Hasson, Brooke

Abstract Background Clostridioides difficile infection (CDI) treatment guidelines suggest varied approaches for patients with first (frCDI) or multiply recurrent CDI (mrCDI). Low microbial diversity, elevated primary bile acids (BA), and low secondary BA concentrations favor germination of C. difficile spores into toxin-producing bacteria and are believed to increase rCDI risk. Greater understanding of the gastrointestinal (GI) microbiome in rCDI may inform management of the disease. We describe a post hoc comparison of GI microbiome and bile acid profiles between patients with frCDI and mrCDI in a Phase 3 open-label trial, ECOSPOR IV, of fecal microbiota spores, live-brpk (VOWST®; VOS, formerly SER-109), an orally-administered live microbiome therapeutic. Methods Patients received VOS following symptom resolution after standard-of-care antibiotics. Pretreatment baseline (within 3 days following antibiotic completion) and Week 1 post-dosing stool samples were collected for whole metagenomic sequencing and metabolomics. Diversity was calculated from MetaPhlAn2 species profiles. Concentrations of primary and secondary BAs were measured via targeted LC-MS/MS. Results rCDI rates through Week 8 were similarly low in both frCDI and mrCDI patients (6.5% versus 9.7%, respectively). Baseline microbial diversity was similarly low between frCDI and mrCDI subgroups (P > .05). Diversity and secondary BA concentrations increased in both subgroups, whereas primary BA concentrations declined following VOS dosing, leading to few differences between subgroups at Week 1. Conclusions These data suggest commonalities in microbiome disruption in patients with frCDI and mrCDI that contribute to recurrence and suggest that antibiotics followed by a live microbiome therapy may be an optimal treatment strategy for rCDI, regardless of number of prior CDI recurrences.

6554 Background: SER-155 is an investigational, oral, live biotherapeutic product (LBP) comprised of 16 bacterial strains designed to decolonize gastrointestinal (GI) pathogens, improve epithelial barrier integrity, and modulate immune responses to prevent bloodstream infections (BSI). In the placebo-controlled cohort 2 of the phase 1b study, SER-155-001 (NCT04995653), SER-155 was generally well tolerated with a safety profile similar to placebo and the incidence of BSIs, a secondary endpoint, was significantly lower after treatment with SER-155 when compared to placebo. We report exploratory analyses of biomarkers of T cell expansion relevant for immune reconstitution after HCT. Methods: Participants were randomized 1:1 to receive 4 days of oral vancomycin (for microbiome conditioning) and 10 days of SER-155 or placebo/placebo administered pre-HCT (course 1) and post-neutrophil engraftment (course 2). Primary endpoints were safety and SER-155 strain engraftment (PK). Exploratory endpoints included plasma cytokine concentrations measured by ELISA and analysis of peripheral blood mononuclear cells (PBMCs) by flow cytometry. Results: Demographics were comparable across treatment arms. 34 of 45 randomized participants were treated and received allo-HCT (SER-155, 20; placebo, 14); 28 received course 2 (SER-155, 19; placebo, 9). SER-155 strain engraftment was observed in the peri-transplant period (median 11.5 strains after course 1) and post-HCT (median 11 strains after course 2 and HCT Day 100). Significant differences and trends in cytokines of systemic inflammation and immune homeostasis were observed relative to placebo prior to HCT Day 0 and post-HCT. On HCT Day 0, both arms had similar concentrations of IL7 and IL15 (Table 1). However, after course 2, and at HCT Day 100, significantly higher concentrations of IL7 were observed in the SER-155 arm relative to placebo (p=0.02, and p=0.003, respectively). In a preliminary analysis of PBMCs from a subset of participants, a high frequency of CD4+ T cells were observed in the SER-155 arm at the same timepoints. For homeostatic cytokine IL15, no significant differences were observed between arms. Conclusions: The significantly higher concentrations of IL7 with SER-155 treatment and observed frequency of CD4+ T cells support the potential role of the GI microbiome in promoting homeostatic expansion of peripheral T cells and immune reconstitution important for successful HCT. Clinical trial information: NCT04995653 . Median plasma IL7 and IL15 (pg/mL), SER-155 vs. placebo (generalized linear model). HCT Day or event SER-155 IL7 Placebo IL7 SER-155 IL15 Placebo IL15 D0 13.8 13.0 31.9 30.4 D7 15.1 14.6 50.9 62.6 D14 12.8 15.5 56.6 69.8 Post-neutrophil engraftment 13.4 9.0 16.3 15.4 Post-course 2 7.4* 3.9 6.2 9.1 D100 7.1** 3.5 6.2 6.2 *p<0.05, **p<0.01.

