Investigational C Diff Therapy Shows Favorable Microbiome Characteristics, Phase 3 Trial Planned
In additional analyses, the novel antibiotic, ibezapolstat, demonstrated favorable gut microbiome changes including increased relative proportion of Actinobacteria in ibezapolstat-treated patients with C diff Infection (CDI).
Investigators are delving into the significance of microbiota and their value in protecting against CDI as well as restoring the health of the gut.
How antimicrobial therapies work against C difficile as well as their effects on the overall flora in the gut's microbiome are significant considerations in research today.
Ibezapolstat is an investigational antibiotic being studied for C diff treatment and specifically against a standard of care therapy, vancomycin. Ibezapolstat is manufactured by Staten Island, NY-based Acurx Pharmaceuticals, and its a novel, orally-administered therapy being developed as a gram-positive selective spectrum antibacterial. It is the first of a new class of DNA polymerase IIIC inhibitors under development by Acurx to treat bacterial infections.1
Additional follow-up results from the ibezapolstat phase 2 clinical trial in patients with C diff were recently presented at the 17th Biennial Congress of the Anaerobe Society of the Americas. Taryn A. Eubank, PharmD, BCIDP, research assistant professor, University of Houston College of Pharmacy, delivered an oral presentation titled: "Clinical Efficacy of Ibezapolstat in CDI: Results from Phase 2 trials."1
Some of the important microbiota highlights from the presentation included the preservation and increased concentrations of beneficial Firmicute (Bacilotta) phylum—known to be involved in bile acid homeostasis and short chain fatty acid metabolism. And Actinobacteria and Bacteroides preservation was also confirmed utilizing quantitative analysis.1
"The ibezapolstat clinical development plan has included the most robust microbiome development plan ever undertaken with prior analyses predicting an anti-recurrence effect of ibezapolstat in patients with CDI," said Kevin Garey, PharmD, MS, FIDSA, professor and chair, University of Houston College of Pharmacy, principal investigator for microbiology and microbiome aspects of the ibezapolstat clinical trial program, and Acurx Scientific Advisory Board member. "Microbiome results from the phase 2b trial are helping to validate this approach as a consistent anti-recurrence effect has been seen along with the microbiome effect explaining the underlying mechanism of action. I would anticipate that these analyses will set a new standard for CDI-directed antibiotics and perhaps for antibiotic development, in general."1
What the Phase 2 Trial Data Showed
In a previous article by Contagion, early data results were reported from the company’s phase 2b trial. In it, 32 patients with C diff were enrolled and randomized in a 1:1 ratio to either ibezapolstat 450 mg every 12 hours or vancomycin 125 mg orally every 6 hours for 10 days and followed for 28 ± 2 days following the end of treatment for recurrence of CDI. The 2 treatments were identical in appearance, dosing times, and number of capsules administered to maintain the blind.2
In terms of safety profile, ibezapolstat was well-tolerated, with 3 patients experiencing 1 mild adverse event assessed by the blinded investigator to be drug- related. All 3 events were gastrointestinal in nature and resolved without treatment. There were no drug-related treatment withdrawals or no drug-related serious adverse events associated with ibezapolstat.2
Acurx had also previously reported that the overall observed clinical cure rate in the combined phase 2 trials in patients with CDI was 96% (25 out of 26 patients), based on 10 out of 10 patients (100%) in phase 2a study in the modified intent to treat population, plus 15 out of 16 (94%) patients in phase 2b in the per protocol population.2
Next Steps
With favorable data, investigators are planning to move forward with a phase 3 clinical trial. Two phase 3, non-inferiority, pivotal trials were confirmed and included agreement on the protocol design, patient population, primary and secondary endpoints, and size of the registration safety database.1
Based on FDA recommendations, and in anticipation of an EMA Scientific Advice Meeting, the primary efficacy analysis will be performed using a Modified Intent-To-Treat (mITT) population consistent with EMA requirements. According to Acurx, this will result in an estimated 450 subjects in the mITT population, randomized in a 1:1 ratio to either ibezapolstat or standard-of-care vancomycin, enrolled into the initial phase 3 trial.1
The trial design not only allows determination of ibezapolstat's ability to achieve Clinical Cure of CDI as measured 2 days after 10 days of oral treatment, but also includes assessment of ibezapolstat's potential effect on reduction of CDI recurrence in the target population. In the event non-inferiority of ibezapolstat to vancomycin is demonstrated, further analysis will be conducted to test for superiority.1
"Ibezapolstat continues to demonstrate favorable effects on the gut microbiome while at the same time curing the C difficile bacterial infection comparable to standard of care antibiotics,” Acurx Executive Chairman Robert DeLuccia, said. “As we continue to prepare for initiation of our Phase 3 clinical program, we expect this feature of ibezapolstat's dual mechanism of action to be an important competitive advantage by reducing the recurrence of the infection, as well as improving the health of the gut microbiome."1
