Antibacterial R&D at a Crossroads: We’ve Pushed as Hard as We Can … Now We Need to Start Pulling!

antibacterial agents, antibiotic resistance, antibiotic innovation, FDA

((See the Major Article by Dheman et al on pages e4444–50.))

In this issue of Clinical Infectious Diseases, Dheman et al [1] present an analysis by experts at the US Food and Drug Administration (FDA) of trends in antibacterial clinical development over the past 4 decades. By turns instructive and disturbing, this 40-year perspective provides insight into the impact of efforts to restore the antibacterial pipeline.

As a preview, the key messages from Dheman et al are all bad news for public health: (1) the number of new antibacterials in clinical development is (again) falling, (2) the risk of failure is rising, (3) the speed of clinical development is slowing, and (4) most large companies with the capability to market agents on a global scale have exited clinical development. Several factors have led to this state of play, as follows.

FINDING COMPELLING NEW ANTIBACTERIAL AGENTS IS VERY, VERY HARD

Although alarms have been sounding for well over a decade about the threat from the rising tide of antibacterial resistance [2, 3], 3 problems loom large when one sets out to discover and develop a new antibacterial. First, the general difficulty of discovering innovative new medicines [4] is made worse by the fact that finding antibacterial compounds that can kill bacteria is not difficult but finding drug-like, nontoxic molecules that do this is consistently very challenging [5, 6]. Second, scientifically necessary trial design upgrades implemented globally over the past 15 years have entailed increased cost and time due to the need to focus on more serious (but less common) forms of infections and as well as the frequent need for relatively larger trial programs to ensure adequate statistical rigor [7]. Finally, the need for careful stewardship of new products leads to a crippled economic model for new antibacterial agents [8–11]. In a nutshell, the economics of antibacterial antibiotics do not recognize their preparedness value, which has been analogized to the value of fire extinguishers and other fire prevention services [12].

CALLS FOR ACTION HAVE BEEN RAISED AND HAVE LED TO SOME CONCRETE ACTIONS

The need for new antibacterial agents and an initial understanding of the core challenges around their creation have led to multiple parallel lines of effort. Antibacterial agents generally do not qualify for orphan drug designation and its entailed incentives—although the resistant strains that drive the need for the new antibacterial might be so rare as to meet orphan drug criteria, the new agent’s activity versus wild-type susceptible strains creates a potential patient pool that exceeds orphan drug limits. The Infectious Diseases Society of America (IDSA) began calling for action in 2002, ultimately leading to its “10×20” call for 10 new antibacterial antibiotics by 2020 [13, 14]. A conference convened by the Swedish European Union (EU) presidency in 2009 led to a call for innovative incentives [15]; the creation of TATFAR (Transatlantic Taskforce on Antimicrobial Resistance), a government-level EU–US collaboration [16]; and the creation of ND4BB (New Drugs For Bad Bugs initiative), an EU-based multidisciplinary collaboration on the challenges facing drug discovery [17]. In 2012, US Congress passed the Generating Antibiotic Incentives Now (GAIN) Act, thereby creating the Qualified Infectious Disease Product (QIDP) designation that makes products eligible for priority review and 5 years of additional marketing exclusivity [18]. In 2015, the US government unveiled a National Action Plan on Combatting Antibiotic-Resistant Bacteria, which led to a collaborative effort with Wellcome Trust to create CARB-X the following year to support preclinical R&D with push funding [19]. Finally, 2016 saw passage of the Limited Population Pathway for Antibacterial and Antifungal Drugs as part of the 21st Century Cures Act, focused on approval of new agents specifically for use in patients with unmet medical needs [20].

BUT, A COMPANY-CRUSHING POSTAPPROVAL ECONOMIC PRESSURE ON ANTIBACTERIAL DEVELOPMENT REMAINS UNABATED

Despite these laudable efforts to incentivize, the data from Dheman et al show that the number of new antibiotics in clinical development in the United States continues to decline. It has become increasingly apparent that stewardship concerns lead (appropriately!) to delayed sales of antibacterial agents and the extended exclusivity approach of the GAIN Act hence has only marginal economic value [21, 22]. With median costs to bring a new drug to FDA approval exceeding $1 billion [23], and initial sales routinely well less than $100 million/year for new antibacterial agents [24], it is little surprise that R&D in this sector is losing ground. As one measure of this, the number of companies doing antibacterial R&D reached a peak in the late 1980s, but by 2013 had fallen to the number of active companies active in 1960 [25]. For large companies, the situation is now even worse: Dheman et al report that only 3 large companies remain with any clinical antibacterial programs in the United States, the lowest level in the past 40 years.

Considered from the perspective of IDSA’s 10×20 initiative, the impact of these pressures is stunning. Although the industry has actually delivered 15 entirely new antibacterial agents since 2009, 5 of these agents have fallen to a market value of effectively zero [26]! As a concrete example, one of those recently registered products (meropenem-vaborbactam) had just under $21 million in US sales in its first 2 years (combined) on the market. The sponsor, Melinta Therapeutics, declared bankruptcy in 2019, despite the compound being recognized in a World Health Organization review as being an innovative novel chemical class [27].

