A Phase 1b Safety Study of SER-287, a Spore-Based Microbiome Therapeutic, for Active Mild to Moderate Ulcerative Colitis

Matthew R Henn, Edward J O'Brien, Liyang Diao, Brian G Feagan, William J Sandborn, Curtis Huttenhower, Jennifer R Wortman, Barbara H McGovern, Sherry Wang-Weigand, David I Lichter, Meghan Chafee, Christopher B Ford, Patricia Bernardo, Peng Zhao, Sheri Simmons, Amelia D Tomlinson, David N Cook, Roger J Pomerantz, Bharat K Misra, John G Auninš, Michele Trucksis, Matthew R Henn, Edward J O'Brien, Liyang Diao, Brian G Feagan, William J Sandborn, Curtis Huttenhower, Jennifer R Wortman, Barbara H McGovern, Sherry Wang-Weigand, David I Lichter, Meghan Chafee, Christopher B Ford, Patricia Bernardo, Peng Zhao, Sheri Simmons, Amelia D Tomlinson, David N Cook, Roger J Pomerantz, Bharat K Misra, John G Auninš, Michele Trucksis

Abstract

Background & aims: Firmicutes bacteria produce metabolites that maintain the intestinal barrier and mucosal immunity. Firmicutes are reduced in the intestinal microbiota of patients with ulcerative colitis (UC). In a phase 1b trial of patients with UC, we evaluated the safety and efficacy of SER-287, an oral formulation of Firmicutes spores, and the effects of vancomycin preconditioning on expansion (engraftment) of SER-287 species in the colon.

Methods: We conducted a double-blind trial of SER-287 in 58 adults with active mild-to-moderate UC (modified Mayo scores 4-10, endoscopic subscores ≥1). Participants received 6 days of preconditioning with oral vancomycin (125 mg, 4 times daily) or placebo followed by 8 weeks of oral SER-287 or placebo. Patients were randomly assigned (2:3:3:3) to groups that received placebo followed by either placebo or SER-287 once weekly, or vancomycin followed by SER-287 once weekly, or SER-287 once daily. Clinical end points included safety and clinical remission (modified Mayo score ≤2; endoscopic subscores 0 or 1). Microbiome end points included SER-287 engraftment (dose species detected in stool after but not before SER-287 administration). Engraftment of SER-287 and changes in microbiome composition and associated metabolites were measured by analyses of stool specimens collected at baseline, after preconditioning, and during and 4 weeks after administration of SER-287 or placebo.

Results: Proportions of patients with adverse events did not differ significantly among groups. A higher proportion of patients in the vancomycin/SER-287 daily group (40%) achieved clinical remission at week 8 than patients in the placebo/placebo group (0%), placebo/SER-287 weekly group (13.3%), or vancomycin/SER-287 weekly group (17.7%) (P = .024 for vancomycin/SER-287 daily vs placebo/placebo). By day 7, higher numbers of SER-287 dose species were detected in stool samples from all SER-287 groups compared with the placebo group (P < .05), but this difference was not maintained beyond day 7 in the placebo/SER-287 weekly group. In the vancomycin groups, a greater number of dose species were detected in stool collected on day 10 and all subsequent time points through 4 weeks post dosing compared with the placebo group (P < .05). A higher number of SER-287 dose species were detected in stool samples on days 7 and 10 from subjects who received daily vs weekly SER-287 doses (P < .05). Changes in fecal microbiome composition and metabolites were associated with both vancomycin/SER-287 groups.

Conclusions: In this small phase 1b trial of limited duration, the safety and tolerability of SER-287 were similar to placebo. SER-287 after vancomycin was significantly more effective than placebo for induction of remission in patients with active mild to moderate UC. Engraftment of dose species was facilitated by vancomycin preconditioning and daily dosing of SER-287. ClinicalTrials.gov ID NCT02618187.

Keywords: Gastrointestinal Microbiome; Inflammatory Bowel Disease; Microbe-Associated Metabolites; Microbiome Therapeutics.

Copyright © 2021. Published by Elsevier Inc.

