Leaky pipe(lines) / When is a molecule a drug? (Part 1 of 2)

Dear All,

I was fascinated by this recent paper in AAC: Neha K. Prasad, Ian B. Seiple, Ryan T. Cirz, and Oren S. Rosenberg. Leaks in the Pipeline: a Failure Analysis of Gram-Negative Antibiotic Development from 2010 to 2020. Antimicrob Agents Chemother. 2022 May 17;66(5):e0005422. doi:10.1128/aac.00054-22. (Addendum: This newsletter has a follow-up newsletter.)

In brief, the authors have surveyed 2010-2020 clinical phase Gram-negative antibacterial candidates to identify development failures (leaks in the pipeline). Although data are not available for all compounds, the authors have provided an insightful compound-by-compound discussion of the public data that do exist and find that the #1 overall cause of failure was unexpected hepato- or nephrotoxicity in early clinical studies.

This is consistent with my personal experience and is also supported by reviews of the relatively poor predictive power of preclinical toxicity studies. There are a number of such commentaries and here’s a recent review (part one, part two) that provides a good survey. As a sample anecdote, TeGenero’s TGN1412t (an antibody for autoimmune disease) produced near-fatal cytokine storm when given at 1/500th the dose found safe in animal testing.

So, what’s to be done about this? Are developers too optimistic? Should these molecules have been terminated sooner? Prasad et al. wish for innovations in preclinical predictive studies to plug the leaks in the pipeline. We can certainly wish for this (yes, please!) … but is it likely? 

My personal view is progress on toxicology tools will be incremental rather than revolutionary. Noting the general commentary (above) on the weakness of preclinical models, I particularly think back to our 3-part series on halicin (SU3227) (part 1, part 2, and XKCD’s witty visual summary in part 3), an antibacterial candidate molecule identified via a machine learning-based approach. I would encourage you to re-read those discussions and especially meditate on the lessons provided by Lynn Silvers’ masterful commentaries. Ultimately, the only system that perfectly mimics human biology is … human biology.

Of note, CARB-X has recognized this problem and in 2020 launched the idea of Portfolio Acceleration Tools (PATs) that would address common issues development issues. First on their list was the idea of predictive and translatable nephrotoxicity models. Also underway is work on tools to (i) provide an early assessment of the likelihood of emergence of resistance, (ii) evaluate antigen conservation in support of vaccine development, (iii) create standardized in vivo translational models, and (iv) evaluate novel adjuvants. Impressive!

It’s encouraging to see that work, but it will take time for those tools to be created … and even then my guess is that surprises will continue to emerge. So, what else could we be doing? Here the authors make a very strong plea for data-sharing. There are some great examples of this (e.g., Achaogen shared data on its LpxC program Forge Therapeutics; Pew Trusts’ SPARK platform has data shared by Merck and Kyorin on a failed program). As noted in a great discussion of ways that data-sharing could enhance R&D efficiency, CARB-X contracts contain language to encourage data sharing and such openness would “help every antibiotic research team to stand on the shoulders of giants, instead of reinventing the wheel.” I could not agree more!

With thanks to Prasad and co-authors for a stimulating paper and all best wishes to the AMR R&D community, –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)


Upcoming meetings of interest to the AMR community (most current list is here):

