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SERES THERAPEUTICS, INC. filed this Form 10-K on 03/06/2019
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In October 2017, we announced positive topline results from our Phase 1b clinical trial of SER-287 in patients with UC. Study results showed no imbalance in adverse events in SER-287 treated patients, as compared to patients treated with placebo. No drug related serious adverse events were observed.

 

Analyses of study patients’ microbiome data, a primary endpoint, indicated that SER-287 induced dose-dependent engraftment of SER-287-derived bacterial species into the colonic microbiome of the patients treated with SER-287. The cohort of patients that received vancomycin pre-treatment followed by daily administration of SER-287 showed the highest level of SER-287 engraftment. We also observed the most meaningful clinical benefit in this patient cohort. Differences in the composition of the microbiome post treatment were also associated with clinical remission. Bacterial engraftment signatures were durable throughout the dosing period of the trial and were also observed at four weeks post administration of the final SER-287 dose. The pharmacologic impact of the SER-287 engraftment was supported by metabolomic and transcriptomic data. Analysis of metabolites and gene expression signatures associated with inflammation and immune modulation, were observed to be correlated with remission in SER-287 treated subjects.

 

Microbiome results showed engraftment of SER-287-derived bacterial species in patients pre-treated with vancomycin who received SER-287, with daily dosing providing the most rapid and robust change in patients’ microbiome. Engraftment observed in these patients was maintained during the entire dosing period and was observed four weeks after the last dose of SER-287 was administered. Thus, engraftment was durable. Vancomycin pre-treatment, as compared to placebo pre-treatment, led to an immediate reduction of microbiome diversity followed by rapid and robust engraftment of SER-287-derived bacterial species. We believe these data suggest that vancomycin pre-treatment may open ecological niches for SER-287 engraftment in the human microbiome of patients with UC.

In December 2017, the FDA granted Orphan Drug Designation to SER-287 for treatment of UC in pediatric patients.

Further Details of Phase 1b clinical study design.

The Phase 1b clinical study was a multicenter, randomized, double-blind, placebo-controlled multiple dose study utilizing weekly or daily dosing with SER-287. We enrolled eligible subjects at approximately 20 sites in the United States. The Phase 1b clinical study was designed to enroll adults 18 years of age and older who had mild-to-moderate UC as defined by a Total Modified Mayo score between 4 and 10, inclusive, with a modified Mayo endoscopic subscore ≥ 1, who were failing current therapies.

Patients were randomized to one of four study arms:

 

Pre-treatment with placebo for 6 days, followed by weekly dosing of SER-287 for 8 weeks

 

Pre-treatment with placebo for 6 days, followed by daily dosing with placebo for 8 weeks

 

Pre-treatment with vancomycin for 6 days, followed by daily dosing of SER-287 for 8 weeks

 

Pre-treatment with vancomycin for 6 days, followed by weekly dosing of SER-287 for 8 weeks

The primary objectives of the study were to evaluate the safety and tolerability of SER-287 compared to placebo; to compare the baseline composition of the intestinal microbiome to the composition at 8 weeks post-initiation of SER-287 or placebo; and to determine the engraftment of SER-287 bacteria into the intestinal microbial community in each of the SER-287 arms compared to the placebo arm.

The secondary objectives of the study were to determine the proportion of subjects in each of the treatment arms who at eight weeks post-initiation of treatment achieve a clinical response, complete remission, and endoscopic improvement; to assess changes in serum and fecal biomarkers from baseline throughout treatment; to determine the complement of metabolic pathways; and to compare the changes in exploratory biomarkers from mucosal biopsies and stool in each of the treatment arms from baseline through eight weeks.

This study was designed to provide evidence of safety of SER-287 compared to placebo for the UC population, describe the changes in the microbiome as a result of treatment with SER-287 and provide potential predictive biomarkers for future studies. UC is characterized by a decrease in microbial diversity and richness, with a lower prevalence of spore-forming organisms within the phylum Firmicutes. Preliminary data using FMT suggest that microbial interventions can affect clinical outcomes in UC, and this study evaluated whether the ecology of bacterial spores in SER-287 could correct the dysbiosis in UC, increase microbial diversity and safely lead to a clinical response in UC patients with mild-to-moderate disease.

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