Antibacterial development pipeline: excerpts from WHO analysis, 2025

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This document summarizes the WHO’s analysis of antibacterial agents in clinical and preclinical development. The global antibacterial development pipeline remains insufficient to address the escalating threat of antimicrobial resistance (AMR). As of February 15, 2025, the clinical pipeline contains 90 antibacterial agents, a decrease from 97 in the previous analysis. While there have been four new drug approvals since December 2023, a significant lack of innovation persists, with only five of 27 traditional agents targeting WHO Bacterial Priority Pathogens (BPPs) demonstrating no known cross-resistance to existing therapies. Key developments include the approval of three traditional agents (Cefepime-Enmetazobactam, Sulopenem, Nafithromycin) and the first-ever approval of a non-traditional agent targeting a WHO priority pathogen (Ftortiazinon). However, ten agents were simultaneously withdrawn from development, highlighting the pipeline’s volatility. The analysis reveals a substantial imbalance in the availability of pediatric formulations and a scarcity of oral options for serious infections. The preclinical pipeline, with 232 products, is characterized by a fragile ecosystem dominated by small and medium-sized enterprises (SMEs), with a high developer turnover rate of approximately 33%. Research and development efforts are geographically concentrated in Europe and the Americas. To strengthen the pipeline, the World Health Organization (WHO) has identified critical priorities, including fostering true innovation, improving global access, increasing pediatric and oral treatment options, providing sustainable funding for SMEs, and expanding R&D for non-traditional agents.

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1. Context:

AMR is one of the most urgent global health threats, causing over a million deaths annually. Projections indicate that without intensified action, 39 million deaths will be attributable to AMR by 2050. To guide the necessary research and development (R&D) of new antibacterial agents, the WHO published its updated Bacterial Priority Pathogens List (BPPL) in 2024. This annual pipeline analysis assesses the global R&D ecosystem’s response to the pathogens on this list, covering traditional direct-acting small molecules and non-traditional agents like antibodies, bacteriophages, and microbiome-modulating agents. The 2025 review covers agents in clinical and preclinical development between December 31, 2023, and February 15, 2025.

2. Clinical pipeline:

a) Status:

As of February 15, 2025, the clinical pipeline comprises a total of 90 antibacterials targeting WHO BPPs, Clostridioides difficile, or Helicobacter pylori. This represents a net decrease from 97 agents in the previous report. Of these, 50 are classified as traditional antibacterial agents and 40 are non-traditional agents.

The distribution of these agents across the clinical development phases is summarized below:

b) Developments (since December 2023):

Between December 2023 and February 2025, the pipeline saw significant changes, including four approvals and ten discontinuations.

i) New Approvals:

Four agents received marketing authorization, though none of the traditional agents are considered innovative based on WHO criteria.

• Cefepime-Enmetazobactam: A β-lactam/β-lactamase inhibitor combination approved by the US FDA and EMA for complicated urinary tract infections (cUTIs), with the EMA also approving it for hospital-acquired bacterial pneumonia (HABP), including ventilator-associated bacterial pneumonia (VABP). It is active against 3rd generation cephalosporin-resistant Enterobacterales (3GCRE).
• Sulopenem: An oral carbapenem (Thiopenem) approved in the United States for cUTIs in adults. It is also active against 3GCRE.
• Nafithromycin: A ketolide active against macrolide-resistant Streptococcus pneumoniae (a WHO high-priority pathogen), approved in India for community-acquired bacterial pneumonia (CABP).
• Ftortiazinon (fluorothiazinone): The first non-traditional anti-virulence agent to be approved, authorized in the Russian Federation for cUTIs caused by E. coli, K. pneumoniae, and P. aeruginosa.

ii) Discontinuations and New entries:

Ten agents were withdrawn from clinical development: three traditional and seven non-traditional. The withdrawal rate was notably higher for non-traditional agents in Phase 1 (30%) and Phase 3 (40%) compared to traditional agents (12.5% and 6%, respectively).

Concurrently, one new traditional agent targeting M. tuberculosis and four new non-traditional agents (one targeting P. aeruginosa and three targeting C. difficile) entered the clinical pipeline.

c) Innovation Assessment:

A critical evaluation of the pipeline reveals a persistent innovation gap. An agent is considered potentially innovative if it shows no known cross-resistance (NCR) to existing antibacterials. Surrogate predictors for this include belonging to a new chemical class, having a new target, or a new mode of action (MoA).

• Traditional Agents (excluding TB): Of the 27 agents targeting BPPs, only five (19%) demonstrate no known cross-resistance. An additional ten agents (37%) lack sufficient data but meet at least one surrogate criterion for innovation.
• Tuberculosis (TB) Pipeline: The TB pipeline is more innovative, with six of 18 traditional agents (33%) showing no known cross-resistance. Three additional products (17%) meet at least one surrogate criterion.

d) Focus on Priority Pathogens:

The pipeline’s alignment with the WHO BPPL shows a concentration of effort on the most urgent threats, though gaps remain.

