Dear All,
Prompted by an excellent talk by GARDP’s Jennifer Cohn at last week’s ASM-ESCMID Developer’s conference, today I’d like to pull together several threads showing how responsible manufacturing and access are intertwined. (And if you missed the ASM-ESCMID meeting, you missed some great talks and great networking … please see the forward calendar for the date of the 2024 meeting and mark your calendar for it NOW).
Here are the links you need along with commentary that enables you to connect the dots:
Step 1: The ideas that underpin responsible manufacturing
- The high-level webpage for the Antibiotic Manufacturing Standard released June 2022 by the AMR Industry Alliance (AMRIA). The standard includes research-based Predicted No-Effect Concentrations [PNECs] for liquid discharge that are key to certifying that manufacturing waste treatment has been sufficient enough to remove antibiotic residues.
- The high-level webpage for an industry-standard manufacturing certification scheme developed by AMRIA in collaboration with BSI Standards Limited (BSI), a well-established and long-running standards institution. Established in 1901, BSI was the world’s first National Standards Body and got its start, in part, by publishing standards for steel sections for tramways!
- A comprehensive August 2023 review by Access to Medicine Foundation entitled “Methods matter: What steps are companies taking to help curb AMR by manufacturing responsibly?” Note that this document contains a very detailed timeline showing the way that work which began in 2006 (!!) led to the 2022-2023 manufacturing standards and certification scheme cited just above.
- As deeper background, see this 4 May 2022 newsletter for Boston Consulting Group’s excellent report on the fragile nature of antibiotic supply chains.
- 20 Sep 2024 addendum: A WHO guidance entitled “Guidance on wastewater and solid waste management for manufacturing of antibiotics” was released on 3 Sep 2024.
Step 2: The (abbreviated!) story of cefiderocol
- Cefiderocol was approved by the European Medicines Agency in 2020 and, separately, by the US Food and Drug Administration in 2019.
- Cefiderocol targets a number of Gram-negative WHO priority pathogens and is on the World Health Organization (WHO) Model List of Essential Medicines.
- As is typical of all antibiotics approved since 2010, access comes only slowly, even in high-income countries.
- See the (19 Aug 2021 newsletter regarding the Outterson et al. 2021 paper entitled “Patient access in fourteen high-income countries to new antibacterials approved by the FDA, EMA, PMDA, or Health Canada, 2010-2020”.
- Also available are a YouTube chat and a slide deck about this report.
Step 3: Ensuring global access for cefiderocol: An ambitious partnership
- A 15 June 2022 press release announced a landmark collaboration between Shionogi, GARDP, and the Clinton Health Access Initiative (CHAI) under which GARDP will manufacture and commercialize cefiderocol through sub-licensees in a large range of countries that have delayed access (if any) to newer antibiotics.
- A 12 Sep 2023 press release reporting a sublicensing agreement between GARDP and India-based Orchid Pharma Ltd (Orchid) to manufacture cefiderocol for use in the 135 countries where GARDP and its partners seek to make cefiderocol available.
- And to pull it all together, the actual manufacturing sublicense agreement is posted online and contains this text (Schedule K, 2nd bullet on page 52 of 53):
- “The Sublicensee shall ensure that any wastewater containing API must achieve, at the very least, the PNEC limits proposed by the AMR Industry Alliance before it is discharged into receiving waters / released into the environment.
- “If data is not yet available for a specific API, a default PNEC of 0.05 μg/L or the limit of detection (LD) will be used as the maximum threshold.”
- And I’m told that the actual discharge from Orchid’s cefiderocol plan is solid waste!
Yow! In summary terms:
- Access requires manufacturing and distribution. The complexity of manufacturing is often under-estimated; for deep insight please review this 9 Jan 2021 newsletter and in particular slides 8-10 form this excellent presentation at a NASEM workshop by Kevin Krause.
- Regional manufacturing can facilitate manufacturing and distribution.
- But, manufacturing discharges can drive antimicrobial resistance.
- GARDP and its partners seek to make a new WHO EML antibiotic available by leveraging high-quality regional manufacturing capabilities that are held to the new responsible antibiotic manufacturing standards.
- And (bringing it all together as shown in this slide from the talk that prompted this newsletter), every access step (beginning with manufacturing) is a potential stewardship lever:
Slide 18 from Jennifer Cohn’s talk … and she has graciously permitted me to post the entire talk here … it contains not only the cefiderocol case study but also a discussion of SECURE, a collaboration between WHO and GARDP that will assist countries to treat drug-resistant infections.
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Impressive! The idea of responsible manufacturing as a part of stewardship is a powerful connection and it’s great to see it emphasized so clearly via this project.
