Looking forward: The global pre-clinical antibacterial pipeline / How will we care for these precious jewels?

​Dear All,

Long note alert! There are two deep and deeply connected topics to share today. Refresh your coffee and settle in…

Today’s first topic: Adding to the recent reviews of the clinical stage pipeline for both traditional products (link to the Sep 2019 Pew Charitable Trusts summary), and non-traditional products (link to an Aug 2019 newsletter summarizing recent papers, link to Sep 2019 Pew summary), we now have a very interesting review of the global pre-clinical pipeline:

  • Ursula Theuretzbacher, Kevin Outterson, Aleks Engel, and Anders Karlen. The global preclinical antibacterial pipeline. Nat Rev Microbiol. 2019 (link)

Analyzing the clinical stage pipeline is relatively simple as the requirement to register studies with clinicaltrials.gov means that it is possible to readily construct a comprehensive list of projects. But, the preclinical pipeline is much harder to define: projects come, projects go, details are scant, and there’s no easy way to know when you’ve found everything.

To address this problem, the authors of this paper pooled data on projects known to CEFAIA (link), CARB-X (link), the Novo REPAIR Impact Fund (link), the IMI ENABLE project (link), and the JPIAMR portfolio (link). Based on projects thought to be active during the period Sep 2016 through 1 May 2019, the authors identified 407 pre-Phase 1 projects from 314 institutions, most of which are small and medium- sized enterprises (SMEs). The breakdown of projects is shown in this figure:


As you can see, the portfolio is very diverse. Intriguingly, there are 135 projects on direct-acting small molecules that represent new classes, new targets or new mechanisms of action! Also interesting is the substantial interest in non-traditional approaches, including antivirulence approaches, microbiome-modifying strategies, engineered phages, and probiotics. The authors offer this summary critique:

  • High level of diversity and interesting scientific approaches, much more so than the clinical pipeline.
  • Less than half of the projects involve direct-acting small molecules.
  • More than half of the projects involve ‘non-traditional,’ potentially adjunctive therapies with an as yet unclear regulatory pathway to show a clinically relevant benefit.
  • Non-traditional approaches may not build on validated predictive preclinical models and therefore have a higher risk of clinical failure.
  • Focus on WHO’s critical priority pathogens (with the exception of antibodies, vaccines and phages for Staphylococcus aureus).
  • Strong trend towards pathogen-specific or patient-specific therapy requiring highly developed health-care systems with advanced rapid diagnostic capabilities.
  • Strong dependence on public and/or philanthropic funding.
  • High volatility due to high-risk strategies and translational challenges pursued by small companies.

It’s great to see all this work and my guess is that these 407 projects will ultimately lead to approximately 4 new products. Although 407 projects sounds like a lot, experience shows that most of these projects will fail to produce an approved therapeutic:

  • You’d predict 1-2% of the 187 preclinical direct-acting small molecules to reach approval — thus 2-4 antibiotics might emerge — and hopefully some will be novel mechanisms or classes.
  • The non-traditional approaches have many issues to resolve (go here for details) and hence I’d estimate that < 1% of these ~200 projects would reach approval — thus an estimate of 1-2 non-traditional products.
  • All together: A midpoint estimate of 4 products

I know those odds sound disappointing, but drug discovery has always been high risk — and that’s especially true for novel mechanism and class products. The converse is that the number of new products would be zero without all these efforts — and the idea that we might have even 1-2 new mechanism antibiotics is encouraging! 

But, what will happen to these products? Will any of them actually come to market? The issues highlighted by the recent bankruptcy of Achaogen (link) have only been reinforced by Melinta (NASDAQ MLNT) stating “there is substantial doubt about our ability to continue as a going concern” in their most recent 10-K filing (link). 

Thus, we have for our second topic a Viewpoints paper in Nature Reviews Microbiology in which the challenges of completing the development of these early projects are considered at length:

  • Christine Ardal, Manica Balasegaram, Ramanan Laxminarayan, David McAdams, Kevin Outterson, John H. Rex, and Nithima Sumpradit. Antibiotic development – economic, regulatory and societal challenges. Nat Rev Microbiol. 2019 (link). If you are not a subscriber to NRM, the publisher has very kindly made the paper available for free viewing via Readcube (link).

This paper has an unusual format: The seven authors were asked to comment on 3 questions: (i) What is driving the decline in antibiotic R&D, (ii) What strategies are underway to reverse this decline, and (iii) What else needs to be done to stay ahead of the emergence of resistance?

The resulting commentary reflects the authors’ multidisciplinary expertise (public health, national action plan implementation economics, game theory, health law, and drug development). Each response is a succinct review from one or more of these perspectives. As examples, we have from Ardal and McAdams a summary of the market collapse of Achaogen, from Balasegaram a comment on GARDP’s vision, from Laxminaryan a 4-step economic view on the decline of antibiotics, from Outterson a summary of the array of global programs now in place, from me a history of how those programs came to be, and from Sumpradit a discussion of how WHO’s global action plans are having national impact.

Running through all of the commentaries are the intertwined yin-yang themes of (a) “In no other drug class do we lock up the most innovative new products to keep sales as low as possible” and (b) “For Achaogen, scientific and regulatory achievement ended in economic disaster. A similar fate awaits other antibiotic companies unless governments enact meaningful pull incentives in the next year.” In brief, “Both push and pull incentives are required to address our pressing problems.” If you are new to this area, see these two blogs for more details (link and link).

