1272. Gastrointestinal Tract Microbiome Dynamics Following Treatment with SER-109, an Investigational Oral Microbiome Therapeutic to Reduce the Recurrence of Clostridium Difficile Infection (CDI)
Session: Poster Abstract Session: C. difficile: From the Bench to Bedside
Friday, October 6, 2017
Room: Poster Hall CD

Background:

Recurrence of CDI occurs within a few weeks after treatment due to antibiotic-induced dysbiosis. SER-109, an investigational, first-in-class microbiome drug, was designed to sustain a clinical response through microbiome restoration with a purified ecology of spores. In an open-label Phase 1b (Ph1b) trial of SER-109 for prevention of recurrent CDI, 26 of 30 subjects did not recur following treatment. In a Phase 2 (Ph2) double-blind controlled trial of SER-109 (n=59) vs placebo (n=30), no significant difference was observed in the proportions of subjects with recurrence (44.1% vs 53.3%, respectively). Here we contrast gut microbiome changes among subjects in both trials to understand differences in clinical outcomes observed 8-weeks after dosing.

Methods:

We used 16S v4 and high-resolution whole metagenomic shotgun (WMS) sequencing to characterize microbiome changes from stool samples collected at baseline and 1, 4, and 8 weeks post-treatment. Microbiome analyses focused on subjects diagnosed with recurrence via EIA toxin testing (high confidence recurrence; HCR).

Results:

Significantly greater richness of commensal spore-former species was observed in Ph2 subjects treated with SER-109 compared to PBO at weeks 1 and 4 post-treatment (Mann-Whitney p=0.008, p=0.044 respectively) consistent with drug engraftment. In addition, the number of spore-forming species at 1 week post-treatment was significantly greater in non-recurrent subjects vs HCR subjects (Mann-Whitney p=0.011).  Furthermore, we identified 10 spore-former species that were significantly more prevalent in both SER-109 and non-recurrent subjects (Fig 1). In comparison to Ph1 subjects, SER-109 engraftment was significantly reduced and delayed among Ph2 subjects at all time points (Fig 2). Moreover, Ph1b subjects who received higher doses of SER-109 than that used in Ph2 had increased levels of engraftment.

Conclusion:

In patients with recurrent CDI and dysbiosis, a focused spore-based therapeutic approach leads to engraftment of SER-109 strains. In addition, microbiome signatures of engraftment were associated with a favorable clinical outcome. Although SER-109 was biologically active, a higher dose may improve the rate and degree of microbiome repair.

Matthew Henn, Ph.D., Christopher Ford, Ph.D., Edward O'Brien, Ph.D., Jennifer Wortman, Ph.D., Sheri Simmons, Ph.D., Liyang Diao, Ph.D., Kevin Litcofsky, Ph.D., Patricia Bernardo, Sc.D., John Aunins, Ph.D., David Cook, Ph.D. and Michele Trucksis, Ph.D., M.D., Seres Therapeutics, Inc., Cambridge, MA

Disclosures:

M. Henn, Seres Therapeutics: Employee and Shareholder , Salary and Stock Options

C. Ford, Seres Therapeutics: Employee and Shareholder , Salary and Stock Options

E. O'Brien, Seres Therapeutics: Employee and Shareholder , Salary and Stock Options

J. Wortman, Seres Therapeutics: Employee and Shareholder , Salary and Stock Options

S. Simmons, Seres Therapeutics: Employee and Shareholder , Salary and Stock options

L. Diao, Seres Therapeutics: Employee and Shareholder , Salary and Stock

K. Litcofsky, Seres Therapeutics: Employee and Shareholder , Salary and stock options

P. Bernardo, Seres Therapeutics: Employee and Shareholder , Salary and Stock options

J. Aunins, Seres Therapeutics, Inc.: Employee and Shareholder , Salary and Stock options

D. Cook, Seres Therapeutics: Employee and Shareholder , Salary and Stock Options

M. Trucksis, Seres Therapeutics Inc.: Employee and Shareholder , Salary and stock options

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