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Therapeutics


Table 1: WHO list of antibacterials in clinical development which are active against all three WHO Critical Priority Pathogens which are carbapenem resistant


Enterobacteriaceae (CRE) Pseudomonas (CRPA) Acinetobacter (CRAB)


Antibiotics which are in clinical development (WHO Antibacterial Agents in Clinical Development 2017) The WHO has identified three Critical Priority pathogens (Table 1) which threaten to significantly contribute to the increase in annual global deaths from 0.7 million now, to 50 million by 2050. These are common bacteria which are highly resistant to antibiotics, including the most sophisticated peni- cillins, namely the carbapenems. The most danger- ous of these are the Carbapenem-resistant Enterobacteriaceae because they are epidemic. This means that they spread rapidly with a dou- bling time of two years. They are also rapidly acquiring resistance to the last resort antibiotic col- istin. There are six antibiotics in clinical trial devel- opment which are active against all three WHO Critical Priority Pathogens (Table 2).


Compounds in clinical development which are active against all three Critical Priority Pathogens As shown in Table 2, of these compounds two have a new target. Five were in Phase I and one in Phase III (as reported by the WHO in 2017). Interestingly,


ANTIBIOTIC


ARB-002 (Azidothymidine) + CMS


VNRX 5133 + cefepime SPR-741 + -lactams AIC 499 + BLI GSK334280 Cefiderocol 1 1 1 1 1 3


CLINICAL TRIAL PHASE


four compounds were in combinations of which two use a beta-lactamase inhibitor plus an old antibiotic. If the beta-lactamase inhibitor has only weak antibacterial action on its own, it is unlikely to reduce the emergence of mutant beta-lactamase which results in resistance. Some betalactamase inhibitors are not active against all carbapene- mases. Of the other two compounds, the mecha- nism of action of the synergy appears to involve increased membrane permeability. The likelihood of the Phase I compounds reach-


ing the market is 14%. (The Helperby compound may have a higher chance of reaching the market because it is a combination of two already market- ed antimicrobials.) The Phase III compound is more likely to reach the market. This pipeline is inadequate because it is uncer-


tain that these compounds will eventually reach the market. Furthermore, according to the WHO this pipeline will not be sufficient to tackle the impend- ing AMR threat. Helperby Therapeutics has developed a new


combination with Azidothymidine (a new class of anti-bacterial with a new target, Figure 1) and col- istimethate sodium (colistin). The mechanism of


COMPANY


Helperby Therapeutics Ltd


VenatoRx Pharmaceuticals


Spero Therapeutics, Inc AiCuris GmbH GlaxoSmithKline plc Shionogi Inc Yes Yes No No No No Table 2: Six companies with compounds active in all three WHO Critical Priority Pathogens Drug Discovery World Summer 2018 27 NEW TARGET


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