Putting it all together, I found these two papers to be good background for each other:

  1. The current clinical pipeline contains the antibiotics of the next 10 years and the 407 preclinical projects reviewed by Theuretzbacher et al. are the seeds of the antibiotics of the following decade.
  2. These are all precious jewels: one estimate (see ref. 20 from Ardal et al.) is that approximately $2b/year is being invested across the entire AMR space.
  3. All of this investment will come to naught unless we follow the ideas in the second paper and do something on a global scale to pay properly for those products that do reach the market.

Many thanks to Ursula, Kevin, Aleks, and Anders for generating their preclinical summary and to Nature Reviews Microbiology for convening and publishing the Viewpoints article! These papers were not deliberately organized to be published at the same time but I found their confluence to be really compelling. Along with the recent CDC update (link) and stories such as the podcast entitled “We can treat your cancer but you’ll die of infection” (link), the need for sustained and expanded action is clear and evident.

The preclinical pipeline review shows that we’ve made progress … now we just need to build on that momentum! Onward!

All best wishes, –jr

John H. Rex, MD | Chief Medical Officer, F2G Ltd. | Expert-in-Residence, Wellcome Trust. Follow me on Twitter: @JohnRex_NewAbx. See past newsletters and subscribe for the future: http://amr.solutions/blog/

Upcoming meetings of interest to the AMR community:

  • 26 Nov 2019 (webinar, 9:30-11:00 CET): REVIVE webinar entitled “Innovation in point-of-care diagnostics for sepsis and bloodstream infections.” Go here to register.
  • 28-29 Nov 2019 (Birmingham, UK): BSAC workshop entitled “ARM (Antibiotic Resistance & Mechanisms)”. This meeting is a research forum for UK-based researchers at all levels, including PhD students and technicians. Go here for details.
  • 5 Dec 2019 (Monthey, Switzerland): The BioArk technology park is holding a one-day workshop on AMR. Entitled “The Ark Life Sciences Series #1”, you can get more details here.
  • 16-18 Dec 2019 (Bangkok, Thailand): 3rd International Symposium on Alternatives to Antibiotics in Animal Production. Go here for details: https://www.ars.usda.gov/alternativestoantibiotics/
  • 16 Jan 2020 (Washington, DC): Duke-Margolis meeting entitled (approximately) “improving Payment Policies for Antibiotics.” This meeting will run 10:30am – 4:30pm ET, details to follow.
  • 21 Jan 2020 (London): BSAC’s 2nd Antimicrobial Chemotherapy Conference – An ABC for everyone involved in developing new antimicrobials. Go here for details.
  • 20 Feb 2020 (London, UK): Westminster Health Forum conference entitled “Antimicrobial resistance – coordinating a global response and progress on the UK strategy.” Go here for details.
  • 26-27 Feb 2020 (Washington, DC): US PACCARB public meeting. Go here for details.
  • 1-6 Mar 2020 (Il Ciocco, Tuscany, Italy): Gordon Research Conference (GRC) on Antibacterial Discovery and Development: “Now is the time to re-boot antibiotic R&D before it’s too little, too late.” Go here for details.
  • [UPDATED] 12-13 Mar 2020 (Basel): BEAM-, Novo REPAIR-, CARB-X-, DZIF-, ND4BB-, ENABLE-supported (among a long list!) Conference on Novel Antimicrobials and AMR Diagnostics. Details are here, poster deadline is 12 Dec 2019.  
  • 16-17 Mar 2020 (London): BSAC Spring Conference entitled: “Bridging the gap between science, policy and effective antimicrobial use.” Go here for details. 
  • 18-21 Apr 2020 (Paris): Annual ECCMID meeting (#30)
  • 25-30 May 2020 (Rotterdam), Annual ESPID meeting (European Society for Pediatric ID, #38)
  • 27-28 Jun 2020 (Bryant University, Rhode Island): Drug Resistance Gordon Research Seminar entitled “Mechanisms and Approaches to Overcoming Drug Resistance in Cancer, Infectious Disease and Agriculture” for graduate students and postdoctoral scientists. Go here for details … this immediately precedes the GRC listed just next
  • 28 Jun-3 Jul 2020 (Bryant University, Rhode Island): Gordon Research Conference (GRC) entitled “Strategies to Disrupt Drug Resistance in Infectious Disease, Cancer and Agriculture.” Go here for details.
  • 1-4 Sep 2020 (Dublin): Annual ASM-ESCMID Conference on Antibiotic Development #5! Mark your calendar now and go here for details.
  • 9-10 Sep 2020 (Washington, DC): US PACCARB public meeting. Go here for details.
  • [NEW] 22-25 Sep 2020 (Albuquerque, New Mexico): Biannual meeting of the MSGERC (Mycoses Study Group Education and Research Consortium). Save-the-date announcement is here, details to follow.
  • [NEW] 17-25 Oct 2020 (Annecy, France): Interdisciplinary Course on Antibiotics and Resistance (ICARe). This is a soup-to-nuts residential course on antibiotics and resistance. The course is very intense, very detailed, and gets rave reviews. The date is set for 2020 and the program will ultimately appear here. Registration is limited to 40 students and opens 15 Mar 2020.
  • 10-13 Apr 2021 (Vienna): Annual ECCMID meeting (#31)


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