Figures

Graphical abstract
Graphical abstract
Figure 1
Figure 1
Proportion of patients achieving end points of clinical remission (A), endoscopic improvement (B), and clinical response (C) at week 8 in intent-to-treat population. Two-sided Fisher exact P value indicated when <.05. PBO, placebo; Vanco, vancomycin; Wkly, weekly.
Figure 2
Figure 2
Engraftment of SER-287 species is dose-dependent and facilitated by vancomycin preconditioning. Boxplots display median (horizontal line), 25th and 75th percentiles (box edges), range of nonoutlier observations (whiskers), and outlier observations (dots; >1.5 times interquartile range). Significance values are in Supplementary Table 5.
Figure 3
Figure 3
Vancomycin preconditioning followed by SER-287 results in a broad shift in overall composition of spore and nonspore microbial species 8 weeks post treatment. The proportion of patients in each arm that gained (positive values) or lost (negative values) a given species compared with baseline is shown (x-axis). Species (y-axis; n = 344) are ordered by average change across arms; species without change in any subject are not depicted (n = 15). Bar colors indicate spore-forming species detected in SER-287 (dark blue), other spore-forming species not detected in SER-287 (light blue), and other non–spore-forming species (gray). SER-287 dose species gained compared with baseline are the same species represented in Figure 2.
Figure 4
Figure 4
Microbe-associated metabolites associated with SER-287 treatment and clinical outcome. Metabolite levels in fecal samples were assessed via targeted (A, B) and global (C, D) metabolomics. In (A) and (C), metabolite fold-changes are shown by treatment arm; black horizontal dashed line indicates whether the metabolite is higher or lower compared with baseline. For (B) and (D), metabolite abundance is shown by remission status. Significance values are provided in Supplementary Table 10, Supplementary Table 11, Supplementary Table 12, Supplementary Table 13.
Supplementary Figure 1
Supplementary Figure 1
Study Schematic. Carats (ˆ) indicate approximate times of stool sampling at baseline (screening endoscopy visit before any treatment) and on days 0 (post-vancomycin preconditioning, before SER-287 dosing), 3, 7, 10, 14, 56, and 84 post-treatment with SER-287. Final samples were collected at the end of treatment, at the end of the short-term safety follow-up period and/or at any early termination visit.
Supplementary Figure 2
Supplementary Figure 2
Consolidated Standards of Reporting Trials diagram.
Supplementary Figure 3
Supplementary Figure 3
Engraftment of SER-287 species is dose-dependent and facilitated by vancomycin preconditioning; preconditioned patient microbiome samples become more similar to SER-287 dose composition after rebound from vancomycin. Similarity between a subject’s microbiome and SER-287 dose composition is quantified with a binary Jaccard similarity coefficient of spore-forming species in subject samples and SER-287 doses; the change in similarity for each subject and timepoint is relative to that subjects’ baseline sample (y-axis) across time (x-axis). Black horizontal dashed line indicates the threshold where a subjects’ spore fraction is more (>0) or less (<0) similar to SER-287 post-treatment. Initial preconditioning with vancomycin moves patient samples further from SER-287 dose composition; by day 10 in the vancomycin/SER-287 daily dosing arm, the patient spore-forming microbiome becomes more similar to SER-287 and remains so through the 8-week dosing period (day 56) and the long-term follow-up at day 84 (P < .05, Wilcoxon signed-rank test, all time points); in the vancomycin/SER-287 weekly dosing arm, only the day 56 time point was statistically significant P < .05, consistent with a dose-dependent effect.
Supplementary Figure 4
Supplementary Figure 4
Enterobacteriaceae species abundance tends to decrease with vancomycin pre-conditioning and SER-287 with remitters having a larger decrease in Enterobacteriaceae compared with non-remitters. (A) Fold-change in Enterobacteriaceae species abundance relative to baseline is shown 8 weeks post treatment (day 56) for subjects in each arm; boxplots are colored by treatment arm. (B) Enterobacteriaceae fold-change is shown across remitters and nonremitters for subjects in vancomycin preconditioning arms only; boxplots are colored by clinical remission status.

