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

Although 86.7% (26/30) of patients with recurrent CDI did not experience a subsequent recurrence over 8 weeks in an open-label phase 1b study, a subsequent double-blindphase 2 study ( NCT02437487 ) did not demonstrate a significant benefit over placebo (rate of recurrence at 8 weeks in SER-109 versus placebo: 44.1% versus 53.3%).

尽管在一项开放标签的1b期研究中，86.7% (26/30) 的复发性CDI患者在8周内没有经历后续复发，但在随后的双盲2期研究(NCT02437487)中，与安慰剂相比，并未显示出显著的益处（8周内复发率在SER-109与安慰剂之间：44.1%对53.3%）。

These discordant outcomes were hypothesized to be due to suboptimal dosing.

这些结果不一致被认为是由于剂量不足所导致。

This hypothesis was addressed in a pivotal phase 3 trial ( NCT03183128 ) using an approximately tenfold higher dose.

这一假设在一个关键的III期临床试验（NCT03183128）中得到了验证，该试验使用了大约十倍于常规剂量的更高剂量。

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).

在第三阶段，仅12%接受VOS治疗的患者与40%接受安慰剂的患者在第8周时出现复发（相对风险0.32，P<0.001）。

Here in this follow-up post hoc analysis, across-trial comparisons confirmed that the higher, efficacious phase 3 dose is associated with improved pharmacokinetics, assessed by VOS engraftment (patients with available samples: phase 1b: 28, phase 2: 79, phase 3: 170).

在这项后续的事后分析中，跨试验比较证实，较高的有效第三阶段剂量与改善的药物动力学相关，通过VOS植入评估（有可用样本的患者：第一b阶段：28人，第二阶段：79人，第三阶段：170人）。

In-depth phase 3 analyses revealed that VOS significantly altered microbial composition, significantly enriching the diversity and abundance of Firmicutes species and reducing the prevalenceand abundance of C. difficile and opportunistic pathogens (for example, Enterobacteriaceae species).

深入的第三阶段分析显示，VOS显著改变了微生物组成，显著增加了Firmicutes物种的多样性和丰度，并减少了C. difficile和机会性病原体（例如，肠杆菌科物种）的流行率和丰度。

Consistent with these taxonomic changes, significant changes in key bioactive metabolites were observed, including depletion of conjugated and deconjugated primary bile acids, enrichment of secondary bile acids and increases in short-chain and medium-chain fatty acids.

与这些分类变化一致，关键生物活性代谢物的变化显著，包括结合型和非结合型初级胆汁酸的耗竭，次级胆汁酸的富集以及短链和中链脂肪酸的增加。

In vitro, VOS batches produced these C. difficile-inhibiting metabolites.

体外实验中，VOS批次产生了这些抑制艰难梭菌的代谢产物。

These findings on the pharmacology of VOS underscore the importance of rapidly restoring key protective functions of the microbiome in patients with recurrent CDI to achieve durable prevention of recurrence, as observed in the phase 3 study; they also highlight the need to include the microbiome in the clinical management of CDI.

这些关于VOS药理学的发现强调了迅速恢复复发性艰难梭菌感染患者肠道微生物群的关键保护功能的重要性，以实现复发的持久预防，如在第三阶段研究中所观察到的；它们还强调了在CDI的临床管理中需要包括微生物群。

ClinicalTrials.gov registrations: NCT02437487 and NCT03183128 .

临床试验注册：NCT02437487 和 NCT03183128。