WHO has today released two exhaustive reviews of the antibacterial R&D universe (and by way of full disclosure, let me say upfront that I participated in the clinical pipeline discussion):
- The preclinical pipeline (link)
- This one includes a fascinating data-mining tool that explores the 252 antibacterial products being developed in 145 institutions around the world (link). Great graphics!
- The clinical pipeline (link)
- WHO’s press release about the documents (link)
The summary bullet points from each report are found below my signature. There is a lot of detail here, but I think you can reduce it to a small number of key points:
- Really compelling novel antibacterials are rare. Seriously rare. Rocking horse manure rare. We should keep looking, but we also need to deal with reality and recognize that …
- Improved versions of existing-class compounds can be really interesting and are somewhat easier to find (e.g., oral agents for difficult Gram-negatives).
- In parallel, the marketplace must be fixed lest lots and lots of hard work go to waste. This point is outside the scope of the WHO review, but is beautifully summarized by this comment (link, search for “mediocre”) from the 2019 ASM-ESCMID meeting: “If industry develops a mediocre antibiotic, it won’t be used, but a very good antibiotic won’t be used either.”
The tension between “I want novelty” and “good enough can be really useful” is going to need more discussion. You can state this in lots of different ways, but the core point is that the first compound in a class is not always the best. I have used data at https://en.wikipedia.org/wiki/Timeline_of_antibiotics plus information from FDA on recent approvals (data are current through 11 Feb 2020) to construct this simple-minded First vs. Best analysis:
In the graphic below, each row is a drug class, years (decades!) go across the page, the numbers show # of drugs approved by year, and colored bars shown first-to-last within each class. Yellow is used for singleton classes, shades of green for multi-drug classes.
Of the 27 discrete classes of antibiotics, 13 are singletons where as one class (beta-lactams) has 67 drugs. In the multi-drug classes, the span from first to next (2nd in class) is years to decades and the span from first to last is usually decades.
The graphic can found in this PowerPoint summary of the WHO, CDC, and ESKAPE pathogen lists (link, see slides 4 and 5). And if you really want to dig down, the Excel worksheet used to create the yellow-green diagram is here.
In summary, the analysis shows that singleton classes and multi-drug classes occur at about the same rate. And as suggested by the extensive creation of variants in some classes, first is not always best. This doesn’t mean that every new addition to a class is equally valuable but it does say that it can take decades to fully mine the chemical space around the first compound in a class. This reminds me of that quote attributed to Sir James Black (discovered propranolol; 1988 Nobel, link) that “The most fruitful basis for the discovery of a new drug is to start with an old drug.” Further discussion is definitely needed on this topic!
Ok, that’s enough for today! With tremendous gratitude for the persistent efforts of this community and all best wishes for 2020, –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-index.html
Executive summary of the preclinical pipeline
- 252 agents are being developed by 145 individual institutions that target the WHO priority pathogens, M. tuberculosis and C. difficile.
- The review captures research projects from institutions with a wide geographical distribution, 66 (45.5%) institutions in the European Region, 51 (35.2%) in the Region of the Americas, 22 (15.2%) in the Western Pacific Region, 5 (3.4%) in the South-East Asia Region and 1 (0.7%) in the African Region.
- 108 (42.9%) are direct-acting small molecules (single agents) and 90 (35.7%) are nontraditional products that include phages, anti-virulence agents, immunomodulators, microbiome-modifying therapies and potentiators, among others.
- 100 (39.7%) agents target a single pathogen, of which 43 target M. tuberculosis.
- Almost 1/3 of the agents target cell wall synthesis or act directly on the membrane.
- Approximately 2-5 direct-acting small molecules and 1 nontraditional product may make it to the market in the next 10 years.
- The preclinical pipeline is dominated by small and medium-sized enterprises (n = 104, 71% of all institutions that submitted data).
- This is the first review of the preclinical pipeline that makes all of the drug development projects and institutions available through a public database.
Executive summary of the Clinical pipeline
- The clinical pipeline remains insufficient to tackle the challenge of increasing emergence and spread of antimicrobial resistance.
- It is primarily driven by small- or medium-sized enterprises (SMEs), with large pharmaceutical companies continuing to exit the field.
- Eight new antibacterial agents have been approved since 1 July 2017, but overall, they have limited clinical benefits.
- One new anti-tuberculosis (anti-TB) agent, pretomanid, developed by a not-for-profit organization, has been approved for use within a set drug-combination treatment for MDR TB.
- The current clinical pipeline contains 50 antibiotics and combinations (with a new therapeutic entity) and 10 biologicals, of which 32 antibiotics are active against the WHO priority pathogens:
- Six of these agents fulfil at least one of the innovation criteria; only two of these are active against the critical MDR Gram-negative bacteria.
- More than 40% of the pipeline targeting WHO priority pathogens consists of additional β-lactam and β-lactamase inhibitor (BLI) combinations, with a major gap in activity against metallo-β-lactamase (MBL) producers.
- The anti-TB and C. difficile antibacterial pipeline is more innovative than the WHO priority pathogens pipeline, with more than half of the antibiotics fulfilling all of the innovation criteria.
Upcoming meetings of interest to the AMR community:
- 21 Jan 2020 (1700-1830 CET, online): GARDP-sponsored webinar entitled “Testing for the potential of emergence of resistance.” Go here to register.
- 28-29 Jan 2020 (Rockville, MD, NIAID campus): Two-day workshop entitled “Understanding the Biology, Antifungal Resistance and Clinical Implications of Candida auris.” Draft agenda is here and registration is here.
- 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.
- 24 Feb 2020 (London, UK): One-day workshop hosted by Royal College of Nursing and the Longitude Prize entitled “Developing point-of-care diagnostics for urinary tract infections (UTIs): addressing clinical need in the UK.” Register here.
- 26-27 Feb 2020 (Washington, DC): US PACCARB public meeting. Go here for details.
- 27 Feb 2020 (1700-1830 CET, online): GARDP-sponsored webinar entitled “PK/PD murine infection models: Focus on study elements, variability, and interpretation of results.” Go here to register.
- 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.
- 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.
- [NEW] 26-30 Mar 2020 (Atlanta, GA): CDC- and SHEA-sponsored 6th International Conference on Healthcare Associated Infections. Go here for details.
- [NEW] 30 Mar 2020 (everywhere): Deadline for applications for the Molecular Mycology pathogenesis course at Marine Biological Laboratory, Woods Hole. Now in its 24th year, the hands-on residential course runs 17 July to 2 Aug and gets rave reviews. Go here for more.
- [NEW] 9 Apr 2020 (everywhere): Final date for applications for NIAID/DMID call (link) for AMR-related vaccines, therapeutics, and diagnostics.
- 18-21 Apr 2020 (Paris): Annual ECCMID meeting (#30)
- 25-30 May 2020 (Rotterdam), Annual ESPID meeting (European Society for Pediatric ID, #38)
- 18-22 Jun 2020 (Chicago), ASM Microbe 2020. Go here for details.
- 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.
- 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.
- 17-25 Oct 2020 (Annecy, France): Interdisciplinary Course on Antibiotics and Resistance (ICARe). This is a soup-to-nuts residential course on antibiotics, antibiotic resistance, and antibiotic R&D. 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)
- 3-7 Jun 2021 (Anaheim), ASM Microbe 2021. Go here for details.