References

    1. Eckburg P.B., Bik E.M., Bernstein C.N., et al. Diversity of the human intestinal microbial flora. Science. 2005;308:1635–1638.
    1. Yatsunenko T., Rey F.E., Manary M.J., et al. Human gut microbiome viewed across age and geography. Nature. 2012;486:222–227.
    1. Structure, function and diversity of the healthy human microbiome. Nature. 2012;486:207–214.
    1. Kostic A.D., Xavier R.J., Gevers D. The microbiome in inflammatory bowel disease: current status and the future ahead. Gastroenterology. 2014;146:1489–1499.
    1. Sartor R.B., Wu G.D. Roles for intestinal bacteria, viruses, and fungi in pathogenesis of inflammatory bowel diseases and therapeutic approaches. Gastroenterology. 2017;152:327–339.e4.
    1. Lloyd-Price J., Arze C., Ananthakrishnan A.N., et al. Multi-omics of the gut microbial ecosystem in inflammatory bowel diseases. Nature. 2019;569:655–662.
    1. Plichta D.R., Graham D.B., Subramanian S., et al. Therapeutic opportunities in inflammatory bowel disease: mechanistic dissection of host-microbiome relationships. Cell. 2019;178:1041–1056.
    1. Paramsothy S., Nielsen S., Kamm M.A., et al. Specific bacteria and metabolites associated with response to fecal microbiota transplantation in patients with ulcerative colitis. Gastroenterology. 2019;156:1440–1454.e2.
    1. Kotlowski R., Bernstein C.N., Sepehri S., et al. High prevalence of Escherichia coli belonging to the B2+D phylogenetic group in inflammatory bowel disease. Gut. 2007;56:669–675.
    1. Halfvarson J., Brislawn C.J., Lamendella R., et al. Dynamics of the human gut microbiome in inflammatory bowel disease. Nat Microbiol. 2017;2:17004.
    1. Morgan X.C., Tickle T.L., Sokol H., et al. Dysfunction of the intestinal microbiome in inflammatory bowel disease and treatment. Genome Biol. 2012;13:R79.
    1. Rubin D.T., Ananthakrishnan A.N., Siegel C.A., et al. ACG Clinical Guideline: ulcerative colitis in adults. Am J Gastroenterol. 2019;114:384–413.
    1. Paramsothy S., Kamm M.A., Kaakoush N.O., et al. Multidonor intensive faecal microbiota transplantation for active ulcerative colitis: a randomised placebo-controlled trial. Lancet. 2017;389:1218–1228.
    1. Costello S.P., Hughes P.A., Waters O., et al. Effect of fecal microbiota transplantation on 8-week remission in patients with ulcerative colitis: a randomized clinical trial. JAMA. 2019;321:156–164.
    1. Moayyedi P., Surette M.G., Kim P.T., et al. Fecal microbiota transplantation induces remission in patients with active ulcerative colitis in a randomized controlled trial. Gastroenterology. 2015;149:102–109.e6.
    1. Carlson P.E., Jr. Regulatory considerations for fecal microbiota transplantation products. Cell Host Microbe. 2020;27:173–175.
    1. Colwell R.K., Coddington J.A. Estimating terrestrial biodiversity through extrapolation. Philos Trans R Soc Lond B Biol Sci. 1994;345:101–118.
    1. Parks D.H., Beiko R.G. Measures of phylogenetic differentiation provide robust and complementary insights into microbial communities. ISME J. 2013;7:173–183.
    1. Lloyd-Price J., Mahurkar A., Rahnavard G., et al. Strains, functions and dynamics in the expanded Human Microbiome Project. Nature. 2017;550:61–666.
    1. Brown E.M., Ke X., Hitchcock D., et al. Bacteroides-derived sphingolipids are critical for maintaining intestinal homeostasis and symbiosis. Cell Host Microbe. 2019;25:668–680.e7.
    1. Franzosa E.A., Sirota-Madi A., Avila-Pacheco J., et al. Gut microbiome structure and metabolic activity in inflammatory bowel disease. Nat Microbiol. 2019;4:293–305.
    1. Sofia M.A., Ciorba M.A., Meckel K., et al. Tryptophan metabolism through the kynurenine pathway is associated with endoscopic inflammation in ulcerative colitis. Inflamm Bowel Dis. 2018;24:1471–1480.
    1. Feagan B.G., Sandborn W.J., D'Haens G., et al. The role of centralized reading of endoscopy in a randomized controlled trial of mesalamine for ulcerative colitis. Gastroenterology. 2013;145:149–157.e2.
    1. Jairath V., Zou G., Parker C.E., et al. Systematic review and meta-analysis: placebo rates in induction and maintenance trials of ulcerative colitis. J Crohns Colitis. 2016;10:607–618.
    1. US Food and Drug Administration . US Food and Drug Administration; Washington, DC: 2016. Ulcerative Colitis: Clinical Trial Endpoints Guidance for Industry.
