Updates from trials of microbiome restoration products

Feb. 13, 2021

The use of microbiome restoration therapies (MRTs) to treat a variety of gastrointestinal disorders is evolving rapidly. Multiple therapies for the treatment of recurrent Clostridioides difficile infection (CDI) are currently being investigated in clinical trials.

Recurrent CDI (rCDI) after a primary infection is a major problem, with the risk being as high as 50% to 60% after three or more infections. Fecal microbiota transplantation (FMT) has become a cornerstone for managing rCDI with a demonstrated efficacy of more than 85% in preventing CDI recurrences, versus the 40% to 50% success rate associated with antibiotic regimens alone.

Although proved effective in multiple clinical trials, the use of FMT has associated adverse events. Because FMT therapies are derived from donor stool samples, transmission of infectious agents from asymptomatic stool donors to FMT recipients is a possible risk. Serious adverse events related to transmission of infectious agents (including extended-spectrum beta-lactamase-producing Escherichia coli, enteropathogenic E. coli and Shiga toxin-producing E. coli) have occurred.

In an article published in the Red Section of The American Journal of Gastroenterology in 2020, Mayo Clinic gastroenterologists Sahil Khanna, M.B.B.S., M.S., and Darrell S. Pardi, M.D., discuss several important issues to consider related to the use of FMT to treat rCDI in the era of COVID-19. Dr. Khanna leads Mayo Clinic’s clinical and research program involving FMT for CDI at Mayo Clinic’s campus in Rochester, Minnesota, and Dr. Pardi is chair of Gastroenterology and Hepatology at the same campus.

As U.S. Food and Drug Administration (FDA) guidance on FMT continues to evolve, Drs. Khanna and Pardi note that traditional FMT will likely be replaced by approved alternative products, including stool treated to remove viruses and bacterial pathogens and synthetically grown, defined microbial consortia. The following summary provides an overview of alternatives to FMT that researchers are currently investigating.

Capsule-based therapies


CP101 is a lyophilized microbiome-based product for one-time oral administration designed to restore microbiome diversity and prevent CDI recurrence in a broad population. PRISM3 is a randomized, double-blind, placebo-controlled phase II trial studying the efficacy, safety and tolerability of CP101 in 206 adults with rCDI at 51 sites in the U.S. and Canada. Results from this trial were presented at the 2020 American College of Gastroenterology annual meeting.

Investigators reported that 74.5% of the 102 enrolled participants receiving CP101 (versus 61.5% who received the placebo) were recurrence-free at eight weeks after treatment, with no treatment-related serious adverse events or deaths reported.


RBX7455 is a nonfrozen, orally administered live biotherapeutic. A Mayo Clinic-led phase I open-label trial examined the effects of RBX7455 on the intestinal microbiome and assessed its safety and efficacy in preventing rCDI recurrence. This trial showed that treatment was successful (recurrence-free at the eight-week endpoint), with durability to six months in 90% of participants and no serious treatment-related adverse events. After treatment, the microbiome composition of participants who responded to treatment showed increased levels of Bacteroidia and Clostridia.

“Our results demonstrated that RBX7455 was ‘safe and effective’ at preventing rCDI, with an average of 90% efficacy,” explains Dr. Khanna, who co-authored the article about the study published in Clinical Infectious Diseases with Dr. Pardi and others. “We also noted that the treatment responders’ microbiomes converged toward the composition of RBX7455. These results support its continued clinical evaluation,” says Dr. Khanna.


SER-109 is an investigational, donor-derived, spore-based microbiome therapeutic. An open-label phase I trial demonstrated that 97% of patients with rCDI treated with SER-109 achieved a cure. Key findings from a phase II study were less conclusive, but misdiagnosis of CDI carriage as infection and suboptimal dosing may have contributed to this trial's lower efficacy.

The ECOSPOR-III trial, a phase III double-blind, placebo-controlled randomized trial, demonstrated that SER-109 is highly efficacious in reducing CDI recurrence in a high-risk patient population. At eight weeks, 88.9% of patients treated with SER-109 achieved a sustained clinical response, compared with 58.7% in the placebo group.

In addition, efficacy was significantly higher in the SER-109 versus placebo treatment groups when participants were stratified by both age and antibiotic used to treat CDI. At 12 weeks, 16.7% of patients treated with SER-109 had rCDI, compared with 47.8% in the placebo group. Researchers noted no serious treatment-related adverse events or deaths in the treatment group during the first eight weeks after treatment. Results from this trial were presented at the 2020 American College of Gastroenterology annual meeting. An open-label trial for patients with first and multiple CDI recurrences also has been initiated.

Enema-based therapies


RBX2660 is a microbiota suspension derived from donor stool and administered via enema. Results from the PUNCH CD study, an open-label phase II trial, were published in Clinical Infectious Diseases in 2016. According to Dr. Pardi and co-investigators, this study demonstrated the safety of RBX2660 at six months and efficacy at eight weeks after administration. RBX2660 had an overall efficacy of 87.1%. No serious treatment-related adverse events were reported.

In a randomized, double-blind, placebo-controlled phase IIB trial, Dr. Khanna and co-investigators demonstrated that the primary endpoint, prevention of rCDI for eight weeks following treatment with two doses of RBX2660, was not met. However, one RBX2660 dose was superior to placebo, and the overall efficacy (including open-label response) for participants treated with RBX2660 was 88.8%. Results from that study were published in Clinical Infectious Diseases in 2018.

Preliminary findings released by investigators from the phase III PUNCH CD study also look promising. This trial was a prospective, randomized, open-label study comparing the efficacy of RBX2660 with a placebo in up to 270 patients.

In summary, several MRTs appear safe and effective for prevention of rCDI. According to Drs. Khanna and Pardi, additional and larger trials of CP101, RBX7455, SER-109 and RBX2660 will help investigators better assess the performance of these treatments for rCDI and other indications.

For more information

Khanna S, et al. Fecal microbiota transplantation for recurrent Clostridioides difficile infection: The COVID-19 era. The American Journal of Gastroenterology. 2020;115:971.

Allegretti JR, et al. An investigational oral microbiome drug, CP101, for the prevention of recurrent C. difficile infection: A randomized, placebo-controlled, multi-center trial (PRISM3). Presentation at: ACG 2020 Virtual Annual Meeting.

Khanna S, et al. RBX7455, a room temperature-stable, orally-administered investigational live bio therapeutic, is safe, effective, and shifts patients' microbiomes in a phase 1 study for recurrent Clostridioides difficile infections. Clinical Infectious Diseases. In press.

Lashner B, et al. 8- and 12-week efficacy and safety data from ECOSPOR-III a phase 3 double-blind, placebo-controlled randomized trial of SER-109 an investigational microbiome therapeutic for the treatment of patients with recurrent Clostridioides difficile infection (rCDI). Presentation at: ACG 2020 Virtual Annual Meeting.

Orenstein R, et al. Safety and durability of RBX2660 (microbiota suspension) for recurrent Clostridium difficile infection: Results of the PUNCH CD study. Clinical Infectious Diseases. 2016;62:596.

Dubberke ER, et al. Results from a randomized, placebo-controlled clinical trial of a RBX2660 — A microbiota-based drug for the prevention of recurrent Clostridium difficile infection. Clinical Infectious Diseases. 2018;67:1198.