activity against M. tuberculosis tion available on whether these countries are development. Fifteen of the company’s pro- through the PDP with TB Alliance. included in Shionogi’s commercialisation plans. It jects target priority pathogens. It has an aver- has signed the Davos Declaration, which includes age-sized pipeline when comparing it to other A.4 Stewardship commitment in place, but a general commitment to ensuring access to large research-based pharmaceutical companies no information regarding access. antimicrobial medicines and vaccines, and to assessed by the Benchmark. Shionogi is the only Shionogi reports that it has a stewardship com- support the appropriate and responsible use of company engaged in antifungal drug develop- mitment in place for its antibiotic candidate in these products. ment. Its preclinical activities have a broad focus late-stage development, but reports no informa-

Pipeline targeting priority pathogens

Discovery Preclinical Phase I Phase II Phase III Approval

• Antibacterial programme 1 – GNB • Antibody – P. • Cefiderocol • Antibacterial programme 2 – GNB aeruginosa (S649266) – • Antibacterial programme 3 – GPB • YF-49-92 – M. CRE, ESBL, P. • Anti-tuberculosis programme – M. tuberculosis aeruginosa, A. tuberculosis baumannii – • Anti-tuberculosis programme 2 – M. BSI, cUTI, HABP/ tuberculosis VABP, Sepsis • Anti-HIV programme 1 – HIV • Anti-HIV programme 2 – HIV • Anti-HIV programme 3 – HIV BSI = Bloodstream infections • Anti-HIV programme 4 – HIV cUTI = Complicated urinary tract infection GNB = Gram-negative bacteria • Anti-HIV programme 5 – HIV GPB = Gram-positive bacteria • Antifungal programme 1 – Candida HABP/VABP = Hospital-acquired/Ventilator- • Antifungal programme 2 – Candida associated bacterial pneumonia

144 Access to Medicine Foundation

B MANUFACTURING & PRODUCTION Indicators 1 2 3 scored on ● ● ●

B.1 Environmental risk-management strat- B.2 Commitment to increase transpar- B.3 Commits to following GMP, including at egy for own sites. ency regarding environmental risk 3rd-party sites. Shionogi has an environmental risk-management management. Shionogi reports that it has mechanisms for strategy to minimise the impact of antibiotic Shionogi does not currently disclose its strat- maintaining a high quality of antibiotic produc- manufacturing discharge that includes audit- egy to minimise the impact of manufacturing tion — namely following GMP standards. This ing and discharge limits. The strategy currently discharge of antibiotics. Notably, however, it has commitment applies to its own manufacturing applies to Shionogi’s own sites. Shionogi has made a commitment to publish this strategy as sites. Shionogi requires its third-party suppli- committed to extending it, within a year, to its well as the identities of its third-party manu- ers of drug products to apply the same quality third-party manufacturers of antibiotic APIs and facturers. It currently does not publish any ele- standards to their production facilities. drug products. The company has made no state- ments looked for by the Benchmark, namely: ment about extending the strategy to external antibiotic discharge levels, audit results, and the waste-treatment plants. identities of its third-party manufacturers of antibiotic APIs and drug products, or of its external waste-treatment plants.

C APPROPRIATE ACCESS & Indicators 1 2 3 4 5 6 7 STEWARDSHIP scored on ● ○ ○ ● ● ● ●

C.1 Newest marketed antibiotics not filed C.4 Some involvement in AMR-related C.6 No information regarding brochure and/ for registration. education. or packaging adaptations. Shionogi reports that it has not filed its newest Shionogi reports that it is involved in educational Shionogi does not provide sufficient information marketed antibiotics for registration in countries programmes for HCPs that include AMR stew- on any language, cultural or literacy adaptations in scope.* ardship, with conflict of interest (COI) mitigation made to its brochures or packaging that would measures in place. It has strategies in place for promote appropriate use. C.2-C.3 No marketed products in countries in independent content development. Half of the scope. programmes disclosed were delivered through C.7 Surveillance programmes focused on Shionogi reports that it is not marketing any courses, while the remaining programmes are Japan. antimicrobials in any countries in scope.* delivered via web pages and leaflets. Shionogi has engaged with academic institutes Hence, in these countries, Shionogi does not for several short-term surveillance programmes. report having equitable pricing approaches C.5 Adopts appropriate promotion practices. These programmes are aimed at measuring or processes in place to improve supply chain The Benchmark measures how companies the current AMR landscape in different regions efficiency and prevent and/or respond to address stewardship through appropriate pro- across Japan. All Shionogi’s studies will be pub- stock-outs. motion practices. Shionogi reports that it takes lished in peer-reviewed journals. After the period action in this regard: it reflects AMR trends in its of analysis, the company reported engagement marketing materials and does not remunerate its in further surveillance programmes in more sales teams based on antibiotic sales volume. countries, details of which are not available.

