Development of new antibacterial agents: a sense of urgency needed

On April 15, 2021, WHO released its annual report on the antibacterial clinical and preclinical pipeline. “The report reveals a near static pipeline with only [a] few antibiotics being approved by regulatory agencies in recent years”, stated WHO. It added that none of the antibiotics currently in clinical development “sufficiently address the problem of drug resistance in the world’s most dangerous bacteria”. The report covered the year to September, 2020. It identified phase 1–3 trials of 43 new antibiotics, targeting drug-resistant bacteria on the WHO Priority Pathogen List, Mycobacterium tuberculosis, or Clostridium difficile. Of the 26 antibiotics active against the priority pathogens, seven satisfy at least one of the criteria for innovation: absence of cross-resistance to existing antibiotics, new chemical class, target, or mechanism of action.

27 non-traditional antibacterials, such as bacteriophages and immunomodulating agents, are in clinical trials, the majority of which are intended for use in combination with standard antibiotics.

Nine of 11 antibiotics approved by the European Medicines Agency or the US Food and Drug Administration since 2017 are derivations of existing classes of antibiotics, raising the prospect of the rapid emergence of resistance. The other two agents, vaborbactam and lefamulin, represented new chemical classes. Vaborbactam was approved in combination with meropenem to treat carbapenem-resistant Enterobacteriaceae. As evidence of the scant rewards on offer for developing antibiotics, the producer of vaborbactam plus meropenem filed for bankruptcy in 2019. The large pharmaceutical firms have absented themselves from antibiotic research and development, leaving

the field to small and medium sized biotechnology companies that struggle to raise the kind of sums necessary to move a product through late-stage clinical trials and regulatory approval.

The preclinical pipeline contains 292 agents, nearly half of which are non-traditional. “Researchers are looking at a lot of interesting avenues in a very open-minded way; they are trying completely new approaches to treat bacterial infections”, said Peter Beyer (Antimicrobial Resistance Division, WHO, Geneva, Switzerland). He attributes the increased innovation to the CARB-X project, which was established in 2016 and has so far invested US$325 million in the preclinical antibiotic pipeline. The $1 billion AMR Action Fund is focused on clinical development. It was launched last year and brings together partners from the pharmaceutical industry, alongside WHO, the European Investment Bank, and the Wellcome Trust. The aim is to bring two to four novel antibiotics to the market by 2030.

“What we really need is new mechanisms of action, unknown to bacteria, that will not lead to resistance in the short-term”, said Otto Cars (Uppsala University, Uppsala, Sweden). “Early drug discovery is the real bottleneck here; there are few scientists who know how to do it.” He advocates a system of global collaboration on early innovation, tied to initiatives such as the Global Antibiotic Research and Development Partnership (GARDP) that bring the products through to development. “We need not only to be priming the pipeline with truly innovative and promising compounds, but also finance their development in a way that ensures they end up being affordable and accessible to all in need”, explained Cars. “The crucial

thing is to make sure that we are not reserving successful compounds for rich countries.”

Governments all over the world will have to commit resources to antibiotic research and development and rethink their reimbursement and procurement policies. Beyer cites the example of a pilot project from the UK, in which manufacturers are contracted to provide as many antibiotics as needed in return for a fixed yearly fee. “This could be the model of the future; it guarantees an income for the pharmaceutical company and takes away the incentive for them to sell large volumes of products.”

Dušan Jasovský is an antimicrobial resistance pharmacist on Médecins Sans Frontières’ Access Campaign. He stresses the importance of including low-income and middle-income countries in the global response to the antimicrobial resistance crisis. “The unmet medical needs of the people in places with the highest burdens of resistance need to be addressed; they should be equal partners in decision making on priority targets, indications, formulations, as well as clinical research”, said Jasovský. “We have to think about what will work in resource-poor settings.”

Simplified diagnostics are sorely needed, so as to curb unnecessary use of antibiotics, particularly in the developing world. Building laboratory capacity is essential, as is investing in bacterial vaccines. “There is not the sense of urgency among governments that the situation regarding anti microbial resistance deserves”, said Jasovský. He recommends deploying the same kind of instruments that expedited the rapid development of the COVID-19 vaccines and diagnostics to the antimicrobial resistance crisis.

Talha Khan Burki