Abstract Background Patients experiencing ≥1 recurrence of CDI are at elevated risk for subsequent recurrences and complications versus those with an initial CDI episode. Treatment selection for recurrent CDI (rCDI) is influenced by the number of recurrences a patient has experienced. Fecal microbiota spores, live-brpk (VOWST™; formerly SER-109, hereafter referred to as VOS for Vowst Oral Spores) is an oral microbiota-based therapeutic to prevent rCDI in adults with rCDI after antibacterial treatment for rCDI, thought to work by enabling rapid restoration of the microbiome. We report results from an integrated analysis of two Phase 3 trials to further describe safety/efficacy of VOS in patients, stratified by number of prior CDI recurrences. Methods The randomized, controlled ECOSPOR III trial enrolled 182 patients with ≥2 CDI recurrences, and the open-label, single-arm ECOSPOR IV trial enrolled 263 patients with ≥1 CDI recurrence. VOS was given as 4 capsules over 3 consecutive days after completing antibiotic treatment. Treatment-emergent adverse events (TEAEs) were collected through Week 8 after VOS; serious TEAEs/AEs of special interest were collected through Week 24. Efficacy endpoint included rCDI (toxin-positive diarrhea requiring treatment) through Week 8. Results A total of 77 patients had 1, 150 patients had 2, and 121 patients had ≥3 prior CDI recurrences; incidence of TEAEs was 44%, 70%, and 67%, respectively (Table 1). No serious TEAEs, TEAEs of special interest, or TEAEs leading to study withdrawal were considered related to VOS by investigators. TEAEs in ≥15% of patients with 1, 2, or ≥3 prior CDI recurrences were flatulence (6%; 29%; 29%), abdominal pain (6%; 27%; 16%), fatigue (1%; 26%; 20%), abdominal distension (3%; 22%; 20%), and diarrhea (27%; 21%; 23%). On-study recurrence rate through Week 8 in the overall population was 9.5% (95% CI: 6.6%–13.0%); in those with 1 or multiple (≥2) CDI recurrences, rates (95% CI) were 6.5% (2.1%–14.5%) and 10.3% (7.0%–14.6%), respectively. Conclusion This integrated analysis confirms VOS was well tolerated and rCDI rates were low/consistent in patients, regardless of the number of CDI recurrences. Results suggest VOS may be considered in patients with rCDI, regardless of the number of prior CDI recurrences. Disclosures Matthew Sims, MD, PhD, Adaptive Phage Therapeutics: Grant/Research Support|Applied Biocode: Advisor/Consultant|Applied Biocode: Grant/Research Support|Astra Zeneca: Grant/Research Support|Biotest AG: Grant/Research Support|ContraFect: Grant/Research Support|Janssen: Grant/Research Support|Leonard-Meron Biosciences: Grant/Research Support|Novozyme: Grant/Research Support|OpGen: Advisor/Consultant|OpGen: Grant/Research Support|Pfizer: Grant/Research Support|Prenosis: Advisor/Consultant|Prenosis: Grant/Research Support|QIAGEN: Grant/Research Support|Seres: Advisor/Consultant|Seres: Grant/Research Support|Summit Therapeutics: Grant/Research Support|Venatorx: Advisor/Consultant Colleen S. Kraft, MD, MSc, Ferring: Advisor/Consultant|Seres: Advisor/Consultant Lisa von Moltke, MD, Cara Therapeutics: Board Member|Cara Therapeutics: Stocks/Bonds (Public Company)|Seres Therapeutics: Employee|Seres Therapeutics: Stocks/Bonds (Public Company) Brooke Hasson, PhD, Seres Therapeutics: employee|Seres Therapeutics: Stocks/Bonds (Public Company) Maximilian von Eynatten, MD, Nestlé Health Science: Employment Darrell Pardi, MD, AMT, Inc: Grant/Research Support|Boehringer Ingelheim: Grant/Research Support|Exe GI: Grant/Research Support|Immunic: Advisor/Consultant|Lilly: Advisor/Consultant|Rise Therapeutics: Advisor/Consultant|Rise Therapeutics: Grant/Research Support|Seres Therapeutics: Advisor/Consultant|Seres Therapeutics: Expert Testimony|Vedanta: Advisor/Consultant|Vedanta: Grant/Research Support