  • [Not to be missed!] 8 Dec 2021: “The New Winds Pushing and Pulling Antibacterial Development.” This FABULOUS program featured talks from the UK team behind the NHS “Netflix” pilot, Kevin Outterson’s recently released report documenting the need for global Pull incentives to have a value of $2.2 – 4.8b, and speakers covering PASTEUR and work in the EU on pull incentives. The video is here — please make time to listen to this program!
  • [Required reading!] The stunning 4 Feb 2022 webinar for the GRAM report (Global Research on Antimicrobial Resistance “1.27 million deaths per year are directly attributable to AMR”) is now available for replay. #AMRSOS! 
  • 13 or 14 Jun 2022 (virtual,  14.00-17.00 (CEST) on 13 Jun, 09.00-12.00 (CEST) on 14 Jun, same agenda both days): “Supporting measures to mitigate AMR in One Health settings,” webinars sponsored by JPIAMR and ICARS that will consider at length the ‘Prevention and Intervention’ pillar of the JPIAMR’s Strategic Research and Innovation Agenda. Go here for details and to register.
  • 16-18 June 2022 (Perth, Australia): Australasian Society for Infectious Diseases Annual Scientific Meeting is a hybrid event for adult and pediatric infectious disease and clinical microbiology specialists. Go here for details.
  • 21 Jun 2022 (virtual, 10:00-11:00 ET | 15:00-16:00 BST): Launch of the AMR Register. Sponsored by Vivli with funding from many partners, this is the launch of an open-access repository for industry-generated surveillance data. Looks interesting! Go here to register.
  • 22-23 Jun 2022 (virtual, 10a to approx. 2.30p ET on both days): Workshop entitled “Strategies for Early-Stage Programs Developing Novel Antibacterial and Antifungal Drugs.” Sponsored by NIAID’s Bacteriology and Mycology Branch (BMB), this 2-day webinar features a very strong faculty (including speakers from FDA) discussing tips and insights for early product discovery including in-depth discussions of funding opportunities. The timing is US-centered but video replay will be available. Do not miss this! Go here to register.
  • 23 Jun 2022 (Virtual, 2-4p CEST): “Tackling the emerging threat of fungal drug resistance,” a webinar sponsored by JPIAMR, the Israeli MoH, and the UK MRC. Go here to register. Yes, that’s the Israeli Ministry of Health getting into AMR … perhaps in part stimulated by a 2015 report on the significant burden of fungal infections in Israel.
  • 6 July 2022 (virtual, 15:00 CET/ 09:00 ET): WHO webinar entitled “Enhanced use of data to monitor safety and effectiveness of paediatric medicines”. Go here for details. 
  • 11-14 July 2022 (Sydney): Australian Society for Microbiology Annual National Meeting is a hybrid event that will feature a range of lectures and symposium sessions, as well as extensive opportunities for networking. Go here for details.
  • 26 July 2022 (virtual, 10a-11.30a ET): REVIVE webinar entitled “New approaches for antibiotic discovery”. Go here for details. 
  • 24-27 July 2022 (Il Ciocco, Tuscany): Gordon Research Conference entitled “New Antibacterial Discovery and Development”. Go here for details, go here for the linked 5-6 Mar Gordon Research Seminar that precedes it.
  • 28-31 July 2022 (Singapore): 10th International Congress of Asia Pacific Society of Infection Control is a hybrid event for professionals in the Asia Pacific region. Go here for details and to register.
  • [NEW] 10 Aug 2022 (virtual, 10a-4.30p ET): USDA ‘s APHIS (Animal and Plant Health Inspection Service) will host a public meeting on Antimicrobial Resistance. Co-hosted with USDA’s FSIS (Food Safety Inspection Service) and REE (Research, Education and Economics) mission area, the webinar will review lessons learned since the first AMR workshop 2012 as well as discuss plans for the future. Go here to register.
  • 23 August 2022 (virtual, 11a-12.30p ET): REVIVE webinar entitled the Challenges and options in developing antibiotic combinations. Go here for details. 
  • 12-13 Sep 2022 (virtual, 9a-5p ET): This meeting of PACCARB is going to “identify key issues and critical policy gaps through a series of facilitated discussions examining a hypothetical large-scale disease outbreak scenario based on historic examples and estimates of future AMR outbreaks.” Sounds like pandemic wargaming (Center for Health Security; pre-COVID 19 May 2020 NPR article) to me! Go here for details.
  • 20-24 Sep 2022 (New Delhi): 21st Congress of the International Society for Human and Animal Mycology (ISHAM). Go here for details.
  • 4-7 Oct 2022 (Dublin, Ireland): The 2022 ASM/ESCMID Joint Conference on Drug Development to Meet the Challenge of Antimicrobial Resistance. This is an excellent meeting, especially for developers … and if you’ve missed it, the recordings from the 2021 meeting are online. Go here for details on the 2022 meeting.
  • 19-23 Oct 2022 (Washington, DC): IDWeek 2022, the joint annual meeting of the Infectious Diseases Society of America (IDSA), Society for Healthcare Epidemiology of America (SHEA), the HIV Medicine Association (HIVMA), the Pediatric Infectious Diseases Society (PIDS), and the Society of Infectious Diseases Pharmacists (SIDP). Go here for details.
  • 15-23 Oct 2022 (in person, residential, Les Pensières, Veyrier-du-Lac, France): The 6th edition of Patrice Courvalin’s fabulous ICARe residential training course covering all things AMR is on for 2022! This is a soup-to-nuts training in AMR: it is very intense, very detailed, and always gets rave reviews from attendees. Registration is open 21 Mar 2022 to 21 June 2022 and is limited, so book your slot as soon as you can. Go here for details.
  • 19-23 Oct 2022 (Washington, DC): IDWeek 2022, the joint annual meeting of the Infectious Diseases Society of America (IDSA), Society for Healthcare Epidemiology of America (SHEA), the HIV Medicine Association (HIVMA), the Pediatric Infectious Diseases Society (PIDS), and the Society of Infectious Diseases Pharmacists (SIDP). Go here for details.
  • 25-28 Oct 2022 (Stellenbosch, South Africa): The University of Cape Town’s H3D Research Centre will celebrate its 10th anniversary with a symposium covering the Centre’s research on Malaria, TB, Neglected Tropical Diseases, and AMR. Go here to register.
  • 17-20 Nov 2022 (Kuala Lumpur, Malaysia): The International Congress on Infectious Diseases will take place for the first time as a hybrid event. Go here for details. 
  • 27-30 Nov 2022 (Perth, Australia): 32nd International Congress of Antimicrobial Chemotherapy is the biennial congress of the International Society of Antimicrobial Chemotherapy (ISAC). Go here for details.

