25March2021

Y-ECCO Literature Review: Djuna de Jong

Djuna de Jong

A phase 1b safety study of SER-287, a spore-based microbiome therapeutic, for active mild to moderate ulcerative colitis

Henn M, O’Brien E, Diao L, et al.

Gastroenterology 2021;160(1):115–27.


Djuna de Jong
© Djuna de Jong

Introduction

In the last decade, research on the human gut microbiome and its influence on health and disease has taken flight. This has strengthened the belief that the underlying pathogenesis of Inflammatory Bowel Disease (IBD) involves an altered immune response to characteristic shifts in the composition of the gut microbiome.

It has been demonstrated that patients with active Ulcerative Colitis (UC) have lower microbial diversity as well as a depletion of one of the dominant bacterial phyla in the human gut microbiome: Firmicutes [1]. These beneficial species (particularly the spore-forming Clostridiaceae, Lachnospiraceae, and Ruminococcaceae) produce metabolites essential for several functions in gut homeostasis, such as gastrointestinal barrier and mucosal immune functions [1].

Faecal microbiota transfer (FMT) can be effective for the induction of remission in mild-to-moderately active UC [2]. However, the most optimal treatment conditions and the underlying mechanism of action have yet to be completely understood. It has been shown that patients treated with FMT show an increased microbial diversity and microbial taxa associated with clinical remission include spore-forming Firmicutes [3].

Bearing this in mind, Seres Therapeutics developed SER-287. SER-287 contains spore-forming Firmicutes relevant in gut homeostasis. These Firmicute spores are isolated and enriched from healthy stool donors and formulated into oral capsules. Henn et al. hypothesised that SER-287 can reduce intestinal inflammation by altering the microbiome composition and consequently increasing the favourable metabolites that play a key role in gut homeostasis [4]. In addition, the authors hypothesised they could increase engraftment of SER-287 by preconditioning with vancomycin. In this way, pre-existing Gram-positive bacteria can be reduced that could otherwise compete for nutrients and space with the administered Firmicutes.

Methods

The authors performed a phase 1b, randomised, double-blind, placebo-controlled trial, which consisted of two treatment phases; six days of pre-treatment with either placebo or vancomycin, followed by eight weeks of treatment with either placebo or SER-287 in a weekly or daily dose, resulting in four treatment arms: placebo/placebo, placebo/SER-287 weekly, vancomycin/SER-287 weekly, vancomycin/SER-287 daily. UC patients with mild to moderately active disease, defined as a modified Mayo score (TMMS) of 4–10 and a Mayo endoscopic subscore (MES) of ³1, were randomised in a 2:3:3:3 ratio, with a 12-week follow-up period. The primary endpoint consisted of safety and changes in the microbiome composition and engraftment. A secondary outcome consisted of clinical remission (TMMS £2 and MES £1). Patients underwent endoscopic assessment before and after the 8-week treatment phase. Stool samples were collected before and after treatment and microbiome composition, engraftment and changes in metabolites were analysed using metagenomic shotgun sequencing and mass spectrometry.

Key findings

Fifty-eight patients with mild to moderate active UC were randomised to one of four treatment arms. Overall safety profile and tolerability were similar across arms. 40% of patients in the vancomycin/SER-287 daily group achieved clinical remission at week eight, compared to none in the placebo/placebo group (p=0.024), 13% in the placebo/SER-287 weekly group and 18% in the vancomycin/SER-287 weekly group.

The authors propose engraftment as the key mechanism of action of microbiome therapy; a greater therapeutic effect can be expected if there is measurable engraftment of the microbiome product with associated functional changes in the host. Treatment with both vancomycin and SER-287 was associated with compositional changes in the microbiome, such as an increase in spore-forming Firmicute diversity, a decrease in pro-inflammatory Enterobacteriaceae and functional changes in favourable microbe-associated metabolites. A greater number of SER-287-associated species was found in the vancomycin/SER-287 daily group, which suggests not only that vancomycin facilitated engraftment but that engraftment is dose dependent, since this effect was not observed in the vancomycin/SER-287 weekly group.

