For years, ReAct has talked about the discovery void: the fact that no truly new antibiotics have been discovered and reached the market since the 1980’s. Unfortunately, this still holds true for non-TB antibiotics, although there may be some hope to be found in the most recent pipeline analyses.
The current pipeline
In September 2018, The Pew Charitable Trusts updated their data visualization of antibiotics in clinical development. In their latest assessment of the antibiotic pipeline, they found 42 antibiotics in clinical development and two antibiotics that had been approved since the last revision. Of the 42 drugs in development, 15 were in phase 1, 12 were in phase 2, 11 were in phase 3 and four have been submitted to national medical authorities.
At least 19 of the drugs are expected to be active against the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp.) that are considered of special interest due to high levels of antibiotic resistance. 21 of the drugs are expected to be active against pathogens on the CDC urgent pathogens list or WHO priority pathogens list with 13 drugs currently targeting pathogens classified as critical needs by WHO. Of these, 8 are beta-lactamase inhibitors, adjuvant drugs that are combined with a beta-lactam antibiotic such as a cephalosporin or a carbapenem, acting on one of the major resistance mechanisms leading to restored susceptibility to the antibiotic.
ESKAPE pathogens: Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp. are considered of special interest due to high levels of antibiotic resistance.
What is a truly novel antibiotic?
The definition of novel drugs and targets used by Pew Trusts in their analyses of the antibiotic pipeline is based on systemic use in humans – either a new core chemical structure (drug) or bacterial structure (target) that has not been previously used in systemic antibiotics for humans. According to this classification, 10 of the drugs are classified as belonging to novel drug classes. Unfortunately, only one of these new drugs target the pathogens of critical interest defined by WHO.
One problem with this definition is the emphasis on systemic use in humans and completely bypassing the One Health perspective. As an interesting example, Lefamulin (a pleuromutilin) is considered to belong to a novel drug class in the analysis. However, pleuromutilins have been used for years both as topical treatment in humans and as systemic treatment in animals. While the drug certainly has novelty in being a new systemic antibiotic, one can question how innovative an approach is that sources drugs that have already been developed for animal use and adapts them to human use.
In the end, true novelty in antibiotics should perhaps be seen as an absence of cross-resistance to any developed antibiotics, regardless of where they are used.
What is missing in the pipeline?
Comparing the pipeline with the WHO list of critical priority pathogens, only one new antibiotic (Murepavadin, an antimicrobial peptide mimetic in Phase 3) is considered novel by the criteria applied by Pew Trusts. The beta-lactamase inhibitors are certainly a welcome addition to antibiotic line-up in dealing with resistance caused by beta-lactamases, but unfortunately represent reclaiming some efficacy for the beta-lactam drugs, rather than a much needed new class of antibiotic.
Interesting read: Could the use of antimicrobial peptides create resistance to ourselves?
There is still a lack of:
- Truly novel or innovative new antibiotics to treat the WHO priority pathogens of critical importance: carbapenem-resistant Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii. Such drugs are desperately needed as carbapenem resistance is spreading globally.
- Narrow-spectrum oral drugs to treat defined diseases, such as urinary tract infections or typhoid, that are commonly caused by antibiotic resistant bacteria.
Innovation is needed
While there are interesting compounds in the clinical development pipeline, the “game-changer” is still missing. There is still a need for new innovation: developing new classes of antibiotics that do not have cross-resistance to any other antibiotics marketed – regardless of administration route or species. Pulling incentives for research and development seem futile as there simply isn’t much in the clinical development pipeline to pull through to treat pathogens of critical importance. Innovation is therefore needed also in other areas like diagnostics, antibiotic stewardship and quality health care in order to preserve the efficacy of the antibiotics that we still have.
Phases of clinical development
Phase 1: First trials in humans. Less than 100 healthy volunteers, often young males, are given the drug in a controlled manner. These studies determine that the drug is not obviously toxic to humans and provide data on pharmacokinetics to guide future dosage regimens.
Phase 2: Trials to determine safety and efficacy of the drug in patients. Usually, the trials are relatively small, enrolling up to 300 patients. These studies provide data on clinical effect and adverse effects of the drug and test dosage regimens.
Phase 3: Large scale trials to further understand safety and clinical effect of the drug. These trials can enroll up to thousands of patients and provide more detail on drug safety, side effects and clinical effect in comparison with the current standard therapy as either superiority or non-inferiority.
Phase 4: Post-marketing studies made after the drug has been approved and released to the market. These studies collect safety data from “real” use of the drug to further clarify safety of the drug and interactions with other drugs.