Increased microbial diversity a sign of restoration therapy success

Last Updated: 2015-10-15

By Megan Brooks

NEW YORK (Reuters Health) - Patients with recurrent Clostridium difficile infection (CDI) who respond to microbiota restoration therapy with RBX2660 (Rebiotix Inc) have a more diverse gut microflora two months after treatment than their peers who fail treatment, a study indicates.

RBX2660 is a live, standardized human-derived microbiome restoration therapy currently under investigation to treat recurrent CDI. This month, the U.S. Food and Drug Administration granted RBX2660 "Breakthrough Therapy" designation for this indication.

Studies have shown that most cases of C difficile infection occur after the normal microorganisms that reside in the gut have been disrupted by antibiotic use. Restoring the balance of microbes is thought to be key to breaking the cycle of recurrence.

Last week, at IDWeek 2015 in San Diego, California, researchers reported fecal microbiota findings in a subset of 17 patients who participated in the Rebiotix-funded phase 2 PUNCH CD study assessing the efficacy of RBX2660 for recurrent CDI. RBX2660 was delivered via enema. The 17 patients included eight successes with one dose of RBX2660, six successes with two doses, and three failures with two doses.

The researchers defined success as the absence of CDI-associated diarrhea (passage of three or more unformed stools in 24 or fewer consecutive hours for at least two consecutive days through eight weeks after the last dose of RBX2660). They defined failure as a recurrence of CDI symptoms less than eight weeks after the last RBX2660 dose, restarting an antibiotic for CDI or a CDI-related hospitalization.

Patients provided stool samples at baseline (pre-treatment) and seven and 60 days after treatment.

At day seven post-treatment, there was no significant difference in gut microflora diversity between successes and failures with RBX2660, although there was a trend toward higher diversity in the successfully treated group, Dr. Sahil Khanna of the Mayo Clinic, Rochester, Minnesota, and colleagues report in a meeting poster.

At day 60 post-RBX2660, "microbial richness" was significantly increased in patient successes compared with patient failures (p=0.008). Successfully treated patients had increased microbial diversity, regardless of whether they received one or two doses of RBX2660.

"The results suggest a time dependence for re-establishing a diverse microbiome," Dr. Khanna noted in email to Reuters Health. "This observed correlation between higher microbial diversity and treatment success could potentially serve as an early indicator of treatment outcomes as well as provide a biomarker for use in future microbiome replacement products."

Because RBX2660 is sourced from human-derived microbes, the company set up a donor program to provide a reliable source of raw material from healthy donors. "We have a cohort of donors that provide the raw material for our product; paying close attention to the health of these donors contributes not only to our product quality, but more importantly, it ensures the safety of our patients in our clinical studies," Courtney Jones, from Rebiotix, explained in email to Reuters Health.

But in a related study presented at IDWeek, Jones and her colleagues reported that a "substantial" number of outwardly healthy donors were found unsuitable due to underlying conditions.

Of 62 potential donors of intestinal microbes for the product, 11 (17.8%) failed initial screening protocols; 51 (82.2%) passed the screening protocols and made at least one donation. But on subsequent retesting, a further 22 donors (43% of the remaining donor pool) were excluded. Twelve failed one or more the blood and pathogen screens and 10 dropped out.

"Reasons for rejection included asymptomatic carriage of an E. coli strain associated with hemorrhagic diarrhea and asymptomatic norovirus and rotavirus, which typically cause symptoms," the authors note in their meeting poster.

"We conducted this study to not only evaluate what 'healthy' means for a donor, but also to highlight the importance of rigorous, continuous controlled screening of donors contributing to our microbiome therapy," Jones told Reuters Health.

"The take-home point from our findings is that an outwardly healthy donor may still be a carrier for a pathogen, so initial screening is simply not enough," Jones said. "Our data demonstrate that it is critical to continuously evaluate donor serum and stool to ensure no pathogens are present in the final product."

She added, "Rebiotix tests every donated stool. Our standardized manufacturing process provides drug product that is traceable to donor, date, diet, daily health status, and rigorous test pathogen testing to ensure the safety of the patient. We carefully manage our donor cohort to ensure only pathogen-free participants are able to contribute to the final product so only safe and quality-controlled product is used in our clinical studies."

Rebiotix funded the studies. Several of the authors are employees of the company.