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 Auninš, Michele Trucksis, 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 Auninš, Michele Trucksis
Abstract
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.
Clinical trials registration: NCT02437487, https://ichgcp.net/clinical-trials-registry/NCT02437487?term=SER-109&draw= 2&rank=4.
Keywords: Clostridioides difficile infection; Clostridium difficile diagnostics; dysbiosis; fecal microbiota transplantation; microbiome.
© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.
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Source: PubMed