The World Health Organization (WHO) has released a new report entitled ‘Antibacterial agents in clinical development – an analysis of the antibacterial clinical development pipeline, including tuberculosis’ .

Key Messages:

The current clinical pipeline is still insufficient to mitigate the threat of antimicrobial
resistance:

• More investment is needed in basic science, drug discovery and clinical development, especially for Mycobacterium tuberculosis and the critical priority Gram-negative carbapenem-resistant pathogens Pseudomonas aeruginosa, Acinetobacter baumannii and Enterobacteriaceae.

• Most of the agents in the pipeline are modifications of existing antibiotic classes. They are only short term solutions as they usually cannot overcome multiple existing resistance mechanisms and do not control the growing number of pan-resistant pathogens.

• More innovative products are required against pathogens with no cross- or co-resistance to existing classes.

• Although oral formulations for community diseases associated with high morbidity are essential globally, few oral antibiotics for infections caused by Gram-negative pathogens are in the pipeline.

Innovativeness:

Among the 33 antibiotics that are being developed for priority pathogens, eight belong to five distinct new antibiotic classes, and they fulfil at least one of the four criteria that were used to assess the extent to which agents in the pipeline can be classified
as innovative:

• absence of cross-resistance to existing antibiotics
• new chemical class
• new target or
• new mechanism of action.

Gram-positive Pathogens:

16 products in the current pipeline show activity against one or more Gram-positive priority pathogens. Among them are two new antibiotic classes, and seven of the
products are biological agents (monoclonal antibodies and endolysins).

Most of the antibiotics and all the anti Gram-positive biologicals specifically target methicillin resistant Staphylococcus aureus, while another highly important pathogen, vancomycin-resistant Enterococcus spp., has received little attention.

Gram-negative Pathogens:

These bacteria have been assessed as the most critical priority for antibiotic research and development (R&D), as strains are emerging worldwide that cannot be treated with
any of the antibiotics currently on the market.

While recent entries in the clinical pipeline (clinical phase 1) show an increased focus on Gram-negative bacteria, almost all the agents are modifications of existing antibiotic classes and address specific resistance mechanisms. They are active only against specific pathogens or a limited subset of resistant strains.

Tuberculosis:

Another neglected area in new product development is treatment against drug-resistant
TB. Only seven new agents for TB are currently in clinical trials. Of these, four are in phase-1, and only one compound is in phase-3. This is especially problematic because treatment of TB infections requires a combination of at least three antibiotics.
Novel treatment regimens of short duration that are assembling non-toxic drugs are desperately needed.

Biologicals:

Of the 11 biological treatments in phase -1 and -2, nine target the priority pathogens S. aureus and P. aeruginosa. Whether such biological treatments could serve as real alternatives to antibiotics is not yet clear; they are being developed to complement
antibiotics as adjunctive or pre-emptive treatment.

The higher costs of monoclonal antibodies than of regular antibiotics may also limit their potential use as alternative treatments, especially in low- and middle income countries.

What is expected to come into the market:

Given the average success rates and development times (average development time from phase-1 until approval is about seven years), the current pipeline of antibiotics and biologicals could lead to around 10 new approvals over the next five years. However, these potential new treatments will add little to the already existing arsenal and will not be sufficient to tackle the impending Antimicrobial Resistance (AMR) threat.

It needs to be kept in mind that the likelihood of future approvals of antibiotics that are in phase-1 has been estimated to be 14%. Hence, of the 10 anti-Gram-negative products in phase-1, only one to two could probably make it to the market.

Infection control and stewardship:

New antibiotics alone will not be sufficient to mitigate the threat of antimicrobial
resistance. Their development should go hand in hand with infection prevention and control activities and fostering of appropriate use of existing and future antibiotics through stewardship measures.

Useful Links:

Link to the WHO news release:

http://who.int/mediacentre/news/releases/2017/running-out-antibiotics/en/

Link to the Report (English) [PDF]:

Click to access WHO-EMP-IAU-2017.11-eng.pdf