Since 2017, the total number of antibiotics approved targeting WHO critical priority pathogens (CPPs) has increased from seven to nine. However, more than half (52%) of the agents targeting BPPs (excluding TB) lack sufficient published data for a robust assessment of their activity.

e) Paediatric development:

Progress in developing antibacterial agents for children remains slow, with a substantial imbalance compared to adult formulations. Of 16 recently authorized antibiotics, only seven (44%) have ongoing paediatric studies. Three are fluoroquinolones, which are not recommended for children. Recently, new paediatric trials have been registered for Imipenem-Cilastatin-Relebactam, Sulbactam-Durlobatam, Meropenem-Vaborbactam, Eravacycline, Omadacycline, and Cefiderocol.

3. Pre-clinical pipeline:

a) Ecosystem:

The preclinical pipeline consists of 232 products worldwide. The ecosystem is marked by a concentration of developers and a high degree of fragility.

• Developer Profile: The majority of institutions are commercial companies (118, or 79.7%), followed by academic institutions (23, or 15.6%). Most companies are privately owned (86.4%) and small, with 90.7% having fewer than 50 employees and 61.9% having fewer than 10.
• Geographical Distribution: R&D is heavily concentrated, with the European Region (45.3%) and the Region of the Americas (41.2%) hosting the vast majority of developers.
• Ecosystem Fragility: The analysis highlights the “ongoing fragility of the therapeutic R&D ecosystem,” underscored by a high developer turnover of approximately 33% since the previous review.

b) Composition:

The composition of the preclinical pipeline has remained relatively stable over recent years.

• Product Types: Direct-acting small molecules are the most common category (109 products, 47%). Non-traditional products represent a significant portion, accounting for 92 products (39.7%), with indirect-acting small molecules (30) and bacteriophages (22) being the largest groups.
• Development Stage: The proportion of projects in lead optimization, preclinical candidate, and IND-enabling stages remains constant, suggesting new programs replace those that either fail or advance. However, of the 52 programs (22.4%) in the late IND-enabling phase, many appear to be stalled, indicating potential bottlenecks due to scientific or funding challenges.

c) Spectrum:

There is a trend toward more targeted therapies, although it has slightly decreased recently.

• Species-Specificity: 75 products (32.3%) target a single pathogen. This includes 35 programs targeting CPPs (21 for M. tuberculosis) and 39 targeting high-priority pathogens (22 for P. aeruginosa).
• Dominant Targets: P. aeruginosa and M. tuberculosis have consistently been the two most dominant targets in the preclinical pipeline across the last five analyses.

4. Priorities:

Based on expert consultation, the WHO identified several key priorities to strengthen the antibacterial pipeline and address the broken R&D market.

• Prioritize Innovation: A culture of continuous innovation is needed to develop therapies that can overcome multiple resistance mechanisms and exert lower selective pressure. Investment in diagnostics is also essential to ensure appropriate use.
• Improve Access: Global equitable access strategies must be integrated into R&D plans. Financial incentives should be sustainable and linked to innovation to ensure novel antibiotics are available and affordable, especially in low- and middle-income countries (LMICs).
• Increase Paediatric and Oral Formulations: There is a significant unmet medical need for treatments tailored to vulnerable populations like children and for oral formulations that facilitate outpatient treatment. Currently, only 34% of agents in the pipeline (excluding TB) have an oral formulation.
• Support R&D in LMICs: Over 90% of clinical programs are led by developers in high-income countries. Greater support is needed to address economic constraints that limit expertise and R&D capacity in LMICs.
• Expand R&D for Non-Traditional Agents: The development of non-traditional agents is complicated by a lack of standardized preclinical models. A global roadmap for bacteriophages, the most prevalent non-traditional class, is recommended to support their integration into clinical practice.

5. Conclusion

The 2025 analysis underscores a persistent and critical challenge: there are still too few agents in clinical development capable of effectively targeting critical Gram-negative bacteria. The pipeline is characterized by limited innovation, with very few candidates showing no cross-resistance to existing drug classes. While the first approval of a non-traditional agent offers a glimpse of progress, these agents do not represent a short-term solution to the AMR crisis. The preclinical ecosystem, essential for future therapies, remains fragile and heavily reliant on under-resourced SMEs. Strengthening the antibacterial pipeline requires a multi-faceted approach focused on fostering innovation, repairing the broken R&D market, ensuring equitable access, and expanding development capacity globally.

_{Citation: Analysis of antibacterial agents in clinical and preclinical development: overview and analysis 2025. Geneva: World Health Organization; 2025. Licence: CC BY-NC-SA 3.0 IGO.}