The impact of an oral purified microbiome therapeutic on the gastrointestinal microbiome.

The phase 3 (higher-dose) VOS treatment was significantly more effective at preventing recurrent CDI than the phase 2 (lower-dose) treatment.

• In phase 3, only 12% of VOS-treated patients versus 40% of placebo patients recurred by week 8 (relative risk 0.32, P < 0.001).
• In the phase 2 double-blind study, the rate of recurrence at 8 weeks in SER-109 versus placebo was 44.1% versus 53.3%, which did not demonstrate a significant benefit over placebo.
• In the open-label phase 1b study, 86.7% (26/30) of patients did not experience a subsequent recurrence over 8 weeks.
• The phase 3 dose was approximately tenfold higher than the phase 2 dose, and the discordant outcomes between phase 1b and phase 2 were hypothesized to be due to suboptimal dosing in phase 2.

The higher efficacious phase 3 dose was associated with improved VOS engraftment compared to lower doses in earlier trials.

• Across-trial comparisons confirmed that the higher, efficacious phase 3 dose is associated with improved pharmacokinetics as assessed by VOS engraftment.
• Patients with available samples for analysis: phase 1b: 28, phase 2: 79, phase 3: 170.
• This post hoc analysis compared engraftment across phase 1b, phase 2, and phase 3 trials.

VOS significantly altered microbial composition in phase 3 patients, enriching Firmicutes diversity and abundance.

• VOS significantly enriched the diversity and abundance of Firmicutes species in phase 3 patients.
• VOS reduced the prevalence and abundance of C. difficile and opportunistic pathogens, for example Enterobacteriaceae species.
• These taxonomic changes were identified through in-depth phase 3 analyses.

VOS treatment was associated with significant changes in key bioactive metabolites relevant to C. difficile inhibition.

• Significant depletion of conjugated and deconjugated primary bile acids was observed following VOS treatment.
• Significant enrichment of secondary bile acids was observed following VOS treatment.
• Increases in short-chain and medium-chain fatty acids were observed following VOS treatment.
• These metabolic changes are consistent with the observed taxonomic shifts and are relevant to C. difficile inhibition.

VOS batches produced C. difficile-inhibiting metabolites in vitro.

• In vitro experiments demonstrated that VOS batches produced C. difficile-inhibiting metabolites.
• These in vitro findings are consistent with the metabolic changes observed in vivo in phase 3 patients.
• This finding supports the mechanistic link between VOS engraftment and prevention of CDI recurrence.

The pharmacological findings underscore the importance of rapidly restoring key protective functions of the microbiome in patients with recurrent CDI.

• Restoration of key protective functions of the microbiome was associated with durable prevention of recurrence as observed in the phase 3 study.
• The findings highlight the need to include the microbiome in the clinical management of CDI.
• The authors conclude that achieving sufficient engraftment through adequate dosing is critical to therapeutic success.