Background: In patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT), low gastrointestinal (GI) microbial diversity is associated with risk of bloodstream infections (BSIs), acute graft-versus-host disease (aGvHD), and death. SER-155 is an investigational cultivated microbiome therapeutic rationally designed to improve clinical outcomes in allo-HCT patients by preventing pathogen domination, promoting epithelial barrier integrity, and reducing colonic inflammation. SER-155-001 is a 2-part, Phase 1b study evaluating the safety, tolerability, pharmacokinetics, and efficacy of SER-155 in adults undergoing allo-HCT. Here, we present preliminary safety and tolerability data from the open-label Cohort 1 through Day 100 post HCT. Study Design and Methods: Adult recipients of allo-HCT were eligible for screening. Patients were excluded if they: a) were planned for umbilical cord blood or ex vivo T-cell depletion, b) had received a fecal microbiota transplant or any live biotherapeutic product within 3 months prior to screening, and/or c) had evidence of relapse or progression of hematologic malignancy (minimal residual disease was allowed). HCT conditioning and aGvHD prophylaxis were per investigator discretion. Following screening, patients received two treatment courses (before conditioning and after neutrophil engraftment) comprised of microbiome conditioning with 4 days of oral vancomycin (to facilitate engraftment of SER-155 strains) followed by 10 days of oral SER-155 (see study design schematic, Figure 1). The primary endpoint was the incidence and severity of adverse events (AEs), serious adverse events (SAEs), and adverse events of special interest (AESIs), designated as invasive infection, BSI, and GI infection. Results: Fifteen adult patients were enrolled and 13 received study drug (safety population). Of these 13 patients, the median age was 67.0, all were White, and 54% were male. Underlying diseases included acute myeloid leukemia (6 patients [46.2%]); myelodysplastic syndromes and myeloproliferative neoplasms (2 patients each [15.4%]; and acute lymphoblastic leukemia, chronic myeloid leukemia, and classic Hodgkin's lymphoma (1 patient each [7.7%]). Ten patients (76.9%) received peripheral blood stem cells; 9 (69.2%) had an unrelated donor, 8 (61.5%) underwent a reduced-intensity conditioning regimen, and 3 (23.1%) received myeloablative conditioning. Eleven patients received allo-HCT, all patients had neutrophil engraftment within the expected timeframe and 10 had 100-day follow-up data available. Nine of these patients (81.8%) received tacrolimus/methotrexate-based GvHD prophylaxis. SER-155 was generally well-tolerated ( Table 1). Treatment-emergent AEs (TEAEs) were observed in all patients as is expected in this patient population. One TEAE considered unrelated to study drug, resulted in study discontinuation. Most AEs were gastrointestinal in nature with diarrhea being the most common AE. No SAEs were considered related to SER 155, and most SAEs and AESIs occurred after HCT and before starting the second course of SER-155. No deaths occurred prior to Day 100. Three deaths occurred after Day 100, all deemed to be unrelated to study drug by the investigators. No BSIs attributable to organisms in SER-155 occurred. Commencement of the double-blind, randomized, placebo-controlled Cohort 2 (n=60) was initiated following approval of the Data Safety Monitoring Committee. Conclusions: In patients enrolled in this open-label Cohort 1 of this Phase 1b study, SER-155 was well-tolerated through Day 100. Although sample size is limited, the observed safety and tolerability profile of SER-155 in this patient population is consistent with multiple preclinical assessments supporting the safety of SER-155 for therapeutic use. Enrollment in the double-blind, randomized, placebo-controlled second cohort to assess safety, efficacy, and changes in microbiome composition and function is ongoing.