145 Antimicrobial Resistance Benchmark 2018 Summit Therapeutics plc

Stock exchanges: XLON; XNAS • Tickers: SUMM; SMMT • HQ: Abingdon, UK • Employees: 40 • Signatory to Davos Decl.: No • Signatory to Industry Roadmap: No

Performance by Research Area How Summit was evaluated: applicable indicators

Summit is a biopharmaceutical company, selected for having lic-private partnerships to develop its antibiotic candidates. a pipeline that targets priority pathogens. It was evaluated in The company reports that it has an access commitment in the area of Research & Development only. It invested USD 5 place for its antibiotic candidate in late-stage development, million in antibiotic drug development in 2016. The company but reports no information on stewardship provisions. performs well compared to other biopharmaceutical companies in scope. It has one project in its antimicrobial R&D pipeline targeting priority pathogens. Summit engages in pub-

OPERATIONS

Summit is a biopharmaceutical company focus- tively target C. difficile bacteria without disrupt- ogy company with a proprietary genetics-based sing on the development of novel medicines for ing the gut flora, thereby reducing CDI recur- platform facilitating the discovery and develop- indications for which current therapies are lack- rence rates—a common clinical issue in this ment of differentiated antibiotics. Summit was ing or inadequate. The company was founded in disease. The company plans to start Phase III listed on the AIM market of the London stock 2003 as a spin-off from the University of Oxford trials for ridinilazole in the first half of 2018. exchange in 2004, after raising GBP 15 mil- and is currently conducting two clinical pro- Summit has no products on the market. In lion from investors. In 2015, it was listed on the grammes: one on the genetic disease Duchenne September 2017, the company was awarded NASDAQ stock exchange, where it raised USD muscular dystrophy and the other on C. difficile a contract from BARDA of up to USD 62 mil- 34 million. infections (CDI). Its only antimicrobial drug can- lion for the development of ridinilazole for the didate is ridinilazole, currently in Phase II devel- treatment of CDI. In December 2017, Summit opment. The compound is designed to selec- acquired UK-based Discuva Ltd, a biotechnol-

ANTIMICROBIAL PORTFOLIO

Summit does not have any products on the market.

OPPORTUNITIES

Plan ahead for access and stewardship during R&D. Summit has committed to ensure access and stewardship provisions are in place for its antibiotic candidate (ridinilazole), through its agreement with the Wellcome Trust. It can ensure that these plans are applied and implemented accordingly.

146 Access to Medicine Foundation

PERFORMANCE BY RESEARCH AREA

A RESEARCH & DEVELOPMENT Indicators 1 2.1 2.2 2.3 3 4 Antimicrobial 1 project scored on ○ ● ● ○ ● ● pipeline 1 target priority pathogens

A.2.1-2.2 One novel antibiotic in the clinical lion from the Wellcome Trust for the preclinical stage development, but reports no information pipeline. and clinical development of ridinilazole. Under on stewardship provisions. The access commit- Biopharmaceutical companies in scope were the agreement, Summit is solely responsible for ment for its investigational antibiotic (ridinila- selected based on their pipelines that target pri- the preclinical and clinical development of the zole) has been made through an agreement with ority bacteria. Summit invested USD 5 million in CDI programme. The Wellcome Trust is eligi- the Wellcome Trust. If the company or its licen- antibiotic drug development in 2016. The com- ble to receive a tiered portion of the net revenue sees do not develop, commercialise or exercise pany has one project in its antimicrobial R&D made by Summit or its affiliates (of up to a low- their IP rights in underserved markets within a pipeline targeting a priority pathogen. Summit’s to mid-single digit percentage) following sign- specified timeframe, the Wellcome Trust is per- antimicrobial pipeline consists of the antibiotic ing of a revenue share agreement in 2017. The mitted to take over exploitation of the IP in ridinilazole, currently in clinical Phase II devel- Wellcome Trust is also eligible to receive a mile- those markets. The IP rights were granted to opment for the treatment of CDI. The drug can- stone of a specified amount if cumulative net Summit for a number of major territories includ- didate is a bis-benzimidazole, a new class of revenues exceed a specified amount. In addition, ing the United States, Europe and Japan. No spe- antibiotics for which the mode of action is yet in September 2017, the company was granted up cific strategy has been made for lower- and mid- unknown. to USD 62 million by BARDA for advancing the dle-income countries. For this indicator, coun- clinical and regulatory development of ridinila- tries in scope are 106 low- and middle-income A.3 One R&D project being developed with zole, including through Phase III clinical trials. countries where access to medicine is likely public partners. limited. Summit is developing one R&D project in its A.4 Access commitment in place, but no priority pathogen pipeline through public-pri- information regarding stewardship. vate partnership (including non-profit organisa- Summit reports that it has an access commit- tions). The company has received GBP 6.3 mil- ment in place for its antibiotic candidate in late-

Pipeline targeting priority pathogens

Discovery Preclinical Phase I Phase II Phase III Approval

• Ridinilazole – C. difficile – Bis-benzimidazole – Novel

B MANUFACTURING & PRODUCTION

As a biopharmaceutical company with no products on the market, Summit was not eligible for this Research Area.

C APPROPRIATE ACCESS & STEWARDSHIP

As a biopharmaceutical company with no products on the market, Summit was not eligible for this Research Area.

147 Antimicrobial Resistance Benchmark 2018 Sun Pharmaceutical Industries Ltd.

Stock exchange: XNSE • Ticker: SUNPHARMA • HQ: Mumbai, India • Employees: > 30,000 • Signatory to Davos Decl.: No • Signatory to Industry Roadmap: No

Performance by Research Area How Sun Pharma was evaluated: applicable indicators

Sun Pharma is a prominent producer of antibiotics glob- publicly available information is limited, specifically regard- ally by sales volume. As a generic medicine manufacturer, ing its approach to manufacturing high quality antibiotics, its Sun Pharma was evaluated in Manufacturing & Production approach to equitable pricing, where it has filed antibiotics and Appropriate Access & Stewardship only. Its performance for registration, its actions to ensure efficient supply and its is low compared to other generic medicine manufacturers involvement in stewardship activities. in scope. It reported no information to the Benchmark, and

