The World Health Organization (WHO) is issuing new warnings about the state of the antibiotic development pipeline.
In two reports issued late last week, the WHO said that most antibiotics in the development pipeline offer little benefit over existing treatments and that too few of them are truly innovative and target the most critical drug-resistant pathogens. Although the WHO found that the preclinical pipeline is more robust, those products are in the very early stages of development, and many will not make it to market.
The WHO said the underlying problem is poor market conditions, declining private investment, and lack of innovation, and WHO director-general Tedros Adhanam Ghebreyesus, PhD, is urging the private and public sectors to come up with a solution.
"Never has the threat of antimicrobial resistance been more immediate and the need for solutions more urgent," Tedros said in a WHO press release. "Numerous initiatives are underway to reduce resistance, but we also need countries and the pharmaceutical industry to step up and contribute with sustainable funding and innovative new medicines."
New antibiotics too similar to existing ones
The two reports echo the growing concern that, despite the approval of several new antibiotics in recent years, including drugs with activity against MDR infections, the products in the pipeline are not all that different from existing antibiotics and do not address the pathogens that the WHO is most worried about.
The agency pointed out that since 2017 eight new antibiotics have been approved, but only two—vaborbactam plus meropenem and lefamulin—meet at least one of the agency's innovation criteria, and the rest are derivatives of known antibiotic classes in which multiple resistance mechanisms are already established. That means that resistance to these drugs could develop quickly.
Because these new drugs are more expensive than existing antibiotics and don't offer significantly greater benefits for patients, clinicians have been reluctant to use them.
"Overall, the newly approved products have limited clinical benefit over existing treatments," the WHO said in the report on the clinical pipeline. "The lack of differentiation against existing treatments, their non-inclusion in clinical guidelines and their higher prices in comparison to existing generic treatments make it difficult to predict their place in the treatment landscape."
The WHO also noted that none of the newly approved antibiotics target carbapenem-resistant Acinetobacter baumannii or Pseudomonas aeruginosa, which are two of the agency's highest-priority MDR pathogens.
Likewise, the products currently in clinical development lack true innovation, according to the WHO report. Of the 60 products currently in clinical development (50 antibiotics and 10 biologics), the WHO identified only 6 as being truly innovative, and said just 2 of are those active against multidrug-resistant (MDR) gram-negative bacteria, which are the most critical pathogens.
While 32 of the antibiotics in clinical development are active against WHO priority pathogens, more than 40% of them are beta-lactam/beta-lactamase inhibitor combinations. Vaborbactam/meropenem is an example of these combination drugs, which have been on the market for more than 30 years.
Furthermore, only two of the beta-lactam/beta-lactamase inhibitor combinations in development are active against metallo-beta-lactamase enzymes such as NDM-1 (New Delhi metallo-beta-lactamase), which confers resistance to most antibiotics. The report noted that NDM-1–producing carbapenem-resistant Enterobacteriaceae (CRE) have caused outbreaks with high mortality in several countries.
Wes Kim, PhD, MBA, senior officer with the Pew Charitable Trusts' antibiotic resistance project, said the WHO's analysis tracks with Pew's evaluation of the antibiotic pipeline.
"The clinical pipeline is absolutely insufficient for the emerging diseases of today, and for tomorrow," Kim said.
In contrast, the WHO found more diversity and innovation in its analysis of antibacterial products in the preclinical pipeline. Overall, 252 products are being developed to treat WHO priority pathogens, Mycobacterium tuberculosis, and Clostridioides difficile. Among these, 42.9% are direct-acting small molecules, followed by non-traditional approaches (35.7%) and antimicrobial peptides (10.7%). Twenty-eight of the non-traditional products are bacteriophages—viruses that attack and kill bacteria—or phage-derived products.
In addition, the analysis found that 40% of the products in preclinical development target a single bacterium, reflecting a trend toward pathogen-focused therapies rather than broad-spectrum agents. Still, the WHO estimates that only 2 to 5 of the 252 preclinical products will make it to the market within the next 10 years, and that many of those projects will fail before they reach the final stages of clinical development.
"Those are not great odds if you're an investor," said Kim. "And that speaks to why antibiotic R&D [research and development] is such a high-risk endeavor."
Market challenges
While antibiotic discovery and development is scientifically challenging, the root problem identified by the WHO is the lack of financial return on new antibiotics. The slow sales of new antibiotics, and low hospital reimbursement for these drugs, has caused several large pharmaceutical companies to abandon the space, leaving a huge hole in antibiotic R&D.
"Not only do they have the institutional knowledge…but they also have the capital and the resources to drive a lot of the R&D, which is very risky," Kim said.
That has left the bulk of antibiotic R&D to smaller biotech companies, which have fewer resources and as a result have a hard time surviving if they can't get a return on investment. Achaogen and Melinta Therapeutics, which both declared bankruptcy in 2019 despite recently receiving US Food and Drug Administration approval for new antibiotics, are prime examples.
Moreover, although public and philanthropic investment in antibiotic development has increased in recent years through public/private partnerships like CARB-X (the Combating Antibiotic Resistant Bacteria Biopharmaceutical Accelerator) and GARDP (the Global Antibiotic Research and Development Partnership), the poor market conditions are making it more difficult for small companies to attract the private investment needed to engage in antibiotic R&D.
While the United States, United Kingdom, and Sweden have taken steps to address antibiotic reimbursement, the WHO says changing the market dynamics for antibiotics, and changing the way antibiotics are valued, will need to be a joint effort between government and industry. Kim said that academics and antibiotic development advocates will also need to play a role in devising solutions.
"It's going to take a broad spectrum of stakeholders to make sure we have a sufficient pipeline," he said.
Industry assessment
In another report addressing antibiotic development, released yesterday, the Access to Medicines Foundation echoed the WHO's assessment of the antibiotic pipeline.
The 2020 Antimicrobial Resistance (AMR) Benchmark report, which evaluates how 30 large and small pharmaceutical companies are responding to the threat of AMR pathogens, found that, of the 138 projects identified in both preclinical and clinical development (including vaccines), 53 target priority bacterial and fungal infections. The report labeled only 9 of the products in the clinical stages of development as novel.
Furthermore, the report noted that, with so many large pharmaceutical companies giving up on antibiotic development, the bulk of R&D activity is being carried out by just a few companies.
"Only a handful of large research-based companies remain broadly engaged in developing new antibiotics, down from more than 20 in the 1980s," Access to Medicines Foundation executive director Jayasree Iyer wrote in the report. "Losing any more big suppliers and innovators will make it extremely hard to ramp up effective drug discovery and development operations, while the tough economics of the market discourage investment in new manufacturing capacity."
In more positive news, the report also found that pharmaceutical companies have made progress in addressing the overselling of antibiotics. Ten companies, up from five in 2018, report that they have implemented responsible promotion practices to prevent inappropriate use of antibiotics or antifungals. This includes not promoting these products at all, or fully or partially decoupling bonuses from sales volume.
In addition, the report found that more companies are supporting or running AMR surveillance programs that track the rise and spread of resistance, and that most have an environmental strategy to minimize the impact of their manufacturing processes in promoting antibiotic resistance.
See also:
Jan 17 WHO press release
Jan 17 WHO clinical pipeline report
Jan 17 WHO preclinical pipeline report
Jan 21 Access to Medicines Foundation 2020 AMR Benchmark report