Introduction: During allogeneic hematopoietic cell transplantation (allo-HCT), conditioning regimens disrupt the epithelial barrier of the gastrointestinal (GI) tract and broad-spectrum antibiotics cause microbiome disruption characterized by low microbial diversity and high abundance of pathogens that can dominate gut communities. Microbiome disruption is associated with increased translocation of pathogenic bacteria leading to risk of bloodstream infections (BSIs) and acute graft-vs-host disease (aGvHD). Nonclinical studies have demonstrated that domination with pathogens leads to immune activation and subsequent GvHD following exposure to bacterial antigens in the gut-associated lymphoid tissue [ Jenq 2015 Biol Blood Marrow Transplant, Stein-Thoeringer 2019 Science, Peled 2020 NEJM]. SER-155, an oral investigational cultivated microbiome therapeutic comprised of 16 bacterial Firmicutes strains, was designed to engraft in the GI tract, improve GI barrier integrity, and restructure the GI microbiome by introducing bacteria with immunomodulatory and anti-inflammatory properties and driving a reduction in abundance of proinflammatory bacteria [ Halvorsen 2021 OFID, 2022 Bone Marrow Transplant]. Herein, we present preliminary clinical data through Day 100 from an open-label cohort of a Phase 1b study in patients undergoing allo-HCT (NCT04995653) and compare the incidence of GI pathogen domination in this cohort to a historical cohort. Methods: Study patients received two treatment courses of SER-155 (before conditioning and after neutrophil engraftment), each comprised of microbiome conditioning with 4 days oral vancomycin (to facilitate engraftment of SER-155 strains into the GI microbiome) followed by 10 days of oral SER-155. The primary endpoint was safety. Stool samples collected pre- and post-HCT were used to evaluate secondary endpoints, including engraftment of SER-155 strains (following each course of SER-155) and GI pathogen domination, defined as a relative abundance of a specific taxa at ≥30% ( Peled, 2020). Engraftment of SER-155 strains was assessed via strain-specific molecular probes (NanoString). Relative abundance of Enterobacteriaceae, Enterococcaceae, Streptococcaceae and Staphylococcaceae was assessed with whole metagenomic shotgun sequencing (WMS). A post-hoc comparison of GI domination was made with a historical cohort of 459 HCT patients with similar patient characteristics from one of the study sites (MSKCC) using stool samples profiled by 16S-amplicon sequencing. Results: Fifteen adults (median age 67 years; 54% male) were enrolled and 13 received study drug. SER-155 was generally well-tolerated. Following each course of SER-155, the majority of the 16 strains in SER-155 were detected in evaluable patients (median = 11 strains in 8 patients before conditioning; median = 12 strains in 7 patients after neutrophil engraftment).Between the day of transplant (Day 0) and Day 30, GI domination with potentially pathogenic bacteria occurred in only 1 of 9 (11%) evaluable patients (Figure 1). In contrast, in the historical comparator cohort, 64% of patients (294 of 459) had pathogen domination during the same timeframe, with domination by Enterococcus being most common. Conclusions: The observation of SER-155 strain engraftment before transplant and low incidence of GI pathogen domination after transplant through Day 30 are encouraging, although these preliminary data are limited by the small size of this open-label cohort of HCT patients. These observations are consistent with the design and preclinical evaluation of SER-155, supporting further development of this investigational cultivated microbiome therapeutic. Enrollment in the second double-blind, randomized, placebo-controlled cohort (approximately 60 participants) has initiated following a preplanned review by the Data Safety Monitoring Committee.