SALES AND OPERATIONS RevenuesSun by product§ RevenuesMade: by regionII Final: no

Sun Pharma, founded in 1983, is an Indian-based central nervous system (CNS). The company has generic medicine manufacturer focussing on the 42 manufacturing sites spread across six conti- . production of generic medicines, specialty prod- nents and markets its products in more than 150 . . . ucts, over-the-counter (OTC) products, antiret- countries worldwide. bn INR bn INR rovirals (ARVs) and active pharmaceutical ingre- In 2015, Sun Pharma completed the acquisi- . . dients (APIs). The company’s business segmen- tion of Ranbaxy Laboratories Limited, an Indian- tation is based on a mix of geographical and based company focused on generic medicines ● Total revenue ● USA therapeutic areas. It listed its anti-infectives seg- with international operations, and a member of ● India ment as its fourth-biggest therapeutic segment the Daiichi Sankyo group (at the time of acqui- ● Emerging Markets ● Rest of World by revenue, after cardiology, neuropsychiatry sition). The merger combined Sun Pharma’s and gastroenterology. The company’s specialty established specialty business with Ranbaxy’s business focuses on the therapeutic areas of global operations in generic medicines. dermatology, ophthalmology, oncology and the Antimicrobial portfolio breakdown

ANTIMICROBIAL PORTFOLIO According to publicly available data, Sun Pharma The remainder (27) of the company’s portfo- markets at least 69 antimicrobial medicines, 35 lio is diverse, comprising antifungals, anthelmin- of which are listed on the WHO EML (Section thics, antiprotozoals and antivirals, 13 of which 6). Forty-two of the company’s antimicro- target HIV. bial medicines are antibiotics, with 18 listed on ● Antibiotics on WHO EML† WHO EML Categories the WHO EML (Section 6), including two in the ● Antibiotics not on ● Access group only EML’s Reserve group (colistin and tigecyclin). WHO EML† ● Access & Watch groups ● Other antimicrobial ● Watch group only medicines ● Reserve group ● Not grouped OPPORTUNITIES

Engage in antimicrobial stewardship. Sun levels of antibiotic discharge. Currently, the company does not disclose such information. Pharma can engage in stewardship activi- pany does not report having an environmental ties, e.g., through surveillance activities, educa- risk-management strategy. Engage in R&D innovation. Sun Pharma can tional activities for healthcare professionals on engage in incremental R&D innovation to AMR (while mitigating conflicts of interest), and Ensure affordability and registration plans for address resistance, improve adherence and the engage in appropriate promotion practices. new and existing antimicrobials. Sun Pharma appropriate use of antimicrobial medicines. can seek to improve access in low- and mid- Ensure transparency regarding environmental dle-income countries through the registration of risk. Sun Pharma can share information on how new and existing antimicrobials, and ensure that it manages environmental risk, e.g., disclose the they are priced affordably. Currently, the com- * Countries in scope are 106 low- and middle-income countries where access to medicine is likely limited 148 † EML Section 6: Anti-Infective Medicines § Revenue from operations; FYE 31 March 2017 || Sales; FYE 31 March 2017 Access to Medicine Foundation

PERFORMANCE BY RESEARCH AREA

A RESEARCH & DEVELOPMENT

As a generic medicine manufacturer, Sun Pharma’s main focus is the manufacturing of generic products and, as such, was not in scope for this Research Area.

B MANUFACTURING & PRODUCTION Indicators 1 2 3 scored on ● ● ●

B.1 Reports no environmental risk- B.2 No transparency on environmental risk B.3 No statement on how antibiotic quality is management strategy. management. maintained. Sun Pharma does not report having an environ- Sun Pharma does not disclose its strategy to Sun Pharma makes no statement regarding how mental risk-management strategy in place to minimise the impact of manufacturing discharge it ensures high-quality antibiotic production fol- minimise the environmental impact of manufac- of antibiotics. It does not publish any element lowing international manufacturing standards turing discharge of antibiotics. looked for by the Benchmark, namely: antibiotic accepted by recognised national and interna- discharge levels, audit results, and the identities tional authorities (such as GMP). of its third-party suppliers of antibiotic APIs and drug products, or of its external waste-treatment plants.

C APPROPRIATE ACCESS & Indicators 1 2 3 4 5 6 7 STEWARDSHIP scored on ● ● ● ● ● ● ●

C.1 No information on filing for registration. C.3 No insight into steps addressing supply C.4-C.7 No apparent involvement in steward- Sun Pharma reports no information on where it chain efficiency. ship activities. has filed its newest antibiotics for registration in Sun Pharma does not disclose how it works with Sun Pharma does not report any involvement in countries in scope.* This information is not oth- stakeholders (e.g., governments, procurers) to stewardship activities (from education to sur- erwise publicly available. align supply and demand for antimicrobial med- veillance to appropriate promotion practices) icines, specifically to prevent or minimise stock- that promote appropriate antibiotic use. C.2 No disclosure on equitable pricing outs in countries in scope.* The company also approach. does not report on whether it has processes in Sun Pharma does not disclose an equitable pric- place to respond to stock-outs in countries in ing approach for its highest-volume antibiotics scope.* and/or antimicrobial medicines.

