In May, it was reported that Vedanta Biosciences had initiated dosing in the Phase 3 RESTORATiVE303 clinical trial. This study evaluates VE303, a live biotherapeutic product aimed at preventing recurrent Clostridioides difficile infection (rCDI). The primary objective is to assess VE303's safety and effectiveness in reducing CDI recurrence at Week 8, following a 14-day treatment regimen with either VE303 or a placebo. The study includes participants with Stage 1 (rCDI) and Stage 2 (high-risk primary CDI) infections.
In an exclusive interview with Contagion, Jeffrey Silber MD, the chief medical officer at Vedanta Biosciences, discussed the trial's design. “The study is randomized and blinded, so neither the patients nor their physicians, nor the Vedanta team, will know whether an individual is receiving the active treatment or the placebo.” This design ensures the trial’s objectivity and minimizes bias, addressing potential limitations in the study.
Participants will receive VE303 or a placebo for 14 days, following standard antibiotic treatment that lasts between 10 to 21 days. Those in the VE303 group will take 3 capsules daily, while the placebo group will take 3 placebo capsules daily.
Silber provided further details on what VE303 is, and its role in the trial. “VE303, like all the consortia in our pipeline, is specifically designed for the diseases it targets. He contrasted this with traditional fecal transplants, which rely on donor stool that, “but the composition and quality can vary greatly from one donation to another." This highlights VE303’s advantage in offering a consistent and controlled treatment.
Silber highlighted another key advantage of VE303, “What sets us apart is that every capsule from every batch of VE303 contains the exact same amount of the same bacteria, ensuring consistency and reliability in what patients receive. This also allows us to scale manufacturing effectively,” He continued, “Unlike donor-derived products, which are challenging to scale and come with the risk of transmitting pathogens from donor to recipient, our method avoids these issues. By eliminating the donor variable, we reduce the risk of transmitting pathogens, making our approach safer and more consistent.” This level of control addresses a limitation of traditional donor-based treatments.
Key Points
- VE303 offers a consistent and controlled treatment, with each capsule containing the exact same bacteria, which contrasts with the variability and potential risks associated with traditional fecal transplants.
- The Phase 2 trial’s success in significantly reducing CDI recurrence has directly influenced the Phase 3 trial design, incorporating improvements based on regulatory feedback and patient needs.
- The Phase 3 RESTORATiVE303 trial emphasizes patient convenience by including home-based study visits and offering open-label VE303 to those with recurrences, ensuring continued support and care.
Role of the Phase 2 Trial in Shaping the Phase 3 Study
The dosing regimen and trial design are informed by insights from a preceding Phase 2 study, where VE303 demonstrated promise by meeting its primary endpoint of reducing CDI recurrence at 8 weeks. Silber provided details on how results from the Phase 2 trial:
“The high-dose VE303 reduced recurrence from over 45% in the placebo group to about 14% in the active group, with an absolute risk reduction of more than 30 percentage points and an odds ratio indicating an over 80% reduction in recurrence. The number needed to treat was approximately 3.1, meaning we could prevent one recurrence for every three patients treated. For Phase 3, the study design is similar to Phase 2, with some tweaks based on regulatory feedback and our learnings. One major change is the inclusion of decentralized or hybrid study sites and visits, which makes the study more patient-centric.”
The phase 2 study was designed to determine dosing for Phase 3 trials, participants were divided into 3 groups, with 30 participants receiving a high dose of VE303 (8.0 × 109 colony-forming units [CFUs]), 27 receiving a low dose (1.6 × 109 CFUs) (n = 27), and 22 receiving a placebo once daily for 14 days. Investigators looked at CDI recurrence at 8 weeks based on combined clinical and laboratory assessment.
“What we do is grow our bacterial strains through fermentation from cell banks, similar to how monoclonal antibodies are developed. Based on extensive preclinical testing, both in vivo, in vitro, and in silico, and translating findings from fecal transplant studies, we identify bacteria strongly associated with a positive response to a disease,” Silber explains. “We confirm this in animal models before moving to human trials. As demonstrated in our Phase 2 study, we then confirm early signs of efficacy before advancing to Phase 3.”
Impact on Patient Care
The shift to having a more patient-centric approach for the phase 3 trials could reduce the risk of healthcare-associated infections, “Many patients, especially those with multiple recurrences, often require hospitalization. VE303 and other microbiome-directed therapies are intended to be used after antibiotic treatment to prevent future infections. For patients recently discharged and recovering, having the option to conduct study visits at home provides both physical safety and emotional reassurance,” Silber said.
Silber reassures they have precautionary measures in place because the recurrence rate in the placebo group is expected to be as high as 40%, “We are offering open-label VE303 to any patient who experiences a non-study recurrence, regardless of whether they were originally in the active or placebo group. We won’t be unblinding the study, but any patient with a recurrence will be eligible to receive open-label VE303.”
Looking Ahead
This international trial is currently in its ramp-up phase, activating sites in the US, and internationally. Silber said they recently activated their first site in Canada, and eventually aim to have about 200 sites across more than 20 countries worldwide.
The Phase 3 RESTORATiVE303 clinical trial represents a significant advancement in the fight against rCD). As the trial progresses, with an expected completion in 2027, the collaborative efforts of Silber, Vedanta Biosciences, researchers, and participants are set to deepen our understanding of this challenging infection, offering hope for improved patient care.
To stay up to date with the RESTORATiVE303 clinical trial, sign up for updates at https://ctv.veeva.com/study/a-phase-3-study-of-ve303-for-prevention-of-recurrent-clostridioides-difficile-infection
References
VE303 for Prevention of Recurrent Clostridioides Difficile Infection (RESTORATiVE303). ClincalTrials.gov. Published May 22, 2024. Accessed August 14, 2024. https://clinicaltrials.gov/study/NCT06237452#study-plan