Abstract Background Treatment for first recurrent Clostridioides difficile infection (frCDI) or multiply recurrent CDI (mrCDI) is complex and may include antibiotics, monoclonal antibodies, or fecal transplantation. Improved understanding of rCDI pathogenesis can help guide treatment. We report microbiome findings of patients (pts) with frCDI and mrCDI from a post hoc analysis of two phase 3 trials with fecal microbiota spores, live-brpk (FMS; formerly SER-109), an FDA-approved, microbiota-based therapeutic comprised of Firmicutes spores. Methods Stool samples were collected from pts with mrCDI in ECOSPOR III (n=158) and with frCDI or mrCDI in ECOSPOR IV (n=218) at baseline (pre-dose) and Week 1 post treatment. Shannon diversity was calculated from species profiles from analysis of whole metagenomic sequencing data using MetaPhlAn2. Primary (1°BA) and secondary bile acid (2°BA) concentrations were measured via targeted liquid chromatography–mass spectrometry panel. Subgroup differences were analyzed with linear mixed models. Results At baseline, Shannon diversity was not significantly different between mrCDI and frCDI groups (P&gt;0.05). At Week 1, Shannon diversity (Fig 1) was greater vs baseline (P&lt; 0.001); gains were not significantly different between subgroups (P&gt;0.05). For pts receiving FMS vs placebo in ECOSPOR III, greater reductions in 1°BA and increases in 2°BA from baseline–Week 1 were observed, similar to FMS-treated pts in ECOSPOR IV. At Week 1, 2°BA concentrations were greater vs baseline (P&lt; 0.001); similar gains were seen between subgroups (P&gt;0.05) (Fig 2). Consistent with these microbiome findings, in an integrated analysis, rCDI rates with FMS at Week 8 were low in both subgroups (frCDI, 6.5% [5/77] vs mrCDI, 10.3% [28/271]). Conclusion After antibiotics, pts with frCDI or mrCDI had low Shannon diversity and 2°BA concentrations that were no different between subgroups, highlighting a need for microbiome restoration. Both subgroups showed rapid, significant improvement in Shannon diversity and 2°BA concentrations and reductions in 1°BA after FMS, with comparable clinical outcomes. These data suggest that regardless of number of prior CDI episodes, FMS therapy following antibiotics may be an optimal treatment. Disclosures Colleen R. Kelly, MD, Openbiome: Advisor/Consultant|Sebela Pharmaceuticald: Advisor/Consultant Tim Straub, MS, Seres Therapeutics: Employee|Seres Therapeutics: Stocks/Bonds Kevin Litcofsky, PhD, Seres Therapeutics: inventor on patents assigned to Seres Therapeutics|Seres Therapeutics: Employment|Seres Therapeutics: Stocks/Bonds Jennifer R. Wortman, MS, Seres Therapeutics: Employee|Seres Therapeutics: Stocks/Bonds Barbara McGovern, MD, Seres Therapeutics: Stocks/Bonds Brooke Hasson, PhD, Sage Therapeutics: Stocks/Bonds|Seres Therapeutics: Stocks/Bonds Dina Hot, PhD, Aimmune Therapeutics: Employee Darrell Pardi, MD, Abbvie: Advisor/Consultant|AMT: Grant/Research Support|BI: Advisor/Consultant|Immunic: Advisor/Consultant|Rise: Advisor/Consultant|Seres Therapeutics: Advisor/Consultant|Seres Therapeutics: Grant/Research Support|Summit: Advisor/Consultant|Takeda: Grant/Research Support|Vedanta: Advisor/Consultant|Vedanta: Grant/Research Support Christopher Ford, PhD, Seres Therapeutics: Employee|Seres Therapeutics: Stocks/Bonds Matthew Henn, PhD, Seres Therapeutics: Employee|Seres Therapeutics: Stocks/Bonds