149 Antimicrobial Resistance Benchmark 2018 Tetraphase Pharmaceuticals, Inc.

Stock exchange: XNAS • Ticker: TTPH • HQ: Watertown, MA, USA • Employees: 66 • Signatory to Davos Decl.: Yes • Signatory to Industry Roadmap: No

Performance by Research Area How Tetraphase was evaluated: applicable indicators

Tetraphase is a biopharmaceutical company, selected for jects in its antimicrobial R&D pipeline, all targeting priority having a pipeline that targets priority pathogens. It was evalu- pathogens. Tetraphase engages in public-private partnerships ated in the area of Research & Development only. It invested to develop its antibiotic candidates. The company has one USD 64 million in antibiotic drug development in 2016, which antibiotic in late-stage clinical development. Tetraphase is the is high compared to other biopharmaceutical companies in only biopharmaceutical company identified by the Benchmark the Benchmark. The company performs well compared with to have both an access and stewardship provision in place for other biopharmaceutical companies in scope. It has three pro- an antibiotic in late-stage clinical development.

OPERATIONS

Tetraphase, founded in 2006, is a biopharma- is currently undergoing Phase III trials for the TP6076, an investigational synthetic fluorocy- ceutical company focusing on the design and treatment of complicated intra-abdominal infec- cline antibiotic that targets multidrug-resist- development of fully synthetic tetracycline anti- tions and complicated urinary tract infections. ant gram-negative bacteria. The company is also biotics targeting multidrug-resistant bacte- Tetraphase has no products on the market. exploring the use of its tetracycline candidate ria. The company’s proprietary chemistry plat- In recent years, Tetraphase has secured sev- compounds in other therapeutic areas, includ- form has resulted in a library of tetracycline ana- eral grants from various partners, including the ing oncology and inflammatory diseases. In 2013, logues containing more than 2,500 compounds. US National Institute of Allergy and Infectious Tetraphase was listed on the NASDAQ stock The company’s most advanced drug candidate, Diseases (NIAID) and BARDA. The latter cur- exchange, where it raised USD 75 million. eravacycline, is a broad-spectrum antibiotic rently supports the joint development of erava- being developed in both oral and intravenous cycline with the R&D company CUBRC. In 2017, formulations for the treatment of resistant and Tetraphase was awarded USD 4 million (over an multidrug-resistant infections. The compound 18-month period) by CARB-X, to further develop

ANTIMICROBIAL PORTFOLIO

Tetraphase does not have any products on the market.

OPPORTUNITIES

Expand stewardship provisions for eravacycline. Tetraphase is the only company to have access and stewardship provisions (involving a surveillance programme), for an antibiotic in late-stage clinical development. It can ensure that further stewardship provisions are in place, e.g., appropriate promotion practices.

150 Access to Medicine Foundation

PERFORMANCE BY RESEARCH AREA

A RESEARCH & DEVELOPMENT Indicators 1 2.1 2.2 2.3 3 4 Antimicrobial 3 projects scored on ○ ● ● ○ ● ● pipeline 3 target priority pathogens

A.2.1-2.2 Pipeline focussed on tetracycline organisation). Tetraphase has received funding Eastern Europe, India, Middle East, North Africa antibiotics. from BARDA for the development of eravacy- and South America. For this indicator, coun- Biopharmaceutical companies in scope were cline, NIAID for TP271 and CARB-X for TP6076. tries in scope are 106 low- and middle-income selected based on their pipelines that target pri- Through CARB-X, Tetraphase also shares IP countries where access to medicine is likely lim- ority bacteria. Tetraphase invested USD 64 mil- rights with the Wellcome Trust for TP6076. ited. Tetraphase has an ongoing global surveil- lion in antimicrobial R&D in 2016. The company This enables the Wellcome Trust to commer- lance programme in collaboration with IHMA, has three projects in its antimicrobial R&D pipe- cialise the medicine in underserved markets, if Inc., which monitors the susceptibility to erava- line targeting priority pathogens, all of which necessary. cycline of gram-negative and gram-positive bac- are broad-spectrum fluorocycline candidates. Its teria and anaerobes in all types of hospitals (gov- leading candidate is eravacycline, a broad-spec- A.4 Only biopharmaceutical company to have ernment, teaching, community, etc.). 1.5 full-time trum antibiotic in development for compli- both an access and stewardship provi- equivalent employees (FTEs) are dedicated to cated intra-abdominal infections and compli- sion in place. the surveillance programme and its Antimicrobial cated urinary tract infections. Its two other tet- Tetraphase reports that it has both an access Voluntary Evaluation Program (AVEP). AVEP racycline compounds (TP271 and TP6076) are in and stewardship provision in place for its antibi- provides strips and disks that enable hospitals to Phase I clinical development for the treatment of otic in late-stage development. It is the only bio- test susceptibility of pathogens to the antibiotic. gram-negative bacterial infections. pharmaceutical company to have these provi- The annual cost of the global surveillance pro- sions in place for an investigational antibiotic gramme is USD 750,000, and the annual cost of A.3 All R&D projects being developed with (eravacycline). Following approval, the company AVEP is USD 350,000 (for US and EU markets). public partners. intends to commercialise eravacycline directly Tetraphase is developing all three R&D projects in the USA and the EU. The company is actively in its priority pathogen pipeline through pub- seeking partners to develop and commercial- lic-private partnership (including a non-profit ise eravacycline in regions including Asia-Pacific,

Pipeline targeting priority pathogens

Discovery Preclinical Phase I Phase II Phase III Approval

• TP271 – ESBL, • Eravacycline – A. baumannii, CRE, ESBL, A. VRE, S. aureus, baumannii, VRE, C. difficile – Flu- S. aureus, C. dif- orocycline – ficile – Fluorocy- CABP cline – cIAI, cUTI • TP6076 – CRE, ESBL, A. bau- CABP = Community-acquired bacterial pneumonia mannii, VRE, S. cIAI = Complicated intra-abdominal infection aureus, C. diffi- cUTI = Complicated urinary tract infection cile – Fluorocy- cline

B MANUFACTURING & PRODUCTION

As a biopharmaceutical company with no products on the market, Tetraphase was not eligible for this Research Area.

