621. Treatment of Recurrent Clostridium difficile Infection with SER-109 Increases the Concentration of Secondary Bile Acids in a Dose-Dependent Manner

BACKGROUND: C. difficile recurs when dormant spores germinate in the dysbiotic gut, facilitated by an increase of 1° vs. 2° bile acids. SER-109, an ecology of bacterial spores purified from stool of healthy donors, is an investigational first-in-class microbiome therapeutic intended to facilitate microbiome restoration and reduce risk of recurrent C. difficile (rCDI). Rapid engraftment of spore-forming species is associated with (i) higher doses of SER-109 in our dose-ranging Phase 1b study (Ph1b) and (ii) reduced rCDI in our Phase 2 trial (Ph2). We explored whether higher doses of SER-109 were associated with an increase in 2° bile acids. METHODS: Whole metagenomic shotgun (WMS) data were generated from stool, and species were identified using a proprietary build of MetaPhlAn. Evaluation of spore-forming species richness and bile acid concentrations identified effects of SER-109 treatment. A triple stage bioreactor model of the human gut and rCDI was used to evaluate the impact of microbial therapeutics. RESULTS: Ph1b subjects who received a higher dose (>1.5 × 10(8) SporQ) had significantly higher spore-forming species richness than subjects who received a low dose (<1.5 × 10(8) SporQ) at Week 1 post-treatment (P = 0.017, Figure 1). Spore-forming species richness in patients receiving a low dose in Ph1b was comparable to that observed in non-recurrent patients in Ph2, who received the same mean dose (Figure 1). Ph1b subjects in the high dose group had a significantly higher concentration of 2° bile acids as compared with Ph1b low dose subjects and non-recurrent Ph2 subjects (P = 0.036, P < 0.001, respectively, Figure 2). A higher dose (3 × 10(8) SporQ × 3 days) suppressed recurrence in a gut model of rCDI; a single dose did not. CONCLUSION: Higher doses of SER-109 are significantly associated with (i) higher spore-forming species richness, (ii) concentrations of secondary bile acids, and (iii) prevention of recurrence in an gut model of CDI. These results suggest that SER-109 in the Phase 2 trial was biologically active and catalyzed a functional change in the microbiome of a subset of subjects; a dose increase may optimize efficacy across a broad population. Seres has initiated a Phase 3 study of SER-109 to reduce rCDI, which includes an increase in dose titer and frequency. [Image: see text] DISCLOSURES: M. Henn, Seres Therapeutics, Inc.: Employee and Shareholder, Salary. C. Ford, Seres Therapeutics, Inc.: Employee and Shareholder, Salary. E. O’Brien, Seres: Employee and Shareholder, Salary. J. Wortman, Seres Therapeutics, Inc.: Employee and Shareholder, Salary. L. Diao, Seres Therapeutics, Inc.: Employee and Shareholder, Salary. C. Desjardins, Seres Therapeutics, Inc.: Employee and Shareholder, Salary. A. Tomlinson, Seres Therapeutics, Inc.: Employee and Shareholder, Salary. K. Litcofsky, Seres Therapeutics, Inc.: Employee and Shareholder, Salary. M. Wilcox, Seres Therapeutics, Inc.: Consultant, Research Contractor, Scientific Advisor and Shareholder, Research support. A. Buckley, Seres Therapeutics, Inc.: Research Contractor, Research support. P. Bernardo, Seres Therapeutics, Inc.: Employee and Shareholder, Salary. B. McGovern, Seres Therapeutics, Inc.: Employee and Shareholder, Salary. J. G. Aunins, Seres Therapeutics, Inc.: Employee and Shareholder, Salary. D. N. Cook, Seres Therapeutics, Inc.: Employee and Shareholder, Salary. M. Trucksis, Seres Therapeutics, Inc.: Employee and Shareholder, Salary.