Abstract Background Although comorbidities are risk factors for recurrent Clostridioides difficile infection (rCDI), many clinical trials exclude patients with medical conditions such as malignancy or immunosuppression. In a phase 3, double-blind, placebo-controlled, randomized trial (ECOSPOR III), fecal microbiota spores, live (VOWST, Seres Therapeutics; hereafter “VOS,” formerly SER-109), an oral microbiota therapeutic, significantly reduced the risk of rCDI at week 8. We evaluated the efficacy of VOS compared with placebo in patients with comorbidities and other risk factors for rCDI. Methods Adults with rCDI were randomized to receive VOS or placebo (4 capsules daily for 3 days) following standard-of-care antibiotics. In this post hoc analysis, the rate of rCDI through week 8 was assessed in VOS-treated participants compared with placebo for subgroups including (i) Charlson comorbidity index (CCI) score category (0, 1–2, 3–4, ≥5); (ii) baseline creatinine clearance (&lt;30, 30–50, &gt;50 to 80, or &gt;80 mL/minute); (iii) number of CDI episodes, inclusive of the qualifying episode (3 and ≥4); (iv) exposure to non-CDI-targeted antibiotics after dosing; and (v) acid-suppressing medication use at baseline. Results Of 281 participants screened, 182 were randomized (59.9% female; mean age, 65.5 years). Comorbidities were common with a mean overall baseline age-adjusted CCI score of 4.1 (4.1 in the VOS arm and 4.2 in the placebo arm). Across all subgroups analyzed, VOS-treated participants had a lower relative risk of recurrence compared with placebo. Conclusions In this post hoc analysis, VOS reduced the risk of rCDI compared with placebo, regardless of baseline characteristics, concomitant medications, or comorbidities.

Abstract Background Although fecal microbiota transplant has been used to prevent recurrent Clostridioides difficile infection (rCDI), documented pathogen transmissions highlight inherent safety risks of minimally processed stool. We describe manufacturing processes for fecal microbiota spores, live (VOWST; VOS, formerly SER-109), a microbiota-based oral therapeutic of Firmicutes spores. Methods Bacterial inactivation kill curves were obtained after ethanol exposure for 4 model organisms spiked into process intermediates. Results Bacterial log reduction factors ranged from 6.5 log10 to 7.4 log10 and lysis of spiked organisms occurred rapidly within 30 seconds. Conclusions These experiments demonstrate substantial and rapid inactivation of representative organisms, supporting the potential benefit of VOS manufacturing processes to mitigate risk.

