Seres Therapeutics learned from its ECOSPOR II (Phase 2) trial in recurrent C. difficile that engraftment, or the growth of bacteria resulting from its oral microbiome therapeutic, was a key indicator of clinical efficacy.
The measure of engraftment, however, highly depends on the sequencing technology used to evaluate bacterial outgrowth, as well as the underlying bacterial genome database that supports the species calls.
Building a Best-in-Class Classification Pipeline
In preparation for its ECOSPOR III (Phase 3) trial, one key activity on the Data Science team was to update the bacterial genome database such that we can maximize the number of detectable species, particularly those from Seres' proprietary strain library.
This involved expanding the underlying genomes in the database from ~17k to ~100k+ (publicly available genomes in 2019), as well as hundreds of proprietary strain genomes. In addition to collecting, QCing, and taxonomically binning the genomes, significant processing needed to be performed in order to identify species-specific marker sequences that were unique to each species.
This project was undertaken as a significant team effort as part of the Seres Therapeutics Data Science team, and resulted in a best-in-class bacterial classification pipeline that enabled unprecedented resolution, enabling capture of species previously rendered "invisible."
Phase 3 Results
The updated pipeline and database was applied to the ECOSPOR III samples, where the microbiome profile was one of the exploratory endpoints. Working closely with the clinical and biostatistics team to draft and execute the microbiome analysis portion of the Statistical Analysis Plan, we then showed that the engraftment of SER-109 dose species was significantly higher in treated subjects compared to placebo.
Treatment with SER-109 resulted in a significant reduction in C. difficile recurrence and was extremely well tolerated.
SER-109 went on to become the first-ever FDA approved oral microbiome therapeutic, now sold under brand-name Vowst.
Citations
Barbara H McGovern, Christopher B Ford, Matthew R Henn, et al. SER-109, an Investigational Microbiome Drug to Reduce Recurrence After Clostridioides difficile Infection: Lessons Learned From a Phase 2 Trial, Clinical Infectious Diseases, Volume 72, Issue 12, 15 June 2021, Pages 2132–2140, https://doi.org/10.1093/cid/ciaa387
Feuerstadt P, Louie TJ, Lashner B, Wang EEL, Diao L, Bryant JA, et al. SER-109, an Oral Microbiome Therapy for Recurrent Clostridioides difficile Infection. New Engl J Med. 2022;386(3):220-229. https://doi.org/10.1056/nejmoa2106516