Dear All,
 
The IDWeek 2024 program committee is again seeking programs on novel antimicrobial agents and novel diagnostics for presentation in pipeline sessions! Here’s what is sought:

  • “Industry partners are invited to submit antimicrobials that are in preclinical stages of development (Phase II and III preferred) or recently approved after January 2024.
  • “The pipeline sessions will include antibacterials, antifungals, and antivirals (excluding COVID-19 and HIV).
  • “The committee also invites companies developing novel diagnostic technologies with a minimum of some preliminary proof of concept data to submit.” 

This is a great opportunity to tell the story of your development project! The deadline to submit is Wednesday, June 26 via the application portal. Any questions should be directed to program@idsociety.org. Please share this email with anyone you think might be interested in applying!
 
In addition, I’ll also note that those with a more general story to tell should look at the BugHub Stage (and the Global BugHub stage). Both BugHub variants seek “presentations that touch on your experience of working in infectious diseases and presentations that ultimately lead to a greater understanding of our diverse field” via a TED Talk-esque speech about your work. The deadline for applications is 26 June, the same as for the pipeline sessions.

I look forward to seeing you there! 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.

John’s Top Recurring Meetings

Virtual meetings are easy to attend, but regular attendance at annual in-person events is the key to building your network and gaining deeper insight. My personal favorites for such in-person meetings are below. Of particular value for developers are the AMR Conference and the ASM-ESCMID conference. Hope to see you there!

  • 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. 
  • 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 save the date!
  • 16-20 Oct 2024 (Los Angeles, USA): IDWeek 2024, the annual meeting of the Infectious Diseases Society of America. Save the date! More details to come!
  • 25-26 February 2025 (Basel, Switzerland): The 9th AMR Conference 2025. Go here to register

Upcoming meetings of interest to the AMR community:

  • [NEW]  9 Apr 2024 (virtual, 830a-10a ET): GARDP’s next REVIVE webinar entitled “Progressing a discovery project – Criteria and challenges.” Register here.
  • [NEW] 9 Apr 2024 (virtual, 10a-1130a ET): CDC webinar “Impacts of Antimicrobial Resistance on Cancer Care.” Click here for details and to register.
  • 10-11 Apr 2024 (virtual): Sepsis Alliance AMR Conference, a 2-day conference focused on “Practical technologies to manage sepsis and counteract the expanding challenge of antimicrobial resistance.” Go here for details and to register.
  • 26 Apr 2024 (Barcelona, Spain): ESCMID workshop entitled “Using Data Science and Machine Learning for Infection Science: A Hands-on Introduction.” Click here to register or here for more details. 
  • 27-30 April 2024 (Barcelona, Spain): 34th ECCMID, the annual meeting of the European Society for Clinical Microbiology and Infectious Diseases. See Recurring Meetings list, above.
  • 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.
  • 28-29 May 2024 (in person, Uppsala, Sweden): Uppsala Antibiotic Days, a broad-ranging 2-day program hosted by the Uppsala Antibiotic Center. Go here for details and to register.
  • [NEW] 30-31 May 2024 (face-to-face in Rockville, Maryland as well as online, 8.30-5.30p ET on 30 May, 9-2.40p on 31 May): NIAID-sponsored workshop entitled “Towards realizing the promise of adjunctive immune therapy for invasive fungal infections”. The agenda covers host immunity to invasive fungal infections, immune modulators in the context of fungal infections; and strategies for testing immune modulators as adjunctive therapy. Go here for more details and to register.
  • 9-13 June 2024 (in person, Ascona, Switzerland): “New Approaches to Combat Antibiotic-Resistant Bacteria, 2nd Edition” is a Sunday-Thursday residential workshop focused on the deep biology of AMR. Sponsored by NCCR AntiResist (a Swiss National Science Foundation consortium), the scientific program has the feel of a Gordon Conference. Space is limited, so you are encouraged to apply promptly — go here for details.
  • 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.
  • 17-20 Sep 2024 (Porto, Portugal): ASM/ESCMID Joint Conference on Drug Development to Meet the Challenge of Antimicrobial Resistance. See Recurring Meetings list, above.
  • 16-20 Oct 2024 (Los Angeles, USA): IDWeek 2024, the annual meeting of the Infectious Diseases Society of America. See Recurring Meetings list, above. 
  • 19-27 Oct 2024 (Annecy, France, residential in-person program): ICARe (Interdisciplinary Course on Antibiotics and Resistance). Now in its 8th year, Patrice Courvalin directs the program with the support of an all-star scientific committee and faculty. The resulting soup-to-nuts training covers all aspects of antimicrobials, is very intense, and routinely gets rave reviews! Seating is limited, so mark your calendars now if you are interested. Applications open in March 2024 — go here for more details.
  • 4-5 Dec 2024 (in person, Washington, DC): “Fungal Dx 2024: Fungal Diagnostics in Clinical Practice” is a 2-day in-person workshop organized by ISHAM‘s Fungal Diagnostics Working Group. The program and registration links are available at https://fungaldx.com/; the agenda is comprehensive and features an all-star global list of speakers.

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