C APPROPRIATE ACCESS & STEWARDSHIP

As a biopharmaceutical company with no products on the market, Tetraphase was not eligible for this Research Area.

ANIMAL HEALTH & DIAGNOSTICS

Activities in this area are not scored by the Tetraphase supports the Antimicrobial Voluntary didate eravacycline. Benchmark. This information is provided given Evaluation Program (AVEP), which provides the importance of animal health and diagnostics strips and disks that enable hospitals to test the on the topic of AMR. susceptibility of pathogens to its antibiotic can-

151 Antimicrobial Resistance Benchmark 2018 Teva Pharmaceutical Industries Ltd.

Stock exchanges: XNYS; XTAE • Ticker: TEVA • HQ: Petach Tikva, Israel • Employees: 56,960 • Signatory to Davos Decl.: Yes • Signatory to Industry Roadmap: No

Performance by Research Area How Teva was evaluated: applicable indicators

Teva is a prominent producer of antibiotics globally by sales nal waste-treatment plants. The company reports that it has volume. As a generic medicine manufacturer, Teva was evalu- mechanisms for maintaining a high quality of antibiotic pro- ated in Manufacturing & Production and Appropriate Access duction, and requires its third-party suppliers to apply the & Stewardship only. The company performs well when com- same quality standards to their production facilities. Teva pared with the other generic medicine manufacturers in reported no information on its access strategies regarding scope. It discloses a comprehensive environmental risk-man- antimicrobial medicines in countries in scope* or its involve- agement strategy, which it does not apply to third-party man- ment in stewardship activities that promote appropriate anti- ufacturers of antibiotic APIs and drug products or to exter- biotic use.

SALES AND OPERATIONS RevenuesTeva by product§ RevenuesMade: by region§ Final: no

Teva is an Israeli-based generic medicine man- Gamble called PGT Healthcare. Teva has the ufacturer founded in 1901. The company oper- highest revenue among the generic medicine . . ates in two business segments: generic and spe- manufacturers included in the Benchmark. The . . cialty medicines. Its specialty medicines seg- company markets its antimicrobial medicines in bn USD bn USD ment focuses on delivering medicines, devices 54 countries globally, seven of which are low- or . and services in the core therapeutic areas of res- middle-income countries.* piratory illness, central nervous system (includ- In 2016, Teva acquired Actavis Generics, the ● Total revenue ● USA ing pain, migraine, movement and neurodegen- global generic pharmaceuticals business from ● Europe erative disorders), oncology and women’s health. Allergan plc, for approximately USD 33.4 billion ● Rest of world It engages in R&D activities within both its busi- cash and 100 million Teva shares. The acquisition ness segments, focusing on the development of required the divestment of certain assets and complex technologies and formulations. Teva is operations in the USA and Europe to meet anti- active in 80 countries and has 87 manufactur- trust regulatory requirements. Later in 2016, the ing facilities, manufacturing and supplying active company completed the acquisition of Anda Inc., pharmaceutical ingredients on a global scale. It a US-based distributor of generic pharmaceuti- also has a global over-the-counter (OTC) busi- cals from Allergan for USD 500 million. ness, including a collaboration with Procter &

ANTIMICROBIAL PORTFOLIO Antimicrobial portfolio breakdown

Teva markets at least 44 antimicrobial medi- ing 16 medicines consist of nine antivirals, four cines, 30 of which are listed on the WHO EML antifungals and three antiprotozoals indicated (Section 6). Twenty-eight of the company’s anti- for treatment of malaria. microbial medicines are antibiotics, with 17 listed on the WHO EML (Section 6), including one on the EML’s Reserve group (linezolid). The remain-

● Antibiotics on WHO EML† WHO EML Categories ● Antibiotics not on ● Access group only WHO EML† ● Access & Watch groups * Countries in scope are 106 low- and middle-income ● Other antimicrobial ● Watch group only countries where access to medicine is likely limited medicines ● Reserve group † EML Section 6: Anti-Infective Medicines ● Not grouped § Net revenues; FYE 31 December 2016

152 Access to Medicine Foundation

OPPORTUNITIES

Engage in antimicrobial stewardship. Teva can Improve transparency regarding environmental ment strategy is applied to external waste treat- engage in stewardship activities, e.g., through risk management. Teva can share more informa- ment plants and can apply its discharge limits surveillance activities, educational activities for tion on how it manages environmental risk, e.g., and auditing processes to third-party suppliers healthcare professionals on AMR (while mitigat- disclose the levels of antibiotic discharge and of antibiotic APIs and drug products. ing conflicts of interest), and engage in appropri- publish the identities of third parties who manu- ate promotion practices. facture antibiotic APIs and drug products on its Engage in R&D innovation. Teva can engage in behalf. Teva currently discloses its environmen- incremental R&D innovation to address resist- Ensure affordability and registration plans for tal risk-management principles. ance, improve adherence and the appropriate new and existing antimicrobials. Teva can seek use of antimicrobial medicines. to improve access in low- and middle-income Expand environmental risk-management strat- countries through the registration of new and egy. Teva has an environmental risk-manage- existing antimicrobials, and ensure that they are ment strategy that includes discharge limits, priced affordably. Currently, the company does which are applied to its own manufacturing sites. not disclose such information. It can ensure its environmental risk-manage-

PERFORMANCE BY RESEARCH AREA

A RESEARCH & DEVELOPMENT

As a generic medicine manufacturer, Teva’s main focus is the manufacturing of generic products and, as such, was not in scope for this Research Area.