Despite the valuable insights that research on FMT has provided, this treatment regimen will likely be replaced by a more targeted approach to modulate the microbiome. This study is one example of a future direction in microbiome-based therapies, as this is the first trial to study the effect of an oral microbiome product in UC patients. Through this work, the authors have demonstrated the potential benefits of treatment with SER-287 compared to FMT. First, the authors claim SER-287 to be preferable to and safer than FMT, as only specific beneficial strains will be transferred to the recipient. Because SER-287 contains specific spore-forming Firmicutes which are isolated and enriched, possible pathogenic microbes such as bacteria, viruses, fungi and parasites are eliminated from the end product. In contrast, FMT transfers a large part of a healthy donor’s microbiome, offering a broad spectrum of microbes to correct dysbiosis. Infections transmitted due to FMT are rare, but the recent COVID-19 pandemic has shown that whole stool transfer will always be vulnerable to unknown or unrecognised pathogens [5, 6]. Second, treatment with an oral microbiome compound seems a more feasible and patient-friendly method of manipulating the microbiome composition. In contrast, FMT is usually administered by multiple infusions through endoscopy and/or a nasojejunal tube, causing this mode of treatment to be invasive, time-consuming and logistically challenging [7]. Considering these challenges, it is debatable whether FMT in its present form is feasible outside a clinical trial setting.

The authors have done an excellent job in optimising the design of the study through use of a double-blind, placebo-controlled setting and the inclusion of central reading of endoscopic assessments. However, one important limitation that has to be addressed is the small sample size. As a result of this limitation, definitive evidence on efficacy has yet to be established. Furthermore, a follow-up period of 12 weeks seems short to establish the long-term results of SER-287. Nevertheless, in this phase 1b safety study, an effect was observed that warrants further research on the efficacy and safety of this novel therapeutic modality, which is currently being performed in a phase 2b trial [8].

Conclusion

This study’s findings offer a potential novel treatment modality in patients with UC. Further studies should confirm the long-term results and safety profile of vancomycin/SER-287 and the efficacy of this oral therapeutic as monotherapy, or in combination with immunosuppressive drugs.

References

  1. Kostic AD, Xavier RJ, Gevers D. The microbiome in inflammatory bowel disease: current status and the future ahead. Gastroenterology. 2014;146(6):1489–99.
  2. Imdad A, Nicholson MR, Tanner-Smith EE, et al. Fecal transplantation for treatment of inflammatory bowel disease. Cochrane Database Syst Rev. 2018;11:CD012774.
  3. Paramsothy S, Nielsen S, Kamm MA, et al. Specific bacteria and metabolites associated with response to fecal microbiota transplantation in patients with ulcerative colitis. Gastroenterology. 2019;156(5):1440–54.
  4. Henn MR, O'Brien EJ, Diao L, et al. A phase 1b safety study of SER-287, a spore-based microbiome therapeutic, for active mild to moderate ulcerative colitis. Gastroenterology. 2021;160(1):115–27.
  5. Ianiro G, Mullish BH, Kelly CR, et al. Screening of faecal microbiota transplant donors during the COVID-19 outbreak: suggestions for urgent updates from an international expert panel. Lancet Gastroenterol Hepatol. 2020;5(5):430–2.
  6. Sartor RB, Wu GD. Roles for intestinal bacteria, viruses, and fungi in pathogenesis of inflammatory bowel diseases and therapeutic approaches. Gastroenterology. 2017;152(2):327–39.
  7. Cammarota G, Ianiro G, Tilg H, et al. European consensus conference on faecal microbiota transplantation in clinical practice. Gut. 2017;66(4):569–80.
  8. ClinicalTrials.gov ID NCT03759041. https://clinicaltrials.gov/ct2/show/NCT03759041

 

Djuna de Jong – Short biography

Djuna de Jong, MD MSc, is a PhD candidate in the Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam. She is currently coordinating the CEASE trial, an RCT to validate a prediction model for safe cessation of anti-TNF therapy in patients with quiescent Crohn’s Disease, as well as two clinical trials on the treatment of acute and chronic pouchitis.

Posted in ECCO News, Y-ECCO Literature Reviews, Committee News, Volume 16, Issue 1, Y-ECCO