It is difficult to eradicate and recurrence after antibiotic treatment is common. A further problem is that although C. difficile is a normal component of the healthy gut microbiome, it can thrive and cause infection if the microbiota is thrown out of balance.
A new potential antibiotic, ibezapolstat, is being developed by Acurx, which might avoid this issue; whereas it is active against C. difficile, it spares other firmicute bacteria and actinobacteria.
This may contribute to the maintenance of a healthy gut microbiome. Ibezapolstat is the first of a new class of Gram-positive DNA polymerase IIIC inhibitors.
As it causes minimal disruption of the gut microbiome, the bacterial production of secondary bile acids continues. This may contribute to preventing the recurrence of infection.
After it showed promise in vitro, a Phase I trial was done in 62 healthy adult volunteers to assess its safety, tolerability and pharmacokinetics, and also to monitor microbiome changes compared with vancomycin treatment.1,2
It had minimal systemic absorption and, in the randomised ascending dose study, concentrations of 2 mg/g of stool were observed by day 2 … and for the remainder of the dosing time period.
It was safe and well tolerated. A functional and metagenomic assessment was made to predict the potential antirecurrence effect of the drug treatment.3
As part of the Phase I study, stool samples were collected from 22 of the healthy volunteers and evaluated for microbiome changes and bile acid concentrations.
Diversity changes showed a significance difference in microbiota between those given ibezapolstat and those given vancomycin. With vancomycin, there was an increased proportion of proteobacteria, whereas there was an increased proportion of actinobacteria with ibezapolstat.
Linear regression analysis showed that vancomycin caused an increase in primary bile acids, which correlated with an overabundance of enterobacteria — suggesting a lower risk of recurrence with ibezapolstat.
In a single arm, open label Phase IIa study, 10 adult patients with C. difficile infections were given oral doses (450 mg) every 12 hours for 10 days.4 They were then followed for a further 28 days.
All achieved a sustained clinical cure, with both favourable pharmacokinetics and minimal adverse events. Importantly, there were also beneficial microbiome and bile acid results.
This was followed by a Phase IIb part in which it was compared with vancomycin; however, this was terminated early when aggregate blinded data showed that there was a high observed clinical cure rate with ibezapolstat (projected to be at least 90% when pooled across the open label Phase IIa part and the blinded Phase IIb part) and no emerging safety concerns.
Ultimately, the overall observed clinical cure rate in the two combined Phase II trials was 96%, with only one out of 26 patients not experiencing a clinical cure with ibezapolstat.
It was well tolerated with three mild adverse events deemed to be drug related, all of which resolved without treatment. The company hopes to start Phase III trials early in 2024.
References
- B. Murray, et al., J. Antimicrob. Chemother. 75, 2149 (2020).
- K.W. Garey, et al., J. Antimicrob. Chemother. 75, 3635 (2020).
- J. McPherson, et al., Antimicrob. Agents Chemother. 66, e0224421 (2022).
- K.W. Garey, et al., Clin. Infect. Dis. 75, 1164 (2022).