SER-109, an Investigational Microbiome Drug to Reduce Recurrence After Clostridioides difficile Infection: Lessons Learned From a Phase 2 Trial

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.

Figures

Figure 1.

CONSORT diagram. One subject randomized to placebo was dosed with SER-109; this subject was analyzed with the placebo intention-to-treat population in all efficacy analyses* and with the SER-109 safety population in all safety analyses* (see Supplementary Materials for further details). Abbreviation: CONSORT, Consolidated Standards of Reporting Trials.

Figure 2.

Rates of recurrence of CDI within 8 weeks of study drug treatment in the ITT population of the phase 2 population. Among all study subjects, SER-109 was not associated with a statistically significant reduction in risk of recurrence. In an age-based subgroup analysis, SER-109 was associated with a significant reduction in recurrence among subjects aged ≥65 years (Mantel-Haenszel test: RR, 1.77; *95% CI, 1.1–2.8) but not in subjects Clostridioides difficile infection; CI, confidence interval; ns, nonsignificant; RR, relative risk.

Figure 3.

Number of SER-109 species stratified by time point and treatment in the phase 2 study. In the phase 2 study, subjects receiving treatment had significantly more SER-109 species than those receiving placebo at weeks 1, 4, and 8 posttreatment (P < .001, all comparisons; Mann-Whitney U test). At pretreatment baseline, SER-109 diversity was not significantly different between subjects receiving placebo or SER-109 (Mann-Whitney U test). Boxplots display the median (horizontal line), 25th and 75th percentiles of distribution (box edges), range of nonoutlier observations (whiskers), and outlier observations (dots; >1.5 times the interquartile range). Sample sizes are shown below the x axis. ***P < .001. Abbreviations: BL, baseline; ns, nonsignificant; wk, week.

Figure 4.

Number of SER-109 species stratified by outcome in the phase 2 study. Nonrecurrent subjects had significantly more SER-109 species than recurrent subjects within the treatment arm 1 week postdosing (wk1; P < .05, Mann-Whitney U test) but not at baseline (Mann-Whitney U test). SER-109 species diversity was not significantly different for subjects receiving placebo at either baseline or 1 week posttreatment (Mann-Whitney U test). Boxplots display the median (horizontal line), 25th and 75th percentiles of distribution (box edges), range of nonoutlier observations (whiskers), and outlier observations (dots; >1.5 times the interquartile range). Sample sizes are shown below the x axis, *P < .05. Abbreviations: BL, baseline; ns, nonsignificant; wk1, week 1.

Figure 5.

Relationship of the engraftment of SER-109 species and concentration of secondary bile acids in the phase 2 study. In the phase 2 study, the number of SER-109 species, assessed in both placebo and SER-109 subjects at week 1, was significantly correlated with the concentration (ng/mg DW of lyophilized samples) of secondary bile acids LCA and DCA. Spearman correlation significance and ρ are shown for each comparison. In the boxplots shown, samples were binned by number of dose-species detected. The concentration of LCA and DCA is shown on the y axis. Boxplots display the median (horizontal line), 25th and 75th percentiles of distribution (box edges), range of nonoutlier observations (whiskers), and outlier observations (dots; >1.5 times the interquartile range). Abbreviations: DCA, deoxycholic acid; DW, dry weight; LCA, lithocholic acid.

Figure 6.

Relationship of engraftment of SER-109 species to dose administered in the phase 1 and phase 2 studies. Subjects receiving the high dose, as defined by SporQ (see Methods), in the open-label phase 1 dose-ranging study (SERES- 001) had significantly more SER-109 species than subjects in the treatment arm of the phase 2 study (SERES-004), who received a fixed dose (wk1; P < .0001, Mann-Whitney U test). The number of SER-109 species was not significantly different between subjects receiving the low dose in the phase 1 trial and subjects receiving the fixed dose in the phase 2 trial (Mann-Whitney U test). The number of SER-109 species stratified by treatment and time point is shown; dots represent outliers. Sample sizes are shown below the x axis. ***P < .0001. Abbreviations: BL, baseline; ns, nonsignificant; wk1, week 1.