FDA workshop on development of therapies for non-tuberculous mycobacterial (NTM) disease

Dear All:

FDA held a workshop (go here for workshop agenda and materials) on 8 Apr 2019 on “Development of Antibacterial Drugs for the Treatment of Nontuberculous Mycobacterial Disease.” I attended by webcast and worked with an on-the-spot attendee (David Melnick of Spero Therapeutics) to develop this summary.

The workshop started with a review of the underlying disease and outcomes with licensed therapies. Following this, several case studies were presented for debate. You will want to review the meeting materials for yourself but as a starting point I offer these takeaway messages:

1. Clearing NTM pulmonary infection is very, very hard and may not be routinely possible. The recent study of amikacin liposome inhaled suspension (ALIS) + a background regiment cleared at most ~30% of subjects.
2. Culture clearance is only loosely linked to clinical improvement. There is a general trend in favor of symptoms being reduced with reduction in bioburden. Examples of the variability here would be the finding of a correlation by Griffith DE et al., Am J Respir Crit Care Med 192:754-60, 2015 and in Insmed’s Study 112 vs. the lack of a correlation in Insmed’s follow-up Study 212 (see slides 20 and 21 from this presentation by Insmed during the workshop).
3. Although you would expect reduced bioburden to be favorable, the correlation between symptoms and bioburden is reduced by (a) significant structural lung disease that probably can’t improve, (b) toxicities from therapy that overlap with the disease, and (c) baseline heterogeneity, including enrollment of subjects with limited baseline symptoms and hence limited ability to improve.

In many ways, this is similar to the problem of HIV: We know we’d like to cure it, we find that this is very difficult, and thus the key is to find compounds and regimens that play to a long-term strategy of keeping the bioburden down with the least possible toxicity due to the therapy itself.

These messages have a number of fairly direct implications for those who want to develop products for this important infection:

1. Good tolerability and ease-of-use should be heavily weighted during candidate selection. You must anticipate the need to play a very long game with your product.
2. The primary endpoint should be clinical improvement at 3-6 months on therapy. The best way to measure this is not completely defined but adapting existing symptom scores would seem a good place to start.
3. In pursuit of this primary endpoint, registrational studies should focus on patients who (a) are early enough in their infection to have only moderate degrees of lung injury and (b) have enough symptoms at baseline to provide room to measure improvement.
4. Monitoring should be done for bioburden and onset of resistance, but these measures are secondary to the primary clinical endpoint.

Net, these insights seem to me to facilitate work in the field. By moving from a primary focus on a TB-like sterilization endpoint (something that could take 2 years to measure) to a 6-month clinical measure, registrational trial durations are limited. A complete program should include a study that rolls participants over to a long-term monitoring arm but the primary registrational trials can be run, closed, and reported in a reasonable timeframe.

Kudos to FDA and the participants for an excellent conversation that points to productive ways to advance the field!

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: https://13.43.35.2/blog/

Upcoming meetings of interest to the AMR community:

• 13-16 Apr 2019 (Amsterdam): Annual ECCMID meeting
• 16-18 Apr 2019 (Utrecht): ICOHAR, International Conference on One Health Antimicrobial Resistance. Organized by the ESCMID Study Group for Veterinary Microbiology (ESGVM).
• 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.
• [NEW] 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.