Background

The advent of antimicrobial-resistant (AMR) “superbugs” is often described as an urgent threat to humanity. The Center for Disease Control (CDC) estimates 2.8 million patients suffer from antibiotic-resistant infections per year in the U.S., and 35,000 of those die from their infections [1]. With AMR representing significant morbidity and mortality it is surprising that the anti-bacterial drug pipeline is so thin.

The World Health Organization (WHO) has defined “priority pathogens” and the CDC has defined “urgent threats”: highly resistant organisms that most existing therapies will fail to treat. What we see is that the clinical picture of AMR is actually a fragmented one of several, different, relatively small unmet needs, with patient numbers often in the thousands per year. As an illustration, the CDC estimates 13,100 annual cases of Carbapenem-resistant Enterobacterales (CRE) and 8500 annual cases of Carbapenem-resistant Acinetobacter [1].

Only six major biopharmaceutical companies maintain small programs in antibiotics, and specialist antibiotic developers have gone bankrupt in recent years. To cover the high cost of expensive and risky investment in developing a new therapeutic, biopharmaceutical companies prefer high-priced drugs for oncology and chronic diseases such as diabetes, auto-immunity and inflammation. Top-performing drugs in these fields generate tens of billions of dollars in revenue annually. The top ten selling medicines in 2022 are listed in Table 1. Notably not one is an antibiotic.

Table 1 Top selling therapeutics globally (2022) [9]
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In contrast, antibiotic revenues are very limited. The top ten selling antibiotics in the United States in 2022 are listed in Table 2. Only three of these drugs are newer, branded agents: Dalbavancin (Dalvance), Ceftazidime/avibactam (Avycaz), and Ceftaroline (Teflaro). Of these three, none has achieved sales greater than $150 million. Novel antibiotic agents are often held in reserve for only the most resistant and difficult to treat cases, such as the categories defined by the WHO and CDC, and have very limited sales volume. Furthermore, they can be expected to have small profit margins, because they must be priced relatively low to compete with generic alternatives, and the cost to manufacture is high due to complicated synthetic routes and intravenous formulations. Thus, novel antibiotics have low sales volume, low pricing power, and high production cost.

Table 2 Top selling antibiotics in the U.S. (2022) [10]
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The choice for a biopharmaceutical investor is easy: put money to work in other therapeutic areas, not in antibiotics.

The “precision medicine” solution to the AMR crisis

Following the lead of the WHO and CDC, much of the recent development work in antibiotics has focused on finding treatments for specific highly resistant pathogens and takes inspiration from other fields of “precision medicine”. However, defining the problem this way may be contributing to the lack of industry interest in novel antimicrobials. First, for any particular resistant pathogen, very few patients are microbiologically confirmed to be infected. As a result, clinical trials are lengthy and expensive, as it is very difficult to recruit patients, even when large numbers of potential patients are screened. Second, even if an antibiotic is developed and approved, limited patient populations and limited pricing power translate to a very small market. Finally, looking to the future, a comprehensive pathogen-specific antibiotic strategy requires a portfolio of innovative medicines, each bringing its own unique cost center. To address adequately the AMR crisis as currently defined, many new pathogen-specific medicines would be needed. Each would require lengthy and costly clinical development, and each on its own would likely not be very profitable. Such a strategy seems neither feasible nor prudent.

Rethinking the problem

The authors, who comprise clinicians, scientists, and business executives, see the situation differently. While the clinical picture may be fragmented, we believe there is a large and comprehensive unmet medical and economic need for better empiric therapy. We propose thinking of the unmet need for antimicrobials as the decreasing efficacy of front-line empiric therapies and the resulting impact on patients and health systems. Indeed, treatment failure rates have been found to be nearly 15% in several clinical settings, such as Community Acquired Pneumonia (CAP) requiring hospitalization [2], and could be even higher. Patients experiencing treatment failure often have longer hospital stays [2]. Long hospital stays are bad for patients as the risk of complications rises, and also bad for payers, with each extra day in the ICU costing more than $3000 per patient, and often many times this amount [3].