B MANUFACTURING & PRODUCTION Indicators 1 2 3 scored on ● ● ●

B.1 Environmental risk-management B.2 Limited transparency regarding environ- B.3 Commits to following GMP, including at strategy for own sites. mental risk management. 3rd-party sites. Teva applies an environmental risk-management Teva publishes its environmental risk-manage- Teva reports that it has mechanisms for main- strategy to minimise the impact of antibiotic ment strategy in its CSR report. It does not dis- taining a high quality of antibiotic production manufacturing discharge that includes audit- close audit results, or the discharge levels of — namely following GMP standards. This coming and discharge limits. The strategy applies antibiotics. The company also does not share the mitment applies to its own manufacturing sites. to Teva’s own sites and to its third-party manu- identities of its third-party suppliers of antibiotic Teva requires its third-party suppliers to apply facturers of antibiotic APIs and drug products; APIs and drug products or external waste-treat- the same quality standards to their production however, the discharge limits and auditing pro- ment plants. facilities. cesses are applicable to its own manufacturing sites only. The strategy does not apply to external waste-treatment plants.

C APPROPRIATE ACCESS & Indicators 1 2 3 4 5 6 7 STEWARDSHIP scored on ● ● ● ● ● ● ●

C.1 No information on filing for registration. C.3 No insight into steps addressing supply C.4-C.7 No apparent involvement in steward- Teva reports no information on where it has filed chain efficiency. ship activities. its newest antibiotics for registration in coun- Teva does not disclose how it works with stake- Teva does not report any involvement in stew- tries in scope.* This information is not otherwise holders (e.g., governments, procurers) to align ardship activities (from education to surveillance publicly available. supply and demand for antimicrobial medicines, to appropriate promotion practices) that pro- specifically to prevent or minimise stock-outs in mote appropriate antibiotic use. C.2 No disclosure on equitable pricing countries in scope.* The company also does not approach. report on whether it has processes in place to Teva does not disclose an equitable pricing respond to stock-outs in countries in scope.* approach for its highest-volume antibiotics and/ or antimicrobial medicines.

153 Antimicrobial Resistance Benchmark 2018 The Medicines Company*

Stock exchange: XNAS • Ticker: MDCO • HQ: Parsippany, NJ, USA • Employees: 410 • Signatory to Davos Decl.: Yes • Signatory to Industry Roadmap: No

Performance by Research Area How The Medicines Company was evaluated: applicable indicators

The Medicines Company is a biopharmaceutical company, received FDA approval for its meropenem/vaborbactam selected for having a pipeline that targets priority pathogens. combination in August 2017. The company engages in pub- At the end of 2017, the company announced that it would lic-private partnerships to develop its antibiotic candidates. divest its infectious disease business to Melinta, another The company reports no information on access or steward- biopharmaceutical company in scope of the Benchmark. ship provisions for its recently FDA-approved antibiotic. The The divestment was completed in January 2108. The Medicines Company was not evaluated in the Manufacturing Medicines Company was evaluated in the area of Research & Production area; however, it is the only company in scope & Development only, although it has a number of antibiot- to disclose identities of third-party manufacturers of its ics on the market. It performs well compared to other biop- antibiotics. harmaceutical companies in scope. The Medicines Company

§ § SALES AND OPERATIONS RevenuesThe Medicines by product Company RevenuesMade: by region Final: no

The Medicines Company is a US-based biophar- tions. The compound was developed with fund- . maceutical company with core therapeutic areas ing from BARDA, first under a contract of USD . in infectious disease care, cardiovascular care, 90 million and, starting in 2016, under a new surgery and perioperative care. The company’s five-year contract of up to USD 132 million. . . mn USD mn USD revenues in the past three years have come pri- At the end of 2017, The Medicines Company marily from the US sales of its cardiovascular announced that it would divest its infectious dis- . medicine bivalirudin (Angiox® or Angiomax®), ease business to Melinta, another biopharma- ● Total revenue ● USA a direct thrombin inhibitor. These revenues ceutical company in scope of the Benchmark. ● Europe include approximately USD 71.2 million in roy- The divestment was completed in January 2018 ● Rest of World alties derived from the authorised sale of the and included three marketed antimicrobial med- generic version of bivalirudin (Angiomax®) by icines: meropenem/vaborbactam (Vabomere™), Sandoz. In August 2017, the company received minocycline (Minocin®) and oritavancin FDA approval to commercialise its intrave- (Orbactiv®). The company’s two other marketed nous formulation of meropenem/vaborbac- antimicrobial medicines (azithromycin and clin- tam (Vabomere™), which is active against mul- damycin) are generic medicines comercialised tidrug-resistant gram-negative bacteria, for the via a licensing and supply agreement with APP treatment of complicated urinary tract infec- Pharmaceuticals, LLC.

