Non-traditional alternatives to antibiotics have excited a lot of interest in the past few years but we’ve seen relatively few of these progress in a meaningful way (go here for Pew’s recent survey of the development landscape). Providing insights into the challenges of this area, two valuable and complementary articles on non-traditional antibiotics have recently been published. (Post-newsletter addition: If you are interested in development issues for veterinary antibacterials, see this paper by Marilyn Martinez and Jeff Watts)
First up, and authored by Ursula Theuretzbacher and Laura Piddock, is “Non-traditional Antibacterial Therapeutic Options and Challenges” (link). This paper is an in-depth review of the non-traditional pipeline and provides both tabular summaries of products in development as well as a by-category commentary on relevant issues. The paper’s key conclusion is that therapeutic non-traditional treatments will generally be used in combination with antibiotics and that “… these new strategies have additional and considerable hurdles before they can be shown safe and efficacious for patient use.”
So, what are those challenges? This brings us to #2 on your reading tour, “Designing development programs for non-traditional antibacterial agents” (link). Along with Holly Fernandez Lynch, Glenn Cohen, Jonathan Darrow & Kevin Outterson, I was a co-author on this one. This paper focuses in depth on development issues for non-traditional products by extending the thinking from Czaplewski et al. 2016 (link), a lecture I gave at ECCMID 2018 (link), and a joint talk with Kevin Outterson at the August 2018 FDA workshop on non-traditional products (link). The core messages here are that (a) the development pathways for non-traditional products are largely the same as for traditional small molecules, (b) the need to show superiority of the combination makes it very difficult to develop non-traditional products that seek to work in combination with an existing drug to augment, restore, or transform the existing drug’s effect, and (c) there may be a need for a broad discussion about products where most of the benefit accrues to the community as a whole rather than the individual.
Let me also note that this second paper is unusual in that its authors include lawyers & ethicists from Boston University, Harvard, and the University of Pennsylvania, together with a lone clinician (me). As a result, the discussion of trial design issues (and especially the deep logic of non-inferiority and superiority trials for antibiotics) is very detailed and exhaustive. If you’ve not previously studied this area in depth, this paper is a good place to start. I also recommend reviewing the blog post from the recent FDA LPAD workshop (link) — wonkish point #4 and this related slide deck (link) are especially on point.
While I know that the messages in these papers will not be happy reading for those seeking to develop non-traditional alternatives to antibiotics, please also know that a personal level I’ve long been fascinated by the idea of non-traditional products and I would love to see some of them reach registration. Given how hard it is to find new traditional antibiotics, it is important that we vigorously pursue any plausible alternatives.
So, please read these papers with the attitude of “Tears today rather than tears tomorrow” and use them as a springboard from which to ensure that current programs anticipate and solve the issues that arise in late development.
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:
- 20 Aug 2019 (webinar, 17:00-18:30 CEST): REVIVE webinar entitled “Models for antimicrobial R&D: Computational modelling for population PK and PKPD.” Go here to register.
- [Mark your calendar now!] 3-6 Sep 2019 (Boston). Annual ASM-ESCMID Conference on Antibiotic Development. The Bootcamp series will continue on 3 Sep with main meeting on 4-6 Sep. Mark your calendar now and check back here for details.
- 6 Sep 2019 (Cambridge): CeBIL Annual Symposium 2019: Legal Innovation to Support the Development of Anti-Microbial Drugs. For more details and to register, go here.
- 6-8 Sep 2019 (Bilbao, Spain): 5th ESCMID conference on Vaccines. Check back here for details.
- 10 Sep 2019 (webinar, 17:00-18:30 CEST): REVIVE webinar entitled “Models for antimicrobial R&D: Advanced and complex in vivo models for infectious disease research.” Go here to register.
- 3 Oct 2019 (webinar, 17:00-18:30 CEST): REVIVE webinar entitled “Natural product antibiotics: from traditional screening to novel discovery approaches.” Go here to register.
- 2-6 Oct 2019 (Washington, DC): IDSA’s annual IDWeek meeting.
- 19-27 Oct 2019 (Annecy, France): International Course on Antibiotics and Resistance (ICARe) – A soup-to-nuts intensive residential training program on all things AMR, especially R&D for new antibiotics. See this link for details.
- 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/
- 1-6 Mar 2020 (Il Ciocco, Tuscany, Italy): 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 (Berlin?): BEAM-, Novo REPAIR-, CARB-X-, DZIF-, ND4BB-, ENABLE-supported (among a long list!) Conference on Novel Antimicrobials and AMR Diagnostics. Final location is TBD, details will appear here, and you should mark your calendar now.
- 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)
- 10-13 Apr 2021 (Vienna): Annual ECCMID meeting (#31)