Vedanta Biosciences' investigational live biotherapeutic product, VE303, has demonstrated promising results in preventing recurrent Clostridioides difficile infection (rCDI). Data from the Phase 2 CONSORTIUM study, published in Nature Medicine, indicate that VE303, an orally administered defined bacterial consortium, significantly reduces the risk of rCDI compared to placebo.
The study's findings offer insights into the mechanisms of action of VE303, highlighting its ability to restore a healthy gut microbial community, decrease inflammation, and increase levels of protective metabolites. These results suggest that VE303 could address a critical unmet need in managing rCDI, a debilitating condition often resulting from antibiotic use.
Mechanism of Action and Clinical Response
VE303 comprises eight bacterial strains, rationally selected to work synergistically in the gut. The Phase 2 CONSORTIUM trial revealed that a higher dose of VE303 was well-tolerated and reduced the odds of CDI recurrence by more than 80% compared to placebo. Further analyses showed that VE303 organisms rapidly colonize the gut in a dose-dependent manner, with colonization predicting greater recurrence-free probability.
"This clinical research offers new insights into the mechanisms of action of VE303, providing a rationale for the drug’s protective effects in rCDI," said Bernat Olle, Ph.D., Chief Executive Officer of Vedanta Biosciences. "Due to VE303’s precisely known, defined composition, we can study its mechanisms of action and PK-PD relationships in a rigorous way, taking a step towards understanding why some patients respond better than others to a microbiome restoration intervention."
Multi-omic Profiling and Predictors of Success
Researchers conducted multi-omic profiling of microbiome composition, fecal metabolites, and host immune function to understand how VE303 prevents rCDI. The analysis identified predictors of VE303 colonization and clinical response, including antibiotic history, baseline stool metabolites, and serum cytokines. Specifically, the abundance of VE303 strains was predictive of remaining recurrence-free, and VE303 colonization correlated with increased levels of short-chain fatty acids and key secondary bile acids, known to confer resistance to CDI.
Clinical Trial Results and Ongoing Phase 3 Study
In the Phase 2 trial, CDI recurrence was reported in 13.8% of participants in the high-dose VE303 group, 37% in the low-dose group, and 45.5% in the placebo group. All recurrences in the high-dose group occurred by Day 11, with most participants experiencing sustained cures through Week 24. The adjusted absolute risk reduction in the high-dose group was 30.5%, compared with other treatment options like fecal microbial transplant (28%), bezlotoxumab (10%), and RBX2660 (12.3%).
The results from the CONSORTIUM study have informed the design and dose selection for the global, pivotal Phase 3 RESTORATiVE303 study, which is currently underway to confirm the efficacy and safety profile of VE303 in the prevention of rCDI. Topline data from this study are expected in 2026.
Addressing Unmet Needs in rCDI Treatment
Clostridioides difficile infection is a significant healthcare burden, with a high rate of recurrence. Current treatment options, including antibiotics and fecal microbiota transplantation, have limitations. VE303 offers a potential first-in-class live biotherapeutic product that bypasses the need for direct sourcing of donor fecal material, providing a standardized drug product in powdered form. If approved, VE303 could offer a more consistent and accessible approach to preventing rCDI.