An implicit assumption in this project is that there will be adequate usage-based sales to cover Orchid’s costs of manufacturing (presumably relatively low given that the manufacturing work is being done in India). This might not work with a compound for really rare pathogens, but sufficient usage-based sales seems plausible in this case given current levels of AMR and is obviously required for this to be self-sustaining.
Well done on the part of all the partners in this enterprise … a series of bold steps! I look forward to seeing how it plays out.
All best wishes, –jr
John H. Rex, MD | Chief Medical Officer, F2G Ltd. | Operating Partner, Advent Life Sciences. Follow me on Twitter: @JohnRex_NewAbx. See past newsletters and subscribe for the future: https://amr.solutions/blog/. All opinions are my own.
Current funding opportunities (most current list is here)
- HERA Invest was launched August 2023 with €100 million to support innovative EU-based SMEs in the early and late phases of clinical trials. Part of the InvestEU program supporting sustainable investment, innovation, and job creation in Europe, HERA Invest is open for application to companies developing medical countermeasures that address one of the following cross-border health threats: (i) Pathogens with pandemic or epidemic potential, (ii) Chemical, biological, radiological and nuclear (CBRN) threats originating from accidental or deliberate release, and (iii) Antimicrobial resistance (AMR). Non-dilutive venture loans covering up to 50% of investment costs are available. Applications are accepted on a rolling basis; go here for all the details.
- The ENABLE-2 consortium has announced a call to support hit-to-lead compound development by researchers at publicly-funded European universities. The call is focused on molecules with the potential to be direct-acting therapies for one or more of the following priority pathogens: ESBL-producing/carbapenem-resistant Enterobacteriaceae (E. coli, K. pneumoniae), P. aeruginosa, A. baumannii, methicillin-resistant S. aureus, or vancomycin-resistant E. faecium. The Call is open continuously, applications are reviewed at intervals, and funding is non-dilutive. Expressions of interest received before 30 Sep 2023 would be considered in November 2023. Applications received after this date will be evaluated in the spring of 2024 (date to be decided). Go to https://www.ilk.uu.se/enable2/apply/ for further details.
- The AMR Action Fund is now open to proposals for funding of Phase 2 / Phase 3 antibacterial therapeutics. Per its charter, the fund prioritizes investment in treatments that address a pathogen prioritized by the WHO, the CDC and/or other public health entities that: (i) are novel (e.g., absence of known cross-resistance, novel targets, new chemical classes, or new mechanisms of action); and/or (ii) have significant differentiated clinical utility (e.g., differentiated innovation that provides clinical value versus standard of care to prescribers and patients, such as safety/tolerability, oral formulation, different spectrum of activity); and (iii) reduce patient mortality. It is also expected that such agents would have the potential to strongly address the likely requirements for delinked Pull incentives such as the UK (NHS England) subscription pilot and the PASTEUR Act in the US. Submit queries to contact@amractionfund.com.
- BARDA’s long-running BAA-18-100-SOL-00003 offers support for both antibacterial and antifungal agents. This BAA has offered 4 deadlines/year since 2018 … check the most current amendment for details.
- INCATE (Incubator for Antibacterial Therapies in Europe) is an early-stage funding vehicle supporting innovation vs. drug-resistant bacterial infections. The fund provides advice, community, and non-dilutive funding (€10k in Stage I and up to €250k in Stage II) to support early-stage ventures in creating the evidence and building the team needed to get next-level funding. Details and contacts on their website (https://www.incate.net/).
- These things aren’t sources of funds but would help you develop funding applications
- AiCuris’ AiCubator offers incubator support to very early stage projects. Read more about it here.
- The Global AMR R&D Hub’s dynamic dashboard (link) summarizes the global clinical development pipeline, incentives for AMR R&D, and investors/investments in AMR R&D.
- Diagnostic developers would find valuable guidance in this 6-part series on in vitro diagnostic (IVD) development. Sponsored by CARB-X, C-CAMP, and FIND, it pulls together real-life insights into a succinct set of tutorials.
- In addition to the lists provided by the Global AMR R&D Hub, you might also be interested in my most current lists of R&D incentives (link) and priority pathogens (link).
Upcoming meetings of interest to the AMR community (most current list is here):
- General note: Virtual meetings are easy to attend, but regular attendance at in-person events is the key to networking and deeper insight. My favorite such in-person meetings are marked below as HIGHLY RECOMMENDED and are the BEAM Alliance’s AMR Conference (March, Europe), ECCMID (April, Europe), the ASM-ESCMID Developer’s meeting (September, alternates sides of the Atlantic), and ID Week (October, USA). Of particular value for developers are the AMR Conference and the ASM-ESCMID conference. Hope to see you there!
