Efficacy and Safety of RBX2660 in PUNCH CD3, a Phase III, Randomized, Double-Blind, Placebo-Controlled Trial with a Bayesian Primary Analysis for the Prevention of Recurrent Clostridioides difficile Infection

Abstract

Background Recurrent Clostridioides difficile infection, associated with dysbiosis of gut microbiota, has substantial disease burden in the USA. RBX2660 is a live biotherapeutic product consisting of a broad consortium of microbes prepared from human stool that is under investigation for the reduction of recurrent C. difficile infection. Methods A randomized, double-blind, placebo-controlled, phase III study, with a Bayesian primary analysis integrating data from a previous phase IIb study, was conducted. Adults who had one or more C. difficile infection recurrences with a positive stool assay for C. difficile and who were previously treated with standard-of-care antibiotics were randomly assigned 2:1 to receive a subsequent blinded, single-dose enema of RBX2660 or placebo. The primary endpoint was treatment success, defined as the absence of C. difficile infection diarrhea within 8 weeks of study treatment. ResultsOf the 320 patients screened, 289 were randomly assigned and 267 received blinded treatment (n = 180, RBX2660; n = 87, placebo). Original model estimates of treatment success were 70.4% versus 58.1% with RBX2660 and placebo, respectively. However, after aligning the data to improve the exchangeability and interpretability of the Bayesian analysis, the model-estimated treatment success rate was 70.6% with RBX2660 versus 57.5% with placebo, with an estimated treatment effect of 13.1% and a posterior probability of superiority of 0.991. More than 90% of the participants who achieved treatment success at 8 weeks had sustained response through 6 months in both the RBX2660 and the placebo groups. Overall, RBX2660 was well tolerated, with manageable adverse events. The incidence of treatment-emergent adverse events was higher in RBX2660 recipients compared with placebo and was mostly driven by a higher incidence of mild gastrointestinal events. Conclusions RBX2660 is a safe and effective treatment to reduce recurrent C. difficile infection following standard-of-care antibiotics with a sustained response through 6 months.

Gut microbiota and microbiota-based therapies for Clostridioides difficile infection

“…The product was approved on November 30, 2022 by the FDA as Rebyota as a live biotherapeutic for the treatment of recurrent C. difficile infection (REBYOTA | FDA) RBX2660 is screened for 29 different species of pathogens as shown in Table 1 . Results from a phase 3 trial of RBX2660, analyzed with a Bayesian hierarchical model formally incorporating data from a phase 2b trial, showed a treatment success rate of 70.6% ( 68 ). Long-term data (up to 24 months) after treatment with RBX2660 in a phase 2 trial showed durable treatment success, with more than 90% of treatment responders remaining CDI-free at 6, 12, and 24 months ( 69 , 70 ).…”

Emerging Options for the Prevention and Management of Clostridioides difficile Infection

“…No bowel preparation is required prior to enema installation, but a washout period of 24–72 h is needed following the final CDI antibiotic dose. RBX2660 has completed a Phase III trial (PUNCH CD3; NCT03244644) [ 72 ] and the FDA approved RBX2660 for the prevention of CDI recurrence in individuals aged ≥ 18 years following antibiotic treatment for recurrent CDI on November 30, 2022 [ 73 ]. An additional, open-label Phase III trial (PUNCH CD3-OLS; NCT03931941) targeting inclusion of a more diverse and real-world patient population is also currently enrolling patients [ 74 , 75 ].…”

“…Given these results, the Phase III trial was designed using a single dose of RBX2660 [ 72 ]. PUNCH CD3 is a randomized, double-blinded, placebo-controlled trial in which 262 patients with at least one CDI recurrence were randomized to receive RBX2660 or placebo.…”

“…However, due to recruiting difficulties associated with the COVID-19 pandemic, the FDA allowed the use of a Bayesian analysis to assess the primary endpoint of 8-week treatment success that incorporated patients receiving one dose of RBX2660 from the PUNCH CD2 trial and patients from the PUNCH CD3 trial. This a priori analysis demonstrated a model-estimated treatment success rate of 70.6% with RBX2660 versus 57.5% with placebo (estimated treatment effect, 13.1%) and a posterior probability of superiority of 99.1%, exceeding the 97.5% threshold that was chosen [ 72 ]. Rates of adverse events were similar between RBX2660 and placebo through 6-month follow-up, and there were no severe adverse events deemed related to RBX2660 or its rectal administration.…”

Final Results from a Phase 2b Randomized, Placebo-Controlled Clinical Trial of RBX2660: A Microbiota-Based Drug for the Prevention of Recurrent Clostridioides difficile Infection

“…RBX2660 is an investigational microbiotabased live biotherapeutic designed to reduce CDI recurrence following standard-of-care antibiotic treatment in individuals with rCDI [12]. RBX2660 has undergone extensive evaluation through five prospective clinical trials, with three completed phase 2 trials, the completed PUNCH CD3 phase 3 trial [13], one ongoing phase 3 trial (NCT03931941), and one retrospective study, with more than 1000 patients in total treated to date [12,[14][15][16].…”