WHO compiles a list of antibacterials in clinical development on a regular basis, the last in mid-2024 [1]. The information is up-to-date and detailed: it provides MoA and antibacterial spectrum, coverage of problem pathogens, the development phase, and whether it can be considered an ‘innovative’ drug (based on a set of criteria). Most clinicians are probably less interested in the country of origin and where a company’s HQ is located but certainly Western countries still dominate antibiotic development. India, Russia and China are not inactive and show up in the WHO list as well.
Overall, the number of NCEs in development has increased in the 2017 to 2023 time frame, which is a good thing.
As in past years, Big Pharma has little interest in anti-infectives; most antibiotic development is done by small companies.
WHO concludes that the existing pipeline is ‘insufficient’. We and others[2] have long come to the same conclusion. However, the situation is actually bleaker than the WHO review suggests.
Let’s dig into the actual raw data to substantiate our claim. We use the WHO list which can be downloaded from the website for free (btw, without pesky ads). Incidentally, the site has some beautiful color graphics.
There are some minor mistakes and omissions but we will refrain from nitpicking. Clearly, this is a dynamic landscape and changes are to be expected. We have, however, an issue with WHO’s definition of what constitutes an ‘innovative’ compound.
We restrict our review to drugs in Phase 1-3 in development that have activity against WHO Priority organisms. We ignore inhalational antibiotics and C. difficile, H. pylori, M. tuberculosis agents
Using these criteria, we come up with N=31 drugs just like WHO. However, there are only few that really deserve being called innovative. Most of them are in the me-too category, i.e., drug candidates from established drug classes providing minor improvements. We also see a lot of duplication in the BL/BLI category.
We would be more thankful for the effort, if we did not know how much more money is being spent on 3rd and 4th line cancer drug development!
Back to the WHO list. Let’s take a closer look now at the 31 “Priority Pathogen Drugs”:
- new colistin / polymyxin derivatives (N=3)
- It would be nice to have better drugs in this class (with less tox and better PK).
- Can Spero succeed with SPR206 / Upleganan where others have failed? The company has fallen on hard times with 2 other antibiotics recently. SPR-206 is cleared for Phase 2, and we are eager to see efficacy data in HABP/VABP.
- QPX9003 from Brii and MRX-8 from MicuRx are still in Ph1; it is too early to assess viability.
- new aminoglycoside (N=1)
- Apramycin from Juvabis is not really a NME. Although structurally unique, it already looked like an interesting drug in 1977 [3]. It is approved in veterinary medicine. It is hard to see how it would do better in the market than plazomicin.
- new macrolides (N=2)
- Given the void left by Ketek, a macrolide without QT issues and liver toxicity would be nice to have
- Solithromycin (aka CEM-101; OP-1068; T-4288) went through (too) many hands already and has a troubled regulatory history: rejected by the FDA and Advisory Board members in 2016 (sic!) for safety concerns and non-conform Phase 3 studies, it is not clear whether its patent life justifies further investment. There are no active studies in clinicaltrials.gov.
- WCK 4873 / nafithromycin from Wockhardt is approved in India for CABP. It is a potent oral ketolide derivative with excellent activity against respiratory pathogens. It is not approved in the US. Its long retention in lung tissue allows short 3-day treatment, analogous to azithromycin.
- new combos of BL/BLI drugs (N=13)
- these drugs follow the Avicaz / Vabomere paradigm – they have predictable efficacy and high LoS
- most combine a 3rd gen cephalosporin with a novel patentable BLI of the DBO class
- most have good to excellent ESBL and CRE activity but none against P. aeruginosa
- differences among the BLI partners seem rather inconsequential (exception: combos that also provide A. baumannii coverage)
- the safety of the 2nd gen DBOs and novel cyclic BLIs remains to be explored further
- lack of major differentiating features among the BL/BLI combos will negatively impact commercial success
- Allecra’s fast development and FDA approval of AAI101 / enmetazobactam as Exblifep in combination with cefepime was a great achievement – albeit for cUTI only In Europe, it garnered additional approvals for HABP and VABP as well.
- Bottom line: there are too many look-alikes in this category. Improvement maybe, innovation not really.
Next, here the list of truly new MoA drugs:
- topoisomerase II inhibitors (N=3)
- ETX0282 / Zoliflodacin is at the submission stage. Entasis studied the drug only in a narrow indication (uncomplicated GC). Progress has been slow, maybe because of limited commercial prospects and its transfer to Innoviva.
- BWC0977 from Bugworks is an interesting compound: a dual gyrase/topoisomerase inhibitor with an unusually broad activity spectrum [4]. It is in Phase 1 development – stay tuned!
- Gepotidacin from GSK is being developed for uUTI and uncomplicated GC, the ABSSSI indication was dropped after a Phase 2 study showed insufficient “clinically significant utility” and low cure rates.[5]
- Doses for these compounds require gram amounts of drug. While not a big problem for IV dosing, COGs and pill burden of the PO formulation may become issues.
- inhibitor of lipopolysaccharide transport (Lpt) proteins (N=1)
- Roche’s RG6006 (Zosurabalpin), described as a ‘tethered macrocytic peptide’ is an interesting compound. Lpt bacterial transporters are needed by Gram-negatives to produce their characteristic LPS outer membrane [6]. The approach is reminiscent of former attempts to develop an LpxC drug with a similar MoA which failed due to cardiac and other toxicities. It is currently in Phase 1.
