Treatment of recurrent CDI: Examining the efficacy and safety of standardized live biotherapeutics as microbiota restoration therapies

Dec. 15, 2022

Clostridioides difficile infection (CDI) affects nearly 500,000 Americans annually and has been classified as an urgent health threat by the Centers for Disease Control and Prevention. CDI typically occurs after a two-step process — antibiotics use that disrupts or creates a gap in the microbiome and exposure to C. difficile spores.

Researchers note that approximately 20% to 25% of patients with CDI experience a recurrence after receiving a course of antibiotics for a primary infection. The risk of recurrences rises after each subsequent episode and can exceed 50% in patients who experience two or more recurrences. Treatments approved by the U.S. Food and Drug Administration (FDA) for CDI include antibiotics (vancomycin and fidaxomicin), sometimes administered with bezlotoxumab, a monoclonal antibody that binds to toxin-B for the prevention of recurrences.

Because neither standard-of-care antibiotics nor bezlotoxumab repairs the disruption of the microbiome, the search for safe and effective microbiota restoration therapies (MRTs) is underway. To date, however, the FDA has not approved any MRTs for the treatment of recurrent CDI.

In a review article published in Antibiotics in 2022, lead author Sahil Khanna, M.B.B.S., M.S., and co-authors discuss the role of the microbiome in CDI pathogenesis and the clinical outcomes associated with SER-109. SER-109 is an investigational, donor-derived, spore-based MRT used to stimulate microbiome and treat patients with recurrent CDI. Dr. Khanna is a gastroenterologist at Mayo Clinic in Rochester, Minnesota, who leads Mayo Clinic's clinical and research program involving CDI.

According to Dr. Khanna, preclinical data has demonstrated the efficacy of using Firmicutes spores to reduce CDI recurrence. "Researchers theorize that spore-forming bacteria may help restore the microbiome and resistance to C. difficile by competing for essential nutrients and by modulating bile acid profiles," says Dr. Khanna.

SER-109 is an MRT, containing live, purified Firmicutes spores. Administered via capsule, SER-109 has received Breakthrough Therapy and Orphan Drug designations by the FDA for the treatment of recurrent CDI following standard-of-care antibiotics.

"Germination of the SER-109 Firmicutes spores allows colonization and replication of metabolically active bacteria within the colon, a process referred to as engraftment," explains Dr. Khanna. "The engraftment that occurs after SER-109 is administered leads to compositional changes in the microbiome of the gastrointestinal tract, which is accompanied by a reciprocal loss of proinflammatory Gram-negative Proteobacteria."

In an original research article published in Drugs in 2022, lead author Dr. Khanna and co-authors demonstrate the safety and efficacy of RBX2660 for recurrent C. difficile infection in a large phase 3 clinical trial. RBX2660 is a live biotherapeutic product consisting of a broad consortium of microbes derived from human stool that is delivered by an enema formulation after standard-of-care antibiotics. This can be done as a simple in-office procedure, without the need for bowel preparation, sedation or a procedure. The study showed a statistically significant difference from placebo in curing recurrent C. difficile infection. RBX2660 was very well tolerated, with an expected adverse event profile and no safety signals.

Manufacturing and quality systems

According to Dr. Khanna and co-authors, the manufacturing steps and quality systems used in the production of SER-109 and RBX2660 are designed to preserve microbial components and standardize the process of donor screening and product manufacturing, mitigating risk of pathogen and disease transmission.

"The methodology built into the manufacturing process of SER-109 goes beyond donor screening alone by inactivating unwanted microbes, further mitigating the risk of pathogen transmission," explains Dr. Khanna.

Efficacy and safety

RBX2660 has been evaluated from early phase through phase 3 clinical trials.

The large phase 3 PUNCH CD 3 was a randomized, double-blind, placebo-controlled trial, with a Bayesian primary analysis integrating data from a previous phase 2b study. Adult patients with one or more C. difficile infection recurrences with a positive stool assay for C. difficile were included. After standard-of-care antibiotics, participants randomly received a blinded, single-dose enema of RBX2660 or placebo. The primary endpoint was treatment success, defined as the absence of C. difficile infection through eight weeks.

Key findings published in the journal Drugs included:

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, suggesting a statistically significant and a clinically meaningful result. No attributable serious side effects were seen. The predominant adverse events were gastrointestinal in nature and were mild to moderate in severity.

To date, SER-109 efficacy and safety has been evaluated in phase 1b, 2b and 3 trials. The ECOSPOR 3 trial was a phase 3 double-blind, placebo-controlled trial of 182 adults with three or more episodes of CDI. After receiving standard-of-care antibiotic treatment, study participants were randomized to receive either SER-109 or a placebo.

The ECOSPOR 3 trial demonstrated that SER-109 was superior to the placebo in reducing CDI recurrence at week eight, the primary endpoint. Key findings, published in the New England Journal of Medicine in 2022, include the following:

At week eight, 88% of patients treated with SER-109 achieved a sustained clinical response, compared with 60% in the placebo group. Researchers from the ECOSPOR 3 trial as well as multiple other clinical trials noted no serious treatment-related adverse events or deaths in patients treated with SER-109.

The results from two trials — SER-109 and RBX2660 — were different in study design, patient population, the kind of stool test required and the need for a bowel preparation prior to the procedure.

"Using a two-pronged treatment approach — antibiotics to kill C. difficile bacteria, followed by SER-109 or RBX2660 to address microbiome disruption — may represent a potential paradigm shift in the clinical management of patients with recurrent CDI," says Dr. Khanna.