THE FINDINGS OF DHEMAN ET AL ARE THUS NOT A SURPRISE

The changes in underlying science that led to a tightening of study design requirements have definitely improved trial quality, but these changes also necessarily resulted in the reduced success rates noted in their review. The economic pressures described above have reduced corporate interest and thus the finding of few drugs and fewer large companies is also not surprising.

THE BEST OF TIMES, THE WORST OF TIMES

Perhaps surprising given the tone of this editorial commentary thus far, we see the current moment as one of opportunity in crisis. The opportunity comes from evidence that the substantial push funding deployed over the past decade is beginning (albeit slowly) to lead to the discovery of truly novel therapeutics in the preclinical pipeline [28–31]. Such novel candidates are few in number and most will fail, but the degree of innovation is impressive. There has also been a meaningful shift in the indications being pursued, with intravenous drugs suitable for serious Gram-negative infections now becoming more common than in the past [32].

Unfortunately, the fundamental economic crisis remains and reform efforts to date have not fully addressed the problem of rewarding a company for an approved antibacterial that we hope is needed only in rare cases. To solve this problem requires a new approach, paying for preparedness, with a focus on high-quality clinical trial data on innovative agents approved by the FDA [12]. If a company had offered a broad-spectrum SARS (severe acute respiratory syndrome) vaccine to the world in 2018, the market value would have been zero. But the preparedness value of such a vaccine would have been trillions of dollars: deferring work on preparedness is analogous to waiting to build fire-fighting infrastructure until after buildings catch fire! Going forward, we must find a way to support approval and commercialization of high-quality antibacterial agents today, before the postantibiotic era that is already a reality for the 38 000 patients who die from resistant infections every year [33] becomes a reality for us all.

After a decade of careful work in several settings—including the Eastern Research Group for the US Department of Health and Human Services [34], Chatham House in London [35], DRIVE-AB for the EU [36], the AMR Review led by Lord Jim O’Neill [8], the Duke-Margolis Center for Health Policy [11], the US Government Accountability Office [37], and others—we understand the pressing need for postapproval “pull” incentives. We must restructure reimbursement for antibacterial agents by providing substantial pull awards that are paid in a volume-independent fashion upon regulatory approval of meaningful new agents. Governments need to buy access to new antibacterial agents as preparedness, in the same way that we invest in fire protection.

And there is hope on this front, prompted in part by the recognition of the value of preparedness. The National Health Service England is progressing on a subscription pull incentive [38] that will be the world’s leading example of innovative thinking on antibacterial antibiotic pull incentives. But the English antibacterial market is too small to single-handedly restore health to the global R&D ecosystem. Other countries, especially G20 countries [39], need to lead. The largest market for novel antibacterial agents is the United States, so enactment of an antibacterial pull incentive in the United States would be an inflection point, reversing the decades-long decline found in this study by Dheman et al.

In summary, our efforts to create innovative antibacterial agents with push funding are beginning to bear fruit and it is now necessary to implement the corresponding pull mechanisms that will keep the needed new antibacterial agents on the market once they reach approval.

Notes

Disclosures. J. H. R. is Chief Medical Officer and Director, F2G Ltd; Operating Partner & Consultant, Advent Life Sciences; and Adjunct Professor of Medicine, McGovern Medical School, Houston, Texas. He sits on the scientific advisory boards of Bugworks Research, Inc; Basilea Pharmaceutica; Forge Therapeutics, Inc; Novo Holdings; and Roche Pharma Research & Early Development. He is a shareholder in AstraZeneca Pharmaceuticals; F2G Ltd; Advent Life Sciences; Zikani Therapeutis; and Bugworks Research, Inc. He has received consulting fees from Phico Therapeutics; ABAC Therapeutics; Polyphor Ltd; Heptares Therapeutics Ltd; Gangagen Ltd; Meiji Seika Pharma; Basilea Pharmaceutica International Ltd; Allecra Therapeutics GmbH; Forge Therapeutics, Inc; SinSa Labs; AtoxBio; Peptilogics; F. Hoffmann-LaRoche Ltd; Novo Holdings; Innocoll; Vedanta; Progenity; Nosopharm SA; Roivant Sciences; and Shionogi Inc. The opinions expressed are his own and do not necessarily reflect the opinion of any of the groups with which he works. K. O. is Professor of Law at Boston University and Executive Director and Principal Investigator for the CARB-X project at Boston University, funded by the US government (the Biomedical Advanced Research and Development Authority and the National Institute for Allergy and Infectious Diseases, both within the US Department of Health and Human Services), the Wellcome Trust, the UK Government (Department of Health and Social Care and the Global AMR Innovation Fund), the German Government (Federal Ministry of Education and Research), and the Bill & Melinda Gates Foundation. The views expressed are personal and do not necessarily represent the opinions of CARB-X or any of its funders. His work was supported by the Social Innovation in Drug Resistance Program and the School of Law, both at Boston University.

Potential conflicts of interest. The authors: J. H. R. works actively in the pharmaceutical industry as noted in the disclosures. K. O. reported no conflicts of interest. Both authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.