- Note that POL7080 / murepavadine, a structurally different LptD inhibitor, is now in Phase 3 development as an inhalational drug by Spexis (formerly Polyphor). Renal toxicity stopped the IV program in 2019.
- FtsZ inhibitor (N=1)
- TXA709 from Taxis Pharma targets FtsZ, a component of a multi-protein array that is important for the formation of a cell during binary division. It is bactericidal and may potentiate the activity of other antibiotics when combined. Selectivity seems adequate and a potential effect on tubulin was not reported in Phase 1 studies.
- Bacteriocin (N=1)
- OMN-6 from Omnix Medical is an AMP derived from the cecropin / cathelicidin class of innate defense peptides or bactericidins. Currently in Phase 1, this is an interesting novel compound with broad antimicrobial and antibiofilm activity. Target delivery is not trivial for AMP peptides but Omnix thinks it has the technology to impart selectivity and stability. AMPs have a checkered history (see our blog on PolyMedx) so we have to wait for actual clinical Phase 2 data on OMN-6 to gauge its potential.
- ATP disruption inhibitor (N=1)
- A synthetic polymer, R-327 seems to have a multi-pronged MoA: it permeabilizes the bacterial cell membrane and enters the cell; it interrupts bacterial cellular energetics via ATP synthesis; it disrupts cellular division and non-dividing cell functions. R-327 is rapidly and irreversibly bactericidal. [7]
- Little clinical data are available for R-327. Recce Pharma (pronounced Re-Key), an Australian company, claims broad activity against EKCAPE pathogens and other bacteria. Recce has conducted several Phase 2a trials for the systemic version of this compound.
- FabI targeting antibiotics (N=1)
- Afabicin / Debio-1450/1452 targets FabI, the staphylococcal enoyl-acyl carrier protein reductase. It has good activity against all staphylococcal species including resistant strains. In fact, WHO lists more than 10 pathogens for which the compound may have useful activity. Surprisingly, only a single international trial (for staphylococcal BJI) is listed in clinicaltrials.gov. The program is slow in moving forward; as most centers are Ukrainian, this may explain why the study seems to be stuck in Phase 2 forever.
- Tetracycline derivatives (N=1)
- KBR-7072 / zifanocycline seems to have great Acinetobacter activity in-vitro. It is still in Phase 1.
- We cannot be sure whether the in-vitro activity against Acinetobacter holds up in real life. After all, these are generally bacteriostatic, not bactericidal drugs.
Several drugs did not make the WHO list for which we had high hopes:
- Quo vadis, TP-6076? This Tetraphase fluorocycline looked like a promising Acinetobacter agent. It is no longer mentioned on the Innoviva portfolio and also not on the WHO list. The last reference we found is from April 2022.
- Where are the non-BL/BLI anti-pseudomonas agents? Murepavadine / POL7080 is now being relegated to inhalational use only given issues with systemic toxicity.
- Where are the phage therapeutics? Contrafect’s MRSA drug CF-301 / exebacase surprisingly failed in a pivotal Phase 3 trial. But why? The results are puzzling and not fully explained. Was there a problem with the drug, or with study design? Were there operational issues during Covid times? We recognize that bacteremia / endocarditis studies are extremely difficult to design and execute. It took the wisdom and expertise of a Dr. Tally and Dr. Eisenstein – past developers of daptomycin – to navigate this indication. Hopefully there will be studies with phage cocktails in the years ahead.
In conclusion, most novel antibiotic drug candidates in development are still in Phase 1. As always, we should expect a high attrition rate given this early stage. These are the only new drugs in the pipeline that cover Acinetobacter. The next approvals will come from the group of BL/BLI inhibitors all competing in (and restricted to) infections in the CRE and ESBL categories. Acinetobacter and Pseudomonas agents will remain in high demand for a while.
REFERENCES
[1] WHO antibacterial preclinical pipeline review
[2] Melchiorri D, Lancet Microbe2024 https://doi.org/10.1016/j.lanmic.2024.100992
[3] Ryden. The in vitro activity of apramycin, a new aminocyclitol antibiotic. J Antimicrob Chemother (1977) 3, 609
[4] Hameed S. Nature Communications (2024) 15:8202
[5] O’Riordan W. AAC. 61, e02095–16 (2017)
[6] Pahil K. Nature 625: 572, 2024
[7] Graham J. SYNTHETIC ANTI-INFECTIVES – Synthetic Polymers Offer a New Class of Anti-Infectives. Drug Devel Delivery 2022
ABBREVIATIONS
ABSSSI acute bacterial skin/skin structure infections
AMP antimicrobial peptide
BJI bone and joint infection
BL/BLI betalactam/betalactamase inhibitor
CABP community-acquired bacterial pneumonia
COGS cost of goods
CRE carbapenem-resistant enterobacteriaceae
DBO diazabicyclooctanes
ESBL extended spectrum betalactamase
ESKAPE E. faecium, S. aureus, K. pneumoniae, A. baumannii, P. aeruginosa, Enterobacter spp.
GC gonorrhea
HABP/VABP hospital/ventilator-acquired bacterial pneumonia
HQ headquarters
LoS likelihood of success
LPS lipopolysaccharide
Ltp lipopolysaccharide transport protein
MRSA methicillin-resistant S. aureus
MoA mode of action
NCE / NME new chemical / molecular entity
QIDP qualified infectious diseases product
uUTI uncomplicated UTI
