Safety of fecal microbiota, live-jslm (REBYOTA^™) in individuals with recurrentClostridioides difficileinfection: data from five prospective clinical trials

Abstract

Background: Microbiota-based treatments reduce the incidence of recurrent Clostridioides difficile infections (rCDIs), but prospectively collected safety data needed to broaden patient access and protect public health have been limited. Objectives: We provide cumulative safety data from five prospective clinical trials evaluating fecal microbiota, live-jslm (RBL) – the first microbiota-based live biotherapeutic product approved by the US Food and Drug Administration – for preventing rCDI in adults. Design: Integrated safety analysis includes three phase II trials (PUNCH CD, PUNCH CD2, PUNCH Open-Label) and two phase III trials (PUNCH CD3, PUNCH CD3-OLS) of RBL. Methods: Trial participants were at least 18 years of age with documented rCDI who completed standard-of-care antibiotic therapy before treatment with RBL. Assigned study treatment regimen was one or two doses of RBL (or placebo) administered rectally, depending on the trial design. In four of the five trials, participants with CDI recurrence within 8 weeks after RBL or placebo administration were eligible for treatment with open-label RBL. Treatment-emergent adverse events (TEAEs) were recorded for at least 6 months following last study treatment; in PUNCH CD2 and PUNCH Open-Label trials, TEAEs and serious TEAEs were collected through 12 and 24 months, respectively. Results: Among the five trials, 978 participants received at least one dose of RBL (assigned treatment or after recurrence) and 83 participants received placebo only. TEAEs were reported in 60.2% of Placebo Only participants and 66.4% of RBL Only participants. Only abdominal pain, nausea, and flatulence were significantly higher in the RBL Only group compared with the Placebo Only group. Most TEAEs were mild or moderate in severity and were most frequently related to preexisting conditions. There were no reported infections for which the causative pathogen was traced to RBL. Potentially life-threatening TEAEs were infrequent (3.0% of participants). Conclusion: Across five clinical trials, RBL was well tolerated in adults with rCDI. In aggregate, these data consistently demonstrated the safety of RBL.

Microbiota-Based Live Biotherapeutic Products for Clostridioides Difficile Infection- The Devil is in the Details

“…Both appear to have only mild to moderate gastrointestinal side effects and no major safety events, though post-marketing surveillance is ongoing. 127 , 132 Some patients may be interested in an oral regimen that can be taken discreetly at their home, while others may prefer a one-time treatment in a clinical setting. A recent survey of LBP-naïve subjects with prior CDI showed that 87% were likely to consider a rectally administered treatment and that patients who had received a rectal LBP found it easy, quick, and appealing due to lack of bowel preparation.…”

Live biotherapeutic products: a capstone for prevention of recurrent Clostridiodes difficile infection

“…A small number of bloodstream infections caused by organisms in FMT have been documented as well (Solari et al, 2014;DeFilipp et al, 2019), however most of such cases have occurred in patients who are immunocompromised and therefore at a high risk of bacterial translocation. In contrast, safety data extracted from LBP trials have revealed a similar frequency of events with the majority being mild to moderate adverse events of similar gastrointestinal nature and thus far there are no reports of infectious diseases being transmitted by LBPs (Lee et al, 2023). Further, controlled clinical trials require more stringent safety reporting, including solicited adverse events and adjudication by independent Drug and Safety Monitoring Boards.…”

Clostridioides difficile Infection: Diagnosis and Treatment Challenges

“…Rebyota is a rectally administered, pre-packaged, single-dose microbiota suspension of 150 mL. Its effectiveness has been evaluated through randomized, double-blind, placebo-controlled, multicenter studies, demonstrating that Rebyota is well-tolerated and safe for use in adults with rCDI [ 72 , 73 ]. Additionally, the FDA recently approved Vowst as the first orally administered fecal microbiota product for preventing CDI recurrence following antibacterial treatment [ 74 ].…”