655. Analysis of Microbiome Diversity and Secondary Bile Acid Synthesis Following SER-109 or Placebo in Patients with First Recurrent or Multiply Recurrent Clostridioides difficile Infection
Authors: Kelly Colleen R , Kraft Colleen S , Straub Tim , Litcofsky Kevin , Wortman Jennifer R , Cohen Stuart H , Berenson Charles , McGovern Barbara , Hasson Brooke , Hot Dina , Pardi Darrell , Ford Christopher , Henn Matthew 
Published: November 2023

Abstract

Background
Treatment for first recurrent Clostridioides difficile infection (frCDI) or multiply recurrent CDI (mrCDI) is complex and may include antibiotics, monoclonal antibodies, or fecal transplantation. Improved understanding of rCDI pathogenesis can help guide treatment. We report microbiome findings of patients (pts) with frCDI and mrCDI from a post hoc analysis of two phase 3 trials with fecal microbiota spores, live-brpk (FMS; formerly SER-109), an FDA-approved, microbiota-based therapeutic comprised of Firmicutes spores.

Methods
Stool samples were collected from pts with mrCDI in ECOSPOR III (n=158) and with frCDI or mrCDI in ECOSPOR IV (n=218) at baseline (pre-dose) and Week 1 post treatment. Shannon diversity was calculated from species profiles from analysis of whole metagenomic sequencing data using MetaPhlAn2. Primary (1°BA) and secondary bile acid (2°BA) concentrations were measured via targeted liquid chromatography–mass spectrometry panel. Subgroup differences were analyzed with linear mixed models.

Results
At baseline, Shannon diversity was not significantly different between mrCDI and frCDI groups (P&gt;0.05). At Week 1, Shannon diversity (Fig 1) was greater vs baseline (P&lt; 0.001); gains were not significantly different between subgroups (P&gt;0.05). For pts receiving FMS vs placebo in ECOSPOR III, greater reductions in 1°BA and increases in 2°BA from baseline–Week 1 were observed, similar to FMS-treated pts in ECOSPOR IV. At Week 1, 2°BA concentrations were greater vs baseline (P&lt; 0.001); similar gains were seen between subgroups (P&gt;0.05) (Fig 2). Consistent with these microbiome findings, in an integrated analysis, rCDI rates with FMS at Week 8 were low in both subgroups (frCDI, 6.5% [5/77] vs mrCDI, 10.3% [28/271]).

Conclusion
After antibiotics, pts with frCDI or mrCDI had low Shannon diversity and 2°BA concentrations that were no different between subgroups, highlighting a need for microbiome restoration. Both subgroups showed rapid, significant improvement in Shannon diversity and 2°BA concentrations and reductions in 1°BA after FMS, with comparable clinical outcomes. These data suggest that regardless of number of prior CDI episodes, FMS therapy following antibiotics may be an optimal treatment.

Disclosures
Colleen R. Kelly, MD, Openbiome: Advisor/Consultant|Sebela Pharmaceuticald: Advisor/Consultant Tim Straub, MS, Seres Therapeutics: Employee|Seres Therapeutics: Stocks/Bonds Kevin Litcofsky, PhD, Seres Therapeutics: inventor on patents assigned to Seres Therapeutics|Seres Therapeutics: Employment|Seres Therapeutics: Stocks/Bonds Jennifer R. Wortman, MS, Seres Therapeutics: Employee|Seres Therapeutics: Stocks/Bonds Barbara McGovern, MD, Seres Therapeutics: Stocks/Bonds Brooke Hasson, PhD, Sage Therapeutics: Stocks/Bonds|Seres Therapeutics: Stocks/Bonds Dina Hot, PhD, Aimmune Therapeutics: Employee Darrell Pardi, MD, Abbvie: Advisor/Consultant|AMT: Grant/Research Support|BI: Advisor/Consultant|Immunic: Advisor/Consultant|Rise: Advisor/Consultant|Seres Therapeutics: Advisor/Consultant|Seres Therapeutics: Grant/Research Support|Summit: Advisor/Consultant|Takeda: Grant/Research Support|Vedanta: Advisor/Consultant|Vedanta: Grant/Research Support Christopher Ford, PhD, Seres Therapeutics: Employee|Seres Therapeutics: Stocks/Bonds Matthew Henn, PhD, Seres Therapeutics: Employee|Seres Therapeutics: Stocks/Bonds