The phase 3 trial of VE303, initiated earlier this year, aims to prevent the recurrence of Clostridioides difficile infection (CDI). The RESTORATiVE303 study is designed to assess the safety and the recurrence rate at week 8 among participants who receive a 14-day course of VE303 or a matching placebo. The study’s objectives and endpoints are identical for Stage 1 (recurrent CDI) and Stage 2 (high-risk primary CDI). ¹

In the trial with 852 participants, individuals will be allocated into 2 groups after undergoing standard antibiotic treatment for CDI, lasting 10 to 21 days. Following this initial antibiotic regimen, participants in the first group, referred to as the VE303 arm, will be instructed to take 3 capsules of VE303 daily for 14 days. Similarly, those in the second group, the placebo arm, will take 3 placebo capsules daily for 14 days. The purpose of this trial is to evaluate the effectiveness of VE303 compared to a placebo in the aftermath of standard-care antibiotic treatment for CDI among a broad participant base.

According to the Centers for Disease Control and Prevention (CDC), “When C diff germs are outside the body, they become spores in an inactive form that have a protective coating allowing them to live for months, sometimes years on surfaces and in the soil. The germs become active again when these spores are swallowed and reach the intestines. About 1 in 6 patients who get C diff will get it again in the subsequent 2-8 weeks.” ²

Findings in the phase 2 trial from 2023 indicate that a high dose of VE303 is effective in preventing recurrent CDI in adults with laboratory-confirmed CDI, including those with one or more prior CDI episodes in the last 6 months, as well as those with primary CDI who are at high risk for recurrence, when compared to a placebo.

Based on a previous report by Contagion, in the phase 2 trial CDI recurrence was reported among 13.8% of participants in the high-dose group, 37% in the low-dose group, and 45.5% in the placebo group. In the high-dose group, all recurrences occurred by Day 11. Most participants experienced sustained cures through Week 24, with only 2 CDI recurrences reported. The investigators also analyzed the fecal microbiota of participants. Those in the high-dose group had a significantly increased detection of VE303 strains, and early colonization was associated with greater treatment efficacy. Microbial diversity recovered most notably in the high-dose group. The adjusted absolute risk reduction was 30.5% in the high-dose group, compared with other treatment options, including fecal microbial transplant (28%), bezlotoxumab (10%), and RBX2660 (12.3%). The treatment was well-tolerated, with no serious treatment-emergent adverse events or deaths reported. ³

“The notorious difficulty of preventing recurrent CDI creates a large population of patients struggling with the condition, with few therapeutic options. VE303 provides an approach that is designed to address the underlying biology in a novel way,” said Darrell Pardi, MD, chair of the division of gastroenterology and hepatology at the Mayo Clinic. “The clinical data to date have been extremely promising, and we are eager to see future updates on this program as it progresses through the clinic.” ³

Overall, in the phase 2 trial in patients at high risk of recurrent CDI, VE303 met its primary efficacy endpoint of preventing CDI recurrence at 8 weeks. The phase 3 trial, expected to be completed in October 2027, aims to confirm these results in a larger population. This trial is important for understanding VE303’s safety and efficacy. Results from this trial could provide a new option for CDI management.

References

1. Vedanta Biosciences. VE303 for Prevention of Recurrent Clostridioides Difficile Infection (RESTORATiVE303). Clincaltrials.gov. Published February 2, 2024. Accessed March 12, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT03788434
2. CDC. C diff (Clostridiodes difficile). Published December 7, 2023. Accessed March 12, 2024. https://www.cdc.gov/cdiff/what-is.html
3. Lorenz J. Oral Bacterial Therapy for Recurrent CDI Shows Promise in Phase 2 Trial. Contagion. Published May 3, 2024. Accessed March 12, 2024. https://www.contagionlive.com/view/oral-bacterial-therapy-for-recurrent-cdi-shows-promise-in-phase-2-trial