Antibiotics under development insufficient to tackle antimicrobial resistance

After a gap of two years, the World Health Organization (WHO) has released its latest report that presents an analysis of antibacterial agents in preclinical and clinical development (as of December 2023). The analysis covers traditional and non-traditional antibacterial agents in development worldwide. 

Traditional agents act by directly targeting components necessary for bacterial growth or to kill the pathogen, whereas non-traditional agents lack intrinsic antibacterial activity and work through other means. 

The report also evaluates to which extent the present pipeline addresses infections caused by drug-resistant bacterial pathogens part of the updated 2024 WHO bacterial priority pathogen list (BPP). Bacterial agents targeting drug-resistant Mycobacterium tuberculosis are discussed separately from drugs targeting the other WHO BPPs. This is done to provide an overview of the current R&D landscape and potentially help steer development towards the most urgent unmet medical needs.

Apart from the bacterial priority pathogen list, the review also includes products intended against Clostridioides difficile and Helicobacter pylori, given the clinical importance of these pathogens and associated resistance.

Clinical pipeline

As per the report, the current clinical antibacterial pipeline contains 97 antibacterial agents and / or combinations, out of which 57 are traditional antibacterial agents and 40 are non-traditional.

Of the 57 traditional antibacterials, 32 are intended against the WHO BPPs and 19 against drug-resistant M. tuberculosis. Additionally, five traditional agents are being developed against C. difficile, and one against H. pylori. 

Of the 40 non-traditional antibacterials, 30 are intended against WHO BPPs, nine are directed against C. difficile and one addresses H. pylori. 

Read more: WHO’s new bacterial priority pathogen list emphasises on public health needs, infection burden of developing countries

As per the last analysis released by WHO in 2022 (updated till November 2021), there were 80 antibacterial products in clinical development, out of which 46 were traditional and 34 were non-traditional. The analysis also addressed infections caused by drug resistant bacterial pathogens according to the WHO priority pathogens list 2017, Mycobacterium tuberculosis and Clostridioides difficile.

It can be noted here that WHO released its priority pathogen list back in 2017 and has been referring to this list while analysing antibacterials under development in its previous reports. However this years since an updated version of the priority pathogen list has been released, the latest antibacterial pipeline analysis takes into consideration the updated list. 

The report also compared the status of antibiotic development and the progress made in the last six years. However, overall, the report mentioned that the antibacterial agents in the clinical pipeline, combined with those approved in the last six years, are still insufficient to tackle the ever-growing threat of the emergence and spread of drug-resistant infections.

The clinical stage is about testing the drug in humans in three phases known as Phase 1, Phase 2 and Phase 3, where the drug is tested for safety, efficacy, dosing and interactions, first in a small group of healthy human subjects followed by a larger number of patients. 

Preclinical pipeline

Before testing in humans, the antibiotics under development go through first, the drug discovery stage that involves selecting and optimising antibiotic leads and then the pre-clinical stage where testing of antibiotic candidates is done such as for safety and efficacy in animals. 

As per the report, there are currently 244 products in preclinical development targeting WHO 2023 bacterial priority pathogen list and C. difficile. The last analysis released in 2022 had 217 antibacterial products in preclinical development. 

Of the commercial developers in the pre-clinical pipeline, 95 per cent are micro, small and medium developers. This trend confirms what has been observed in previous years, which is that a significant majority of the preclinical pipeline developers are very small, privately funded organisations. This is also indicative of the number of large pharmaceutical firms that have exited the antibacterial discovery area.

Last year, researchers from Delhi-based think tank Centre for Science and Environment (CSE) wrote about the antibiotic pipeline in the article A Developing Crisis, for the July 16-31, 2023 edition of the Down To Earth magazine. In the assessment, the researchers highlighted how the global antibiotic pipeline is weak and fragile and how the big pharmaceutical companies, which were once the pioneers of antibiotic development, have exited this space. 

Read more: What could the future antibiotic pipeline look like: IFPMA releases its latest report

The 2023 analysis also captured 62 programmes (25.4 per cent) that are listed as being in the investigational new drug (IND)-enabling phase of preclinical development. This is the last stage after which the drug enters the clinical trial phase. This number is a significantly larger number than in earlier pipeline reports, as the last analysis of 2022 had 34 programmes listed in the IND-enabling stage. 

“Antimicrobial resistance is only getting worse. Yet, we’re not developing new trailblazing products fast enough to combat the most dangerous and deadly bacteria,” said Yukiko Nakatani, WHO’s assistant director-general for antimicrobial resistance, ad interim, in the press release for the report. “Innovation is badly lacking yet, even when new products are authorised, access is a serious challenge. Antibacterial agents are simply not reaching the patients who desperately need them, in countries of all income levels,” added Yukiko.