621. Treatment of recurrent Clostridium difficile infection with SER-109 increases the concentration of secondary bile acids in a dose dependent manner.
Session: Poster Abstract Session: Microbiome and Beyond
Thursday, October 4, 2018
Room: S Poster Hall

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 1) higher doses of SER-109 in our dose-ranging Phase 1b study (Ph1b) and 2) 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 was 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 (> 1.5x108 SporQ) had significantly higher spore-forming species richness than subjects who received a low dose (< 1.5x108 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 (3x108 SporQ x 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 1) higher spore-forming species richness, 2) concentrations of secondary bile acids, and 3) 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.

 

Figure 1

Figure 2  

 

Matthew Henn, Ph.D.1, Christopher Ford, PhD1, Edward O'Brien, Ph.D.1, Jennifer Wortman, Ph.D.1, Liyang Diao, Ph.D.1, Christopher Desjardins, PhD1, Amelia Tomlinson, PhD1, Kevin Litcofsky, Ph.D.1, Mark Wilcox, MD2, Anthony Buckley, PhD3, Patricia Bernardo, Sc.D.1, Barbara McGovern, MD1, John G. Aunins, Ph.D.1, David N. Cook, Ph.D.1 and Michele Trucksis, Ph.D., M.D.1, (1)Seres Therapeutics, Inc., Cambridge, MA, (2)Healthcare Associated Infections Research Group, Leeds Teaching Hospitals NHS Trust and University of Leeds, Leeds, United Kingdom, (3)University of Leeds, Leeds, United Kingdom

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 .

Findings in the abstracts are embargoed until 12:01 a.m. PDT, Wednesday Oct. 3rd with the exception of research findings presented at the IDWeek press conferences.