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Clinical Trial
. 2023 Feb 1;6(2):e2255758.
doi: 10.1001/jamanetworkopen.2022.55758.

Safety and Tolerability of SER-109 as an Investigational Microbiome Therapeutic in Adults With Recurrent Clostridioides difficile Infection: A Phase 3, Open-Label, Single-Arm Trial

Matthew D Sims  1   2   3 , Sahil Khanna  4 , Paul Feuerstadt  5   6 , Thomas J Louie  7 , Colleen R Kelly  8 , Edward S Huang  9 , Elizabeth L Hohmann  10 , Elaine E L Wang  11 , Caterina Oneto  12 , Stuart H Cohen  13 , Charles S Berenson  14 , Louis Korman  15 , Christine Lee  16 , Bret Lashner  17 , Colleen S Kraft  18 , Mayur Ramesh  19 , Michael Silverman  20 , Darrell S Pardi  4 , Ananya De  11 , Asli Memisoglu  11 , David A Lombardi  11 , Brooke R Hasson  11 , Barbara H McGovern  11 , Lisa von Moltke  11 ; ECOSPOR IV Investigators
Collaborators, Affiliations
Clinical Trial

Safety and Tolerability of SER-109 as an Investigational Microbiome Therapeutic in Adults With Recurrent Clostridioides difficile Infection: A Phase 3, Open-Label, Single-Arm Trial

Matthew D Sims et al. JAMA Netw Open. .

Abstract

Importance: A 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.

Objectives: To evaluate the safety and rate of CDI recurrence after administration of investigational microbiome therapeutic SER-109 through 24 weeks.

Design, setting, and participants: This 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.

Interventions: SER-109 given orally as 4 capsules daily for 3 days following symptom resolution after antibiotic treatment for CDI.

Main outcomes and measures: The 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.

Results: Of 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 relevance: In 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 registration: ClinicalTrials.gov identifier: NCT03183141.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Sims reported receiving grants from Seres Therapeutics during the conduct of the study; receiving grants from AstraZeneca, ContraFect, DiaSorin Molecular LLC, Epigenomics Inc, EUROIMMUN US, Finch Therapeutics, Genentech USA Inc, Janssen Research & Development, LLC, Kinevant Sciences GmbH, Leonard-Meron Biosciences, Merck, OpGen, Pfizer, Prenosis, Regeneron Pharmaceuticals, Shire, Summit Therapeutics, and Crestone outside the submitted work; serving as an advisory board member for Prenosis and Venatorx Pharmaceuticals; and serving as a principal investigator or coinvestigator for AstraZeneca, ContraFect, Crestone, Curetis GmbH, Pfizer, DiaSorin Molecular LLC, Epigenomics Inc, EUROIMMUN US, Finch Therapeutics, Genentech USA Inc, Janssen Research & Development LLC, Kinevant Sciences GmbH, Leonard-Meron Biosciences, Lysovant, Merck, Prenosis, QIAGEN Sciences CLC, Regeneron Pharmaceuticals, Roche, Seres Therapeutics, Shire, and Summit Therapeutics. Dr Khanna reported receiving grants from Rebiotix/Ferring, Vedanta, Finch, and Pfizer outside the submitted work and serving as a consultant for Probiotech, Takeda, Niche, and Immuron. Dr Feuerstadt reported enrolling patients in a clinical trial for Seres Therapeutics during the conduct of the study; receiving personal fees from Seres Therapeutics, Rebiotix/Ferring, Merck and Co, and Summit Therapeutics outside the submitted work; and serving on speaker bureaus and consulting or advisory boards for Seres Therapeutics, Rebiotix/Ferring, and Takeda Pharmaceuticals. Dr Louie reported receiving grants and personal fees from Seres Therapeutics, Finch Therapeutics, Artugen, Summit PLC, Ferring, Vedanta Biosciences, and Crestone and grants from Vedanta Biosciences, Rebiotix, Finch, and Crestone during the conduct of the study. Dr Kelly reported receiving grants from the National Institute of Allergy and Infectious Diseases (Fecal Micribiota Transplantation National Registry) and consulting fees from Sebela Pharmaceuticals, serving as a site investigator for Seres Therapeutics and Finch Therapeutics, and holding an unpaid position on the clinical advisory board for OpenBiome outside the submitted work. Dr Huang reported receiving nonfinancial support from Seres Therapeutics during the conduct of the study and owning stock in Seres Therapeutics outside the submitted work. Dr Hohmann reported serving as a clinical investigator for Seres Therapeutics and receiving payment to her institution during the conduct of the study; receiving personal fees from Gilead and Kowa Pharmaceuticals outside the submitted work; being a paid author for UpToDate; and receiving a grant from Tend, Inc, through Massachusetts General Hospital outside the submitted work. Dr Oneto reported research collaborations with Rebiotix, Seres Therapeutics, Abbvie, Salix, Intercept, Exact Sciences, Janssen, and Vedanta and serving on speaker bureaus for AbbVie, Salix, Bristol Myers Squibb, and Pfizer. Dr Korman reported receiving grants from Chevy Chase Clinical Research during the conduct of the study. Dr Lee reported receiving grants from Rebiotix/Ferring, Merck, and Summit Therapeutics and serving as an advisory board member for Rebiotix/Ferring outside the submitted work. Dr Kraft reported serving on the scientific advisory boards for Seres Therapeutics and Rebiotix/Ferring and consulting for Rebiotix/Ferring during the conduct of the study and having a patent issued. Dr Silverman reported receiving stipends from Seres Therapeutics for patient enrollment into the trial during the conduct of the study. Dr Pardi reported receiving grants from Vedanta, Finch, Takeda, and Applied Molecular Transport; receiving personal fees from Vedanta, Otsuka, and Ferring; and serving as a consultant for Seres Therapeutics, Vedanta, Immunic Therapeutics, AbbVie, Otsuka, Ferring, Rise Therapeutics, Boehringer Ingelheim, and Summit. Dr Hasson reported being a stockholder in Seres Therapeutics during the conduct of the study. Dr McGovern reported being a stockholder in Seres Therapeutics during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Flow Diagram of Cohorts 1 and 2
aOther reasons for exclusion included inadequate response to antibiotics (n = 4), could not receive treatment within 4 days of antibiotic completion (n = 3), currently taking or expected to take other antibiotics (n = 3), absolute neutrophil count less than 500 cells/μL (to convert to ×109/L, multiply by 0.001; n = 2), history of fecal microbiota transplantation (n = 1), investigator decision due to concurrent medical risks (n = 1), unable to stop loperamide (n = 1), did not meet unformed stool requirement (n = 1), received human monoclonal antibody (n = 1), known or suspected toxic megacolon (n = 1), and other (n = 3). CDI indicates Clostridioides difficile infection; PCR, polymerase chain reaction.
Figure 2.
Figure 2.. Forest Plot of Clostridioides difficile Infection (CDI) Recurrence Rates up to 8 Weeks After Treatment as Determined by a Toxin Assay by Subgroup in the Intent-to-Treat Population
Patients who were lost to follow-up, terminated the study prematurely, or died without a recorded recurrence before the end of the time interval were assumed to have had a recurrence. The handling of other types of missing data are described in the statistical analysis plan (Supplement 1). The 95% CIs and recurrence rates (proportion of patients with CDI recurrence) were calculated using the Clopper-Pearson exact method. PCR indicates polymerase chain reaction.
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