Not enough “trail-blazing” drugs to fight deadly bacteria

Medicines

Penang, 22 Jun (Kanaga Raja) — Although the number of antibacterial agents in the clinical pipeline, including antibiotics, increased from 80 in 2021 to 97 in 2023, there is still a pressing need for new, innovative agents to tackle serious infections and to replace those becoming ineffective due to widespread use, according to the World Health Organization (WHO).

In its latest report analysing antibacterial agents in preclinical and clinical development, WHO said that not only are there too few antibacterials in the pipeline, given how long is needed for research and development (R&D) and the likelihood of failure, there is also not enough innovation.

It said that 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 report evaluates whether the current R&D pipeline properly addresses infections caused by the drug-resistant bacteria most threatening to human health, as detailed in the 2024 WHO bacterial priority pathogen list (BPPL).

WHO said that of the 32 antibiotics under development to address BPPL infections, only 12 can be considered innovative.

In addition, just 4 of these 12 are active against at least one WHO “critical” pathogen – critical being the BPPL’s top risk category, over “high” and “medium” priority.

There are gaps across the entire pipeline, including in products for children, oral formulations more convenient for outpatients, and agents to tackle rising drug resistance, WHO warned.

On an encouraging note, WHO said that non-traditional biological agents, such as bacteriophages, antibodies, anti-virulence agents, immune-modulating agents and microbiome-modulating agents, are increasingly being explored as complements and alternatives to antibiotics.

However, it noted that studying and regulating non-traditional agents is not straightforward.

Further efforts are needed to facilitate clinical studies and assessments of these products, to help determine when and how to use these agents clinically, WHO added.

“Antimicrobial resistance is only getting worse yet we’re not developing new trail-blazing products fast enough to combat the most dangerous and deadly bacteria,” said Dr Yukiko Nakatani, WHO Assistant Director-General for Antimicrobial Resistance ad interim.

He said innovation is badly lacking, yet, even when new products are authorized, access is a serious challenge.

“Antibacterial agents are simply not reaching the patients who desperately need them, in countries of all income levels,” Dr Nakatani added.

AMR A MAJOR THREAT

According to the WHO report, antimicrobial resistance (AMR) continues to pose a significant global public health threat, ranking among the top 10 challenges faced by humanity.

In 2019 alone, AMR was associated with the deaths of 4.95 million individuals. One out of every five deaths related to AMR occurred in children under the age of 5, underscoring the urgent need for a global, coordinated action, it said.

Beyond its devastating impact on human lives, AMR also jeopardizes the global economy, with implications for international trade, health care expenditures and overall productivity.

If left unaddressed, by 2050, the economic toll of AMR could reach a staggering US$100 trillion, said the report.

It also pointed out that the link between AMR and use of antibiotics is well established.

Additionally, it said the misuse of medically important antibiotics in farms, aquaculture and in agriculture is a significant contributor to the rising prevalence of AMR.

The report said that AMR is influenced by a wide array of additional risk factors, encompassing environmental, governance and socioeconomic elements.

“To effectively address AMR, adoption of a multi-faceted approach is crucial. This includes implementation of surveillance and tracking systems, antibiotic stewardship, and infection prevention and control measures.”

The report said that at the same time, it is imperative to bolster laboratory capabilities, monitor drug use while enhancing access and invest in the development of innovative and effective antibacterial agents as well as novel diagnostic approaches and vaccines.

The urgent need for effective antibacterial drugs is further highlighted by increasing resistance trends, it said.

WHO said the 2022 WHO report on the Global Antimicrobial Resistance and Use Surveillance System (GLASS) revealed alarming levels of resistance.

The report said the resistance rate towards cephalosporin exceeds 50% in Klebsiella pneumoniae, which typically necessitate the use of carbapenems (i.e., “Reserve” antibiotics), while over 50% resistance towards carbapenems in Acinetobacter spp leaves patients with very few options.

Over 60% of N. gonorrhoeae isolates showed resistance to ciprofloxacin, one of the most frequently prescribed oral antibacterials.

Similarly, the report said that more than 20% of isolates of E. coli, the primary pathogen responsible for urinary tract infection (UTI), demonstrated resistance to both first-line (ampicillin and co-trimoxazole) and second-line (fluoroquinolone) treatment.

It said while some resistance trends have remained stable over the past 4 years, the rates of BSI (bloodstream infection) caused by resistant E. coli, Salmonella spp., and resistant N. gonorrhoeae infections have increased by at least 15% compared to 2017 figures.

THE CLINICAL PIPELINE

According to the WHO report, the current clinical antibacterial pipeline contains 97 antibacterial agents and/or combinations that include at least one new therapeutic entity. Of these, 57 are traditional antibacterial agents and 40 are non-traditional.

