SER-109, an Investigational Microbiome Drug to Reduce Recurrence after Clostridioides difficile Infection: Lessons Learned from a Phase 2 Trial

Barbara H. McGovern, Christopher B. Ford, Matthew R. Henn, Darrell S. Pardi, Sahil Khanna, Elizabeth L. Hohmann, Edward J. O'Brien, Christopher A. Desjardins, Patricia Bernardo, Jennifer R. Wortman, Mary Jane Lombardo, Kevin D. Litcofsky, Jonathan A. Winkler, Christopher W.J. McChalicher, Sunny S. Li, Amelia D. Tomlinson, Madhumitha Nandakumar, David N. Cook, Roger J. Pomerantz, John G. AuninšMichele Trucksis

Research output: Contribution to journalArticlepeer-review


Background: Recurrent Clostridioides difficile infection (rCDI) is associated with loss of microbial diversity and microbe-derived secondary bile acids, which inhibit C. difficile germination and growth. SER-109, an investigational microbiome drug of donor-derived, purified spores, reduced recurrence in a dose-ranging, phase (P) 1 study in subjects with multiple rCDIs. Methods: In a P2 double-blind trial, subjects with clinical resolution on standard-of-care antibiotics were stratified by age (< or ≥65 years) and randomized 2:1 to single-dose SER-109 or placebo. Subjects were diagnosed at study entry by PCR or toxin testing. Safety, C. difficile-positive diarrhea through week 8, SER-109 engraftment, and bile acid changes were assessed. Results: 89 subjects enrolled (67% female; 80.9% diagnosed by PCR). rCDI rates were lower in the SER-109 arm than placebo (44.1% vs 53.3%) but did not meet statistical significance. In a preplanned analysis, rates were reduced among subjects ≥65 years (45.2% vs 80%, respectively; RR, 1.77; 95% CI, 1.11-2.81), while the <65 group showed no benefit. Early engraftment of SER-109 was associated with nonrecurrence (P <. 05) and increased secondary bile acid concentrations (P <. 0001). Whole-metagenomic sequencing from this study and the P1 study revealed previously unappreciated dose-dependent engraftment kinetics and confirmed an association between early engraftment and nonrecurrence. Engraftment kinetics suggest that P2 dosing was suboptimal. Adverse events were generally mild to moderate in severity. Conclusions: Early SER-109 engraftment was associated with reduced CDI recurrence and favorable safety was observed. A higher dose of SER-109 and requirements for toxin testing were implemented in the current P3 trial.

Original languageEnglish (US)
Pages (from-to)2132-2140
Number of pages9
JournalClinical Infectious Diseases
Issue number12
StatePublished - Jun 15 2021


  • Clostridioides difficile infection
  • Clostridium difficile diagnostics
  • dysbiosis
  • fecal microbiota transplantation
  • microbiome

ASJC Scopus subject areas

  • Microbiology (medical)
  • Infectious Diseases


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