ImportanceA safe and effective treatment for recurrent Clostridioides difficile infection (CDI) is urgently needed. Antibiotics kill toxin-producing bacteria but do not repair the disrupted microbiome, which promotes spore germination and infection recurrence.ObjectivesTo evaluate the safety and rate of CDI recurrence after administration of investigational microbiome therapeutic SER-109 through 24 weeks.Design, Setting, and ParticipantsThis phase 3, single-arm, open-label trial (ECOSPOR IV) was conducted at 72 US and Canadian outpatient sites from October 2017 to April 2022. Adults aged 18 years or older with recurrent CDI were enrolled in 2 cohorts: (1) rollover patients from the ECOSPOR III trial who had CDI recurrence diagnosed by toxin enzyme immunoassay (EIA) and (2) patients with at least 1 CDI recurrence (diagnosed by polymerase chain reaction [PCR] or toxin EIA), inclusive of their acute infection at study entry.InterventionsSER-109 given orally as 4 capsules daily for 3 days following symptom resolution after antibiotic treatment for CDI.Main Outcomes and MeasuresThe main outcomes were safety, measured as the rate of treatment-emergent adverse events (TEAEs) in all patients receiving any amount of SER-109, and cumulative rates of recurrent CDI (toxin-positive diarrhea requiring treatment) through week 24 in the intent-to-treat population.ResultsOf 351 patients screened, 263 were enrolled (180 [68.4%] female; mean [SD] age, 64.0 [15.7] years); 29 were in cohort 1 and 234 in cohort 2. Seventy-seven patients (29.3%) were enrolled with their first CDI recurrence. Overall, 141 patients (53.6%) had TEAEs, which were mostly mild to moderate and gastrointestinal. There were 8 deaths (3.0%) and 33 patients (12.5%) with serious TEAEs; none were considered treatment related by the investigators. Overall, 23 patients (8.7%; 95% CI, 5.6%-12.8%) had recurrent CDI at week 8 (4 of 29 [13.8%; 95% CI, 3.9%-31.7%] in cohort 1 and 19 of 234 [8.1%; 95% CI, 5.0%-12.4%] in cohort 2), and recurrent CDI rates remained low through 24 weeks (36 patients [13.7%; 95% CI, 9.8%-18.4%]). At week 8, recurrent CDI rates in patients with a first recurrence were similarly low (5 of 77 [6.5%; 95% CI, 2.1%-14.5%]) as in patients with 2 or more recurrences (18 of 186 [9.7%; 95% CI, 5.8%-14.9%]). Analyses by select baseline characteristics showed consistently low recurrent CDI rates in patients younger than 65 years vs 65 years or older (5 of 126 [4.0%; 95% CI, 1.3%-9.0%] vs 18 of 137 [13.1%; 95% CI, 8.0%-20.0%]) and patients enrolled based on positive PCR results (3 of 69 [4.3%; 95% CI, 0.9%-12.2%]) vs those with positive toxin EIA results (20 of 192 [10.4%; 95% CI, 6.5%-15.6%]).Conclusions and RelevanceIn this trial, oral SER-109 was well tolerated in a patient population with recurrent CDI and prevalent comorbidities. The rate of recurrent CDI was low regardless of the number of prior recurrences, demographics, or diagnostic approach, supporting the beneficial impact of SER-109 for patients with CDI.Trial RegistrationClinicalTrials.gov identifier: NCT03183141

Clostridioides difficile infection (CDI) is classified as an urgent health threat by the Centers for Disease Control and Prevention (CDC), and affects nearly 500,000 Americans annually. Approximately 20–25% of patients with a primary infection experience a recurrence, and the risk of recurrence increases with subsequent episodes to greater than 40%. The leading risk factor for CDI is broad-spectrum antibiotics, which leads to a loss of microbial diversity and impaired colonization resistance. Current FDA-approved CDI treatment strategies target toxin or toxin-producing bacteria, but do not address microbiome disruption, which is key to the pathogenesis of recurrent CDI. Fecal microbiota transplantation (FMT) reduces the risk of recurrent CDI through the restoration of microbial diversity. However, FDA safety alerts describing hospitalizations and deaths related to pathogen transmission have raised safety concerns with the use of unregulated and unstandardized donor-derived products. SER-109 is an investigational oral microbiome therapeutic composed of purified spore-forming Firmicutes. SER-109 was superior to a placebo in reducing CDI recurrence at Week 8 (12% vs. 40%, respectively; p < 0.001) in adults with a history of recurrent CDI with a favorable observed safety profile. Here, we discuss the role of the microbiome in CDI pathogenesis and the clinical development of SER-109, including its rigorous manufacturing process, which mitigates the risk of pathogen transmission. Additionally, we discuss compositional and functional changes in the gastrointestinal microbiome in patients with recurrent CDI following treatment with SER-109 that are critical to a sustained clinical response.