ANTIMICROBIAL PORTFOLIO Antimicrobial portfolio breakdown

According to publicly available data, The lations of two other antibiotics: the broad-spec- Medicines Company’s portfolio of antimicro- trum agent minocycline (Minocin®), approved to bial medicines consists of five antibiotics. treat Acinetobacter species infections, and the One of these antibiotics, clindamycin, is listed antibiotic oritavancin (Orbactiv®), active against on the WHO EML (Section 6), in the Access gram-positive pathogens and indicated for the group. The remaining four medicines are the treatment of acute bacterial skin and skin struc- recently approved meropenem/vaborbactam ture infections in adults, including those due to (Vabomere™), azithromycin (for intravenous methicillin-resistant S. aureus (MRSA). administration) and powder-for-injection formu- ● Antibiotics on WHO EML† WHO EML Categories ● Antibiotics not on ● Access group only WHO EML† ● Access & Watch groups † EML Section 6: Anti-Infective Medicines * In January 2018, The Medicines Company completed ● Other antimicrobial ● Watch group only § Net revenues; FYE 31 December 2016 the divestment of its infectious disease business to medicines ● Reserve group Melinta Therapeutics, Inc. ● Not grouped

154 Access to Medicine Foundation

PERFORMANCE BY RESEARCH AREA

A RESEARCH & DEVELOPMENT Indicators 1 2.1 2.2 2.3 3 4 Antimicrobial 1 projects scored on ○ ● ● ○ ● ● pipeline 1 target priority pathogens

A.2.1-2.2 One antibiotic recently approved. A.3 One R&D project being developed with A.4 No information on access or stewardship Biopharmaceutical companies in scope were public partners. provisions. selected based on their pipelines that target pri- The Medicines Company developed merope- The Medicines Company reports no informa- ority bacteria. The Medicines Company received nem/vaborbactam (Vabomere™) in partnership tion on access or stewardship provisions for its FDA approval for its meropenem/vaborbac- with BARDA, which began with a five-year con- recently FDA-approved antibiotic. It has signed tam (Vabomere™, formerly Carbavance™) in tract in 2014, followed by a new five-year con- the Davos Declaration, which includes a gen- August 2017. Vaborbactam is a ß-lactamase tract in 2016 (≤ USD 132 million). eral commitment to ensuring access to antimi- inhibitor (BLI) with a novel chemical struc- crobial medicines and vaccines, and to support ture. Meropenem is an existing carbapenem the appropriate and responsible use of these ß-lactam. Vaborbactam restores susceptibil- products. ity to meropenem in carbapenem-resistant Enterobacteriaceae (CRE).

Pipeline targeting priority pathogens

Discovery Preclinical Phase I Phase II Phase III Approval

• Meropenem/ vaborbactam (Vabomere™) – CRE – Novel ß-lactamase inhibitor vaborbactam and existing ß-lactam – cUTI cUTI = Complicated urinary tract infection – FDA approval 2017 – Novel

B MANUFACTURING & PRODUCTION

The Medicines Company is a biopharmaceutical B.2 Only company to disclose identities of company that did not meet the criteria for eval- third-party suppliers. uation in this Research Area. It does, however, On reviewing publicly available information, the have products on the market, and notable prac- Benchmark found that The Medicines Company tices relevant to this area are mentioned. has disclosed the identities of third-party manufacturers of its antibiotics, per product, in its annual report. It is the only company to publish this information.

C APPROPRIATE ACCESS & STEWARDSHIP

The Medicines Company is a biopharmaceutical company that did not meet the criteria for evaluation in this Research Area. It does, however, have products on the market.

155 Antimicrobial Resistance Benchmark 2018 Wockhardt Limited

Stock exchange: XNSE • Ticker: WOCKPHARMA • HQ: Mumbai, India • Employees: 6,768 • Signatory to Davos Decl.: Yes • Signatory to Industry Roadmap: Yes

Performance by Research Area How Wockhardt was evaluated: applicable indicators

Wockhardt is a biopharmaceutical company, selected for in-house and/or with private-sector partners to develop its having a pipeline that targets priority pathogens. It was eval- antibiotic candidates. The company reports no information on uated in the area of Research & Development only, although access or stewardship provisions for its five antibiotic candi- it has a number of antimicrobials on the market. Although its dates in late-stage development. Wockhardt was not evalu- performance in the Benchmark is lower compared to other ated in the Appropriate Access & Stewardship area. However, biopharmaceutical companies in scope, all five of its R&D pro- it engages in patient and community educational programmes jects target priority pathogens. Wockhardt does not engage in India and also coordinates an AMR surveillance programme in public-private partnerships; however, it conducts R&D to monitor resistance trends in India.

SALES AND OPERATIONS RevenuesWockhardt by product§ RevenuesMade: by region§ Final: no

Wockhardt is an Indian-based biopharmaceutical susceptibility testing (AST) relevant to its novel company with a focus on R&D. Besides pharma- antibacterial drugs under development. ceutical research, the company’s research pro- Wockhardt sells antimicrobial medicines in . . gramme includes areas such as genomics, bio- the USA, the UK, Ireland, Puerto Rico, Russia, mn USD mn USD technology and novel drug delivery systems. Norway, India and Vietnam. The latter two are Wockhardt is currently developing a new drug considered low- or middle-income countries.* Its discovery programme focussing on unmet needs vaccines are sold exclusively in India. In the fiscal ● Vaccines & ● India in bacterial infections (both gram-negative and year 2016, Wockhardt sold 142 million Standard antimicrobials ● Europe gram-positive). The company is also involved in Units (SUs) of antimicrobial medicines and 1.1 ● Other revenue ● USA ● Rest of World the development of diagnostics for antibiotic million SUs of vaccines.

