Orally delivered microbial therapy has potential beyond CDI

The incidence of Clostridium difficile infection (CDI) has increased markedly in the last decade; close to half a million cases were reported in the United States in 2014 alone. Multiple relapses are also increasingly common, with 20 to 30 percent of patients experiencing at least one recurrence two to four weeks after completing standard antibiotic therapy. Patients who have one recurrence are also at high risk of multiple additional recurrences.

These patients may have poor outcomes and typically present many clinical challenges. In the last few years, however, fecal microbiota transplants (FMTs) have been shown to be a safe and effective intervention for recurrent disease, with reports from many centers confirming a 90 percent or greater cure rate.

In most people, CDI occurs when antibiotics disrupt the protective function of a healthy gut microbiome. FMT prevents recurrences by restoring the microbiome to a more balanced state. The procedure has practical drawbacks, however, especially the procurement and testing of donor stool. Various technologies are under investigation that would make this process less onerous, including enema-type FMT for colonic delivery and encapsulated microbial formulations for oral delivery.

Mayo Clinic is currently involved in the study of a unique oral microbial therapeutic, SER-109, which contains commensal spores but no live bacteria — an approach that eliminates potential pathogens. According to Darrell S. Pardi, M.D., a gastroenterologist specializing in C. difficile at Mayo Clinic's campus in Rochester, Minnesota, preliminary data show that the spore-only pill is highly effective.

In a single-arm, open-label, multicenter study of SER-109 in 30 patients with recurrent CDI — defined as two recurrences or more — only one patient had CDI recurrence that required antibiotic therapy. Furthermore, analysis of participant microbiomes showed that SER-109 not only repaired antibiotic-induced dysbiosis but also led to the expansion of healthy bacteria not contained in the product.

"Proliferation of the bacteria that prevent C. difficile overgrowth allows other beneficial species to flourish," Dr. Pardi explains.

Based on the results of these studies and the product's strong safety profile, the Food and Drug Administration granted SER-109 breakthrough therapy designation in June 2015. Breakthrough therapy designation expedites the development and review of therapeutics for life-threatening conditions when clinical evidence suggests a product offers significant improvement over existing therapies. A double-blind, placebo-controlled phase 2 trial of SER-109 for CDI is underway.

The future of ecobiotics

SER-109 and similar products have been dubbed "ecobiotics" to distinguish them from over-the-counter probiotics.

"Ecobiotics are combinations of a small number of selected organisms that work by enabling a shift from a disease state to a healthy one. They rapidly and safely target important diseases by positively reshaping the microbiome," Dr. Pardi says.

As such, they have the potential to treat many other diseases, not just CDI. Microbial therapy may be used to successfully decolonize vancomycin-resistant enterococcus and other resistant organisms in the gut, for example. Extraintestinal diseases, including autism, multiple sclerosis and diabetes are also associated with alterations in the microbiome, but studying FMT in these cases is inconvenient and expensive, suggesting a critical need for an effective, orally delivered microbial therapeutic for use in clinical trials.

"It's hard to believe that we can give people stool and they get better," Dr. Pardi says. "But the evidence is so compelling in CDI that we now believe some patients with other diseases can also be cured or treated by FMT or other microbial therapies."

For more information

Seres Therapeutics Inc. Open label extension study of SER-109 to prevent recurrent Clostridium difficile infection (ECOSPOR II). ClinicalTrials.gov.

Seres Therapeutics Inc. SER-109 versus placebo to prevent recurrent Clostridium difficile infection (RCDI) (ECOSPOR). ClinicalTrials.gov.