Scary, Scarier, Scariest: Achaogen / FT editorial / CBS “60 Minutes” on AMR

There is a follow-up to this note.  Go here to read it.

Dear All: I don’t like writing about doom and gloom, but a sequence of events in the past few days really drives home both the importance of the work we do to create new antibiotics as well as the fragile state of the ecosystem supporting that work. Here we go…

Scary: Alan Carr today posted a superb summary of Achaogen’s bankruptcy (html version, pdf version; you might also want to review his recent broader survey of the antibiotic sector). If you’ve not followed the Achaogen story closely, the key plot line is that the company (a) developed plazomicin (Zemdri), a novel intravenous aminoglycoside antibiotic with activity against carbapenem-resistant Enterbacteriaceae (CRE), (b) brought it successfully through registration to US approval, (c) had sales of $0.8m during 2018 and (d) declared bankruptcy (link) last week. As you read his full note, focus on the timeline:

  • “Achaogen initiated clinical development of Zemdri in 2009 with a focus on CRE.”
  • “Achaogen initiated a Phase 3 trial of Zemdri against colistin in CRE in 2014 (CARE trial)” but this trial was difficult to enroll with “2100 patients screened and 37 randomized over 2.5 years.”
    • Aside: When this study started in 2014, the only antibiotic on the market with even moderately reliable activity for CRE was colistin, an ancient and toxic antibiotic from the polymyxin class.
  • “A Phase 3 cUTI trial completed in Dec 2016 demonstrated impressive efficacy relative to meropenem (EPIC trial).”
  • “Allergan and Melinta launched Avycaz and Vabomere in 2015 and 2017.”
    • Aside: Avycaz and Vabomere are intravenous antibiotics that also cover CRE. Notably, they are both from the beta-lactam antibiotic class whereas Zemdri is from the aminoglycoside class.
  • “Zemdri was launched in the U.S. in Jul 2018.”
  • “Achaogen filed for Chapter 11 bankruptcy last week (April 2019).

Note how long it takes to bring a new antibiotic to market. It’s also expensive: per an estimate from Alan (personal communication), Achaogen raised around $450m in VC and public funds from founding to bankruptcy, not counting non-dilutive support and debt. Then, note that Zemdri is an especially welcome addition to the very small number of agents for CRE by virtue of being a different class of antibiotic relative to Avycaz & Vabomere (beta-lactam class) and colistin (polymyxin class). Finally, note how Alan summarizes the market dynamics for these four agents:

  • “Avycaz gained traction in the CRE market, but four years after launch, polymyxins still dominate.
  • “We assumed Vabomere and Zemdri would displace Avycaz and accelerate a decline in polymyxin use.
  • “Instead, polymyxin use is stable while Vabomere and Zemdri are essentially not used at all.”

So, what went wrong (and is still going wrong) here? We’ll doubtless be talking about this at many future meetings, but the basis for a key paradox can be seen in the slow recruitment into the CARE trial of plazomicin vs. colistin for CRE: 2,100 screened to enroll 37 … and at a cost (by verbal report) of $70m. While we do need new drugs for CRE, we work really hard in parallel to make CRE infections rare and hence it is difficult to run a study of CRE. And, of course, we also do everything we can to limit use of new antibiotics once approved.

For more on this complex topic, please see my current lecture (link) on Funding, Filing, and Finance, especially slides 11-15. And also be sure to attend the 6-9 Sep ASM-ESCMID Conference on Antibiotic Development (link) where one of the Bootcamp sessions on 3 Sep will focus on post-approval antibiotic economics. For now, we need to move on to…

Scarier: Yesterday (21 Apr 2019), Jeremy Farrar, Director of Wellcome Trust, wrote an editorial in the Financial Times (link)

  • The editorial briefly reviews the Achaogen story.
  • The editorial’s core theme: “There is no viable path for new drugs, however valuable they are to society.”

Yes, and Achaogen would certainly seem to be the poster child for this! The editorial concludes by calling for “creative new models to stabilise the antibiotics market and stimulate private sector innovation without exposing public funders to all the risk.” For more on the approaches that are needed and especially the lonely state of Pull incentives, see this note (link). And with this we come to…

Scariest: Finally, and also yesterday, CBS aired a superb 60 Minutes episode on AMR (link). In it, you can see:

  • E. coli becoming visibly resistant to ciprofloxacin over about 10 days,
  • Colistin purchased over-the-counter in Delhi, and
  • How easy it is for any of us to acquire highly resistant bacteria, especially during global travel.

The clip in which the reporter purchases OTC colistin is stunning. 

Inhale, exhale, and keep working. 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:

  • 24-26 Apr 2019 (Boston): Annual SHEA (Soc. for Hospital Epidemiology of America) Spring meeting
  • 6-11 May 2019 (Ljubljana, Slovenia): 37th Annual Meeting of the European Society for Paediatric Infectious Diseases (ESPID). Details here.
  • 20 May 2019 (everywhere): Application deadline for NIAID solicitation (HHS-NIH-NIAID-BAA2019-1) for proposals to support new vaccine or therapeutics candidates targeting antibiotic-resistant bacterial infections. Go here for more details.
  • 3-6 Jun 2019 (Philadelphia): Annual BIO meeting
  • 20-24 June 2019 (San Francisco): Annual ASM Microbe meeting.
  • 10-11 Jul 2019 (Madison, WI): Tiny Earth Symposium, a teaching consortium that uses crowd-sourcing of antibiotic-producing microbes to improve undergraduate education. Details here.
  • 12 July 2019 (FDA, White Oak Campus): Public workshop to discuss the 2018 LPAD guidance. Register here.
  • [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.
  • 6-8 Sep 2019 (Bilbao, Spain): 5th ESCMID conference on Vaccines. Check back here for details.
  • 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.
  • [Mark your calendar now!] 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.” Not yet online, but the date is firm. Will share a link when it becomes available.
  • 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. 
  • 18-21 Apr 2020 (Paris): Annual ECCMID meeting (#30)
  • 10-13 Apr 2021 (Vienna): Annual ECCMID meeting (#31)

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