    1. Horn H.S. The ecology of secondary succession. Annu Rev Ecol Syst. 1974;5:25–37.
    1. Walter J., Maldonado-Gomez M.X., Martinez I. To engraft or not to engraft: an ecological framework for gut microbiome modulation with live microbes. Curr Opin Biotechnol. 2018;49:129–139.
    1. Dethlefsen L., Huse S., Sogin M.L., et al. The pervasive effects of an antibiotic on the human gut microbiota, as revealed by deep 16S rRNA sequencing. PLoS Biol. 2008;6
    1. Seekatz A.M., Young V.B. Clostridium difficile and the microbiota. J Clin Invest. 2014;124:4182–4189.
    1. McGovern B.H., Ford C.B., Henn M.R., et al. SER-109, an investigational microbiome drug to reduce recurrence after Clostridioides difficile infection: lessons learned from a phase 2 Trial. Clin Infect Dis. 2020 Apr 7
    1. Lopetuso L.R., Scaldaferri F., Petito V., et al. Commensal Clostridia: leading players in the maintenance of gut homeostasis. Gut Pathog. 2013;5:23.
    1. Garrett W.S., Gallini C.A., Yatsunenko T., et al. Enterobacteriaceae act in concert with the gut microbiota to induce spontaneous and maternally transmitted colitis. Cell Host Microbe. 2010;8:292–300.
    1. Coyte K.Z., Schluter J., Foster K.R. The ecology of the microbiome: networks, competition, and stability. Science. 2015;350:663–666.
    1. Johnson K.V., Burnet P.W. Microbiome: should we diversify from diversity? Gut Microbes. 2016;7:455–458.
    1. McCormick B.A. Bacterial-induced hepoxilin A3 secretion as a pro-inflammatory mediator. FEBS J. 2007;274:3513–3518.
    1. Mumy K.L., Bien J.D., Pazos M.A., et al. Distinct isoforms of phospholipase A2 mediate the ability of Salmonella enterica serotype typhimurium and Shigella flexneri to induce the transepithelial migration of neutrophils. Infect Immun. 2008;76:3614–3627.
    1. US Food and Drug Administration . US Food and Drug Administration; Washington, DC: 2019. Important Safety Alert Regarding Use of Fecal Microbiota for Transplantation and Risk of Serious Adverse Reactions Due to Transmission of Multi-Drug Resistant Organisms.
    1. US Food and Drug Administration . US Food and Drug Administration; Washington, DC: 2020. Safety Alert Regarding Use of Fecal Microbiota for Transplantation and Risk of Serious Adverse Events Likely Due to Transmission of Pathogenic Organisms.
    1. Wilcox M.H., McGovern B.H., Hecht G.A. The efficacy and safety of fecal microbiota transplant for recurrent Clostridium difficile infection: current understanding and gap analysis. Open Forum Infect Dis. 2020;7:ofaa114.
    1. Wu Y., Guo C., Tang L., et al. Prolonged presence of SARS-CoV-2 viral RNA in faecal samples. Lancet Gastroenterol Hepatol. 2020;5:434–435.
    1. Blaser M.J. Fecal microbiota transplantation for dysbiosis—predictable risks. N Engl J Med. 2019;381:2064–2066.
    1. Rubin D.T. Curbing our enthusiasm for fecal transplantation in ulcerative colitis. Am J Gastroenterol. 2013;108:1631–1633.
    1. Tomkovich S., Dejea C.M., Winglee K., et al. Human colon mucosal biofilms from healthy or colon cancer hosts are carcinogenic. J Clin Invest. 2019;130:1699–1712.
    1. Strauss J., Kaplan G.G., Beck P.L., et al. Invasive potential of gut mucosa-derived Fusobacterium nucleatum positively correlates with IBD status of the host. Inflamm Bowel Dis. 2011;17:1971–1978.
    1. Thorpe C.M., Kane A.V., Chang J., et al. Enhanced preservation of the human intestinal microbiota by ridinilazole, a novel Clostridium difficile-targeting antibacterial, compared to vancomycin. PLoS One. 2018;13
    1. Kump P., Wurm P., Grochenig H.P., et al. The taxonomic composition of the donor intestinal microbiota is a major factor influencing the efficacy of faecal microbiota transplantation in therapy refractory ulcerative colitis. Aliment Pharmacol Ther. 2018;47:67–77.
Supplementary References
    1. Bolger A.M., Lohse M., Usadel B. Trimmomatic: a flexible trimmer for illumina sequence data. Bioinformatics. 2014;30:2114–2120.
    1. Langmead B., Salzberg S.L. Fast gapped-read alignment with Bowtie 2. Nat. Methods. 2012;9:357–359.
    1. Segata N., Faust K., Izard J., et al. Microbial co-occurrence relationships in the human microbiome. PLoS Comput Biol. 2012;8
    1. Truong D.T., Franzosa E.A., Tickle T.L., et al. MetaPhIAn2 for enhanced metagenomic taxonomic profiling. Nat Methods. 2015;12:902–903.

Source: PubMed

スポンサーと協力者

医学的状態

薬物療法

3
購読する