There are four products in New Drug Application /Marketing Authorization Application (NDA/MAA) stages: three traditional agents and one non-traditional agent.

WHO said of the 57 traditional antibacterials, 12 new products entered the clinical pipeline since the last report.

In addition, three agents were either discontinued or no recent information was available since the last report.

Looking at newly approved antibacterials, WHO said that since 1 July 2017, 13 new antibiotics have obtained marketing authorization but only 2 represent a new chemical class and can be termed innovative, underscoring the scientific and technical challenge in discovering novel antibacterials that are both effective against bacteria and safe for humans.

In addition, it said that 3 non-traditional agents have been authorized, all are faecal-based products for restoring the gut microbiota, to prevent recurrent Clostridioides difficile infection (CDI) following antibiotic treatment in adults.

The report said antibiotics approved since 2017 show a limited degree of innovation. Only two of the approved agents are considered innovative, representing a new chemical class, while more than 80% of recently approved agents are derivatives of known classes to which multiple resistance mechanisms already exist.

Having no newly authorized agents with a new MoA (mode of action) or addressing a new target underlines the scientific and technical challenge in discovering novel compounds that are both effective against bacteria and safe for humans, it added.

In the field of antibacterial R&D, effectively combatting the emergence of drug resistance stands as a primary challenge, the report emphasized.

“However, this critical issue remains inadequately addressed by newly authorized agents.”

When assessing the absence of cross-resistance, nearly all compounds exhibit cross-resistance with other agents, while inconclusive data are associated with two compounds: vaborbactam in combination with meropenem, and lefamulin, said the report.

Of the 32 traditional antibiotics under development against WHO bacterial priority pathogen (BPPs) (excluding TB drugs), 12 meet at least one of the four WHO innovation criteria; only two meet all four criteria.

WHO said of these 12, only four are active against a critical Gram-negative bacterium; none of them meet all four innovation criteria.

The traditional antibacterial pipeline lacks sufficient innovation, the report underlined.

WHO also said the preclinical pipeline is active and innovative, with many non-traditional approaches, as part of a stable number of preclinical candidates over the last 4 years.

Its focus remains Gram-negative pathogens, which are resistant to last-resort antibiotics.

Gram-negative bacteria have built-in abilities to find new ways to resist treatment and can pass along genetic material that allows other bacteria to become drug-resistant as well, it added.

Highlighting the gaps and constraints in the current clinical R&D landscape, the report said that traditional antibacterial agents under development still do not adequately address the enormous threat posed by AMR.

Moreover, there is a major gap in developing products that address pathogens possessing a broad spectrum of resistance to current antibacterial agents.

In its conclusions, the report said despite the critical role of antimicrobials in modern health care, the review of antibacterial agents in clinical and preclinical development reveals a glaring insufficiency in novel approaches in the R&D pipeline to effectively combat the increasing emergence and spread of AMR.

“The innovation, research and development of new antibacterials is led by small and medium enterprises in a system too costly and fragile to fully enable them to deliver.”

Furthermore, countries across all income levels struggle with availability and access to both new and authorized antibiotics, including generics, said the report.

Policy efforts on R&D and use should focus on financial and non-financial incentives and efforts to optimize the use of authorized antibiotics, develop novel antibacterial agents and explore new fixed-dose combinations of antibiotics for treating serious bacterial infections such as neonatal sepsis, it said.

Additionally, it said regulatory measures should be implemented to restrict the use of antibiotics to situations where they are strictly necessary, coupled with stewardship programmes that include avoiding over-the-counter selling and access to diagnosis at all levels including rapid, affordable diagnostic tests at point of care.

These efforts to support the R&D of pharmaceutical and non-pharmaceutical solutions to curb AMR need to be matched by equal efforts to ensure global and equitable access, including in low- and middle-income countries, the report emphasized.

“Such access strategies should be sustainable, underpinned by stewardship programmes and strong, streamlined supply chains and strengthened regulatory systems to ensure safe use of antibiotics and maximum impact from R&D.”

Efforts to regulate the availability of antibiotics in various parts of the world, including limiting their use in agriculture, hold significant potential to mitigate the AMR crisis, said the report.

It said that as the battle against AMR intensifies, it is imperative that stakeholders collaborate and prioritize investments in research, development and implementation of comprehensive, multi-faceted strategies to combat AMR effectively.

By doing so, the future of health care can be safeguarded and generations to come can be protected from the dire consequences of AMR, the report concluded.

Meanwhile, the UN General Assembly’s 78th session in September this year will have a High-Level Meeting on antimicrobial resistance. Negotiations on a declaration are ongoing at the UN headquarters in New York.- Third World Network