653. Rapid Change in Microbiome Profiles Regardless of Diagnostic Method in a Post Hoc Comparative Analysis of Phase 3 Trials of Fecal Microbiota Spores, Live-brpk (formerly SER-109) for the Prevention of Recurrent Clostridioides difficile Infection (rCDI)
Authors: Gonzales-Luna Anne J , Litcofsky Kevin , Straub Tim , Hot Dina , McGovern Barbara , Hasson Brooke , Sims Matthew , Ford Christopher , Henn Matthew 
Published: November 2023

Background

rCDI is characterized by diarrhea reemergence after symptom resolution on standard-of-care antibiotics and positive test for C. difficile toxin production or toxin gene presence. In two phase 3 trials with varied diagnostic testing methods, dosing with fecal microbiota spores, live-brpk (FMS; formerly SER-109) was associated with low rCDI rate ≤8 wks (ECOSPOR III: FMS, 12% vs placebo, 40%; ECOSPOR IV: FMS, 9%). In ECOSPOR IV, recurrence rates with FMS ≤8 wks were similar by diagnostic method (10.4% [95% CI, 6.5%–15.6%] in patients [pts] toxin-positive by EIA with/without PCR vs 4.3% [95% CI, 0.9%–12.2%] in pts with toxin gene detection by PCR only [PCR+]). We evaluated (post hoc) if pt microbiome profiles differed by diagnostic method at study entry.

Methods

Baseline (pre-dose) stool samples were obtained from pts in a) ECOSPOR III, a placebo-controlled trial in pts with ≥2 prior rCDI episodes and diagnosis by toxin EIA (TOX+) and b) ECOSPOR IV, an open-label trial in pts with ≥1 prior rCDI and diagnosis by TOX+ with/without PCR or PCR+. Pts had ≥3 unformed stools/day for 2 consecutive days and symptom resolution on antibiotics before enrolling. Samples were analyzed for alpha diversity and engraftment of dose species not present at baseline using whole metagenomic sequencing. Concentrations of primary bile acids (1°BA), which cause C. difficile spore germination, were measured by targeted LC–MS panel. Statistical analyses in FMS-treated pts compared Shannon diversity, engraftment, and 1°BA concentration changes from paired baseline–Week 1 samples between subgroups.

Results

Baseline Shannon diversity was similarly low across TOX+ and PCR+ subgroups (P&gt;0.05); engraftment magnitude after FMS was comparable across trials (P&gt;0.05) (Fig 1). Baseline 1°BA concentrations were comparable across trials (P&gt;0.05) and subgroups (P&gt;0.05) and decreased by Week 1 after FMS in TOX+ (P&lt; 0.001) and PCR+ (P&lt; 0.001) subgroups (Fig 2).

Conclusion

Regardless of diagnostic method, microbiota diversity appeared similarly disrupted at baseline and improved rapidly by 1 wk after FMS. Engraftment magnitude and 1°BA concentration changes appeared similar across diagnostic subgroups. These data further support the low recurrence rates shown in trials of FMS.

Disclosures

Anne J. Gonzales-Luna, PharmD, BCIDP, Cidara Therapeutics: Grant/Research Support|Ferring Pharmaceuticals: Personal Fees|Paratek Pharmaceuticals: Grant/Research Support|Seres Therapeutics: Grant/Research Support Kevin Litcofsky, PhD, Seres Therapeutics: inventor on patents assigned to Seres Therapeutics|Seres Therapeutics: Employment|Seres Therapeutics: Stocks/Bonds Tim Straub, MS, Seres Therapeutics: Employee|Seres Therapeutics: Stocks/Bonds Dina Hot, PhD, Aimmune Therapeutics: Employee Barbara McGovern, MD, Seres Therapeutics: Stocks/Bonds Brooke Hasson, PhD, Sage Therapeutics: Stocks/Bonds|Seres Therapeutics: Stocks/Bonds Matthew Sims, MD, PhD, Adaptive Phage Therapeutics: Grant/Research Support|Applied Biocode: Advisor/Consultant|Biotest AG: Grant/Research Support|ContraFect: Grant/Research Support|Finch: Grant/Research Support|Janssen: Grant/Research Support|Leonard-Meron Biosciences: Grant/Research Support|Merck and Co: Grant/Research Support|Novozyme: Grant/Research Support|OpGen: Advisor/Consultant|OpGen: Grant/Research Support|Pfizer: Grant/Research Support|Prenosis: Advisor/Consultant|Prenosis: Grant/Research Support|QIAGEN: Grant/Research Support|Seres: Grant/Research Support|Summit Therapeutics: Grant/Research Support Christopher Ford, PhD, Seres Therapeutics: Employee|Seres Therapeutics: Stocks/Bonds Matthew Henn, PhD, Seres Therapeutics: Employee|Seres Therapeutics: Stocks/Bonds