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:

  1. It was noted the microdosing human studies, also sometimes called Phase 0 testing, are underutilized. The idea here is that tiny single doses (< 1/100th of the predicted active dose) can be used to estimate PK earlier in a program and at much lower cost and effort. This approaches makes use of ultra-sensitive measures of drug and was in its early days criticized for not being predictive of full-dose PK. Subsequent work has shown that PK in microdosing is often (but not always) predictive. Burt et al. Nat Rev Drug Discov 19:801–818, 2020, https://doi.org/10.1038/s41573-020-0080-x provides a current review; Kaplan et al. Eur J Pharm Sci. 50:440-6, 2013, https://doi.org/10.1016/j.ejps.2013.08.019 provides an example of using this approach with a candidate antibacterial.
  2. One line of queries led to a re-review of the the excellent Molecule-vs-Drug discussions we had in early 2020 following the description of halicin, a candidate antibacterial proposed based on machine-based discovery. See this 21 Feb 2020 newsletter (“Chemicals Vs. Drugs (Part 1): The End Of Bacitracin / The Buzz Around Halicin) for the first paper in that 3-part series. Your reward for reading all 3 newsletters is a fabulous graphic critique of things that kill in a petri dish — don’t miss it. You will also encounter links to the masterful commentaries of Lynn Silver, one of our true gurus of drug discovery. 
  3. I wove the Molecule-vs-Drug ideas into this talk at NIAID’s 22-23 June 2022 antibacterial workshop. Of particular value in this talk is the summary of Read, Listen, and Learn resources on Slide 12.
  4. Finally, I was asked about ways to reduce cost. The fact that most programs fail means that most of the cost of bringing a new antibiotic to market is in the failures. As was discussed in a 9 Jan 2021 newsletter, a realistic average cost to first approval is ~$1.3b. Even if it only costs 25% of that to develop the (ultimately) successful product, the discovery of that product requires you (us, the community) to spend the other 75%! Better predictive toxicology and pharmacology would help … but someone has to do that initial search … and this is how we find true innovation (17 Mar 2021 newsletter).

Next up, and on the theme of discovering that new antibiotic, it was great to recently learn that CARB-X had been rebooted for another 10 years. Funding rounds have not yet been announced, but there was a 30-minute webinar on 9 June 2022 that surveyed work to date by CARB-X, gave hints about the next funding rounds, looked at the CARB-X accelerator networks, reviewed the CARB-X approach to stewardship/access, and overviewed recent strategic plans from both BARDA and NIAID:

Relatedly, it was exciting to see that BARDA, CARB-X, and anti-fungal R&D got clear a shout-out in the recently proposed FY2023 US budget. The full budget is here; the bit about CARB-X and anti-fungals is at the bottom of page 234 of the supporting report to the Appropriations committee. Net, the draft text recommends $845 million for BARDA, a $100M increase over its current level. Here are two important excerpts:

  • “Antifungal Research: The Committee provides an increase to support the research and development of novel antifungal therapies, particularly for multi-drug resistant fungal pathogens, to bolster national health security and minimize their impact on public health. Antifungal development faces similar challenges to antibacterial development and BARDA’s Advanced Research and Development program support will be critical to generate additional antifungal products, including for endemic fungal diseases, like Valley Fever. In addition, the Committee urges the Secretary to update the scope of support for the CARB–X program to include pathogens listed in the 2019 CDC Antibiotic Resistant Threats report, which includes products that target fungal pathogens. The Committee requests a report within the 180 days of the date of enactment of this Act on actions taken. 
  • “Antimicrobial Resistance: The Committee provides an increase for efforts to combat antimicrobial resistance, recognizing the importance and challenges of this threat. BARDA’s Advanced Research and Development program support will be critical to support new products. The Committee requests within 180 days of the date of enactment of this Act a professional judgement budget estimate to support a comprehensive, long-term program for the development and procurement of novel antibiotics.”

Finally, WHO have released their review through mid-2021 of the clinical and preclinical antibacterial pipeline (including products for M. tuberculosis and Clostridioides difficile). We’ve known this report was coming (see this 17 Jan 2022 newsletter), but now is good time to re-review it. You should look at the report itself, a related press release, and a related paper in AAC (Butler et al., https://journals.asm.org/doi/10.1128/aac.01991-21).

As you will have expected, the conclusion is that the pipeline is much too thin. Here are a few key bullet points:

  • “The current clinical antibacterial pipeline contains 77 antibiotics and/or combinations that include at least one new therapeutic entity.
  • (paraphrased slightly) Of the traditional small molecules, six fulfil at least one of the WHO innovation criteria but only two are active against at least one critical category multidrug-resistant (MDR) Gram-negative bacterium (i.e. CRAB, CRPA, CRE).
  • “Overall, the clinical pipeline and the recently approved antibacterial agents are insufficient to tackle the challenge of increasing emergence and spread of antimicrobial resistance”

While that may sound negative, keep in mind that it takes years to find true novelty and we are definitely seeing signs of great things in the preclinical portfolios. We just have to keep going!

With thanks to all who are putting their hearts (and minds!) into making new antibiotics happen, 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: 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):

  • 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.
  • 10 Aug 2022 (virtual, 11a-12.30p ET): REVIVE webinar entitled “Animal models to study the activity of antibiotics.” Go here for details. 
  • 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. 
  • 30 August 2022 (virtual, 8.30a-5.00p ET): Webinar sponsored by CDC and FDA entitled “Drug Development Considerations for the Prevention of Healthcare-Associated Infections.” This is very timely as developing products for prevention is surprisingly hard. As just one example, see this 20 Dec 2018 newsletter about a valiant  (but failed, sadly) effort to develop a S. aureus vaccine. Go here for additional details and to register. 
  • 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.


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