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.

Share

Leaky pipe(line)s, Part 2 / CARB-X reboot / WHO 2021 pipeline review

Dear All, We have a 3-part discussion today on the theme of “I want a new drug … so how do I find it?” Off we go! First, the 14 June 2022 newsletter entitled “Leaky Pipe(lines) / When Is A Molecule A Drug” generated further discussions that are worth sharing: It was noted the microdosing

Antibiotic procurement models for LMICs / G7 Leaders call for Pull!

Dear All, Two stops on our tour today: (i) an excellent survey of incentive models and (ii) a final communique from the recent G7 meetings. First up, CGD (Center for Global Development) have released a report (link) entitled “Leveraging Purchasing Systems to Ensure Access, Stewardship, and Innovation: A Landscape Review of Current and Potential Market Structures

FDA/CVM: Antimicrobial use in companion animals

Dear All, Post-newsletter addendum: I’ve learned that USDA will host a 10 Aug 2022 (virtual, 10a-4.30p ET) workshop on AMR in food agriculture. See the meetings calendar for more details; go here to register. I’ll confess to having missed entirely the request back in February 2022 from FDA’s Center for Veterinary Medicine (CVM) for comments on antimicrobial

ATMF on Access in LMICs/Progress, but wishing for more

Dear All, Last fall, the team at ATMF (Access to Medicine Foundation) released the 3rd update to the AMR Benchmark series and Damiano de Felice was a guest author for a newsletter about the findings. That report offered a wealth of granular data, in-depth analyses and revealing graphs about what pharmaceutical companies in the global antibiotic and

Scroll to Top