TY - JOUR
T1 - SER-109, an Investigational Microbiome Drug to Reduce Recurrence after Clostridioides difficile Infection
T2 - Lessons Learned from a Phase 2 Trial
AU - McGovern, Barbara H.
AU - Ford, Christopher B.
AU - Henn, Matthew R.
AU - Pardi, Darrell S.
AU - Khanna, Sahil
AU - Hohmann, Elizabeth L.
AU - O'Brien, Edward J.
AU - Desjardins, Christopher A.
AU - Bernardo, Patricia
AU - Wortman, Jennifer R.
AU - Lombardo, Mary Jane
AU - Litcofsky, Kevin D.
AU - Winkler, Jonathan A.
AU - McChalicher, Christopher W.J.
AU - Li, Sunny S.
AU - Tomlinson, Amelia D.
AU - Nandakumar, Madhumitha
AU - Cook, David N.
AU - Pomerantz, Roger J.
AU - Auninš, John G.
AU - Trucksis, Michele
N1 - Publisher Copyright:
© 2020 The Author(s). Published by Oxford University Press for the Infectious Diseases Society of America.
PY - 2021/6/15
Y1 - 2021/6/15
N2 - 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.
AB - 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.
KW - Clostridioides difficile infection
KW - Clostridium difficile diagnostics
KW - dysbiosis
KW - fecal microbiota transplantation
KW - microbiome
UR - http://www.scopus.com/inward/record.url?scp=85091845389&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85091845389&partnerID=8YFLogxK
U2 - 10.1093/cid/ciaa387
DO - 10.1093/cid/ciaa387
M3 - Article
C2 - 32255488
AN - SCOPUS:85091845389
SN - 1058-4838
VL - 72
SP - 2132
EP - 2140
JO - Clinical Infectious Diseases
JF - Clinical Infectious Diseases
IS - 12
ER -