美国Seres Therapeutics制药公司Barbara H. McGovern团队研究了SER-109口服微生物疗法治疗复发性艰难梭菌感染的疗效。相关论文于2022年1月19日发表在《新英格兰医学杂志》上。

目前治疗复发性艰难梭菌感染的方法并没有解决被破坏的微生物群，这些微生物群支持艰难梭菌孢子萌发成产毒细菌。SER-109是一种探索性的微生物治疗，由纯化的厚壁菌孢子组成，用于治疗复发性艰难梭菌感染。

研究组进行了一项临床3期、双盲、随机、安慰剂对照试验，招募有3次及以上艰难梭菌感染（包括符合条件的急性发作）的患者，将其随机分组，在标准护理抗生素治疗后接受SER-109或安慰剂治疗。

主要观察指标为治疗后8周内，与安慰剂相比，SER-109在降低艰难梭菌感染复发风险方面是否具有优势。在试验开始时进行毒素检测诊断，并根据年龄和接受的抗生素药物进行随机分层。还进行了安全性、微生物组移植和代谢物分析。

在281例筛查患者中，共纳入182例。SER-109组的艰难梭菌感染复发率为12%，显著低于安慰剂组的40%，相对风险为0.3。在根据年龄分层的分析中（65岁以下患者的相对风险为0.24，≥65岁的患者为0.36）和接受抗生素的分析中（万古霉素的相对风险为0.41，非达霉素为0.09），SER-109导致的复发率均低于安慰剂。

大多数不良事件为轻到中度，且属于胃肠道不良事件，在两组中发生率相似。早在第1周就检测到SER-109剂量种类，并且与已知抑制艰难梭菌孢子萌发的胆汁酸谱相关。

研究结果表明，在使用标准护理抗生素治疗后艰难梭菌感染症状缓解的患者中，口服SER-109在降低复发感染风险方面优于安慰剂。且SER-109的安全性与安慰剂相似。

附：英文原文

Title: SER-109, an Oral Microbiome Therapy for Recurrent Clostridioides difficile Infection

Author: Paul Feuerstadt, M.D.,, Thomas J. Louie, M.D.,, Bret Lashner, M.D.,, Elaine E.L. Wang, M.D.,, Liyang Diao, Ph.D.,, Jessica A. Bryant, Ph.D.,, Matthew Sims, M.D., Ph.D.,, Colleen S. Kraft, M.D.,, Stuart H. Cohen, M.D.,, Charles S. Berenson, M.D.,, Louis Y. Korman, M.D.,, Christopher B. Ford, Ph.D.,, Kevin D. Litcofsky, Ph.D.,, Mary-Jane Lombardo, Ph.D.,, Jennifer R. Wortman, M.Sc.,, Henry Wu, Ph.D.,, John G. Auni, Ph.D.,, Christopher W.J. McChalicher, B.Ch.E.,, Jonathan A. Winkler, Ph.D.,, Barbara H. McGovern, M.D.,, Michele Trucksis, M.D., Ph.D.,, Matthew R. Henn, Ph.D.,, and Lisa von Moltke, M.D.

Issue&Volume: 2022-01-19

Abstract:

Background

Current therapies for recurrent Clostridioides difficile infection do not address the disrupted microbiome, which supports C. difficile spore germination into toxin-producing bacteria. SER-109 is an investigational microbiome therapeutic composed of purified Firmicutes spores for the treatment of recurrent C. difficile infection.

Methods

We conducted a phase 3, double-blind, randomized, placebo-controlled trial in which patients who had had three or more episodes of C. difficile infection (inclusive of the qualifying acute episode) received SER-109 or placebo (four capsules daily for 3 days) after standard-of-care antibiotic treatment. The primary efficacy objective was to show superiority of SER-109 as compared with placebo in reducing the risk of C. difficile infection recurrence up to 8 weeks after treatment. Diagnosis by toxin testing was performed at trial entry, and randomization was stratified according to age and antibiotic agent received. Analyses of safety, microbiome engraftment, and metabolites were also performed.

Results

Among the 281 patients screened, 182 were enrolled. The percentage of patients with recurrence of C. difficile infection was 12% in the SER-109 group and 40% in the placebo group (relative risk, 0.32; 95% confidence interval [CI], 0.18 to 0.58; P<0.001 for a relative risk of <1.0; P<0.001 for a relative risk of <0.833). SER-109 led to less frequent recurrence than placebo in analyses stratified according to age stratum (relative risk, 0.24 [95% CI, 0.07 to 0.78] for patients <65 years of age and 0.36 [95% CI, 0.18 to 0.72] for those ≥65 years) and antibiotic received (relative risk, 0.41 [95% CI, 0.22 to 0.79] with vancomycin and 0.09 [95% CI, 0.01 to 0.63] with fidaxomicin). Most adverse events were mild to moderate and were gastrointestinal in nature, with similar numbers in the two groups. SER-109 dose species were detected as early as week 1 and were associated with bile-acid profiles that are known to inhibit C. difficile spore germination.

Conclusions

In patients with symptom resolution of C. difficile infection after treatment with standard-of-care antibiotics, oral administration of SER-109 was superior to placebo in reducing the risk of recurrent infection. The observed safety profile of SER-109 was similar to that of placebo.

DOI: 10.1056/NEJMoa2106516

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2106516