Dear All (long-ish, wonk-ish note alert … lots of details to absorb):
This newsletter has a followup here.
Sadly, Melinta Therapeutics, Inc. declared bankruptcy just before the end of 2019 (link). Formerly known as Rib-X (link), Melinta went public in 2017 through a reverse merger with Cempra (link); and via a series of deals had four approved antibacterial antibiotics at bankruptcy:
- Minocin (minocycline, IV): A tetracycline for treatment of a variety of bacteria including Acinetobacter
- Baxdela (delafloxacin, oral & IV): A fluoroquinolone for skin infections (including MRSA) and community-acquired pneumonia
- Vabomere (meropenem-vaborbactam, IV): A BL/BLI combination with activity against difficult Gram-negative bacteria, including many strains resistant to the carbapenems (CRE or Carbapenem-Resistant Enterobacteriaceae)
- Orbactiv (oritiavancin, IV): A lipoglycopeptide for skin infections, including MRSA
Per Alan Carr’s 3 Sep 2019 sales summary (link), the sales for the 12-month period Aug-2018 to Jul-2019 were $10.7m (Minocin), $11.9m (Baxdela), $10.9m (Vabomere), and $24.6m (Orbactiv). Given that these products would have required approximately $25m/year EACH in running costs to maintain a supply chain (all 4 have an IV formulation that requires sterile manufacture), it’s not hard to see why this was unsustainable.
Why did this happen? David Shlaes’ blog (link) provides more detailed comments on the relative utility of the agents, but the simple summary from my perspective is that none of these products were especially differentiated and similar agents were generally available (e.g., generic tigecycline would have competed with Minocin). The net effect was that use of these four agents was limited.
But all of these products have value in certain circumstances and it’s also hard to know a product’s full value until a few years have passed. Further, it is important to be aware of the reason the products were initially advanced, how long it sometimes takes to bring them to market, and how things can change during the many years required to bring a product to market.
As an example, consider oritavancin and delafloxacin, Melinta’s two products for MRSA. Both were initially moved towards the clinic 20 or more years ago at a time when MRSA was a profound concern: oritavancin was discovered in the 1990s (link) and delafloxacin (formerly ABT-492) appears to have been discovered ca. 2000 (link). Due to various twists and turns (e.g., the extensive 2006-9 project of rewriting FDA antibacterial guidance documents, link), initial US approvals did not occur until 2014 and 2017, respectively. By that time, of course, other agents had emerged to address the problem of MRSA: as two examples, linezolid had gone from approval in 2000 to being generic in 2015 (link), and ceftaroline had been approved in 2010 (link).
That said, and whether reaching approval quickly or slowly, all 4 agents would have faced the financial pressures that are so well summarized in Andrew Jacob’s 25 Dec 2019 excellent article in The New York Times (link) and an equally well-written 5 Jan 2020 article in the Wall Street Journal by Denise Roland (link). Also relevant are prior comments such as those from the 2014-17 DRIVE-AB project (link), from FDA Commissioner Gottleib in 2018 (link), and from many other written sources (link).
While it’s one thing for a preclinical company to fail (e.g., the bankruptcy of Aradigm, link), it is something else altogether when two companies (Achaogen [link] and Melinta) go bankrupt despite having 5 approved antibiotics between them … and the WSJ article notes that a 3rd company with an approved product (Tetraphase with Xerava/eravacycline) is seeking a loan to enable it to say afloat after 3Q20. A decade ago, IDSA called for 10 new antibiotics by 2020. Industry over-delivered in number (20 by 20 might occur, link), but sadly many of those deliveries are being marked “Return to Sender” after approval! While some of this may be useful pruning and market discipline, a continued exit by all private funders could mean that the momentum of recent years will come to naught and that the novel agents now in the pipeline are the last we’ll see for some time.
Never let a good crisis go to waste! So, what’s to be done? I’ve written before about the steps we could all be taking (link) and those ideas remain current. In particular, developers should be VERY careful about choice of projects … I’d rate novelty, novelty, novelty, and clinical utility as the top 4 things to prioritize. Strong scientific differentiation based on novelty cuts through so many issues!
In parallel, we all need to keep pushing for updated guidelines and pull incentives. There’s certainly some hope for both: the 18-19 Nov 2019 FDA-IDSA-Pew-NIAID workshop (link) seems to have sparked some interest in better approaches to guidelines and we’ve also heard that the UK’s pilot antibiotic purchase program (link) is progressing steadily. In the US, we’re grateful for the recent CMS actions to provide DRG codes covering this area, and stakeholders are filing comments with CMS calling for carving hospital antibiotics out of the DRG in the 2020 Medicare annual update rulemaking. In Congress, efforts to advance the DISARM Act as well as a delinked incentive remain active (link).
And, we need to keep telling the story about why we need a diverse, vibrant ecosystem capable of maintaining a pipeline. Because new challenges can emerge at any time (who would have predicted Candida auris, for example?), we simply can’t stop with one or two new agents as any or all could suddenly become inadequate. Podcasts explaining why it could be the case that “Yes, your cancer will be controlled, but then you may die of infection” (link) are real attention grabbers! You (yes, YOU, personally) could lobby Congress via the Working to Fight AMR project (link) and you should also ensure that your messages build on the principles for good communication about AMR that were identified by Wellcome Trust’s recent work (link).
Whew! That’s a long list! Well, it’s the start of 2020 and we need to keep the pressure on. The crisis of AMR is complex and requires actions from all of us. Get to it!
With thanks for this energetic community, –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: http://amr.solutions/blog/
Upcoming meetings of interest to the AMR community:
- 16 Jan 2020 (Washington, DC): Duke-Margolis meeting entitled (approximately) “improving Payment Policies for Antibiotics.” This meeting will run 10:30am – 4:30pm ET. Go here to register.
- 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.
- 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.