A Phase 1b Safety Study of SER-287, a Spore-Based Microbiome Therapeutic, for Active Mild to Moderate Ulcerative Colitis

Abstract

Background & aims: Firmicutes bacteria produce metabolites that maintain the intestinal barrier and mucosal immunity. Firmicutes are reduced in the intestinal microbiota of patients with ulcerative colitis (UC). In a phase 1b trial of patients with UC, we evaluated the safety and efficacy of SER-287, an oral formulation of Firmicutes spores, and the effects of vancomycin preconditioning on expansion (engraftment) of SER-287 species in the colon.

Methods: We conducted a double-blind trial of SER-287 in 58 adults with active mild-to-moderate UC (modified Mayo scores 4-10, endoscopic subscores ≥1). Participants received 6 days of preconditioning with oral vancomycin (125 mg, 4 times daily) or placebo followed by 8 weeks of oral SER-287 or placebo. Patients were randomly assigned (2:3:3:3) to groups that received placebo followed by either placebo or SER-287 once weekly, or vancomycin followed by SER-287 once weekly, or SER-287 once daily. Clinical end points included safety and clinical remission (modified Mayo score ≤2; endoscopic subscores 0 or 1). Microbiome end points included SER-287 engraftment (dose species detected in stool after but not before SER-287 administration). Engraftment of SER-287 and changes in microbiome composition and associated metabolites were measured by analyses of stool specimens collected at baseline, after preconditioning, and during and 4 weeks after administration of SER-287 or placebo.

Results: Proportions of patients with adverse events did not differ significantly among groups. A higher proportion of patients in the vancomycin/SER-287 daily group (40%) achieved clinical remission at week 8 than patients in the placebo/placebo group (0%), placebo/SER-287 weekly group (13.3%), or vancomycin/SER-287 weekly group (17.7%) (P = .024 for vancomycin/SER-287 daily vs placebo/placebo). By day 7, higher numbers of SER-287 dose species were detected in stool samples from all SER-287 groups compared with the placebo group (P < .05), but this difference was not maintained beyond day 7 in the placebo/SER-287 weekly group. In the vancomycin groups, a greater number of dose species were detected in stool collected on day 10 and all subsequent time points through 4 weeks post dosing compared with the placebo group (P < .05). A higher number of SER-287 dose species were detected in stool samples on days 7 and 10 from subjects who received daily vs weekly SER-287 doses (P < .05). Changes in fecal microbiome composition and metabolites were associated with both vancomycin/SER-287 groups.

Conclusions: In this small phase 1b trial of limited duration, the safety and tolerability of SER-287 were similar to placebo. SER-287 after vancomycin was significantly more effective than placebo for induction of remission in patients with active mild to moderate UC. Engraftment of dose species was facilitated by vancomycin preconditioning and daily dosing of SER-287. ClinicalTrials.gov ID NCT02618187.

Keywords: Gastrointestinal Microbiome; Inflammatory Bowel Disease; Microbe-Associated Metabolites; Microbiome Therapeutics.

Graphical abstract

Figure 1

Proportion of patients achieving end points of clinical remission (A), endoscopic improvement (B), and clinical response (C) at week 8 in intent-to-treat population. Two-sided Fisher exact P value indicated when <.05. PBO, placebo; Vanco, vancomycin; Wkly, weekly.

Figure 2

Engraftment of SER-287 species is dose-dependent and facilitated by vancomycin preconditioning. Boxplots display median (horizontal line), 25th and 75th percentiles (box edges), range of nonoutlier observations (whiskers), and outlier observations (dots; >1.5 times interquartile range). Significance values are in Supplementary Table 5.

Figure 3

Vancomycin preconditioning followed by SER-287 results in a broad shift in overall composition of spore and nonspore microbial species 8 weeks post treatment. The proportion of patients in each arm that gained (positive values) or lost (negative values) a given species compared with baseline is shown (x-axis). Species (y-axis; n = 344) are ordered by average change across arms; species without change in any subject are not depicted (n = 15). Bar colors indicate spore-forming species detected in SER-287 (dark blue), other spore-forming species not detected in SER-287 (light blue), and other non–spore-forming species (gray). SER-287 dose species gained compared with baseline are the same species represented in Figure 2.

Figure 4

Microbe-associated metabolites associated with SER-287 treatment and clinical outcome. Metabolite levels in fecal samples were assessed via targeted (A, B) and global (C, D) metabolomics. In (A) and (C), metabolite fold-changes are shown by treatment arm; black horizontal dashed line indicates whether the metabolite is higher or lower compared with baseline. For (B) and (D), metabolite abundance is shown by remission status. Significance values are provided in Supplementary Table 10, Supplementary Table 11, Supplementary Table 12, Supplementary Table 13.

Supplementary Figure 1

Study Schematic. Carats (ˆ) indicate approximate times of stool sampling at baseline (screening endoscopy visit before any treatment) and on days 0 (post-vancomycin preconditioning, before SER-287 dosing), 3, 7, 10, 14, 56, and 84 post-treatment with SER-287. Final samples were collected at the end of treatment, at the end of the short-term safety follow-up period and/or at any early termination visit.

Supplementary Figure 2

Consolidated Standards of Reporting Trials diagram.

Supplementary Figure 3

Engraftment of SER-287 species is dose-dependent and facilitated by vancomycin preconditioning; preconditioned patient microbiome samples become more similar to SER-287 dose composition after rebound from vancomycin. Similarity between a subject’s microbiome and SER-287 dose composition is quantified with a binary Jaccard similarity coefficient of spore-forming species in subject samples and SER-287 doses; the change in similarity for each subject and timepoint is relative to that subjects’ baseline sample (y-axis) across time (x-axis). Black horizontal dashed line indicates the threshold where a subjects’ spore fraction is more (>0) or less (<0) similar to SER-287 post-treatment. Initial preconditioning with vancomycin moves patient samples further from SER-287 dose composition; by day 10 in the vancomycin/SER-287 daily dosing arm, the patient spore-forming microbiome becomes more similar to SER-287 and remains so through the 8-week dosing period (day 56) and the long-term follow-up at day 84 (P < .05, Wilcoxon signed-rank test, all time points); in the vancomycin/SER-287 weekly dosing arm, only the day 56 time point was statistically significant P < .05, consistent with a dose-dependent effect.

Supplementary Figure 4

Enterobacteriaceae species abundance tends to decrease with vancomycin pre-conditioning and SER-287 with remitters having a larger decrease in Enterobacteriaceae compared with non-remitters. (A) Fold-change in Enterobacteriaceae species abundance relative to baseline is shown 8 weeks post treatment (day 56) for subjects in each arm; boxplots are colored by treatment arm. (B) Enterobacteriaceae fold-change is shown across remitters and nonremitters for subjects in vancomycin preconditioning arms only; boxplots are colored by clinical remission status.