- [UPDATED WITH SPEAKER DATA — DON’T MISS THIS ONE!] 27 Sep 2023 (virtual, 10a-11a ET): Milken Institute webinar entitled “What’s Next for the UK’s Subscription Model in the Fight Against Antimicrobial Resistance”. Based on the announcement email from Milken, this will be a deep dive from key UK experts (Sophie Cooper from NICE and David Glover from NHS England) who have been integral to the UK’s thinking. Note also that Milken has published (2022) an excellent deep dive into this area. Go here to register.
- [NEW] 26 Sep 2023 (virtual or in-person, 1.00-1.50p ET): Webinar entitled “When antibiotics fail: Solving the deadly superbug threat” sponsored by the Harvard School of Public Health. Go here for details and to register.
- [NEW] 27 Sep 2023 (in-person at BBC Studios, 1120 Avenue of the Americas, New York City 5p ET): Screening (with panel discussion) of “Race Against Resistance: The life and death struggle to save antibiotics”, the fabulous new BBC Storyworks film. Go to https://www.youtube.com/watch?v=5U3k9ruszxI to see the film online; go here to register for the in-person screening.
- [NEW] 27 Sep 2023 (virtual, 2-3p CET, 8-9a ET): GARDP-sponsored webinar entitled “Antibiotic shortages: causes, consequences and solutions.” Go here to register.
- 4 Oct 2023 (Museum of Science, Boston, MA; in person, 11.30a-2.30p ET): Co-sponsored by the Boston’s Museum of Science and the Rijksmuseum Boerhaave (Netherlands), you can attend a luncheon and panel discussion entitled “Celebrating 300 Years of Innovation and Beyond: How van Leeuwenhoek’s Discovery of the Microworld Sparked a Medical Revolution, with a Focus on Antimicrobial Resistance.” Go here for details and to register. I knew about Boston’s MOS but did not know about the exceptional collection of the Rijksmuseum Boerhaave which seeks to “… show what science is all about: curiosity, guts, creativity and perseverance.” Fascinating!
- 7-15 Oct 2023 (residential, Annecy, France): ICARe, the Interdisciplinary Course on Antibiotics and Resistance. Now in its 7th year, this course is a deep-dive into the world of antibiotic development. Intense, rigorous, and HIGHLY recommended. Seats are always limited … apply sooner rather than later! Go here for details.
- 11-15 Oct 2023 (Boston, USA): IDWeek 2023, the annual meeting of the Infectious Diseases Society of America. Go here for details and to register. HIGHLY RECOMMENDED.
- [NEW] 12 Oct 2023 (virtual, 2-3p CET) GARDP-sponsored webinar entitled “Market interventions to improve access to antibiotics for resistant infections.” Go here to register.
- 20-23 Oct 2023 (Athens, Greece): 11th TIMM (Trends in Medical Mycology). Go here for details.
- 6-7 Feb 2024 (online): Antimicrobial Chemotherapy Conference. This is an annual, free of charge conference that is co-organized by GARDP and the British Society for Antimicrobial Chemotherapy (BSAC). Details to follow — for now, just mark your calendar.
- [NEW] 6-7 Mar 2024 (Basel, 6-7 Mar 2024): Sponsored by the BEAM Alliance, the AMR Conference is now in its 8th year and is consistently an excellent meeting for developers. You can’t register yet but you can mark your calendar and signup for notifications about the meeting. HIGHLY RECOMMENDED.
- [NEW] 17-22 Mar 2024 (Ventura Beach, CA, in person): Gordon Research Conference (GRC) entitled “New Antibacterial Discovery and Development” with a 16-17 Mar 2024 pre-conference Gordon Research Seminar (GRS) for young doctoral and post-doctoral researchers. An intensive residential meeting, GRCs are highly recommended for networking and deep research insights. Apply here for the GRC and here for the GRS.
- 27-30 April 2024 (Barcelona, Spain): 34th ECCMID, the annual meeting of the European Society for Clinical Microbiology and Infectious Diseases. Go here for details. HIGHLY RECOMMENDED.
- 26-31 May 2024 (Montreal, Canada): EDAR7, the McGill AMR Centre’s 7th edition of their Environmental Dimension of Antimicrobial Resistance conference. Go here for details; final abstract deadline is 21 Dec 2023.
- [NEW] 13-17 June 2024 (Atlanta, Georgia): ASM Microbe, the annual meeting of the American Society for Microbiology. You can’t register yet, but you can go here for general details.
- [NEW] 17-20 Sep 2024 (Porto, Portugal): ASM/ESCMID Joint Conference on Drug Development to Meet the Challenge of Antimicrobial Resistance. Go here for the meeting’s general website. You can’t register (yet) for the 2024 event, but you can mark your calendar. HIGHLY RECOMMENDED.