027: Engraftment of Investigational Microbiome Therapeutic SER-109 is Durable Through 24 Weeks in a Randomized Trial (ECOSPOR III) for the Treatment of Recurrent Clostridioides Difficile Infection
Vice President, Clinical Discovery and Research Technologies Seres Therapeutics Cambridge, Massachusetts, United States
Statement of Purpose: In ECOSPOR III, a double-blind, placebo-controlled trial of subjects with recurrent Clostridioides difficile infection (CDI), SER-109, an investigational oral microbiome therapeutic composed of purified Firmicutes spores, was superior to placebo in reducing CDI recurrence at week 8, the primary endpoint (12.4% vs. 39.8%, respectively; RR 0.32; 95% CI, 0.18-0.58; P < 0.001). Clinical response was associated with SER-109 species engraftment, defined as the germination and replication of metabolically active dose species. Rapid engraftment at week 1 was associated with conversion of primary to secondary bile acids, which may inhibit the life cycle of C. difficile. However, the durability of engraftment of microbiome therapeutics is unknown. Herein, we present encore data on SER-109 species engraftment through 24 weeks in ECOSPOR III.
Description of Methods & Materials: Subjects with ≥3 CDI episodes were randomized to SER-109 or placebo following standard-of-care antibiotics. Clinical endpoints included reduction of recurrence at week 8 (primary) and through week 24 (secondary). In this exploratory pre-planned analysis, the durability of engraftment was assessed as the number of newly appearing SER-109 species observed post dosing through week 24 but not present at baseline in subject stool samples. Metagenomic sequencing was used in conjunction with the Metaphlan microbiome compositional profiling tool to identify bacterial species. Two-sided Mann-Whitney U test was used to determine statistical significance between SER-109 and placebo arms.
Data & Results: 182 subjects were randomized in ECOSPOR III. At week 24, stool samples were available from 53 subjects in the SER-109 arm compared to 44 subjects in the placebo arm. The main reason for loss of subjects was CDI recurrence (19 recurrences in the SER-109 arm compared to 44 in the placebo arm). Engraftment was durable through week 24 and significantly higher than placebo at all time points (p value < 0.001 for all comparisons; Figure A). These observations were associated with reduction of absolute risk of rCDI through all time points measured (22.1% at week 4, 27.4% at week 8, 28.3% at week 12 and 26.0% at week 24).
Interpretation, Conclusion or Significance: Engraftment of SER-109 species was durable through week 24 and associated with a sustained absolute reduction in CDI recurrence rate. These data support a two-pronged approach for the treatment of recurrent CDI with standard-of-care antibiotics to kill vegetative C. difficile bacteria followed by investigational agent SER-109 to durably repair the disrupted microbiome through engraftment of Firmicutes bacteria.