Pathogen-general potentiation: an alternative strategy

Instead of focusing on pathogen-specific molecules and/or development plans, a more promising strategy might be the pursuit of innovative antibiotic approaches that are applicable across a wide range of pathogens and thus suitable for empiric therapy- “pathogen-general”. In particular, we propose a focus on innovative general potentiators which could be included in empiric therapy. To name a few plausible mechanisms, potentiators could be disablers of bacterial defenses, disrupters of bacterial DNA damage repair, broad-spectrum virulence factor inhibitors, or immune modulators, and beyond [4].

The advantages of adding a pathogen-general potentiator to standard empiric antibiotic administration are many. It could be used in combination with existing antibiotic agents across many infections, caused by both susceptible and resistant pathogens, both gram-positive and gram-negative bacteria, without a need to rely upon bacterial diagnostics. By considering novel chemical classes, potentiators might avoid the costly manufacturing typically involved with novel beta-lactams. A pathogen-general potentiator added to standard antibiotic agents may optimize clinical care particularly in critically ill and/or immunosuppressed patients. Finally, a potentiator may help extend the lifespan of existing, older antibiotics, which would be a boon in the developing world, and be helpful even in developed countries which are struggling with resistant pathogens and the attendant high rates of treatment failure.

We are not naïve to the challenges of potentiator discovery and development, which is likely a more difficult technical problem than a next-generation version of a known drug class. When considering bacterial targets, few potentiation targets have been found to be relevant across a range of pathogens or partner antibiotics. The few suitable targets have been difficult to drug with a single agent across bacterial genera. Resistance development to the potentiator and combination partners must be considered, as would the pharmacokinetics of the potentiator with respect to the partner drug. Novel regulatory pathways might be required, particularly involving broader definitions of treatment failure. But, in some respects, clinical development could be easier. If used as empiric therapy, enrollment would likely be much easier than in a pathogen-specific setting. A potentiator studied as empiric therapy would be amenable to existing regulatory endpoints, such as Early Clinical Response (ECR). The regulatory innovation of non-inferiority trials allowed for the successful development of novel antibacterials in recent decades. We envision a similar outcome for novel regulatory pathways spurred by potentiators. Given high rates of treatment failure of existing empiric therapies, superiority trials designs could even be possible. For example, one could evaluate a potentiator versus placebo, each on top of standard of care antibiotic, in empiric response for all patients (both those with susceptible and resistant infections). To illustrate the feasibility of pathogen-general potentiators, an anti-biofilm antibody under development by Clarametyx is already in Phase 1b/2a clinical studies [5].

Pathogen-general potentiators can be commercially attractive

In addition to the clinical benefits, a more widely-used agent would provide an economic return that could encourage and reinvigorate research and development. The potentiator strategy utilizing a pathogen-general potentiator could conceivably be used in millions of patient treatment cases per year and deliver billions of dollars in revenue. High-volume drugs at this scale are typically manufactured at a cost of less than $10 per dose for a biologic, and even $1 per dose for a small molecule and has been reported as low as $0.10 per dose [6]. The resulting profit potential of a therapy of this profile is large enough to attract investor interest even in the absence of pricing reform.

For a concrete example, there are an estimated five million annual cases of CAP in the United States [7]. Suppose a potentiator were used in empiric therapy for the 1.5 million severe cases resulting in hospitalization [8], and suppose it were demonstrated to reduce average length of stay by one day. Such a therapy would be saving the healthcare system at least $3000 per patient and could be priced at $1500 per treatment course, providing over $2 billion of revenue while still providing significant savings to the healthcare system. Accounting for other severe infectious syndromes and other major geographic markets increases the revenue opportunity. This strategy has the potential to be commercially attractive to major pharmaceutical companies and investors (akin to the dynamics that made remdesivir a blockbuster drug at its peak).

Conclusion

We acknowledge that from a technical perspective, pathogen-general potentiators present a significantly greater challenge than an iteration on an existing class. However, pathogen-general potentiators could be widely used, unlike agents based on existing antibiotic frameworks. A pathogen-general potentiator that successfully reaches advanced clinical trials could more easily attract the significant industry capital needed for commercialization. As such, they are worth investment by the early-stage research community, despite the higher technical risk. The antibiotic pipeline would be strengthened with the addition of more commercially viable pathogen-general potentiator technologies.