Study confirms safety, efficacy of SER-109

Although the incidence of hospital-onset Clostridium difficile infection (CDI) may be declining slightly, the Centers for Disease Control and Prevention estimates that close to half a million cases still occur in the United States each year. Multiple relapses also remain common, with approximately 30 percent of patients experiencing at least one recurrence two to four weeks after completing standard antibiotic therapy. Patients who have one recurrence are at high risk of multiple additional recurrences, with a 60 percent chance of relapse after the third recurrence. These patients tend to have poor outcomes and present major clinical challenges.

Until recently, treatment for recurrent CDI was based on limited options backed by relatively poor evidence. The landscape changed radically in 2013, when results of the first randomized controlled trial of fecal microbiota transplantation (FMT) for CDI were published in the New England Journal of Medicine. In that study, 81 percent of patients receiving FMT— the reconstitution of gut flora using donor stool — had complete resolution of symptoms at 10 weeks compared with 31 percent of patients receiving vancomycin. Subsequent meta-analyses of uncontrolled cases and reports from many centers have confirmed a 90 percent or greater cure rate.

Still, FMT remains logistically unwieldy, and various centers are exploring ways to minimize the difficulties involved in procuring, testing and administering donor stool. In a study published in JAMA in 2014, researchers at Massachusetts General Hospital found that the most promising strategy to date — frozen oral capsules from pre‑screened donors — was as effective at treating CDI as delivery via colonoscopy or nasogastric tube.

Despite this significant development, some questions remain, especially concerning screening, which may potentially leave some pathogens undetected. That problem has now been addressed by SER-109, a new oral microbiota therapeutic that contains commensal spores but no live bacteria.

According to Sahil Khanna, M.B.B.S., a gastroenterologist at Mayo Clinic's campus in Rochester, Minnesota, preliminary data show that the spore-only pill is highly effective. Dr. Khanna was lead author of an exploratory study evaluating the safety and efficacy of SER-109 published in The Journal of Infectious Diseases in February 2016.

In the multicenter study, 30 patients with recurrent CDI were divided into two cohorts. Patients in the first cohort received 15 capsules of SER-109 on two consecutive days and those in the second cohort received a fixed dose of 1.1 x 108 spores. At eight weeks' follow-up, 96.7 percent of patients (29 of 30) had achieved clinical remission, the primary endpoint. As important, Dr. Khanna says, analysis of participant microbiomes showed that SER-109 not only repaired dysbiosis but also led to healthy expansion of beneficial bacteria not contained in the product.

Several participating centers, including Mayo Clinic's campuses in Arizona and Minnesota, are currently enrolling patients for a double-blind, placebo-controlled phase 2 trial of SER-109 for CDI.

Other indications

Although SER-109 is a significant step forward in the treatment of CDI, it has limitations. For instance, it doesn't yet allow for alterations in the makeup of encapsulated spores.

"In the future, when we have more-defined species, we will know exactly what a particular patient needs," Dr. Khanna says. "With a simple stool test, we may be able to see that someone is deficient in five or 10 species and provide those with a single probiotic. A patient with different deficiencies would receive a different probiotic, so treatment would be highly individualized."

Individualization will likely be the hallmark of future research and treatment of many diseases with microbial therapy, not just CDI. In a study published in Gastroenterology in 2015, 75 patients with active ulcerative colitis (UC) were randomized to receive either enema-delivered donor stool or placebo. At seven weeks, 24 percent of patients receiving FMT were in remission compared with 5 percent in the placebo group. Benefit seemed to derive mainly from the stool of one donor, suggesting that outcomes of FMT may depend, at least in part, on the donor's microbial makeup.

In another study in the same 2015 issue of Gastroenterology, patients with UC were randomized to receive fecal transplants from healthy donors or autologous transplants via nasogastric tube. Although no statistically significant difference was seen between the two groups, FMT responders developed gut microbiota closely resembling that of healthy donors and significantly different from that of nonresponders.

Dr. Khanna notes that these studies highlight the need for further research on FMT for different indications. In that regard, the Center for Individualized Medicine at Mayo Clinic's campus in Minnesota is collaborating with Seres Therapeutics, the manufacturer of SER-109, to define diseases such as ulcerative colitis, diabetes and autism that might benefit from a microbiome-based intervention.

"The evidence is so compelling in CDI that we now believe some patients with other diseases can also be cured or treated by microbial therapies," he says.

For more information

van Nood E, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. The New England Journal of Medicine. 2013;368:407.

Youngster I, et al. Oral, capsulized, frozen fecal microbiota transplantation for relapsing Clostridium difficile infection. JAMA. 2014;312:1772.

Khanna S, et al. A novel microbiome therapeutic increases gut microbial diversity and prevents recurrent Clostridium difficile infection. The Journal of Infectious Diseases. In press.

Moayyedi P, et al. Fecal microbiota transplantation induces remission in patients with active ulcerative colitis in a randomized controlled trial. Gastroenterology. 2015;149:102.

Rossen NG, et al. Findings from a randomized controlled trial of fecal transplantation for patients with ulcerative colitis. Gastroenterology. 2015;149:110.