It started all so well with fanfare and great expectations. Fifteen years ago, the 10 x ’20 initiative got underway.
Its goals were spelled out clearly: To ‘Pursue a Global Commitment to Develop 10 New Antibacterial Drugs by 2020 ’[3]. It was driven by ID clinicians and by antibiotic developers concerned about a dry pipeline, rising resistance and industry abandoning anti-infective R&D [1]. They wanted to make the public aware of the situation and came up with a nice catchy phrase which still resonates today: “Bad Bugs, No Drugs”, “Bad Bugs, No Drugs: no ESKAPE!” [2]. And a cool logo as well.
Looking back, we’d expect a publication from stakeholders taking stock and assessing achievements against plan. Amazingly, there is no report from IDSA or others touting 10 x ’20 achievements. Why this silence? Was there really no progress?
We compiled a table of all approvals between 2010 and 2019 (inclusive), together with our ratings of these newcomers.
The Pew Trust website provides an elegant animated graphic showing antibiotics in development since 2014 [4]; an earlier Annals article provides additional information on approvals between 2010 – 2015 [5]. Together these 2 sources are the basis of our 10-year analysis and score card.
A total of 18 new antibiotics received FDA approval in the last decade. What at first glance looks like a respectable number, is less impressive on closer inspection.
As indicated in our color coding, most of these ‘new’ drugs are not really new, as most belong to established antibiotic classes, most being β-lactams. In general – but not always – we get minor improvements in PK or in antimicrobial spectrum.
But wait, not all is bleak. There was real progress with at least some newcomers. The MVP title can be claimed by 2 drugs: cefiderocol/FETROJA which adds an interesting new MoA (Fe channel) to its β-lactam profile, and lefamulin/XENLETA, the long-awaited first pleuromutilin drug. Honorable mention goes to ceftazidime/avibactam and ceftolozane/tazobactam, both excellent drugs for CRE and P. aeruginosa, respectively. In the supporting category we have omadacycline, fidaxomicin and bedaquiline. And vabomere, too, perhaps.
How about the remainder of the 10 x ’20 harvest? It’s slim pickings once you subtract all the me-too drugs. Some long-acting glycopeptides came to market providing convenient once-weekly dosing, and a few drugs added MRSA coverage (delafloxacin, ceftaroline) at the expense of Gram-negative spectrum activity. None of these me-too’s saw much adoption in clinical practice.
Speaking of the markets: they have not been kind to undifferentiated newcomers. Indeed, 2 narrow-spectrum companies disappeared shortly after their drug was launched:
- Achaogen’s plazomicin takes top price for uninspired management and poor strategy: after all this effort, only a cUTI indication followed by a fire sale!
- Tetraphase’s eravacycline never recovered after two IGNITE UTI disasters (see our earlier blogs), another good case study on how not to develop an antibiotic!
Melinta’s delafloxacin may have been a decent MRSA quinolone in the late ‘90s. But the competition, esp. Pfizer’s linezolid, proved too strong. It just shows that slow / protracted / delayed development can kill projects, as exemplified also by Cempra’s solithromycin and Arpida’s iclaprim.
What made tedizolid so attractive? Why it was acquired by Merck is hard to fathom. It has almost no differentiation from linezolid, apart for qd dosing. The drug went through so many hands until it was eventually picked up by Merck where it joined daptomycin – another Cubist drug.
Somehow Nabriva managed to beat the odds: lefamulin/XENLETA was approved in 2019 after 15 yrs of drug development. Not a minor achievement! Lefamulin is a pleuromutilin, a class of antibiotics which have been in veterinary use for decades, just never in humans. It has good bacteriostatic activity against respiratory pathogens including atypicals and was approved for CABP. It is an IV+PO drug just like omadacycline that we discussed in earlier blogs and which garnered US approval for ABSSSI and CABP in 2018.