ANTIMICROBIAL PORTFOLIO Antimicrobial portfolio breakdown

Wockhardt markets at least 25 antimicrobial listed on the WHO EML (Section 6). The compa- medicines, 19 of which are listed on the WHO ny’s vaccines target hepatitis A (Biovac A®) and EML (Section 6). Twenty-one of the compa- chickenpox (Biovac V®). ny’s antimicrobial medicines are antibiotics, with 15 listed on the WHO EML (Section 6), including one in the EML’s Reserve group (colistin, Wockstin®). The remainder (four) of the company’s portfolio consists of two antifungals, the antimalarial quinine and the antiviral aciclovir, all ● Antibiotics on WHO EML† WHO EML Categories ● Antibiotics not on ● Access group only WHO EML† ● Access & Watch groups ● Other antimicrobial ● Watch group only OPPORTUNITIES medicines ● Reserve group ● Not grouped Plan ahead for access and stewardship during R&D. Wockhardt is developing five antibiotic candidates in late-stage clinical development. Wockhardt can ensure access and stewardship provisions are in place for these candidates, for * Countries in scope are 106 low- and middle-income example, through partnerships. countries where access to medicine is likely limited † EML Section 6: Anti-Infective Medicines § Revenue from operations; FYE 31 March 2017

156 Access to Medicine Foundation

PERFORMANCE BY RESEARCH AREA

A RESEARCH & DEVELOPMENT Indicators 1 2.1 2.2 2.3 3 4 Antimicrobial 5 projects scored on ○ ● ● ○ ● ● pipeline 5 target priority pathogens

A.2.1-2.2 Five broad-spectrum antibiotics biotic. The other four medicines in the compa- private-sector partners. It does not participate targeting priority pathogens. ny’s pipeline are: one macrolide (nafithromycin); in public-private partnerships, or in partner- Biopharmaceutical companies in scope were two broad-spectrum antibiotic fluoroquinolones ships with non-profit organisations, for antimi- selected based on their pipelines that target (alalevonadifloxacin and levonadifloxacin), which crobial R&D. priority bacteria. Wockhardt has five antibiot- are being developed specifically for gram-posi- ics that target priority pathogens, one of which tive bacterial infections (including MRSA infec- A.4 No information on access or stewardship is a combination of two existing agents. All five tions and community-acquired bacterial pneu- provisions. medicines are in Phase III clinical stage devel- monia); and a new high-dose combination of Wockhardt reports no information on access or opment. The company’s pipeline includes a new cefepime/tazobactam, which is active against stewardship provisions for its five antibiotic candi- ß-lactam enhancer (zidebactam), developed in multidrug-resistant Enterobacteriaceae, includ- dates in late-stage development. It has signed the combination with ß-lactam cefepime for the ing ESBL-, KPC- and OXA-181-expressing strains. Davos Declaration, which includes a general com- treatment of multidrug-resistant gram-nega- mitment to ensuring access to antimicrobial med- tive bacterial infections. In 2017, the FDA agreed A.3 No public-private partnerships reported. icines and vaccines, and to support the appropri- to an abridged Phase III clinical trial for this anti- Wockhardt conducts R&D in-house and/or with ate and responsible use of these products.

Pipeline targeting priority pathogens

Discovery Preclinical Phase I Phase II Phase III Approval

• Cefepime/zidebactam (WCK5222) – CRE, ESBL, P. aeruginosa, A. baumannii – New ß-lactam enhancer & existing ß-lactam – BSI, CABP/HABP cIAI, cUTI • Levonadifloxacin (WCK771) – S. pneumoniae, S. aureus, Hib – Fluoro- quinolone – ABSSSI, HABP/VABP, DFI • Alalevonadifloxacin (WCK2349) – S. pneumoniae, S. aureus, Hib – Oral prodrug of levonadifloxacin – ABSSSI, ABSSSI = Acute bacterial skin and skin structure CABP/HABP, DFI infections • Nafithromycin (WCK4873) – S. pneu- BSI = Bloodstream infection moniae, S. aureus, Hib – Macrolide – CABP/HABP = Community-/Hospital-acquired bacterial pneumonia CABP/HABP, chlamydial urethritis, oti- cIAI = Complicated intra-abdominal Infection tis media, URTI cUTI = Complicated urinary tract infection • Cefepime/tazobactam (WCK4282) – DFI = Diabetic foot infection CRE, ESBL, P. aeruginosa – Adaptation FDC = Fixed dose combination URTI = Upper respiratory tract infection (new FDC of existing ß-lactam & ß-lacta- VABP = Ventilator-associated bacterial pneumonia mase inhibitor) – BSI, cIAI, cUTI, HABP

B MANUFACTURING & PRODUCTION

Wockhardt is a biopharmaceutical company that Research Area. It does, however, have products did not meet the criteria for evaluation in this on the market.

C APPROPRIATE ACCESS & STEWARDSHIP

Wockhardt is a biopharmaceutical company that Wockhardt was not eligible for this indicator, C.7 Only biopharmaceutical company did not meet the criteria for evaluation in this and does not provide any information in AMR- to report running a surveillance Research Area. It does, however, have products related education for HCPs. Notably, however, programme. on the market, and notable practices relevant to the company engages in patient education with Wockhardt was not eligible for this indica- this area are mentioned. its Mobile 1000 programme in India through tor. Notably, however, the company coordi- the Wockhardt Foundation. This programme nates a surveillance programme in India, which C.4 No apparent involvement in AMR-related includes Water, Sanitation and Hygiene (WASH) works with hospitals and laboratories to monitor education for HCPs. education and other health promotion activities. resistance trends. This programme is completely funded by Wockhardt.

ANIMAL HEALTH & DIAGNOSTICS

Activities in this area are not scored by the Wockhardt is involved in the development of Benchmark. This information is provided given diagnostics for antibiotic susceptibility testing the importance of animal health and diagnostics (AST) relevant to its novel antibacterial drugs on the topic of AMR. under development. 157 Antimicrobial Resistance Benchmark 2018

158