The approval of cefiderocol/FETROJA was the highlight of the past decade. It is a β-lactam drug with an impressively broad spectrum which includes P. aeruginosa and Acinetobacter. It has activity against CPEs and is resistant to most BLase classes. Cefiderocol was first approved in cUTI, later in HABP/VABP. However, an imbalance of deaths in the nosocomial pneumonia program is worrisome and mentioned in the label [7][8].
Of note, an earlier drug with a similar siderophore-targeting MoA (Basilea’s BAL30072) did not make it through clinical development.
Let’s admit it, this was not a good decade for antibacterial drug developers. The exodus of Big Pharma from the once so active anti-infective field has not been reversed, and many small and mid-size companies have left the field for greener pastures, i.e., oncology. It was, however, the decade that brought us break-through HCV therapy, new influenza drugs, new monoclonals against important infections like anthrax and C. difficile, and the first meningococcal Group B vaccine (Menveo). FDA’s LPAD approval pathway was helpful – to a degree. But progress was certainly not noticeable on the antibacterial front.
Most of the drugs in our approval list actually had their roots in the years between 2000 – 2010; companies just kept development efforts going. For the 2020 – 2030 timeframe we predict a continued downward trend . The Anti-Infectives division at the FDA must have run out of work: no new Guidances needed, few new NDAs to review. Ed Cox has left the FDA and joined industry. If IDSA were working on a new initiative, it would have to be called 1 x ’30 !
The 10 x ’20 initiative was probably doomed from the beginning. The much talked-about ‘perfect storm’ of overwhelming antibiotic resistance did not materialize. No wonder, corporate strategists keep investing elsewhere. This initiative never had much industry support and it fizzled out for lack of incentives. IDSA did not look too good in all of this; the Gates Foundation, BARDA and CARB-X kept the lights on in a few companies.
Is it time for a new initiative with less ambitious goals? Don’t count on Covid-19 or a new pandemic to rekindle interest in antibacterials: as long as the business model is not fixed, there will be no change in investment flows [6]. It is naive to think that medical need alone would convince corporate strategists to invest in a therapeutic area characterized by short term therapies and stewardship restrictions. Without commercial incentives and attractive market conditions, pharma bosses will just walk away and never look back.
REFERENCES
[1] Talbot G. Bad Bugs Need Drugs: An Update on the Development Pipeline From the Antimicrobial Availability Task Force of the Infectious Diseases Society of America. CID 2006; 42:657
[2] Boucher H. Bad Bugs, No Drugs: no ESKAPE! an update from the IDSA. CID 2009; 48
[3] IDSA. The 10 x ‘20 Initiative: Pursuing a Global Commitment to Develop 10 New Antibacterial Drugs by 2020, CID 2010; 50:1081
[4] https://www.pewtrusts.org/en/research-and-analysis/data-visualizations/2014/antibiotics-currently-in-clinical-development
[5] Deak D. Progress in the Fight Against Multidrug-Resistant Bacteria? A Review of U.S. Food and Drug Administration–Approved Antibiotics, 2010–2015
[6] Mossiakos E. Policies and incentives for promoting innovation in antibiotic research. LSE 2010
[7] Naseer S. US Food and Drug Administration (FDA): Benefit-Risk Considerations for Cefiderocol (Fetroja®). Clin Infect Dis 2021;72:e1103
[8] Clevenburg P. Reply to: ‘Clinical efficacy and safety of cefiderocol in the treatment of acute bacterial infections: a systematic review and meta-analysis of randomised controlled trials’
ABBREVIATIONS
ABSSSI acute bacterial skin/skin structure infection
BARDA Biomedical Advanced Research and Development Authority
CABP community-acquired bacterial pneumonia
CARB-X Combatting antibiotic-resistant bacteria
CRE carbapenem-resistant enterobacteriaceae
cUTI complicated urinary tract infection
DD differentiated drug
GCP Gram-Positive Cocci
HABP hospital-acquired bacterial pneumonia
LPAD limited population pathway for antibacterial and antifungal drugs
MRSA methicillin-resistant S. aureus
VABP ventilator-associated bacterial pneumonia
